American Society of Transplantation and Cellular Therapy Series, 1: Enterobacterales Infection Prevention and Management after Hematopoietic Cell Transplantation - Satlin, Michael J.; Weissman, Scott J.; Carpenter, Paul A.; Seo, Susan K.; Shelburne, Samuel A. (Transplantation and Cellular Therapy, 2021)
The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to update its 2009 compendium-style infectious diseases guidelines for hematopoietic cell transplantation (HCT). A completely fresh approach was taken, with the goal of better serving clinical providers by publishing each stand-alone topic in the infectious diseases series in a concise format of frequently asked questions (FAQs), tables, and figures [1]. Adult and pediatric infectious diseases and HCT content experts developed and then answered FAQs, and then finalized topics with harmonized recommendations that were made by assigning a strength of recommendation ranging from A to E paired with a level of supporting evidence graded I to III. The first topic in the series focuses on potentially life-threatening infections in HCT caused by Enterobacterales, relevant infection risk factors, and practical considerations regarding prevention and treatment of these infections in the setting of emerging multidrug resistance.
Keywords: Cell transplant; Enterobacterales; Epidemiology; Guidelines; Hematopoietic; Prevention; Treatment

Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial - Wunderink, Richard G; Matsunaga, Yuko; Ariyasu, Mari; Clevenbergh, Philippe; Echols, Roger; Kaye, Keith S; Kollef, Marin; Menon, Anju; Pogue, Jason M; Shorr, Andrew F; Timsit, Jean-Francois; Zeitlinger, Markus; et al. (The Lancet Infectious Diseases, 2021)
Background Nosocomial pneumonia due to multidrug-resistant Gram-negative pathogens poses an increasing challenge. We compared the efficacy and safety of cefiderocol versus high-dose, extended-infusion meropenem for adults with nosocomial pneumonia. Methods We did a randomised, double-blind, parallel-group, phase 3, non-inferiority trial in 76 centres in 17 countries in Asia, Europe, and the USA (APEKS-NP). We enrolled adults aged 18 years and older with hospital-acquired, ventilator-associated, or health-care-associated Gram-negative pneumonia, and randomly assigned them (1:1 by interactive response technology) to 3-h intravenous infusions of either cefiderocol 2 g or meropenem 2 g every 8 h for 7–14 days. All patients also received open-label intravenous linezolid (600 mg every 12 h) for at least 5 days. An unmasked pharmacist prepared the assigned treatments; investigators and patients were masked to treatment assignment. Only the unmasked pharmacist was aware of the study drug assignment for the infusion bags, which were administered in generic infusion bags labelled with patient and study site identification numbers. Participants were stratified at randomisation by infection type and Acute Physiology and Chronic Health Evaluation II (APACHE II) score (≤15 and ≥16). The primary endpoint was all-cause mortality at day 14 in the modified intention-to-treat (ITT) population (ie, all patients receiving at least one dose of study drug, excluding patients with Gram-positive monomicrobial infections). The analysis was done for all patients with known vital status. Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference between cefiderocol and meropenem groups was less than 12·5%. Safety was investigated to the end of the study in the safety population, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03032380, and EudraCT, 2016-003020-23. Findings Between Oct 23, 2017, and April 14, 2019, we randomly assigned 148 participants to cefiderocol and 152 to meropenem. Of 292 patients in the modified ITT population, 251 (86%) had a qualifying baseline Gram-negative pathogen, including Klebsiella pneumoniae (92 [32%]), Pseudomonas aeruginosa (48 [16%]), Acinetobacter baumannii (47 [16%]), and Escherichia coli (41 [14%]). 142 (49%) patients had an APACHE II score of 16 or more, 175 (60%) were mechanically ventilated, and 199 (68%) were in intensive care units at the time of randomisation. All-cause mortality at day 14 was 12·4% with cefiderocol (18 patients of 145) and 11·6% with meropenem (17 patients of 146; adjusted treatment difference 0·8%, 95% CI −6·6 to 8·2; p=0·002 for non-inferiority hypothesis). Treatment-emergent adverse events were reported in 130 (88%) of 148 participants in the cefiderocol group and 129 (86%) of 150 in the meropenem group. The most common treatment-emergent adverse event was urinary tract infection in the cefiderocol group (23 patients [16%] of 148) and hypokalaemia in the meropenem group (23 patients [15%] of 150). Two participants (1%) of 148 in the cefiderocol group and two (1%) of 150 in the meropenem group discontinued the study because of drug-related adverse events. Interpretation Cefiderocol was non-inferior to high-dose, extended-infusion meropenem in terms of all-cause mortality on day 14 in patients with Gram-negative nosocomial pneumonia, with similar tolerability. The results suggest that cefiderocol is a potential option for the treatment of patients with nosocomial pneumonia, including those caused by multidrug-resistant Gram-negative bacteria. Funding Shionogi.

Ten years of donor-derived disease: A report of the disease transmission advisory committee - Kaul, Daniel R.; Vece, Gabe; Blumberg, Emily; La Hoz, Ricardo M.; Ison, Michael G.; Green, Michael; Pruett, Timothy; Nalesnik, Michael A.; Tlusty, Susan M.; Wilk, Amber R.; Wolfe, Cameron R.; Michaels, Marian G. (American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2021)
Despite clinical and laboratory screening of potential donors for transmissible disease, unexpected transmission of disease from donor to recipient remains an inherent risk of organ transplantation. The Disease Transmission Advisory Committee (DTAC) was created to review and classify reports of potential disease transmission and use this information to inform national policy and improve patient safety. From January 1, 2008 to December 31, 2017, the DTAC received 2185 reports; 335 (15%) were classified as a proven/probable donor transmission event. Infections were transmitted most commonly (67%), followed by malignancies (29%), and other disease processes (6%). Forty-six percent of recipients receiving organs from a donor that transmitted disease to at least 1 recipient developed a donor-derived disease (DDD). Sixty-seven percent of recipients developed symptoms of DDD within 30 days of transplantation, and all bacterial infections were recognized within 45 days. Graft loss or death occurred in about one third of recipients with DDD, with higher rates associated with malignancy transmission and parasitic and fungal diseases. Unexpected DDD was rare, occurring in 0.18% of all transplant recipients. These findings will help focus future efforts to recognize and prevent DDD.

Risk Factors and Impact of Perioperative Prophylaxis on the Risk of Extended-spectrum β-Lactamase–producing Enterobacteriaceae–related Infection Among Carriers Following Liver Transplantation - Logre, Elsa; Bert, Frédéric; Khoy-Ear, Linda; Janny, Sylvie; Giabicani, Mikhaël; Grigoresco, Bénédicte; Toussaint, Amélie; Dondero, Fédérica; Dokmak, Safi; Roux, Olivier; Francoz, Claire; Soubrane, Olivier; et al. (Transplantation, 2021)
Background. Extended-spectrum β-lactamase–producing Enterobacteriaceae (ESBL-E) carriage is frequent among liver transplant (LT) recipients, thereby fostering a large empirical carbapenem prescription. However, ESBL-E infections occur in only 10%–25% of critically ill patients with rectal colonization. Our aim was to identify risk factors for post-LT ESBL-E infection in colonized patients. The effect of perioperative antimicrobial prophylaxis (AP) was also analyzed in patients with prophylaxis lasting <48 hours and without proven intraoperative infection. Methods. Retrospective study from a prospective database including patients with a positive ESBL-E rectal screening transplanted between 2010 and 2016. Results. Among the 749 patients transplanted, 100 (13.3%) were colonized with an ESBL-E strain. Thirty-nine (39%) patients developed an infection related to the same ESBL-E (10 pulmonary, 11 surgical site, 13 urinary, 5 bloodstream) within 11 postoperative days in median. Klebsiella pneumoniae carriage, model for end-stage liver disease ≥25, preoperative spontaneous bacterial peritonitis prophylaxis, and antimicrobial exposure during the previous month were independent predictors of ESBL-E infection. We propose a colonization to infection risk score built on these variables. The prevalence of infection for colonization to infection score of 0, 1, 2, and ≥3 were 7.4%, 26.3%, 61.9%, and 91.3%, respectively. Of note, the incidence of post-LT ESBL-E infection was lower in case of perioperative AP targeting colonizing ESBL-E (P = 0.04). Conclusions. Thirty-nine percentage of ESBL-E carriers develop a related infection after LT. We identified predictors for ESBL-E infection in carriers that may help in rationalizing carbapenem prescription. Perioperative AP targeting colonizing ESBL-E may be associated with a reduced risk of post-LT ESBL-E infections.

The Clinical Conundrum of Cannabis: Current Practices and Recommendations for Transplant Clinicians: An Opinion of the Immunology/Transplantation PRN of the American College of Clinical Pharmacy - Melaragno, Jennifer I.; Bowman, Lyndsey J.; Park, Jeong M.; Lourenco, Laura M.; Doligalski, Christina T.; Brady, Bethany L.; Descourouez, Jillian L.; Chandran, Mary M.; Nickels, Mark W.; Page, Robert L. II (Transplantation, 2021)
Cannabis, or marijuana, comprises many compounds with varying effects. It has become a treatment option for chronic diseases and debilitating symptoms, and evidence suggests that it has immunomodulatory and antiinflammatory properties. Transplant centers are more frequently facing issues about cannabis, as indications and legalization expand. As of February 2020, 33 states and the District of Columbia have legalized medical cannabis, and 14 have legalized recreational cannabis. Moreover, 8 states have passed legislation prohibiting the denial of transplant listing solely based on cannabis use. Studies demonstrate the potential for significant pharmacokinetic and pharmacodynamic interactions between cannabis and immunosuppression. Additionally, safety concerns include increased risk of myocardial infarction, ischemic stroke, tachyarrhythmias, malignancy, neurocognitive deficits, psychosis, other neuropsychiatric disorders, cannabis use disorder, respiratory symptoms, and infection. A recent retrospective database study found a negative association between documented cannabis use disorder and graft survival, but little additional evidence exists evaluating this relationship. In the absence of robust clinical data, transplant centers need a clear, reasoned, and systematic approach to cannabis. The results of our national survey, unfortunately, found little consensus among institutions. As both recreational and medicinal cannabis become more ubiquitous nationwide, transplant centers will need to develop comprehensive policies to address its use.

Oral ribavirin is a highly effective treatment for lower respiratory tract infections due to respiratory syncytial virus or parainfluenza after allogeneic stem cell transplantation - Stamouli, Maria; Tsonis, Ioannis; Gkirkas, Konstantinos; Economopoulou, Christina; Siafakas, Nikolaos; Pournaras, Spyridon; Antoniadou, Anastasia; Chondropoulos, Spyros; Karagiannidi, Angeliki; Meletiadis, Josef; Gigantes, Stavros; Baltadakis, Ioannis; et al. (Bone Marrow Transplantation, 2021)
Number: 2 Publisher: Nature Publishing Group

¿Qué debo hacer si tengo COVID-19? - Power2Save (2021)

What should I do if I have COVID-19? - Power2Save (2021)

Human Herpesvirus 6 Infection in Pediatric Liver Transplantation: Single-Center Study of Incidence, Outcomes, and Management - Mysore, Krupa R; Phan, Tuan L; Himes, Ryan W; Schady, Deborah; Eldin, Karen W; Prusty, Bhupesh K; Munoz, Flor M (Journal of the Pediatric Infectious Diseases Society, 2021)
Distinctions between HHV-6 primary infection in seronegative patients and HHV-6 reactivation in seropositive patients remains largely undescribed in pediatric liver transplant (LT) recipients. We implemented pretransplant serology testing of HHV-6 in a large pediatric hospital and retrospectively assessed the incidence, manifestations and outcomes of HHV-6 infections over a 3-year period. Among 101 pediatric LT recipients, 96 had pretransplant HHV-6 serologies; 34 (35.4%) were seronegative and 62 (64.6%) seropositive. Posttransplantation, 8/25 (32%) seronegative patients had HHV-6 DNAemia (primary infection) compared to 2/48 (4%) seropositive patients (p=0.002). Compared to seropositive patients, seronegative patients with HHV-6 DNAemia were younger, and had symptoms of fever and/or elevated aminotransferases in association with higher viral loads, in the first month post-transplant. More than 90% of seronegative patients and 77.8% of seropositive patients had HHV-6 detected by PCR in liver biopsy obtained for concerns of allograft rejection, but most had no detectable concomitant DNAemia. Active replication of virus in the liver was confirmed by in situ hybridization in select cases. While HHV-6 infection occurred among patients on prophylaxis doses of antivirals for CMV, HHV-6 DNAemia and presenting symptoms resolved on treatment doses. HHV-6 DNA-emia occurred more frequently in seronegative pediatric LT recipients, usually in the early posttransplant period, and was subsequently detected in allograft biopsies. HHV-6 cannot be ruled out as a cause of hepatitis in the absence of allograft tissue testing and specialized virological assays, as HHV-6 may disrupt local allograft immune homeostasis while evading traditional screening methods using blood or plasma. The assessment of pre-transplant HHV-6 serological status may be important for risk stratification and post-transplant management of pediatric LT recipients

Home Monitoring for COVID-19 Exposure or Infection - Power2Save (2021)

Monitoreo en el Hogar para Exposición o Infección de COVID-19 - Power2Save (2021)

Epidemiology of Left Ventricular Assist Device Infections: Findings From a Large Nonregistry Cohort - Blanco-Guzman, Merilda O; Wang, Xiaowen; Vader, Justin M; Olsen, Margaret A; Dubberke, Erik R (Clinical Infectious Diseases, 2021)
Infection is a major complication during circulatory support with a left ventricular assist device (VAD). Changes in device characteristics and treatment practices in the last decade can affect the epidemiology of infection. The International Society for Heart and Lung Transplantation (ISHLT) has published recommendations on the prevention and management of VAD infections, but data to support these recommendations remain sparse.We performed a retrospective review of 455 patients who underwent VAD placement from 2009 to 2015. Infection episodes were defined using ISHLT criteria and were also grouped as endovascular or local. Analysis included descriptive statistics.There were 174 patients (38.6%) with a VAD infection. Infection incidence was 36.9 cases per 100 person-years of VAD support. The driveline was the most common infection site (67.2%). Systemic inflammatory response syndrome (SIRS) criteria were not satisfied in 29.2% of patients with endovascular infections, and computed tomography (CT) examinations were normal in 37.7% of cases. Gram-positive bacteria caused 65.6% of infections in patients with an available culture. Antimicrobial suppression was used in 72.3% of patients who survived treatment. Median survival after infection was 35 months for patients with VAD-related infections versus 14 months for patients with VAD-specific infections.VAD infections continue to be a major complication after implantation. Clinical criteria alone were not predictive of serious infections, and many patients with confirmed infection had normal CTs. Patients with VAD-specific infections had lower median survival than patients with VAD-related infections.

BK Virus Epidemiology, Risk Factors, and Clinical Outcomes: An Analysis of Hematopoietic Stem Cell Transplant Patients at Texas Children’s Hospital - Ruderfer, Daniel; Wu, Mengfen; Wang, Tao; Srivaths, Poyyapakkam R; Krance, Robert A; Naik, Swati; Bocchini, Claire E (Journal of the Pediatric Infectious Diseases Society, 2021)
BK virus-associated hemorrhagic cystitis (BKV-HC) is a serious complication after hematopoietic stem cell transplantation (HSCT).A retrospective review was performed to determine the frequency of BKV-HC and identify risk factors and renal morbidity associated with BKV-HC in pediatric HSCT recipients at our institution.A total of 314 pediatric recipients underwent allogeneic HSCT for either malignant (173, 55.1%) or nonmalignant disorders (141, 44.9%) from January 1, 2011, to December 31, 2015, with a minimum follow-up of 5 years post-HSCT. Severe BKV-HC (grades 3 and 4) was prevalent in 46 out of 67 (68.7%) recipients. Timing to presentation of severe BKV-HC (grades 3 and 4) occurred at a median of 37 days (26, 74; IQ1, IQ3) post-HSCT, with the duration of macroscopic hematuria lasting a median of 37.5 days (18, 71; IQ1, IQ3). In the first 60 days post-HSCT, peak acute kidney injury (AKI) stages 2 and 3 were seen more frequently in HSCT recipients who developed BKV-HC than those without (P = .004). Similarly, during post-HSCT days 61 to 100, peak AKI stage 3 was also more frequently seen in HSCT recipients who already developed BKV-HC prior to or during this time period than those without BKV-HC (P = .0002). Recipients who developed BKV-HC within 1 year of HSCT had more frequent mild to moderate chronic kidney disease (CKD stages 2-3) than those without BKV-HC (P = .002 and .007, respectively). On multivariate analysis, BKV-HC was associated with all-cause mortality (hazard ratio [HR]: 2.22; 95% confidence interval [CI]: 1.35-3.65). The following clinical variables were associated with time to development of HC on multivariate analysis: age (subdistribution HR [sHR] 1.11; 95% CI: 1.06-1.16) and myeloabalative conditioning regimen (sHR 4.2; 95% CI: 2.12-8.34).Pediatric HSCT patients with BKV-HC experience significant morbidity and mortality. Renal morbidity, including AKI and CKD, is associated with BKV-HC.

Establishing essential metrics for antifungal stewardship in hospitals: the results of an international Delphi survey - Khanina, A.; Urbancic, K. F.; Haeusler, G. M.; Kong, D. C. M.; Douglas, A. P.; Tio, S. Y.; Worth, L. J.; Slavin, M. A.; Thursky, K. A. (The Journal of Antimicrobial Chemotherapy, 2021)
BACKGROUND: Guidance on assessment of the quantity and appropriateness of antifungal prescribing is required to assist hospitals to interpret data effectively and structure quality improvement programmes. OBJECTIVES: To achieve expert consensus on a core set of antifungal stewardship (AFS) metrics and to determine their feasibility for implementation. METHODS: A literature review was undertaken to develop a list of candidate metrics. International experts were invited to participate in sequential web-based surveys to evaluate the importance and feasibility of metrics in the area of AFS using Delphi methodology. Three surveys were completed. Consensus was predefined as ≥80% agreement on the importance of each metric. RESULTS: Eighty-two experts consented to participate from 17 different countries. Response rate for each survey was >80%. The panel included adult and paediatric physicians, microbiologists and pharmacists with diverse content expertise. Consensus was achieved for 38 metrics considered important to routinely include in AFS programmes, and related to antifungal consumption (n = 5), quality of antifungal prescribing and management of invasive fungal infection (IFI) (n = 24), and clinical outcomes (n = 9). Twenty-one consensus metrics were considered to have moderate to high feasibility for routine collection. CONCLUSIONS: The identified core AFS metrics will provide a framework to comprehensively assess the quantity and quality of antifungal prescribing within hospitals to develop quality improvement programmes aimed at improving IFI prevention, management and patient-centred outcomes. A standardized approach will support collaboration and benchmarking to monitor the efficacy of current prophylaxis and treatment guidelines, and will provide important feedback to guideline developers.
Keywords: Adult; Antifungal Agents; Benchmarking; Child; Hospitals; Humans; Invasive Fungal Infections; Quality Improvement

Infectious complications of CAR T-cell therapy: a clinical update - Stewart, Adam G.; Henden, Andrea S. (Therapeutic Advances in Infectious Disease, 2021)
Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary treatment modality used to treat haematological malignancies. Lymphocytes are engineered to produce CARs directed towards tumour cell antigens. Clinical trials have demonstrated impressive malignancy-related outcomes. Unfortunately, numerous off-target effects can cause toxicity-related adverse events in this population, the main being cytokine release syndrome and immune effector cell neurotoxicity syndrome. This causes significant patient morbidity and poor outcomes. Patients who receive CAR T-cell therapy are also profoundly immunosuppressed and often cytopenic, which is caused by a multitude of patient- and treatment-related factors. Thus, infection-related complications are also common in this group. Indeed, up to one third of patients will suffer a serious bacterial infection in the first 30 days after therapy. Viral respiratory tract infection appears to be the most common during the late phase and can be severe; one patient has died of influenza A infection. Fungal infection and cytomegalovirus (CMV) reactivation appear to be uncommon. Although institutional guidelines on infection-prevention strategies are available, there is a dearth of evidence to support their approach. Future research needs to target important unanswered questions that remain in this patient population in order to improve their short- and long-term outcomes.
Publisher: SAGE Publications
Keywords: chimeric antigen receptor; immunotherapy; infectious complications

Role and Interpretation of Antifungal Susceptibility Testing for the Management of Invasive Fungal Infections - Lamoth, Frederic; Lewis, Russell E.; Kontoyiannis, Dimitrios P. (Journal of Fungi, 2021)
Invasive fungal infections (IFIs) are associated with high mortality rates and timely appropriate antifungal therapy is essential for good outcomes. Emerging antifungal resistance among Candida and Aspergillus spp., the major causes of IFI, is concerning and has led to the increasing incorporation of in vitro antifungal susceptibility testing (AST) to guide clinical decisions. However, the interpretation of AST results and their contribution to management of IFIs remains a matter of debate. Specifically, the utility of AST is limited by the delay in obtaining results and the lack of pharmacodynamic correlation between minimal inhibitory concentration (MIC) values and clinical outcome, particularly for molds. Clinical breakpoints for Candida spp. have been substantially revised over time and appear to be reliable for the detection of azole and echinocandin resistance and for outcome prediction, especially for non-neutropenic patients with candidemia. However, data are lacking for neutropenic patients with invasive candidiasis and some non-albicans Candida spp. (notably emerging Candida auris). For Aspergillus spp., AST is not routinely performed, but may be indicated according to the epidemiological context in the setting of emerging azole resistance among A. fumigatus. For non-Aspergillus molds (e.g., Mucorales, Fusarium or Scedosporium spp.), AST is not routinely recommended as interpretive criteria are lacking and many confounders, mainly host factors, seem to play a predominant role in responses to antifungal therapy. This review provides an overview of the pre-clinical and clinical pharmacodynamic data, which constitute the rationale for the use and interpretation of AST testing of yeasts and molds in clinical practice.
Number: 1 Publisher: Multidisciplinary Digital Publishing Institute
Keywords: clinical breakpoints; invasive aspergillosis; invasive candidiasis; minimal inhibitory concentration; mucormycosis; pharmacodynamics; therapeutic response

Clinical characteristics and outcomes of toxoplasmosis among transplant recipients at two US academic medical centers - Adekunle, Ruth O.; Sherman, Amy; Spicer, Jennifer O.; Messina, Julia A.; Steinbrink, Julie M.; Sexton, Mary Elizabeth; Lyon, George Marshall; Mehta, Aneesh K.; Phadke, Varun K.; Woodworth, Michael H. (Transplant Infectious Disease, 2021)
Toxoplasma gondii can cause severe opportunistic infection in immunocompromised individuals, but diagnosis is often delayed. We conducted a retrospective review of solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients with toxoplasmosis between 2002 and 2018 at two large US academic transplant centers. Patients were identified by ICD-9 or ICD-10 toxoplasmosis codes, positive Toxoplasma polymerase chain reaction test result, or pathologic diagnosis. Data were collected regarding transplant type, time from transplant to toxoplasmosis diagnosis, clinical and radiographic features, and mortality at 30 and 90 days. Twenty patients were identified: 10 HSCT recipients (80% allogeneic HSCT) and 10 SOT recipients (60% deceased donor renal transplants). Rejection among SOT recipients (70%) and graft-versus-h ost disease (GVHD) prophylaxis among HSCT recipients (50%) were frequent. Median time from transplant to toxoplasmosis diagnosis was longer for SOT than HSCT (1385 vs. 5 days, P-value .002). Clinical manifestations most commonly were encephalitis (65%), respiratory failure (40%), renal failure (40%), and distributive shock (40%). Cohort 30-day mortality was 45%, and 90-day mortality was 55%. Diagnosis was postmortem in 25% of the cohort. Further evaluation of toxoplasmosis screening is needed for noncardiac SOT recipients, HSCT recipients with GVHD, and periods of increased net immunosuppression.
Keywords: Hematopoietic stem cell transplant; Solid organ transplantation; Toxoplasmosis

Infectious complications in allogeneic hematopoietic cell transplant recipients: Review of transplant-related risk factors and current state of prophylaxis - Akhmedov, Mobil (Clinical Transplantation, 2021)
Allogeneic hematopoietic cell transplantation is a complex procedure that carries a significant risk of complications. Infections are among the most common of them. Several direct factors such as neutropenia, hypogammaglobulinemia, lymphopenia, mucosal barrier injury, and graft-versus-host disease have been shown to be associated with increased infectious risk post-transplant. Apart from direct factors, there are also indirect transplant-related factors that are the primary trigger to the formers' development. The most important of them are type of preparative regimen, graft source, donor type, graft-versus-host disease prophylaxis, and graft manipulation techniques. In this review, an attempt has been made to summarize the role of the transplant-related factors in the development of infectious complications and provide evidence underlying the current concept of infectious disease prophylaxis in patients after allogeneic hematopoietic cell transplantation.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ctr.14172
Keywords: allogeneic hematopoietic cell transplantation; infections; prophylaxis; risk factors

Approaches to safe living and diet after solid organ transplantation - Albert, Jonathan; Hanisch, Benjamin; Sgambat, Kristen (Pediatric Transplantation, 2021)
SOT recipients are at high risk for developing severe infectious complications following discharge from the hospital. Comprehensive anticipatory guidance surrounding everyday lifestyle choices can potentially prevent exposure to infectious agents from the environment. This paper reviews the risks that pediatric and adolescent SOT recipients encounter through exposures such as household contacts, outdoor activities, travel, animal exposures, and dietary choices. Although strong evidence is lacking, this paper makes recommendations aimed at minimizing the risk of infectious complications and hospitalization in pediatric SOT recipients.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/petr.13783
Keywords: behaviour; immunocompromised host; infectious risk; literature review; pediatric transplantation; solid organ transplantation

Nocardia Infections in Transplantation: Diagnosis, Management, and Impact on Outcomes - Arasaratnam, Reuben J.; Restrepo, Alejandro (Emerging Transplant Infections, 2021)
Nocardia species are ubiquitous, environmental, Gram-positive bacteria belonging to the Actinomycetaceae family. Immunocompromised hosts such as recipients of solid organ and hematopoietic stem cell transplants are more susceptible to infection, and the most commonly affected organ is the lung. The net state of immunosuppression is an important risk factor for development of infection in transplant recipients. Isolation of Nocardia spp. in culture from a clinically suspected site of infection is sufﬁcient for the diagnosis. As part of the evaluation, disease involvement of the central nervous system should always be ruled out with imaging even if no neurological symptoms are present. Successful treatment entails reduction of immunosuppression and months of antimicrobial therapy guided by antimicrobial susceptibility testing. The use of combination antimicrobials and surgical debridement may be warranted in select circumstances, in particular central nervous system disease. In transplant recipients, myelosuppression and nephrotoxicity are important treatment-associated toxicities and warrant close monitoring and potential adjustment of therapy. Although trimethoprim-sulfamethoxazole (TMP-SMX) has proven in vitro and in vivo activity against Nocardia spp., its use as prophylaxis for Pneumocystis jirovecii pneumonia should not be considered efﬁcacious against Nocardia infection in transplant recipients.

Histoplasmosis - Araúz, Ana Belén; Papineni, Padmasayee (Infectious Disease Clinics of North America, 2021)

Emerging Diagnostics for Transplant Infectious Diseases - Azar, Marwan M.; Gaston, David C.; Malinis, Maricar F. (Emerging Transplant Infections, 2021)
Following solid organ and hematopoietic stem cell transplantation, patients are at increased risk for community-acquired infections, opportunistic and uncommon pathogens, coinfections, and multidrug-resistant organisms. Given the increased predilection for serious infection in this population, diagnostics applicable to the practice of transplant infectious diseases are essential. In the last decade, diagnostic microbiology has witnessed a shift toward culture-independent methods such as molecular testing, mass spectrometry, and magnetic resonance-based technologies that have greatly increased diagnostic capabilities. More recently, another wave of diagnostic modalities including highly multiplexed polymerase chain reaction (PCR) panels directly applicable to clinical specimens and with the potential for resistance detection, metagenomic sequencing, and breath-based diagnosis of volatile metabolites has emerged with signiﬁcant potential for transplant infectious diseases. At present, many of these technologies continue to have certain drawbacks that limit their applicability, but despite shortcomings, emerging technologies have already demonstrated a diagnostic advantage and a positive impact on patient outcomes. Though data on test performance characteristics and clinical impact among transplant patients remains scarce, it is likely that these modalities will translate into even greater utility given the increased risk for infection in this population. In this review, we examine emerging diagnostic methods for infectious diseases with a focus on the application to transplant patients.

Added Diagnostic Utility of Clinical Metagenomics for the Diagnosis of Pneumonia in Immunocompromised Adults - Azar, Marwan M.; Schlaberg, Robert; Malinis, Maricar F.; Bermejo, Santos; Schwarz, Toni; Xie, Heng; Dela Cruz, Charles S. (Chest, 2021)

Management of Cryptococcosis in Transplant Candidates and Recipients - Baddley, John W.; Forrest, Graeme N. (Emerging Transplant Infections, 2021)
Cryptococcosis is the third most common invasive fungal infection in solid organ transplant (SOT) recipients, but is rare among recipients of hematopoietic stem cell transplant (HSCT). Infection often occurs a year after transplantation; however early infections are common in HSCT. Among SOT patients, donorderived infections have been described within 3 months after transplant. The most common disease manifestations are meningitis and pneumonia. The fungi Cryptococcus neoformans and C. gattii are the main causes of cryptococcosis.

Vaccine-induced protection against hepatitis B in pediatric solid organ transplant patients - Ball, Michael; Liverman, Rochelle; Serluco, Anastacia; Yildirim, Inci (Pediatric Transplantation, 2021)
Background Vaccination against hepatitis B virus (HBV) has led to a worldwide reduction in disease burden and mortality. Vaccine immunogenicity data in transplanted children are limited, and vaccine-induced protection may be reduced. We evaluated HBV vaccination coverage, seroprotection rates, and factors influencing vaccine immunity among pediatric solid organ transplant (SOT) patients. Methods We retrospectively identified patients ≤21 years of age evaluated for SOT and/or transplanted at our center between January 1, 2015, and December 31, 2018. A detailed chart review was conducted using a standard questionnaire to gather information on demographic, clinical, and laboratory features of patients’ HBV vaccination, and hepatitis B surface antibody (HBsAb) titers. Results A total of 381 patients undergoing evaluation and/or transplantation were included: 139 (36.5%) liver, 138 (36.2%) kidney, and 104 (27.3%) heart. Overall, HBsAb at evaluation was reactive in 216 (56.7%), indeterminate in 17 (4.5%), non-reactive in 138 (36.2%), and not available in 10 (2.6%). Of those that completed a primary HBV vaccine series (n = 304), HBsAb was reactive in 164 (53.9%), indeterminate in 13 (4.3%), non-reactive in 119 (39.1%), and not available in 8 (2.6%). For those up to date for age on HBV vaccinations with non-reactive/indeterminate titers at evaluation, revaccination and a follow-up HBsAb were available in 45 patients of which 33 (73.3%) seroconverted to a reactive HBsAb titer. Conclusion Vaccine-induced protection against HBV infection among high-risk pediatric SOT recipients can be improved by serology-based intervention. Though the absence of HBsAb does not always indicate loss of protection, boosting or completing primary series is recommended.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/petr.13920
Keywords: Solid organ transplantation; hepatitis B vaccine; pediatrics; vaccine-induced protection

Management of Acinetobacter Infections in the Immunosuppressed Host - Baneman, Emily; Rana, Meenakshi M. (Emerging Transplant Infections, 2021)
Acinetobacter infections have emerged as an important pathogen in transplant recipients. It is a major cause of multidrug-resistant nosocomial infections, particularly pneumonia and bloodstream infections, and is associated with high morbidity and mortality. Given the organism’s propensity to develop resistance to multiple classes of antibiotics, treatment options can be limited but frequently include carbapenems, polymyxins, sulbactams, tetracyclines, and glycylcyclines. Infection prevention measures are critical for preventing transmission among patients and avoiding hospital outbreaks.

Candida Infections in Solid Organ Transplantation - Barros, Nicolas; Mansour, Michael K. (Emerging Transplant Infections, 2021)
Candida remains a common infectious complication in the setting of solid organ transplantation. The rates of invasive Candida infection vary among organ transplant, with small bowel accounting for the majority of cases. In this chapter, we review the epidemiology of Candida infections following organ transplantation. While C. albicans continues to be the most common fungal species isolated, more recent data show that non-albicans Candida species are on the rise, specifically drug-resistant C. glabrata. These non-albicans Candida species are associated with an increase in mortality compared to C. albicans. In addition, we examine the available tools for the diagnosis of invasive Candida infections, including traditional culture techniques, fungal cell wall markers, antibody serologies, and more efﬁcient approaches using nucleic acid-based detection. A special section discusses the emergence of the highly drug-resistant fungal pandemic agent, C. auris. That said, improved surgical technique, patient-speciﬁc chemoprophylaxis, and early use of anti-fungal agents have resulted in decreased mortality due to Candida infection. Therapeutic drug monitoring of speciﬁc agents is reviewed. Finally, future consideration for more rapid diagnostics and a personalized approach to risk stratiﬁcation and identiﬁcation of those individuals who would beneﬁt the most from pre-emptive strategies following transplantation are discussed.

Coccidioidomycosis - Bays, Derek J.; Thompson, George R. (Infectious Disease Clinics of North America, 2021)

Resistance to Antifungal Drugs - Ben-Ami, Ronen; Kontoyiannis, Dimitrios P. (Infectious Disease Clinics of North America, 2021)

Slow-Growing Nontuberculous Mycobacteria in Transplant - Benamu, Esther; Nelson, Joanna (Emerging Transplant Infections, 2021)
Nontuberculous mycobacteria (NTM) are ubiquitous environmental organisms found in soil and water. The expansion of the transplant population combined with an increase in environmental exposures and improvements in mycobacterial diagnosis has contributed to a rise in the diagnosis of NTM infections among transplant recipients, who are at particular risk for infection as well as increased associated morbidity and mortality.

Preventative Health in Solid Organ Transplant: Safe Living Post-transplant - Blair, Barbra M. (Emerging Transplant Infections, 2021)
In order to minimize a solid organ transplant (SOT) recipient’s risk for infection and injury, it is important to anticipate the risks post-transplantation inherent in routine and not so routine activities of daily living. The benefits of longevity by virtue of organ transplantation need to be closely protected by education before, during, and after transplantation about potential infectious risks and measures to mitigate such exposures. SOT recipients cannot stand alone in their efforts toward modifying their risks. Household contacts should be considered and advice offered toward moderating their contribution to risk by encouraging updating their vaccines and encouraging them to assume responsibility of daily tasks/chores that should be avoided by SOT recipients. A longitudinal preventative health strategy based on the topics addressed here can assist with maintenance of health and avoidance of infection and its associated morbidity and mortality.

Challenges of Human Papillomavirus Infection in Solid Organ and Hematopoietic Stem Cell Transplant Recipients - Brickman, Cristina; Chin-Hong, Peter (Emerging Transplant Infections, 2021)
Infection of the anogenital tract with human papillomavirus (HPV) is very common. Approximately 15–20 anogenital HPV types are oncogenic or “high-risk” and are associated with 99.9% of cervical cancers, 90% of anal cancers, 70% of oropharyngeal cancers, and a high proportion of vaginal, penile, and vulvar cancers. Defects in cellular immunity make solid organ transplant (SOT) recipients particularly susceptible to persistent high-risk HPV infection, development of the cancer precursor lesion, high-grade squamous intraepithelial lesion (HSIL), and, in some cases, progression to malignancy. Hematopoietic stem cell transplant (HSCT) recipients may also be at risk for HPV-related malignancies, particularly those who require long-term immunosuppression for graft-versus-host disease. This highlights the need for cancer screening programs to detect and eliminate HSIL prior to progression to malignancy. While clear evidence exists to support the effectiveness of cervical cancer screening, the role for anal cancer screening is less clear. Anal cancer screening is recommended in high-risk SOT recipients like men who have sex with men (MSM) and can be considered in high-risk HSCT recipients. While HPV vaccines are highly effective at preventing initial HPV infection and HSIL in the general population, studies on their efficacy in SOT and HSCT recipients are limited. Ongoing work to optimize both screening and vaccination programs is currently the best option to decrease HPV-related complications in SOT and HSCT recipients.

Transplant Tourism and the Traveling Transplant Recipient: Infection Mitigation and Treatment Strategies - Buchan, C. Arianne (Emerging Transplant Infections, 2021)
Transplant tourism and travel posttransplant, both solid organ and hematopoietic stem cell, are important and distinct topics, and each poses a risk of infection for transplant recipients. As solid organ transplant becomes a more common treatment option for end-stage organ disease, wait lists and wait times for these organs grow. Transplant tourism involves traveling abroad for the purposes of organ transplant and often involves commercial transactions. This process has been discouraged on ethical grounds and is illegal in many countries, however it still occurs. Patients may also travel abroad for stem cell therapies, which include experimental treatments for a growing number of diseases. Physicians managing patients who have received transplants abroad should be aware of the risk of infection in these patients which will be outlined in this chapter. Separate to this, the second part of this chapter addresses the topic of travel in post transplant patients. Solid organ and hematopoietic stem cell transplant recipients may wish to travel as part of their return to regular activities and lifestyle posttransplant. All transplant recipients should seek medical advice prior to travel abroad, and risk of infection will depend on destination(s) and type of travel. Risk reduction strategies are important for these patients to allow for safe travel posttransplant and will be discussed in detail in this chapter.

Aspergillosis - Cadena, Jose; Thompson, George R.; Patterson, Thomas F. (Infectious Disease Clinics of North America, 2021)

Cytomegalovirus in Hematopoietic Stem Cell Transplant Recipients: Prevention, Diagnosis, and Treatment - Camargo, Jose F. (Emerging Transplant Infections, 2021)
Human herpesvirus 5, better known as cytomegalovirus (CMV), infects 50–90% of the adult population worldwide and is the most common opportunistic infection in allogeneic hematopoietic stem cell transplant (HSCT) recipients, causing significant morbidity and mortality [1–6]. Without prophylaxis, CMV reactivation occurs in up to 70–80% of CMV-seropositive individuals [6–9]. This chapter will review the current understanding of CMV infection in HSCT recipients focusing on emerging concepts and updated recommendations for CMV prevention, diagnosis, and management.

Emerging Tropical Viral Infections: Dengue, Chikungunya, and Zika - Carvalho, Alexandre Machado de Sant’ Anna; Machado, Clarisse Martins (Emerging Transplant Infections, 2021)
The purpose of this review is to describe the characteristics of dengue (DENV), chikungunya (CHIKV), and Zika (ZIKV) in transplant recipients. The majority of reported cases were transmitted by mosquito bite, but blood and graft transmission may occur. These arbovirus infections are clinically similar, resembling inﬂuenza-like illness or frequent transplant syndromes. Therefore, laboratory conﬁrmation is necessary. In the acute phase, nucleic acid tests are preferred. DENV and ZIKV serology may cross-react. The assessment of epidemiological risk is mandatory in donors and patients returning from endemic areas. Current data show that DENV may be severe, with a protracted course, prolonged viremia, and bleeding complications. Transient graft dysfunction and altered liver enzymes are expected. No speciﬁc treatment is currently available, and the management of arboviruses is mainly supportive, with attention to warning signs of decompensation. Reduction of immunosuppression is not recommended as it may trigger rejection or graft-versus-host disease. Available DENV vaccines are not recommended in transplant recipients. CHIKV and ZIKV vaccines are in early stages of development. Arbovirus persistence in organ and tissues is generally unknown. Consequently, screening and deferral recommendations are still controversial. Donor screening can be considered in symptomatic donors or in those returning from endemic areas. Donor deferral for 30 days has been recommended in suspected or conﬁrmed DENV or CHIKV, while in case of suspected ZIKV, longer quarantine period has been proposed (up to 6 months). Prospective studies are necessary to determine the impact of DENV, CHIKV, and ZIKV in this special population.

Diarrhea in the pediatric solid organ transplantation recipient: A multidisciplinary approach to diagnosis and management - Chaudhuri, Abanti; Goddard, Elizabeth Anne; Green, Michael; Ardura, Monica I. (Pediatric Transplantation, 2021)
Diarrhea in the pediatric solid organ transplantation (SOT) recipient is a frequent complaint that is associated with significant morbidity and impaired quality of life. There are limited published data regarding the specific epidemiology, diagnostic evaluation, and treatment of diarrhea after SOT in children. Pediatric SOT recipients have an increased risk of developing diarrhea because of a generalized immunosuppressed state, epidemiologic exposures, and polypharmacy. There is a need to standardize the diagnostic evaluation of diarrhea in children after SOT to facilitate an accurate diagnosis and timely treatment. Herein, we review the available published data and propose a systematic, stepwise approach to the evaluation of diarrhea in this high-risk population, focusing on timely diagnosis of both infectious and non-infectious causes, in order to provide focused management. Prospective studies are needed to better assess the true prevalence, risk factors for, etiologies, and complications of diarrhea in pediatric SOT patients that will guide optimal management. Development of effective vaccines and antiviral therapies for enteric viruses may also contribute to improved outcomes.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/petr.13886
Keywords: diarrhea; pediatric; solid organ transplantation

Increased incidence and unusual presentations of CMV disease in kidney transplant recipients after conversion to belatacept - Chavarot, Nathalie; Divard, Gillian; Scemla, Anne; Amrouche, Lucile; Aubert, Olivier; Leruez-Ville, Marianne; Timsit, Marc O.; Tinel, Claire; Zuber, Julien; Legendre, Christophe; Anglicheau, Dany; Sberro-Soussan, Rebecca (American Journal of Transplantation, 2021)
Belatacept may increase cytomegalovirus (CMV) disease risk after conversion from CNI-based therapy. We analyzed CMV disease characteristics after belatacept conversion. Propensity score matching was used to compare CMV disease incidence in belatacept- and CNI-treated kidney transplant recipients (KTRs). CMV disease characteristics and risk factors under belatacept were analyzed. In total, 223 KTRs (median age [IQR] 59.2 years [45.4–68.5]) were converted to belatacept (median of 11.5 months [2.5–37.0] post-transplantation); 40/223 (17.9%) developed CMV disease. Independent risk factors included increased age (p = .0164), D+/R− CMV serostatus (p = .0220), and low eGFR at conversion (p = .0355). Among 181 belatacept-treated patients matched to 181 controls, 32/181 (17.7%) experienced CMV disease (vs. 5/181 controls [2.8%]). CMV disease cumulative incidences were 6.33 and 0.91/100 person-years (p-y) in belatacept and control groups, respectively. CMV disease risk was particularly high in elderly patients (converted >70 years) and those with eGFR <30 ml/min; cumulative incidences were 18.4 and 5.2/100 p-y, respectively. CMV diseases under belatacept were atypical, with late-onset disease (24/40 patients [60%]), high CMV seropositivity (27/40, 67%), increased severe and tissue-invasive disease rates (gastrointestinal involvement in 32/40 [80%]) and life-threatening diseases (4/40 [10%]). These findings should stimulate further research to secure the use of belatacept as a valuable rescue therapy in KTRs.

Management of Mucorales Infections in Transplant Patients - Chen, Sharon C.-A.; Slavin, Monica A. (Emerging Transplant Infections, 2021)
Infections due to Mucorales fungi in hematopoietic stem cell transplantation (HSCT) and solid organ transplant (SOT) recipients may be increasing. Disease is severe and rapidly progressive and carries high mortality. Both the prevalence and species epidemiology vary with geography. Rhizopus species is the most common pathogen followed by Mucor species. Risk factors in SOT patients include renal failure, diabetes mellitus, and immunosuppression to prevent rejection. Additional risks in HSCT patients include corticosteroid use, neutropenia, iron overload, newer immunomodulating therapies, and graft-versus-host disease Breakthrough mucormycosis has occurred in patients receiving voriconazole and caspofungin as well as with posaconazole oral solution. Outbreaks of infection occur.

Leishmaniasis in Transplant Candidates and Recipients: Diagnosis and Management - Clemente, Wanessa T.; Mourão, Paulo H. O. (Emerging Transplant Infections, 2021)
Leishmaniasis is a rare disease in both solid-organ and hematopoietic stem cell transplantation. Additionally, the frequency of disease is likely related to the leishmaniasis prevalence in the general population. Although cutaneous leishmaniasis (CL) presentation is more prevalent than that of visceral leishmaniasis (VL) in the general population, the opposite occurs in transplant patients. The current available knowledge is based on small series, case reports, or extrapolations from studies conducted in the general population or in immunocompromised subjects. Therefore, recommendations for disease management are based on the opinion of experts. Leishmania transmission through organ grafts has not been conclusively demonstrated, and there are relatively low rates of transfusion-transmitted leishmaniasis (TTL). To date, compulsory screening for VL in organ donors and the deferral criteria have still not been established. In the context of transplant recipients, diagnosis and management remain a challenge. Delayed diagnosis frequently occurs because of low clinical suspicion and atypical disease presentation. Liposomal amphotericin is the drug of choice and the most commonly used therapy. However, patient proﬁle, Leishmania species, disease extent, drug availability or toxicity, presence of concomitant infections, and especially response can inﬂuence this choice. Immunosuppression dose reduction is often recommended, but such decisions must be taken on an individual basis. The main challenges include donor screening and organ deferral, duration of therapy, secondary prophylaxis, and follow-up.

Toxoplasmosis Among 38 751 Hematopoietic Stem-cell Transplant Recipients: A Systematic Review of Disease Prevalence and a Compilation of Imaging and Autopsy Findings - Contopoulos-Ioannidis, Despina G.; Cho, Stephanie M.; Bertaina, Alice; Leung, Ann N.; Fischbein, Nancy; Lanzman, Bryan; Schwenk, Hayden T.; Montoya, Jose G. (Transplantation, 2021)

Liver Transplantation of HCV-viremic Donors Into HCV-negative Recipients in the United States: Increasing Frequency With Profound Geographic Variation - Cotter, Thomas G.; Aronsohn, Andrew; Reddy, K. Gautham; Charlton, Michael (Transplantation, 2021)

Antibiotics versus no therapy in kidney transplant recipients with asymptomatic bacteriuria (BiRT): a pragmatic, multicentre, randomized, controlled trial - Coussement, Julien; Kamar, Nassim; Matignon, Marie; Weekers, Laurent; Scemla, Anne; Giral, Magali; Racapé, Judith; Alamartine, Éric; Mesnard, Laurent; Kianda, Mireille; Ghisdal, Lidia; Catalano, Concetta; et al. (Clinical Microbiology and Infection, 2021)
Objectives: Many transplant physicians screen for and treat asymptomatic bacteriuria (ASB) during postkidney-transplant surveillance. We investigated whether antibiotics are effective in reducing the occurrence of symptomatic urinary tract infection (UTI) in kidney transplant recipients with ASB.

American Society of Transplantation and Cellular Therapy Series, 2: Management and Prevention of Aspergillosis in Hematopoietic Cell Transplantation Recipients - Dadwal, Sanjeet S.; Hohl, Tobias M.; Fisher, Cynthia E.; Boeckh, Michael; Papanicolaou, Genofeva; Carpenter, Paul A.; Fisher, Brian T.; Slavin, Monica A.; Kontoyiannis, D.P. (Transplantation and Cellular Therapy, 2021)
The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to update its 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). A completely fresh approach was taken with the goal of better serving clinical providers by publishing each standalone topic in the infectious disease series as a concise format of frequently asked questions (FAQs), tables, and ﬁgures. Adult and pediatric infectious disease and HCT content experts developed, then answered FAQs, and ﬁnalized topics with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. This second guideline in the series focuses on invasive aspergillosis, a potentially lifethreatening infection in the peri-HCT period. The relevant risk factors, diagnostic considerations, and prophylaxis and treatment approaches are reviewed.

Antifungal Prophylaxis After Lung Transplantation: Where Are We Now? - De Mol, Wim; Bos, Saskia; Beeckmans, Hanne; Lagrou, Katrien; Spriet, Isabel; Verleden, Geert M.; Vos, Robin (Transplantation, 2021)

Species distribution, azole resistance and related molecular mechanisms in invasive Candida parapsilosis complex isolates: Increase in fluconazole resistance in 21 years - Demirci-Duarte, Selay; Arikan-Akdagli, Sevtap; Gülmez, Dolunay (Mycoses, 2021)
Background Candida parapsilosis complex consists of three species, the prevalence and geographical distribution of which might vary. Increasing rates of fluconazole resistance among C. parapsilosis complex were reported from various centres. Objectives Aim of this study was to identify invasive C. parapsilosis complex strains up to species level, explore rates and molecular mechanisms of azole resistance and analyse temporal changes at a single centre. Methods Isolates from blood cultures from 1997 to 2017 were included. Species were identified using RFLP of the SADH gene and confirmed with ITS sequencing when needed. In vitro susceptibility to fluconazole, voriconazole and posaconazole was tested and evaluated using EUCAST guidelines. Sequences of ERG11 and MRR1 genes were analysed for fluconazole non-susceptible isolates. Results A total of 283 isolates from 181 patients were tested for azole susceptibility. All were C. parapsilosis sensu stricto, except one C. orthopsilosis. All three azoles were effective against 213 of the isolates from 135 patients, including one C. orthopsilosis. Fluconazole resistance was 13.3% (24/181 patients). While the first fluconazole-resistant isolates were detected in 2004, increase was evident after 2011. In ERG11, Y132F mutation was the most common among fluconazole non-susceptible isolates (71.7%), followed by G458S (10.9%) and D421N (4.3%). In MRR1, R405K (56.5%) and G927C (8.7%) were detected. However, association of these mutations to azole resistance is yet to be investigated. Conclusions Rising azole resistance rates in C. parapsilosis sensu stricto isolates particularly after 2011 were of concern. The well-known Y132F mutation was the predominant mechanism of azole resistance while accompanied with other genetic mutations.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/myc.13296
Keywords: Candida parapsilosis; ERG11; MRR1; candidemia; epidemiology; fluconazole resistance

Outcomes of repeat kidney transplantation following prior graft failure secondary to BK nephropathy: A single-center retrospective study - Dong, Rachel; Shetty, Aneesha; Tambur, Anat R; Ison, Michael G. (Transplant Infectious Disease, 2021)
Background BK virus is associated with development of nephropathy (BKVN) that can lead to graft failure after renal transplantation. There are limited data on rates of recurrence and outcomes of repeat renal transplantation after prior graft loss caused by BKVN. Methods After IRB approval, data on all patients who underwent a repeat renal transplantation after prior graft failure as a result of BKVN were identified. Data on management of patients prior to retransplantation, induction and maintenance immunosuppression, and key clinical and virologic outcomes were collected. Descriptive statistics were used for analysis. Results Thirteen patients were identified over a 13-year period, and follow-up of these patients occurred for a median of 4.7 years. Most patients have previous renal transplants removed prior to (7/13, 53.8%) or at the time of retransplantation (3/13, 23.1%). Close virologic monitoring of serum and urine, coupled with early immunosuppression minimization, was associated with few patients developing BK viruria above 1 × 107 c/mL (4/13, 30.8%), BK viremia above 10,000 c/mL (2/13, 15.4%), and biopsy-proven BKVN (1/12, 8.3%); most (8/13, 61.5%) developed BK viruria at any level. Renal function at 1 year post-retransplantation was generally excellent and only 1 patient developed graft failure caused by recurrent focal segmental glomerulosclerosis. In our review of the literature, 2 large observational studies of the UNOS database as well as our analysis of case reports showed excellent graft survival and very low rates of recurrent BKVN leading to graft loss. Conclusions Retransplantation after prior graft failure caused by BKVN generally has low rates of recurrence when coupled with close monitoring and early immunosuppression minimization. Removal of failed renal transplant may allow easier monitoring for recurrence.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/tid.13672
Keywords: BK nephropathy; kidney transplantation

A prospective multicenter pilot study of HIV-positive deceased donor to HIV-positive recipient kidney transplantation: HOPE in action - Durand, Christine M.; Zhang, Wanying; Brown, Diane M.; Yu, Sile; Desai, Niraj; Redd, Andrew D.; Bagnasco, Serena M.; Naqvi, Fizza F.; Seaman, Shanti; Doby, Brianna L.; Ostrander, Darin; Bowring, Mary Grace; et al. (American Journal of Transplantation, 2021)
HIV-positive donor to HIV-positive recipient (HIV D+/R+) transplantation is permitted in the United States under the HIV Organ Policy Equity Act. To explore safety and the risk attributable to an HIV+ donor, we performed a prospective multicenter pilot study comparing HIV D+/R+ vs HIV-negative donor to HIV+ recipient (HIV D−/R+) kidney transplantation (KT). From 3/2016 to 7/2019 at 14 centers, there were 75 HIV+ KTs: 25 D+ and 50 D− (22 recipients from D− with false positive HIV tests). Median follow-up was 1.7 years. There were no deaths nor differences in 1-year graft survival (91% D+ vs 92% D−, P = .9), 1-year mean estimated glomerular filtration rate (63 mL/min D+ vs 57 mL/min D−, P = .31), HIV breakthrough (4% D+ vs 6% D−, P > .99), infectious hospitalizations (28% vs 26%, P = .85), or opportunistic infections (16% vs 12%, P = .72). One-year rejection was higher for D+ recipients (50% vs 29%, HR: 1.83, 95% CI 0.84-3.95, P = .13) but did not reach statistical significance; rejection was lower with lymphocyte-depleting induction (21% vs 44%, HR: 0.33, 95% CI 0.21-0.87, P = .03). In this multicenter pilot study directly comparing HIV D+/R+ with HIV D−/R+ KT, overall transplant and HIV outcomes were excellent; a trend toward higher rejection with D+ raises concerns that merit further investigation.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ajt.16205
Keywords: clinical research/practice; clinical trial; donors and donation: deceased; ethics and public policy; infection and infectious agents; infection and infectious agents – viral: human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS); infectious disease; kidney transplantation/nephrology; law/legislation; rejection

Survival after heart transplantation for Chagas cardiomyopathy using a conventional protocol: A 10-year experience in a single center - Echeverría, Luis E.; Figueredo, Antonio; Rodriguez, María J.; Salazar, Leonardo; Pizarro, Camilo; Morillo, Carlos A.; Rojas, Lyda Z.; Gómez-Ochoa, Sergio A.; Castillo, Victor R. (Transplant Infectious Disease, 2021)
Background Heart transplant (HT) remains the most frequently indicated therapy for patients with end-stage heart failure that improves prognosis in Chagas cardiomyopathy (CCM). However, the lack of benznidazole therapy and availability of RT-PCR follow-up in many centers is a major limitation to perform this life-saving intervention, as there are concerns related with the risk of reactivation. We aimed to describe the outcomes of a cohort of patients with CCM who underwent HT using a conventional protocol with mycophenolate mofetil, without benznidazole prophylaxis or RT-PCR follow-up. Methods Retrospective cohort study. Between 2008 and 2018, 43 patients with CCM underwent HT. A descriptive analysis to characterize outcomes as rejection, infectious and neoplastic complications and a survival analysis was carried out. Results Median of follow-up was 4.3 (IR 4.28) years. Survival at 1 month, 1 year, and 5 years was 95%, 85%, and 75%, respectively, infections being the main cause of death (60%). Reactivations occurred in only three patients (7.34%) and were not related to mortality. Conclusion This cohort showed a favorable survival and a low reactivation rate without an impact on mortality. Our results suggest that performing HT in patients with CCM following conventional guidelines and recommendations for other etiologies is a safe approach.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/tid.13549
Keywords: Chagas disease; heart failure; heart transplantation

Bacteremia in solid organ transplant recipients as compared to immunocompetent patients: Acute phase cytokines and outcomes in a prospective, matched cohort study - Eichenberger, Emily M.; Ruffin, Felicia; Dagher, Michael; Lerebours, Reginald; Jung, Sin-Ho; Sharma-Kuinkel, Batu; Macintyre, Andrew N.; Thaden, Joshua T.; Sinclair, Matthew; Hale, Lauren; Kohler, Celia; Palmer, Scott M.; et al. (American Journal of Transplantation, 2021)
We undertook a prospective, matched cohort study of patients with Staphylococcus aureus bacteremia (SAB) and gram-negative bacteremia (GNB) to compare the characteristics, outcomes, and chemokine and cytokine response in transplant recipients to immunocompetent, nontransplant recipients. Fifty-five transplant recipients (GNB n = 29; SAB n = 26) and 225 nontransplant recipients (GNB n = 114; SAB n = 111) were included for clinical analysis. Transplant GNB had a significantly lower incidence of septic shock than nontransplant GNB (10.3% vs 30.7%, p = .03). Thirty-day mortality did not differ significantly between transplant and nontransplant recipients with GNB (10.3% vs 15.8%, p = .57) or SAB (0.0% vs 11.7%, p = .13). Next, transplant patients were matched 1:1 with nontransplant patients for the chemokine and cytokine analysis. Five cytokines and chemokines were significantly lower in transplant GNB vs nontransplant GNB: IL-2 (median [IQR]: 7.1 pg/ml [7.1, 7.1] vs 32.6 pg/ml [7.1, 88.0]; p = .001), MIP-1β (30.7 pg/ml [30.7, 30.7] vs 243.3 pg/ml [30.7, 344.4]; p = .001), IL-8 (32.0 pg/ml [5.6, 53.1] vs 59.1 pg/ml [39.2, 119.4]; p = .003), IL-15 (12.0 pg/ml [12.0, 12.0] vs 12.0 pg/ml [12.0, 126.7]; p = .03), and IFN-α (5.1 pg/mL [5.1, 5.1] vs 5.1 pg/ml [5.1, 26.3]; p = .04). Regulated upon Activation, Normal T Cell Expressed and Secreted (RANTES) was higher in transplant SAB vs nontransplant SAB (mean [SD]: 750.2 pg/ml [194.6] vs 656.5 pg/ml [147.6]; p = .046).
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ajt.16388
Keywords: clinical research/practice; cytokines/cytokine receptors; immunosuppression/immune modulation; infection and infectious agents – bacterial; infectious disease; organ transplantation in general; translational research/science

The respiratory microbiome after lung transplantation: Reflection or driver of respiratory disease? - Eskind, Caroline C.; Shilts, Meghan H.; Shaver, Ciara M.; Das, Suman R.; Satyanarayana, Gowri (American Journal of Transplantation, 2021)
With the introduction of high-throughput sequencing methods, our understanding of the human lower respiratory tract's inhabitants has expanded significantly in recent years. What is now termed the “lung microbiome” has been described for healthy patients, as well as people with chronic lung diseases and lung transplants. The lung microbiome of lung transplant recipients (LTRs) has proven to be unique compared with nontransplant patients, with characteristic findings associated with disease states, such as pneumonia, acute rejection, and graft failure. In this review, we summarize the current understanding of the lung microbiome in LTRs, not only focusing on bacteria but also highlighting key findings of the viral and the fungal community. Based on our knowledge of the lung microbiome in LTRs, we propose multiple opportunities for clinical use of the microbiome to improve outcomes in this population.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ajt.16568
Keywords: infectious disease; lung transplantation/pulmonology; lung transplantation: living donor; microbiome; translational research/science

Oral decontamination with colistin plus neomycin in solid organ transplant recipients colonized by multidrug-resistant Enterobacterales: a multicentre, randomized, controlled, open-label, parallel-group clinical trial - Fariñas, Maria Carmen; González-Rico, Claudia; Fernández-Martínez, Marta; Fortún, Jesús; Escudero-Sanchez, Rosa; Moreno, Asunción; Bodro, Marta; Muñoz, Patricia; Valerio, Maricela; Montejo, Miguel; Nieto, Javier; Ruiz-San Millan, Juan Carlos; et al. (Clinical Microbiology and Infection, 2021)
Objectives: To evaluate the efﬁcacy of oral colistin-neomycin in preventing multidrug-resistant Enterobacterales (MDR-E) infections in solid organ transplant (SOT) recipients. Methods: Multicentre, open-label, parallel-group, controlled trial with balanced (1:1) randomization in ﬁve transplant units. SOT recipients were screened for MDR-E intestinal colonization (extended-spectrum b-lactamase or carbapenemase producing) before transplantation and þ7 and þ 14 days after transplantation and assigned 1:1 to receive treatment with colistin sulfate plus neomycin sulfate for 14 days (decolonization treatment (DT) group) or no treatment (no decolonization treatment (NDT) group). The primary outcome was diagnosis of an MDR-E infection. Safety outcomes were appearance of adverse effects, mainly diarrhoea, rash, nausea and vomiting. Patients were monitored weekly until 30 days after treatment. Intention-to-treat analysis was performed.

Comparison of β-D-Glucan levels between Candida auris and other Candida species at the time of candidaemia: a retrospective study - Farooqi, Joveria; Niamatullah, Hammad; Irfan, Seema; Zafar, Afia; Malik, Faisal; Jabeen, Kauser (Clinical Microbiology and Infection, 2021)
Objectives: To compare serum b-D-glucan (BDG) levels in candidaemia with different Candida species, especially C. auris. Methods: Aga Khan University clinical laboratory database was retrospectively reviewed from January 2015 to December 2019. Blood culture positive cases with any Candida species and concomitant BDG level were included.

Secondary syphilis with liver involvement in a liver transplant recipient - Ferrándiz-Pulido, Carla; Ferrer, Berta; Salcedo, Maria Teresa; Velasco, Marta; Len, Oscar; Castells, Lluis (Transplant Infectious Disease, 2021)
Syphilis is capable of compromising almost any organ; however, syphilitic hepatitis is a rare manifestation that has been described most often in HIV-infected patients. Herein, we present a 33-year-old male liver transplant recipient who presented with progressive liver dysfunction characterized by mild ALT elevation and rising cholestasis, malaise, skin rash, and alopecia. Skin biopsy was characteristic of secondary syphilis, confirmed by both skin and liver biopsy-positive immunohistochemical staining for Treponema pallidum. The patient was treated with benzathine penicillin G 2.4 million units IM q week × 3 weeks. Three months later, the patient was asymptomatic and recovered from his general malaise. He showed no skin lesions and demonstrated complete regrowth of the hair on his scalp, beard, and eyebrows. The presence of liver dysfunction with cholestasis in a transplant recipient should alert transplant providers to the possibility of syphilitic hepatitis, particularly in men who have sex with men. Though not an early manifestation, cutaneous signs of secondary syphilis may be a helpful diagnostic indicator in most cases.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/tid.13431
Keywords: lues; solid organ transplant recipients; syphilis; syphilitic hepatitis

Diarrhea in Transplant: Diagnosis and Management - Florescu, Diana F.; Zimmer, Andrea (Emerging Transplant Infections, 2021)
Diarrhea affects up to 52% of solid organ transplant recipients and up to 80% of hematopoietic stem cell transplant recipients. Diarrhea can lead to dehydration, electrolyte imbalance, acute renal failure, hypotension, drug toxicity, rejection, and malnutrition. Diarrhea has a signiﬁcant impact on patients’ quality of life.

BK Polyomavirus After Solid Organ and Hematopoietic Cell Transplantation: One Virus – Three Diseases - Graf, Fabrice E.; Hirsch, Hans H. (Emerging Transplant Infections, 2021)
Polyomavirus-associated nephropathy (PyVAN) and hemorrhagic cystitis (PyVHC) occur almost exclusively after kidney transplantation (KT) and allogeneic hematopoietic stem cell transplantation (HSCT), respectively. In addition, PyV-associated urothelial cancer (PyVUC) is emerging after KT. These diseases are attributed to BK polyomavirus (BKPyV), a small non-enveloped, doublestranded DNA virus infecting >90% of the general population followed by renal persistence. PyVAN causes premature allograft failure in 1–15% of KT, while PyVHC complicates 5–25% of allogeneic HSCT with excess morbidity. PyVUC is currently diagnosed in <1% of KT but impacts graft and patient survival. Insufﬁcient antiviral immunity post-transplant is key to extensive replicative cytopathic damage seen in PyVAN and PyVHC by epithelial denudation, inﬂammation, and ﬁbrotic scarring while permitting genetic accidents including chromosomally integrated viral genomes in PyVUC. However, immunosuppression alone is not sufﬁcient since heart and lung transplant recipients are rarely affected despite more intense immunosuppression. Speciﬁc cofactors have been postulated in addition to the allogeneic constellation between the BKPyVreplicating host cell and the respective immune effectors. In KT, a mismatch between a high renal BKPyV load in the transplant and a low number of recipient immune effector functions is proposed in addition to tacrolimus, mycophenolate, and steroids. In allogeneic HSCT, bladder-toxic conditioning, e.g., by cyclophosphamide, is proposed to cause subclinical rareﬁcation of the bladder urothelium, which becomes clinically overt by high-level BKPyV replication and inﬂammatory exacerbation post-engraftment. Long-standing failure to resume immune control may allow for genetic replicative accidents and outgrowth of PyVUC. In PyVAN and PyVHC, high-level viruria and plasma BKPyV-DNAemia correlate with disease activity and could assist in developing antiviral drugs currently lacking. Early stepwise reduction of immunosuppression is recommended in KT, an option severely limited in PyVHC by imminent graft-versus-host disease. Phase I/II study results are awaited investigating mTOR (mechanistic target of rapamycin) inhibitors, low-dose cyclosporine, leﬂunomide, intravenous immunoglobulin, monoclonal antibodies, and T-cell therapy. Until then, PyVAN, PyVHC, and PyVUC will continue to represent signiﬁcant unmet clinical needs in transplant medicine jeopardizing otherwise successful outcomes.

8th European Conference on Infections in Leukaemia: 2020 guidelines for the diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or post-haematopoietic cell transplantation - Groll, Andreas H; Pana, Dorothea; Lanternier, Fanny; Mesini, Alessio; Ammann, Roland A; Averbuch, Dina; Castagnola, Elio; Cesaro, Simone; Engelhard, Dan; Garcia-Vidal, Carolina; Kanerva, Jukka; Ritz, Nicole; et al. (The Lancet Oncology, 2021)

Toxoplasma gondii in Solid Organ and Stem Cell Transplant: Prevention and Treatment - Guegan, Hélène; Robert-Gangneux, Florence (Emerging Transplant Infections, 2021)
Transplant recipients are a population at high risk for various opportunistic infections, including toxoplasmosis. Toxoplasma infection is particularly lifethreatening in hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients, primarily occurring through reactivation of latent infection or primary infection, respectively. Epidemiological, clinical features and levels of risk vary according to the transplanted organ, the pretransplant serologic status of both donor and recipient, and the time after engraftment. The diagnosis is guided by clinical symptoms and signs (although frequently nonspeciﬁc), imaging, and other diagnostic ﬁndings. Molecular methods, i.e., real-time PCRs, are the mainstay of Toxoplasma detection and should be performed for diagnosis in the blood or any other pertinent site. Despite the lack of transplantspeciﬁc therapeutic guidelines, the combination of pyrimethamine-sulfadiazine has been proposed as the ﬁrst-line curative treatment, based on clinical trials in HIV-infected population. Prevention of toxoplasmosis includes patient education about hygienic rules to prevent primary infection, but also serologic screening of donors and recipients, chemoprophylaxis, and follow-up of patients after transplantation. Although there are not well-standardized protocols adapted to the type of graft, patient management is extensively discussed in this chapter, which provides an overview of the usual diagnostic, therapeutic, and preventive strategies aimed at improving the clinical management of transplant recipients.

Outcomes of short-duration antiviral prophylaxis for hepatitis C positive donor kidney transplants - Gupta, Gaurav; Yakubu, Idris; Zhang, Yiran; Kimball, Pamela; Kang, Le; Mitchell, Kimberly; Ijioma, Stephen; Carroll, Norman; Patterson, Julie; Shinbashi, Meagan; Kumar, Dhiren; Moinuddin, Irfan; et al. (American Journal of Transplantation, 2021)
Trials describing 4- to 12-week courses of direct-acting antiviral drugs (DAAs) to treat hepatitis C virus (HCV) transmission from infected donors to uninfected kidney transplant recipients (D+/R− transplants) may be limited in “real-world” application by costs and delayed access to DAAs. We previously reported HCV transmission of 13% among D+/R− transplants with 2- to 4-day pangenotypic sofosbuvir/velpatasvir (SOF/VEL) perioperative prophylaxis, where one patient with HCV transmission was a nonresponder to first-line full-course DAA. Here, we report new data with a 7-day prophylaxis protocol (N = 50), as well as cumulative treatment and outcome data on all HCV D+/R− transplants (N = 102). Overall, nine patients (9/102; 9%; 95% CI: 5%–16%) developed HCV transmission, with a significant decline noted in the 7-day group (2/50; 4%; 95% CI: 0%–13%) compared with 2- to 4-day prophylaxis (7/52; 13%; 95% CI: 5%–25%). All patients with HCV transmission achieved sustained virologic response post full-course therapy (including one nonresponder from initial trial). A 1:1 matched analysis (N = 102) with contemporary HCV D−/R− transplants (controls) showed that although the pretransplant wait time was significantly shorter for D+/R− compared with D−/R− (mean: 1.8 vs. 4.4 years; p < .001), there were no differences in infections, rejection, development of de novo donor-specific antibody, or transplant outcomes up to 6 months of transplant.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ajt.16747
Keywords: clinical research/practice; clinical trial; complication: infectious; infection and infectious agents – viral; infection and infectious agents – viral: hepatitis C; infectious disease; kidney transplantation/nephrology

Cryptococcosis - Gushiken, Alexis C.; Saharia, Kapil K.; Baddley, John W. (Infectious Disease Clinics of North America, 2021)

HHV-6, HHV-7, and HHV-8: Forgotten Viruses in Transplantation - Haidar, Ghady (Emerging Transplant Infections, 2021)
Human herpesviruses (HHV)-6, HHV-7, and HHV-8 were identified as causes of infection in solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients nearly three decades ago. HHV-6 infection occurs early posttransplant and may cause fever of unknown origin, diarrhea, rash, pneumonitis, and encephalitis. Chromosomal integration of HHV-6 can complicate diagnostic testing for HHV-6, as these patients have markedly elevated HHV-6 DNA levels due to the presence of HHV-6 in every nucleated cell. Umbilical cord transplant recipients are at the highest risk for HHV-6 infection after HSCT, but the risk factors after SOT are ill-defined. HHV-6 is thought to mediate graft rejection and loss, delayed engraftment, and graft versus host disease and may also increase the risk of cytomegalovirus infection. However, no study has unequivocally proven the pathogenicity of HHV-6, the presence of which may simply be a marker of immune dysregulation. Even less is known about HHV-7 infection, which is largely asymptomatic and resolves without intervention. HHV-8 is well-recognized as the cause of Kaposi sarcoma (KS), multicentric Castleman disease, primary effusion lymphoma, and nonmalignant inflammatory syndromes. Extensively described after SOT, it is most common in endemic areas, where active research efforts are evaluating the benefit of screening donors and recipients for anti-HHV-8 antibodies prior to transplant. Little is known about HHV-8 infections after HSCT; KS and bone marrow failure are the only described entities. Antivirals (ganciclovir, foscarnet, and cidofovir) are of questionable efficacy against these viruses. Reduction of immunosuppression is the mainstay of treatment of HHV-8 infection.

American Society for Transplantation and Cellular Therapy Series: #3—Prevention of Cytomegalovirus Infection and Disease After Hematopoietic Cell Transplantation - Hakki, Morgan; Aitken, Samuel L.; Danziger-Isakov, Lara; Michaels, Marian G.; Carpenter, Paul A.; Chemaly, Roy F.; Papanicolaou, Genovefa A.; Boeckh, Michael; Marty, Francisco M. (Transplantation and Cellular Therapy, 2021)
The Practice Guidelines Committee of the American Society for Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to update its 2009 compendium-style infectious diseases guidelines for the care of hematopoietic cell transplant (HCT) recipients. A new approach was taken with the goal of better serving clinical providers by publishing each standalone topic in the infectious disease series as a concise format of frequently asked questions (FAQ), tables, and ﬁgures. Adult and pediatric infectious disease and HCT content experts developed and answered FAQs. Topics were ﬁnalized with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. The third topic in the series focuses on the prevention of cytomegalovirus infection and disease in HCT recipients by reviewing prophylaxis and preemptive therapy approaches; key deﬁnitions, relevant risk factors, and diagnostic monitoring considerations are also reviewed.

Microsporidiosis in Humans - Han, Bing; Pan, Guoqing; Weiss, Louis M (Clinical Microbiology Reviews, 2021)

Antimicrobial Prophylaxis in the Age of Emerging Transplant Infections - Hand, Jonathan (Emerging Transplant Infections, 2021)
Solid organ transplantation and hematopoietic cell transplantation are life-saving procedures, yet carry signiﬁcant infection risk due to the signiﬁcant and prolonged immunosuppression they entail. Infection prevention strategies using antibiotic prophylaxis can mitigate problems that arise through immunosuppression, especially if clinicians have a keen awareness for local epidemiology and patient-speciﬁc microbiological factors. Antifungal prophylaxis, especially in stem cell transplantation, is now standard of care for most institutions. Although there is variability in the incidence and seasonality of viral disease in transplanted populations, a tailored approach to antiviral prophylaxis can also substantially attenuate the risk of post-transplant disease.

Lung Transplantation for Severe Post–coronavirus Disease 2019 Respiratory Failure - Hawkins, Robert B.; Mehaffey, J. Hunter; Charles, Eric J.; Mannem, Hannah C.; Roeser, Mark (Transplantation, 2021)

Managing the significant drug-drug interaction between tacrolimus and letermovir in solid organ transplant recipients - Hedvat, Jessica; Choe, Jason Y.; Salerno, David M.; Scheffert, Jenna L.; Kovac, Danielle; Anamisis, Anastasia; Shertel, Tara L.; Lee, Jennifer H.; Liu, Esther C.; Lange, Nicholas W. (Clinical Transplantation, 2021)
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ctr.14213

Global guideline for the diagnosis and management of rare mould infections: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology and the American Society for Microbiology - Hoenigl, Martin; Salmanton-García, Jon; Walsh, Thomas J; Nucci, Marcio; Neoh, Chin Fen; Jenks, Jeffrey D; Lackner, Michaela; Sprute, Rosanne; Al-Hatmi, Abdullah M S; Bassetti, Matteo; Carlesse, Fabianne; Freiberger, Tomas; et al. (The Lancet Infectious Diseases, 2021)

The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin - Hoenigl, Martin; Sprute, Rosanne; Egger, Matthias; Arastehfar, Amir; Cornely, Oliver A.; Krause, Robert; Lass-Flörl, Cornelia; Prattes, Juergen; Spec, Andrej; Thompson, George R.; Wiederhold, Nathan; Jenks, Jeffrey D. (Drugs, 2021)
The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug–drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.
Keywords: Animals; Antifungal Agents; Drug Development; Drug Interactions; Drug Resistance; Fungal; Fungi; Humans; Invasive Fungal Infections

Pseudomonas aeruginosa Infections in Transplant: Epidemiology and Emerging Treatment Options - Hogan, John I.; Hill, Brandon K.; Sifri, Costi D. (Emerging Transplant Infections, 2021)
As one of the most formidable bacterial pathogens encountered in clinical practice, infections related to Pseudomonas aeruginosa (PsA) present a number of challenges to the infectious disease physician. In immunocompromised hosts in particular, PsA has the potential to manifest with unique, recurrent, and often severe clinical syndromes that warrant infectious disease consultation. A staggering array of virulence factors combined with a host of intrinsic and acquired genetic elements conferring resistance to antimicrobials can make this pathogen exceptionally difﬁcult to manage. As the epidemiology of PsA infection in transplant patients has evolved over the past several decades, so too has this organism’s spectrum of antimicrobial resistance. The emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) isolates in recent years underscores the importance of emerging therapeutics in the treatment of complicated infections.

Multidrug-Resistant Organisms: Posttransplant Management for Extended-Spectrum Beta-Lactamase Producers and Carbapenem-Resistant Enterobacterales - Howard-Anderson, Jessica; Pouch, Stephanie M. (Emerging Transplant Infections, 2021)
The incidence of extended-spectrum β-lactamase (ESBL)-producing Enterobacterales (ESBL-EB) and carbapenem-resistant Enterobacterales (CRE) infections has been increasing worldwide, although the prevalence and mechanism of resistance vary by geographic region and institutional patterns of resistance. These multidrug-resistant infections are challenging to diagnose and treat and can cause significant morbidity and mortality in transplant patients. In this chapter we highlight recent trends in epidemiology, including risk factors for acquiring ESBL-EB and CRE, clinical outcomes, and new strategies for diagnosis and treatment in both solid organ and hematopoietic stem cell transplant patients with ESBL-EB and CRE infections.

Altered Mental Status in the Solid Organ Transplant Recipient - Ince, Dilek (Emerging Transplant Infections, 2021)
Altered mental status is common in the solid organ transplant recipient. A variety of etiologies, including infections, metabolic abnormalities, medications, malignancies, and rejection, can lead to altered mental status in a transplant patient. Timeline after transplantation as well as organ transplanted have signiﬁcant impact on etiology. Detailed physical examination, comprehensive laboratory evaluation, and in many cases imaging can help elucidate the etiology. Urgent treatment of underlying etiology can improve prognosis.

Invasive Fungal Disease Among Pediatric and Adolescent Patients Undergoing Itraconazole Prophylaxis After Hematopoietic Stem Cell Transplantation - Itsaradisaikul, Suluk; Pakakasama, Samart; Boonsathorn, Sophida; Techasaensiri, Chonnamet; Rattanasiri, Sasivimol; Apiwattanakul, Nopporn (Transplantation Proceedings, 2021)
Background. Invasive fungal disease (IFD) is a major cause of morbidity and mortality in patients after hematopoietic stem cell transplantation (HSCT). Itraconazole has been used for prevention of IFD, but data related to incidence and associated factors of IFD in pediatric and adolescent patients on itraconazole prophylaxis remain scarce. Objectives. To identify incidence and risk factors associated with IFD among pediatric and adolescent patients receiving itraconazole prophylaxis after HSCT. Methods. Patients younger than 21 years who received itraconazole prophylaxis after HSCT from January 2007 to December 2016 were retrospectively enrolled. Incidence of IFD within 1 year and associated factors were analyzed. Results. All patients received itraconazole during the pre-engraftment period. Of 170 patients, 29 had IFD, with an incidence of 17.1% at 1 year. IFD at 1 year was signiﬁcantly associated with increased mortality. Of 29 patients with IFD, only 9 developed IFD while on itraconazole prophylaxis (5.3%), all of whom had invasive pulmonary aspergillosis. No invasive candidiasis occurred during itraconazole prophylaxis. Prolonged neutropenia (hazard ratio [HR] = 1.08; 95% conﬁdence interval [CI], 1.02-1.13), graft-versus-host disease within 100 days after transplantation (HR = 3.17; 95% CI, 1.17-8.57), and using etoposide in preconditioning regimens (HR = 21.60; 95% CI, 2.44-190.95) were signiﬁcantly associated with IFD at 1 year. No patients had to discontinue itraconazole because of its adverse effects. Conclusions. Itraconazole proffered good efﬁcacy for prevention of candidiasis during the pre-engraftment period. Most IFD episodes occurred after the engraftment period when itraconazole had been discontinued. During this period, patients with risk factors require appropriate fungal prophylaxis.

Vaccination Strategies in Solid Organ and Stem Cell Transplant - Jain, Shilpa R.; Kumar, Deepali (Emerging Transplant Infections, 2021)
Solid organ and hematopoietic stem cell transplant recipients are at high risk of contracting infectious diseases, including vaccine-preventable illnesses, in the post-transplant period. Given the high degree of immunosuppression immediately post-transplant, infection in the transplant patient results in higher morbidity and mortality than in the general population. Thus, it is the responsibility of the care team to ensure appropriate vaccines are given in an attempt to mitigate this risk. Timing of vaccination in the solid organ or hematopoietic stem cell transplant recipient is critical in order to strike a balance between providing protection against vaccine-preventable illnesses as early as possible, and vaccinating at a time when it is safe and the host’s immune response to vaccination will be adequate. This chapter will focus on providing a rationale for and summary of the specific recommendations pertaining to vaccination of both the solid organ and hematopoietic stem cell transplant recipient.

Antifungals in Clinical Use and the Pipeline - Johnson, Melissa D. (Infectious Disease Clinics of North America, 2021)

A pilot study of an intensified ganciclovir dosing strategy for treatment of cytomegalovirus disease in kidney and/or pancreas transplant recipients - Jorgenson, Margaret R.; Descourouez, Jillian L.; Leverson, Glen E.; Saddler, Christopher M.; Smith, Jeannina A.; Garg, Neetika; Parajuli, Sandesh; Mandelbrot, Didier A.; Odorico, Jon S. (Clinical Transplantation, 2021)
Methods: Adult kidney and/or pancreas transplant recipients admitted with CMV (4/29/19–7/15/20) received IV ganciclovir(10 mg/kg Q12 h × 7 days) with step-down to standard-of-care (SOC) dosing thereafter (5 mg/kg Q12). A SOC cohort admitted before implementation of the dosing strategy (10/20/16–3/2/19) served as a comparator. Primary objective: rate of viral clearance (delta log CMV) at therapy day 7. Secondary objective: safety/short term efficacy. Results: Fifty-four patients met inclusion criteria; 22 high-dose, 32 SOC. Demographics were similar with the exception of more women (45.4% vs. 15.6%,P = .03) and higher presenting viral-load in the high-dose group (log 6.0±.7 vs. log 5.2±1.2, P = .02). Highdose resulted in significantly greater response to therapy at day 7 (log -.92±.51 vs. log -.56±.79, P = .04). Change in WBC at day 7 was not different (-.49±1.92 vs. .45±5.1, P = .97). Short-term clinical outcomes were similar between groups including mean hospital length-of-stay (P = .52), readmission rates (30 d: P = .38; 90 d: P = .5) and achievement of CMV viral-load less-than-lower-limit-of-quantification by day 90 (73% vs. 84%, P = .06). Rejection after CMV as well as graft/patient survival were similar between groups (P = .56, P > .99, P > .99). Conclusion: A high-dose IV ganciclovir strategy results in improved viral clearance kinetics without safety concerns and similar short term clinical outcomes.

Comparing posaconazole and itraconazole for antifungal prophylaxis in critically ill lung transplant recipients: Efficacy and plasma concentrations - Kallee, Simon; Scharf, Christina; Schroeder, Ines; Paal, Michael; Vogeser, Michael; Irlbeck, Michael; Zander, Johannes; Zoller, Michael; Jung, Jette; Kneidinger, Nikolaus; Schneider, Christian; Michel, Sebastian; et al. (Transplant Infectious Disease, 2021)
Background Posaconazole and itraconazole are commonly used for systemic antifungal prophylaxis after lung transplantation. The aim of this study on critically ill lung transplant recipients was to assess the rate of adequate plasma concentrations and the frequency of fungal-induced transitions from antifungal prophylaxis to therapy after the administration of either posaconazole or itraconazole for systemic prophylaxis. Methods Critically ill lung transplant recipients with postoperative posaconazole or itraconazole prophylaxis and therapeutic drug monitoring from February 2016 to November 2019 were retrospectively included in the study. Positive fungal cultures or Aspergillus antigen tests resulting in a transition from antifungal prophylaxis to therapy were analyzed from the first day of prophylaxis until 7 days after the last sample for each patient. Adequate plasma concentrations were defined as ≥500 µg/L for itraconazole and ≥700 µg/L for posaconazole. Results Two hundred seventy-five samples from 73 patients were included in the analysis. Overall, 60% of the posaconazole and 55% of the itraconazole concentrations were subtherapeutic. Administration of posaconazole suspension resulted significantly (P < .01) more often in subtherapeutic concentrations than tablets (68% vs 10%). Patients treated with posaconazole showed less positive fungal records resulting in a transition from prophylaxis to therapy than patients treated with itraconazole (10% vs 33%, P-value: .029). The detection of a fungal pathogen was not associated with the measured plasma concentrations or the achievement of the target concentrations. Conclusion Our findings suggest that posaconazole should be used instead of itraconazole for systemic prophylaxis in critically ill lung transplant recipients.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/tid.13675
Keywords: antifungal prophylaxis; critically ill; itraconazole; lung transplant; posaconazole; therapeutic drug monitoring

Viral Encephalitides Including Rabies and Lymphocytic Choriomeningitis Virus: Impact in Transplant Donors and Recipients - Khole, Aalok; Theodoropoulos, Nicole M. (Emerging Transplant Infections, 2021)
This chapter is a review of rare yet clinically relevant viral encephalitides that have been transmitted from organ donors to recipients. We will discuss the potential pitfalls in diagnosing and managing these illnesses and also discuss the challenges and next steps to better outcomes from these infections.

Antifungal Susceptibility Testing and Identification - Kidd, Sarah E.; Crawford, Lucy C.; Halliday, Catriona L. (Infectious Disease Clinics of North America, 2021)

Hepatitis B and Hepatitis D Infections in the Transplant Setting - Kim, Brian; Terrault, Norah A. (Emerging Transplant Infections, 2021)
Hepatitis B virus (HBV) and hepatitis D virus (HDV) are hepatotropic viruses that can have a significant impact on patients undergoing solid organ and hematopoietic stem cell transplants. In the setting of transplant immunosuppression, patients with HBV or HDV coinfection can have acceleration in the natural history of their liver diseases with increased risk of developing cirrhosis, decompensation, and hepatocellular carcinoma. Immunosuppression can also reactivate HBV in patients with previous immune control. Moreover, with the national organ shortage and worsening opioid epidemic, increasing rise in donor transmission and de novo HBV can be expected. Appropriate screening, vaccination, prophylaxis, and treatment of those patients at risk for these potential complications can have a great impact on their post-transplant outcomes. Management of HBV and HDV can be complex and depends on the type of organ transplant, degree of immunosuppression, and donor/recipient HBV exposure/immune status. This process of evaluation and management starts before the transplant event with serologic screening of donors and recipients and pre-transplant vaccination of susceptible recipients, and it continues well after transplant with close monitoring and careful consideration of antiviral prophylaxis and treatment. If done successfully, outcomes of patients at risk for HBV complications can be similar to those without HBV.

Solid organ transplant–specific antibiogram in a tertiary pediatric hospital in Canada - Kitano, Taito; Science, Michelle; Nalli, Nadya; Timberlake, Kathryn; Allen, Upton; Teoh, Chia Wei; Campigotto, Aaron (Pediatric Transplantation, 2021)
SOT recipients are more vulnerable to infections with antimicrobial-resistant organisms, and therefore, it may be useful for transplant centers to create transplant-specific antibiograms to direct empirical antimicrobial regimens and monitor trends in antimicrobial resistance. SOT-specific antibiograms were created using antimicrobial susceptibility data on isolates from 2012 to 2018 at The Hospital for Sick Children, Toronto, Ontario, Canada. The CLSI guidelines were followed to generate the antibiograms except that results from 2 years of data were pooled on a rolling basis to achieve larger sample sizes. The 3 most frequent organisms in one analysis period of the SOT antibiogram were Escherichia coli (average sample size ±standard deviation; n = 28.7 ± 3.8), Staphylococcus aureus (n = 27.8 ± 5.0), and Pseudomonas aeruginosa (non-CF) (n = 19.8 ± 8.8). For E.coli, susceptibilities in the SOT antibiogram were significantly lower than those in the hospital-wide antibiogram in 2017–2018 for ampicillin (27% vs 47%; p = .014), piperacillin/tazobactam (55% vs 88%; p < .001), cefotaxime (59% vs 89%; p < .001), ciprofloxacin (71% vs 88%; p = .007), and trimethoprim-sulfamethoxazole (41% vs 69%; p = .001), but not significantly different for aminoglycosides and meropenem. In the SOT antibiogram of E. coli, decreased susceptibility trend was confirmed in some antibiotics, including piperacillin/tazobactam (83% in 2012–2013 vs 55% in 2017–2018). At our center, the solid organ transplant–specific antibiogram revealed important differences in E. coli susceptibilities and trends in antimicrobial resistance. Developing a SOT antibiogram will assist in revising and improving empiric treatment guidelines as well as monitoring antimicrobial resistance in this population.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/petr.13980
Keywords: antibiogram; antibiotic resistance; antimicrobial stewardship; antimicrobial susceptibility; solid organ transplant

Respiratory viral testing and antibacterial treatment in patients hospitalized with community-acquired pneumonia - Klompas, Michael; Imrey, Peter B.; Yu, Pei-Chun; Rhee, Chanu; Deshpande, Abhishek; Haessler, Sarah; Zilberberg, Marya D.; Rothberg, Michael B. (Infection Control & Hospital Epidemiology, 2021)
Objective: Viruses are more common than bacteria in patients hospitalized with community-acquired pneumonia. Little is known, however, about the frequency of respiratory viral testing and its associations with antimicrobial utilization. Design: Retrospective cohort study. Setting: The study included 179 US hospitals. Patients: Adults admitted with pneumonia between July 2010 and June 2015. Methods: We assessed the frequency of respiratory virus testing and compared antimicrobial utilization, mortality, length of stay, and costs between tested versus untested patients, and between virus-positive versus virus-negative patients. Results: Among 166,273 patients with pneumonia on admission, 40,787 patients (24.5%) were tested for respiratory viruses, 94.8% were tested for influenza, and 20.7% were tested for other viruses. Viral assays were positive in 5,133 of 40,787 tested patients (12.6%), typically for influenza and rhinovirus. Tested patients were younger and had fewer comorbidities than untested patients, but patients with positive viral assays were older and had more comorbidities than those with negative assays. Blood cultures were positive for bacterial pathogens in 2.7% of patients with positive viral assays versus 5.3% of patients with negative viral tests (P < .001). Antibacterial courses were shorter for virus-positive versus -negative patients overall (mean 5.5 vs 6.4 days; P < .001) but varied by bacterial testing: 8.1 versus 8.0 days (P = .60) if bacterial tests were positive; 5.3 versus 6.1 days (P < .001) if bacterial tests were negative; and 3.3 versus 5.2 days (P < .001) if bacterial tests were not obtained (interaction P < .001). Conclusions: A minority of patients hospitalized with pneumonia were tested for respiratory viruses; only a fraction of potential viral pathogens were assayed; and patients with positive viral tests often received long antibacterial courses.

Cytomegalovirus in Solid Organ Transplant Recipients: Prevention, Diagnosis, and Treatment - Kotton, Camille Nelson (Emerging Transplant Infections, 2021)
Cytomegalovirus (CMV) is among the most common of infections after transplant. In addition to causing viral infection, it increases the risk for a negative outcome for the organ or bone marrow graft, as well as for higher overall morbidity and mortality. Risk of CMV is especially high in transplant recipients previously nonimmune to the virus. Prevention is key for optimal outcomes, both for individuals and for transplant programs. Optimal disease recognition, diagnostics, prevention, and treatment result in better outcomes with this significant and virulent virus termed the “troll of transplantation” [1].

Early success transplanting kidneys from donors with new SARS-CoV-2 RNA positivity: A report of 10 cases - Koval, Christine E.; Poggio, Emilio D.; Lin, Yi-Chia; Kerr, Hannah; Eltemamy, Mohamed; Wee, Alvin (American Journal of Transplantation, 2021)
Transplantation of solid organs from donors with active SARS-CoV-2 infection has been advised against due to the possibility of disease transmission to the recipient. However, with the exception of lungs, conclusive data for productive infection of transplantable organs do not exist. While such data are awaited, the organ shortage continues to claim thousands of lives each year. In this setting, we put forth a strategy to transplant otherwise healthy extrapulmonary organs from SARS-CoV-2-infected donors. We transplanted 10 kidneys from five deceased donors with new detection of SARS-CoV-2 RNA during donor evaluation in early 2021. Kidney donor profile index ranged from 3% to 56%. All organs had been turned down by multiple other centers. Without clear signs or symptoms, the veracity of timing of SARS-CoV-2 infection could not be confirmed. With 8–16 weeks of follow-up, outcomes for all 10 patients and allografts have been excellent. All have been free of signs or symptoms of donor-derived SARS-CoV-2 infection. Our findings raise important questions about the nature of SARS-CoV-2 RNA detection in potential organ donors and suggest underutilization of exceptionally good extrapulmonary organs with low risk for disease transmission.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ajt.16765
Keywords: clinical decision-making; clinical research/practice; donors and donation: deceased; infection and infectious agents—viral; infectious disease; kidney transplantation/nephrology

Measles outbreak risk assessment for transplant candidates and recipients - Kreiger-Benson, Elana; Gelb, Bruce; Neumann, Henry J.; Hochman, Sarah; Lighter, Jennifer; Mehta, Sapna A. (American Journal of Transplantation, 2021)

Oropharyngeal candidiasis outcomes in renal transplant recipients receiving nystatin versus no antifungal prophylaxis - Ky, Trung Q.; Park, Jeong M.; McMurry, Katie A.; Tischer, Sarah M.; Fitzgerald, Linda J.; Cotiguala, Laura (Transplant Infectious Disease, 2021)
Objective To compare the incidence of oropharyngeal candidiasis (OC), or thrush, in renal transplant recipients receiving nystatin versus no antifungal prophylaxis. Methods This was a single-center, retrospective, non-inferiority study of adult renal transplant recipients (RTRs) who received nystatin for 30 days for OC prophylaxis (nystatin group) or no antifungal prophylaxis therapy (No PPX group). The primary outcome was the incidence of OC within 3 months post-transplant. Secondary outcomes included time to OC occurrence and severity of OC. The pre-specified non-inferiority margin was 10%. Results The incidence of OC within 3 months post-transplant among 257 RTRs was 7.8% (10/128) in the No PPX group and 4.7% (6/129) RTRs in the nystatin group, a risk difference of 3.2% (95% CI, −2.7% to 9.1%, non-inferiority P = .04). The median time to OC was 7.5 days (IQR 6.3-34.3 days) in the nystatin group and 9.5 days (IQR 5.3-30.5 days) in the No PPX group (P = .64). Esophageal candidiasis was observed in 10% (1/10) of RTRs with OC in the No PPX group compared to 16.7% (1/6) RTRs in the nystatin group (P = 1.00). All RTRs with OC achieved symptom resolution with fluconazole and/or nystatin. Two patients in the No PPX group required readmission for decreased oral intake, and OC was diagnosed and treated during their hospital day. Conclusions In this retrospective study of adult RTRs, the absence of antifungal prophylaxis demonstrated non-inferiority to 30-day nystatin prophylaxis at reducing the incidence of OC within 3 months of transplant. OC prophylaxis may not be warranted after renal transplant.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/tid.13559
Keywords: antifungal prophylaxis; esophageal candidiasis; kidney transplant; nystatin; oropharyngeal candidiasis; renal transplant; thrush

8th European Conference on Infections in Leukaemia: 2020 guidelines for the use of antibiotics in paediatric patients with cancer or post-haematopoietic cell transplantation - Lehrnbecher, Thomas; Averbuch, Dina; Castagnola, Elio; Cesaro, Simone; Ammann, Roland A; Garcia-Vidal, Carolina; Kanerva, Jukka; Lanternier, Fanny; Mesini, Alessio; Mikulska, Malgorzata; Pana, Dorothea; Ritz, Nicole; et al. (The Lancet Oncology, 2021)

West Nile Virus and Transplantation - Levi, Marilyn E.; Michaels, Marian G. (Emerging Transplant Infections, 2021)
Infections are an important cause of morbidity and mortality after transplantation. Some of these infections are environmental and geographically or seasonally important. West Nile virus is one such infection, tied to the epidemiology of infected mosquitos which varies over time. It can cause disease for a transplant recipient either from direct inoculation from an infected mosquito or as a donorderived infection. This chapter reviews current data about the epidemiology of West Nile virus, looking at the risk of infection (naturally occurring and donor derived), disease manifestation, diagnosis, management, and suggestions for prevention.

Letermovir treatment of cytomegalovirus infection or disease in solid organ and hematopoietic cell transplant recipients - Linder, Kathleen A.; Kovacs, Christopher; Mullane, Kate M.; Wolfe, Cameron; Clark, Nina M.; La Hoz, Ricardo M.; Smith, Jeannina; Kotton, Camille N.; Limaye, Ajit P.; Malinis, Maricar; Hakki, Morgan; Mishkin, Aaron; et al. (Transplant Infectious Disease, 2021)
Background Few options are available for cytomegalovirus (CMV) treatment in transplant recipients resistant, refractory, or intolerant to approved agents. Letermovir (LET) is approved for prophylaxis in hematopoietic cell transplant (HCT) recipients, but little is known about efficacy in CMV infection. We conducted an observational study to determine the patterns of use and outcome of LET treatment of CMV infection in transplant recipients. Methods Patients who received LET for treatment of CMV infection were identified at 13 transplant centers. Demographic and outcome data were collected. Results Twenty-seven solid organ and 21 HCT recipients (one dual) from 13 medical centers were included. Forty-five of 47 (94%) were treated with other agents prior to LET, and 57% had a history of prior CMV disease. Seventy-seven percent were intolerant to other antivirals; 32% were started on LET because of resistance concerns. Among 37 patients with viral load < 1000 international units (IU)/ml at LET initiation, two experienced >1 log rise in viral load by week 12, and no deaths were attributed to CMV. Ten patients had viral load > 1000 IU/ml at LET initiation, and six of 10 (60%) had a CMV viral load < 1000 IU/ml at completion of therapy or last known value. LET was discontinued in two patients for an adverse event. Conclusions Patients treated with LET with viral load < 1000 IU/ml had good virologic outcomes. Outcomes were mixed when LET was initiated at higher viral loads. Further studies on combination therapy or alternative LET dosing are needed.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/tid.13687
Keywords: cytomegalovirus infection; letermovir; solid organ transplantation; stem cell transplantation

Antimicrobial Stewardship for Transplant Candidates and Recipients - Liu, Catherine; Stohs, Erica J. (Emerging Transplant Infections, 2021)
Antimicrobial stewardship is an essential component of transplant programs to improve patient outcomes, reduce the threat of antimicrobial resistance, and lower the risk of drug toxicity. A multidisciplinary approach that leverages the existing team-based infrastructure of transplant programs and encompasses partnership with pharmacy, infection prevention, and microbiology is important for successful implementation. This chapter outlines the importance of stewardship in transplantation, describes implementation strategies, and provides examples of syndrome-or drug-speciﬁc antibiotic, antiviral, and antifungal stewardship targets for transplant patients. Finally, program process and outcome metrics should be chosen to assess the impact of interventions and identify opportunities for improvement.

Entecavir Monotherapy Prevents Hepatitis B Virus Recurrence After Liver Transplant for Chronic Hepatitis B Patients: A Long-Term Retrospective Study - Liu, Ying; Ho, Wai I.; Deng, Feiwen; Peng, Siwei; Lau, Wan Yee; Chen, Huanwei (Transplantation Proceedings, 2021)
Background. Limited data are available on the use of oral antiviral therapy, particularly the long-term use of entecavir monotherapy in patients with hepatitis B virus (HBV)−related diseases after liver transplant (LT). Methods. The clinical data on consecutive patients who underwent LT for HBV-related diseases from 2011 to 2019 were prospectively collected and retrospectively analyzed. All patients received entecavir monotherapy alone during the follow-up period; viral serology/load and liver biochemical tests were performed regularly. Results. Among the total of 89 patients were patients with decompensated cirrhosis (n = 27 [30%]), acute-on-chronic HBV (n = 21 [24%]), and hepatocellular carcinoma (HCC) (n = 41 [46%]). The median age of the patients was 50 years (range, 42-58 years), and the median follow-up was 37 months (range, 1-96 months). Before LT, 45 (51%) patients did not receive, whereas 44 (49%) were currently receiving, oral antiviral therapy. At the time of LT, serum level of HBV DNA of 34 (38%) patients was >20 IU/mL, with the median level being 270,000 IU/mL (range, 4270-2,020,000), and 53 patients (59%) had undetectable levels of HBV DNA (≤20 IU/mL). The cumulative rate of hepatitis B surface antigen loss was 79.8%, 100%, and 100% after 1 month, 1 year, and 5 years, respectively. Hepatitis B surface antigen positivity returned after seroclearance in 1 patient, who died of HCC recurrence with an undetectable level of HBV DNA. The overall survival rates at 1, 3, and 5 years after LT were 94.51%, 86.84%, and 85.27%, respectively. During the follow-up period, no entecavir adverse reactions or dose reductions were observed. Conclusions. Long-term entecavir monotherapy was highly effective in preventing HBV reactivation and HBV-related diseases.

Alternative pneumocystis prophylaxis in solid organ transplant recipients at two large transplant centers - Lum, Jessica; Echenique, Ignacio; Athans, Vasilios; Koval, Christine E. (Transplant Infectious Disease, 2021)
Background: Trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice for Pneumocystis jirovecii pneumonia (PJP) prophylaxis and has activity against other opportunistic infections (OIs) after solid organ transplant (SOT). We aimed to describe the incidence, reasons for and outcomes of use of alternative prophylactic agents (APAs) across SOT programs in our high volume centers. Methods: Solid organ transplant recipients (SOTRs) at our centers from 1/2015- 12/2016 were identified. Pharmacy records identified APA (pentamidine, atovaquone, or dapsone) use within 1 year. Records were reviewed for allergies, laboratory values at APA initiation, diagnostic tests for TMP-SMX-preventable OIs, and APA side effects. Results: An APA was initiated in 105/1173 (8.9%) SOTRs. Of these, 51 (48.6%) were because of sulfonamide allergy recorded pre-SOT, mostly rash/hives (58.8%). The remaining 54 (51.4%) had TMP-SMX discontinued post-SOT, mostly for neutropenia (48%) and renal effects (34%). Differences occurred across programs, with kidney transplant never stopping TMP-SMX for renal issues. Of those changed to APAs post-transplant, 19 (35%) were later successfully re-challenged with TMP-SMX. With thresholds in mind, 67 (64%) received an APA unnecessarily, accounting for up to $100 000/y excess cost. Potential TMP-SMX-preventable OIs occurred in 7 (5 Nocardia; 2 PJP). APA side effects occurred in 14/105 (13.3%). Conclusions: Use of APAs for PJP prophylaxis after SOT is less than previously reported but often unwarranted. Such decisions require scrutiny to avoid TMP-SMX- preventable OIs, cost and important APA side effects. Use of reasonable thresholds for cessation of TMP-SMX and data-driven approaches to re-challenge would substantially reduce APA use.

Notes from the Field: Transmission of Pan-Resistant and Echinocandin-Resistant Candida auris in Health Care Facilities ― Texas and the District of Columbia, January–April 2021 - Lyman, Meghan (MMWR. Morbidity and Mortality Weekly Report, 2021)
This report describes transmission of the multi-drug-resistant ...

Characteristics and outcomes among patients with community-acquired respiratory virus infections during the first year after lung transplantation - Mahan, Luke D.; Kanade, Rohan; Mohanka, Manish R.; Bollineni, Srinivas; Joerns, John; Kaza, Vaidehi; Torres, Fernando; La Hoz, Ricardo M.; Banga, Amit (Clinical Transplantation, 2021)
Background The current study describes the spectrum of community-acquired respiratory infections (CARV) during the first year after lung transplantation (LT). Additionally, we elucidate variables associated with CARV, management strategies utilized, and impact on early and late outcomes. Methods This was a retrospective study among patients transplanted between 2012 and 2015 (n = 255, mean age 55.6 ± 13.5 years, M: F 152:103). The diagnosis of CARV was based on the multiplex PCR on nasopharyngeal swab samples. Baseline characteristics, post-transplant variables, and outcomes were compared among patients with and without CARV. Results Eighty CARV infections developed among a quarter of the study group (n = 62, 24.3%). Rhinovirus/enterovirus was the most commonly isolated CARV (n = 24) followed by coronavirus (n = 17) and RSV (n = 9). A significant proportion of episodes (43.8%) required hospitalization. The use of nasal corticosteroids and left single LT was independently associated with an increased risk of CARV. CARV infections did not impact the lung functions during the first year or the CLAD-free survival at 3 years. Conclusions There is a significant burden of CARV infections during the first year after LT. The use of nasal corticosteroids may increase the risk of CARV infection. CARV infections did not impact outcomes.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ctr.14140
Keywords: CLAD; Coronavirus infections; chronic lung allograft dysfunction; coronavirus infections; inhaled Ribavirin; inhaled ribavirin; nasal corticosteroids

Transplant Adenovirus Infection: Clinical Syndromes, Diagnosis, and Management - Malinis, Maricar; Azar, Marwan M. (Emerging Transplant Infections, 2021)
Infections due to adenoviruses confer significant morbidity and mortality in immunocompromised hosts. Manifestations of disease in the setting of hematopoietic stem cell and solid organ transplantation may range from asymptomatic shedding or viremia to localized infection and disseminated disease. In solid organ transplant recipients, adenoviral disease often involves the allograft and can lead to graft dysfunction and/or graft loss. Several diagnostic methods are available for adenovirus infections, which include viral culture, direct antigen detection, molecular techniques, and histopathology. The cornerstone of treatment is the reduction of immunosuppression. Adjunct antiviral therapy is used if there is an inadequate clinical response to immunosuppression reduction. Immunotherapy is an option for those who fail to respond to established therapeutic options.

BK virus nephropathy in non‐renal solid organ transplant recipients: Are we looking hard enough? - Mallavarapu, Ravi K.; Sanoff, Scott L.; Howell, David N.; Roberts, John K. (Clinical Transplantation, 2021)
We retrospectively examined the clinical characteristics, pathological features, and outcomes of BK viremia and nephropathy in a population of non-renal solid organ transplant patients (NRSOT) referred for outpatient nephrology consultation over a period of 5 years. In the entire cohort of liver, heart, and lung transplant recipients referred to this clinic, 14% percent were found to have BK viremia with a median peak serum BK viral load of 35 500 copies/ml (range 250 to 21 100 000 copies/ml). BK viremia resolved in six of the seventeen patients (35%). Four out of five patients biopsied showed BK virus (BKV) nephropathy. Eleven out of seventeen patients with BK viremia developed advanced (stage 4 or 5) chronic kidney disease. Four patients developed rejection of their solid organ transplant within the first year post detection of BK viremia after immunosuppression reduction. We conclude that a multi-center study is required to evaluate whether implementation of a systematic BK screening program would be effective in early detection and management of this problem in the NRSOT population.

How do I manage nocardiosis? - Margalit, Ili; Lebeaux, David; Tishler, Ori; Goldberg, Elad; Bishara, Jihad; Yahav, Dafna; Coussement, Julien (Clinical Microbiology and Infection, 2021)
Background: Nocardiosis is a rare infection that is often difﬁcult to treat and may be life-threatening. There is no consensus on its management. Objectives: Our aim was to provide the current evidence for the diagnosis and management of individuals with nocardiosis, and to propose a management approach for this uncommon infection. Sources: We systematically searched the medical literature on nocardiosis for studies published between 2010 and 2020 and describing ten or more individuals. Content: Nocardiosis, a primarily opportunistic infection which may occur in immunocompetent persons, most commonly involves the lungs and frequently disseminates to other sites including the central nervous system. The reference standard for Nocardia species identiﬁcation is molecular biology, and the preferred method for antibiotic susceptibility testing (AST) is broth microdilution. Monotherapy seems appropriate for patients with primary skin nocardiosis or non-severe pulmonary disease; we reserve a multidrug regimen for more severe infections. Species identiﬁcation and AST results are often missing at initiation of antibiotics. Trimethoprim-sulfamethoxazole is the preferred agent for initial therapy, because Nocardia is very often susceptible to this agent, and because it has been the keystone of nocardiosis treatment for years. Linezolid, to which Nocardia is almost always susceptible, may be an alternative. When combination therapy is required, the repertoire of companion drugs includes thirdgeneration cephalosporins, amikacin and imipenem. Therapeutic modiﬁcations should take into account clinical response to initial therapy and AST results. Treatment duration of 6 months is appropriate for most situations, but longer durations are preferred for disseminated nocardiosis and shorter durations are reasonable in low-risk situations. Secondary prophylaxis may be considered in selected individuals with permanent immunosuppression.

Hepatitis E Infections in Transplants - Marion, Olivier; Kamar, Nassim (Emerging Transplant Infections, 2021)
The hepatitis E virus (HEV) is one of the main causative agents of acute viral hepatitis worldwide. Over the past decade, HEV genotypes 3 and 4 have been responsible for chronic infections in immunocompromised patients, especially solid organ transplant recipients. A rapid progression of liver fibrosis and the development of HEV-related cirrhosis have been documented in this specific population. HEV infections have also been associated with extrahepatic manifestations such as neurological disorders and kidney injuries. Despite a reduction in immunosuppressive regimens, approximately two-thirds of HEV-infected immunocompromised patients progress to chronic hepatitis and require antiviral therapy. Within the past years, ribavirin has been successfully used to treat chronic HEV infections. Current international guidelines recommend ribavirin monotherapy for a period of 12 weeks as the anti-HEV treatment of choice. The associated sustained virological response is approximately 80%. Nevertheless, a few cases of ribavirin failure have been documented. Further studies are needed to identify novel antiviral therapies for patients who are refractory to ribavirin.

Malaria in Transplant Candidates and Recipients: Diagnosis and Management - Martín-Dávila, Pilar; Norman, Francesca F.; López-Vélez, Rogelio (Emerging Transplant Infections, 2021)
Cases of malaria infection have been reported in solid organ and hematopoietic stem cell transplantation; malaria infections may occur as a consequence of a donor-derived infection (from organ or blood), as a relapse of previous P. vivax or P. ovale infection, or as newly acquired infections after transplantation in endemic areas. In donors or candidates with epidemiological risk of malaria infection, sensitive techniques in laboratory surveillance, including molecular tests, to rule out Plasmodium spp. infection should be used, and prompt diagnosis and specific therapy are needed. Pre-travel health advice and malaria prophylaxis are recommended for those traveling to endemic areas. Potential interactions between some malarial and immunosuppressive drugs should be checked.

Blastomycosis - Mazi, Patrick B.; Rauseo, Adriana M.; Spec, Andrej (Infectious Disease Clinics of North America, 2021)

Candidemia and Invasive Candidiasis - McCarty, Todd P.; White, Cameron M.; Pappas, Peter G. (Infectious Disease Clinics of North America, 2021)

Blastomycosis in solid organ transplant recipients—A retrospective series from southeastern Wisconsin - Mehta, Tej I.; Kurman, Jonathan; Dolan, Stephen; Gill, Harpreet; Thapa, Bipin (Transplant Infectious Disease, 2021)
Blastomycosis is a fungal infection caused primarily by Blastomyces dermatitis. The fungus is endemic to the Ohio, Mississippi, and St. Lawrence River areas of the United States. Organ transplant recipients are at risk of blastomycosis due to pharmacologic immunosuppression. Over a 20-year period, 30 cases of blastomycosis post-solid organ transplantation were identified at our center. The cumulative incidence of blastomycosis among SOT recipients was 0.99%. There was a male predominance (70% male) and a median age of 59 at the time of diagnosis. Regarding transplant type, 23 patients received kidney transplants, 4 received liver transplants, 2 received pancreas transplants and 1 received a heart transplant. Median time to blastomycosis identification post-transplant was 67.8 months (range: 1-188 months). Amphotericin B was used as initiation therapy in most cases, followed by itraconazole, voriconazole, or in select cases fluconazole or posaconazole maintenance therapy. Regarding comorbid conditions, 87% of patients had diabetes, 50% had congestive heart failure, and 20% had chronic pulmonary disease. Nine patients (30%) developed blastomycosis-related acute respiratory distress syndrome, 33% of these died with a median time to death of 22 days (range 20 days to 2 months); these were the only deaths attributable to blastomycosis.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/tid.13671
Keywords: Blastomycosis; Fungal; Fungal infection; Invasive fungal infection; Transplant; blastomycosis; fungal; fungal infection; invasive fungal infection; transplant

Bimonthly viral monitoring for late-onset cytomegalovirus infection in kidney transplant recipients - Melgarejo, Ivy; Jorgensen, Dana; Hariharan, Sundaram; Puttarajappa, Chethan M. (Clinical Transplantation, 2021)
Kidney transplant recipients with high-risk cytomegalovirus (CMV) serostatus (seropositive donor to seronegative recipient) are at risk for late-onset CMV after cessation of antiviral prophylaxis. We report findings from a strategy of bimonthly (every 2 weeks) CMV screening for late-onset CMV. This is a single-center retrospective cohort study of 70 high-risk CMV kidney transplant recipients transplanted between June 2016 and September 2018. Patients were monitored at 6–12 months post-transplantation for late-onset CMV using bimonthly CMV nucleic acid testing (NAT). Adherence to screening and its correlation with CMV-related hospitalizations were assessed. Failure to prevent CMV-related hospitalization was classified into three categories (non-adherence to CMV testing, rapid CMV progression, and health system failure). Twenty-one (30%) patients developed CMV DNAemia, of whom 10 (14%) required hospitalization. Reasons for CMV-related hospitalization despite screening were (i) screening non-adherence (50%), (ii) rapid progression (40%), and (iii) health system failure (10%). Adherence to screening was associated with lower viral counts at diagnosis (r = -.44, p = .049) and a trend towards lower risk of CMV-related hospitalization (OR: 0.97 per 1% increase in adherence; 95% CI: 0.94–1.00; p = .06). Bimonthly monitoring for late-onset CMV allows for early CMV detection and may lower CMV-related hospitalization.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ctr.14259
Keywords: Cytomegalovirus; High-risk CMV; Kidney transplantation; Screening; cytomegalovirus; high-risk CMV; kidney transplantation; screening

Legionellosis after hematopoietic stem cell transplantation - Mikulska, Malgorzata; Tridello, Gloria; Hoek, Jennifer; Gil, Lidia; Yañez, Lucrecia; Labussière-Wallet, Hélène; Passweg, Jakob; Xhaard, Aliénor; Pioltelli, Pietro; Caillot, Denis; Michel, Gerard; Veelken, Hendrik; et al. (Bone Marrow Transplantation, 2021)
Limited data are available on legionellosis after hematopoietic stem cell transplant (HSCT). The aim of this study was to report the cases of legionellosis and to identify predictors of legionellosis, legionellosis-associated death, and non-relapse mortality (NRM). All cases of post-HSCT legionellosis from the EBMT registry were included and matched with controls in a 3:1 ratio for the analyses of risk factors. In the years 1995–2016, 80 cases from 52 centers in 14 countries were identiﬁed (mainly from France, Italy, and Spain). Median time from HSCT to legionellosis was 203 days (range, 0–4099); 19 (23.8%) patients developed early legionellosis (within-day +30 post-HSCT). Patients were mainly male (70%), after allogeneic HSCT (70%), with acute leukemia (27.5%), lymphoma (23.8%), or multiple myeloma (21.3%), and the median age of 46.6 (range, 7.2–68.2). Predictors of legionellosis were allogeneic HSCT (OR = 2.27, 95%CI:1.08–4.80, p = 0.03) and recent other infection (OR = 2.96, 95%CI:1.34–6.52, p = 0.007). Twenty-seven (33.8%) patients died due to legionellosis (44% after early legionellosis), NRM was 50%. Predictors of NRM were female sex (HR = 2.19, 95%CI:1.13–4.23, p = 0.02), early legionellosis (HR = 2.24, 95%CI:1.13–4.46, p = 0.02), and south-eastern geographical region (HR = 2.16, 95% CI:1.05–4.44, p = 0.036). In conclusion, legionellosis is a rare complication after HSCT, mainly allogeneic, occurring frequently within 30 days after HSCT and associated with high mortality.

Transplant Infectious Disease Evaluation of Cytopenias - Miller, Rachel; Schlueter, Annette (Emerging Transplant Infections, 2021)
Cytopenias are a common occurrence in both hematopoietic stem cell and solid organ transplant recipients, particularly in the early post-transplant time period. The etiology is frequently multifactorial, reflecting the simultaneous interplay of infection, immunologic derangements, and medication effects in this patient population. These factors continually change over time, further adding to the complexity of diagnosis and management. Thorough evaluation of the individual’s medical history, physical exam, and preliminary laboratory values can assist with prioritizing the differential diagnosis and focusing the diagnostic workup. While absolute cytopenia cutoff values to trigger urgent intervention are variably defined and patient-specific, it is important to recognize those conditions that are life-threatening in order to initiate prompt and aggressive interventions. In less urgent clinical situations, a more methodical approach to diagnosis and treatment is favored, often beginning with modification of immunosuppressive and/or other medications. In most instances, optimal management of transplant-associated cytopenias requires a multidisciplinary approach. This chapter discusses the range of etiologies of transplant-associated cytopenias, followed by a general approach to diagnosis and management.

Emerging Transplant Infections: Cystic Fibrosis - Mohamedaly, Omar H.; Johnson, Carrie A. (Emerging Transplant Infections, 2021)
Cystic fibrosis is an autosomal recessive inherited disorder of salt transport. The natural history of the disease is determined by the development of chronic bronchiectasis and ensuing chronic colonization with multidrug-resistant bacteria and fungi. End-stage lung disease commonly necessitates lung transplant, and occasionally even combined lung/liver or lung/kidney transplant may be the only way forward for affected patients. Due to the common organisms colonizing the lungs of patients with cystic fibrosis, infections pre- and posttransplant are often complex and multidrug resistant and require the engagement of multidisciplinary teams for effective management.

Impact of Infection on Transplant Outcomes: Transplant Infectious Disease Expertise as an Essential Component of Transplant Programs - Morris, Michele I. (Emerging Transplant Infections, 2021)
Infectious complications are a major cause of morbidity and mortality in both solid organ and hematopoietic stem cell transplant patients. The risk of infection by common opportunistic pathogens like cytomegalovirus can be mitigated with the optimal use of molecular diagnostics and antiviral prophylaxis. Novel and emerging bacterial, viral, fungal, and parasitic pathogens may be more successfully managed with early diagnosis and therapy. In the care of solid organ and hematopoietic stem cell transplant candidates and recipients, involvement of physicians with expertise in transplant infectious diseases has been shown to improve outcomes. In addition to their essential role in decreasing patient morbidity and mortality, infectious disease specialists also add value to the transplant program through the development and implementation of infection prevention protocols. These specialists are on the front line of the response to new organisms that may present atypically or be difﬁcult to recognize in patients receiving immunosuppressive therapies pre- and post-transplant. In this rapidly changing ﬁeld, the Emerging Transplant Infections textbook provides updated information on the diagnosis, treatment, and prevention of signiﬁcant infections often seen in this highly immunocompromised population.

Changing Definition of Immunosuppression: Targeted Therapies and Resulting Emerging Infections and Their Prevention - Mueller, Nicolas J. (Emerging Transplant Infections, 2021)
While some biologicals have been routinely used in solid organ and hematopoietic stem cell transplant patients for years, a number of newer compounds have been added to the armamentarium for varying indications spanning from the underlying disease to complications of transplantation. This chapter aims at describing the infectious risk of a selection of compounds. The specific chapters list a number of recommendations to consider for infection prevention, in addition to the standard preventive measures in place. Given the nature of the available data, these suggestions are meant to be neither exhaustive nor mandatory and must be applied in the context of the individual patient.

Solid Organ Transplantation in HIV Positive Patients - Muller, Elmi; Stock, Peter (Emerging Transplant Infections, 2021)
Transplantation in recent years has become a viable option to treat end stage organ failure in people living with HIV infection. Signiﬁcant advances in the understanding of appropriate immunosuppression management and infection prevention have resulted in graft and patient survival comparable to HIV-negative recipients in many cases. Given the higher incidence of end stage organ disease in HIV positive patients, particularly liver cirrhosis and dialysis dependent renal failure, transplant should be considered as a viable pathway for these patients. Furthermore, encouraging results are starting to emerge regarding using HIVpositive organ donors, both living and deceased.

Incidence and impact of community respiratory viral infections in post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis and haploidentical stem cell transplantation - Mulroney, Carolyn M.; Abid, Muhammad Bilal; Bashey, Asad; Chemaly, Roy F.; Ciurea, Stefan O.; Chen, Min; Dandoy, Christopher E.; Diaz Perez, Miguel A.; Friend, Brian D.; Fuchs, Ephraim; Ganguly, Siddhartha; Goldsmith, Scott R.; et al. (British Journal of Haematology, 2021)
Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA-haploidentical HCT recipients who receive post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin-based GVHD prophylaxis (SibCNI, N = 1605) or PTCy (SibCy, N = 403), and related haploidentical transplants receiving PTCy (HaploCy, N = 757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment-related mortality [hazard ratio (HR) 2⋅14, 99% confidence interval (CI) 1⋅13–4⋅07; P = 0⋅002] and inferior 2-year overall survival (HR 1⋅65, 99% CI 1⋅11–2⋅43; P = 0⋅001) compared to SibCNI with no CRVI. This finding justifies further research into long-term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long-term outcomes in such patients.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/bjh.17563
Keywords: Allogeneic transplant; Post Transplant Cyclophosphamide; Respiratory viral infection

Pretransplant Screening for Infection Exposure: Approach to the Patients with Epidemiologic and Geographic Risk Factors - Nanayakkara, Deepa; Schaenman, Joanna (Emerging Transplant Infections, 2021)
Characteristics of transplant candidates can signiﬁcantly impact risk for infection after transplantation and immunosuppression start. These characteristics include a wide variety of risk factors for potential infection ranging from country of origin and travel history to history of immunosuppression, to certain comorbid conditions, and to diet and occupation. Increased mobility and medical complexity of transplant patients, and the changing epidemiology of pathogen distribution, can complicate the estimation of infection risk. We review here speciﬁc risk factors for each type of infection, from bacterial to fungal, viral, and parasitic, with regard to patient risk factors including potential for geographic exposure.

Influenza Infections in Solid Organ and Stem Cell Transplant Recipients - Natori, Yoichiro (Emerging Transplant Infections, 2021)
Inﬂuenza virus is a common respiratory virus in solid organ and stem cell transplant recipients. Inﬂuenza infection in immunocompromised hosts can result in severe disease, as compared to general population. Risk factors for severe inﬂuenza infection in transplant recipients include treatment with antilymphocyte globulin, presence of lower respiratory disease, and infection early after transplantation. Transplant programs should act to optimize prevention, early diagnosis, and treatment of inﬂuenza infection in this population in order to achieve better transplant outcomes.

Emerging Epidemics in Transplant: Histoplasmosis, Blastomycosis, and Paracoccidioidomycosis - Nel, Jeremy; Lachiewicz, Anne; van Duin, David (Emerging Transplant Infections, 2021)
The endemic fungi are a group of thermally dimorphic fungi that occupy speciﬁc deﬁned environmental ranges. They count Histoplasma, Blastomyces, Paracoccidioides, Coccidioides, Talaromyces, Emergomyces, and Sporothrix among their number. In the environment, they exist as molds, and at body temperature, they transform into their pathogenic yeast form (or, in the case of coccidioidomycosis, into a specialized structure called a spherule). Histoplasma, Blastomyces, and Paracoccidioides are covered in this chapter. Transplant recipients are at increased risk for severe and disseminated infection with these pathogens. Histoplasmosis and blastomycosis usually manifest as pulmonary disease. Extrapulmonary disease can occur with or without concomitant pulmonary disease in immunocompromised hosts. Commonly infected sites include the liver, spleen, lymph nodes, bone marrow, gastrointestinal tract, and skin. Skin involvement is especially common in blastomycosis. Paracoccidioidomycosis may present in an acute disseminated form in young patients. However, in 90% of symptomatic paracoccidioidomycosis, pulmonary chronic disease is observed, which is a reactivation of prior acquired infection. Oral mucosa and skin are common sites of dissemination in chronic disease. Diagnosis of endemic mycoses is difﬁcult and often delayed. Combining various diagnostic modalities is usually needed. The treatment of choice for all the endemic mycoses are amphotericin B and the azoles. In general, treatment must be given for a prolonged period (frequently a year or more) in order to prevent a relapse.

Multidrug-Resistant Organisms: Pre-transplant Evaluation and Management - Nellore, Anoma; Lee, Rachael A. (Emerging Transplant Infections, 2021)
Multidrug-resistant organisms (MDROs) cause morbidity and mortality after organ transplantation. Infection from these organisms may arise from pre-transplant colonization/infectious events, and these organisms may be donor-derived. Here we review the epidemiology, clinical manifestations, disease diagnostics, and therapeutic modalities for six common MDRO bacterial pathogens in the context of solid organ and bone marrow transplantation.

Pre-transplant vaccination compliance in adult heart and lung transplant recipients - Neuhaus, Kristen A.; Mossad, Sherif B.; Pallotta, Andrea; Srinivas, Pavithra; West, Lucianne; Budev, Marie M.; Rivard, Kaitlyn (Clinical Transplantation, 2021)
Background Vaccine preventable diseases can affect solid organ transplant recipients post-transplant. Therefore, the administration of vaccines and assessment of serologic response should be prioritized in the pre-transplant period. Methods This single-center, retrospective study included 349 adult heart or lung transplant candidates between December 1, 2017 and November 30, 2019. We describe vaccination or serologic status for hepatitis A, hepatitis B, tetanus, pneumococcal, influenza, and other recommended vaccinations among heart or lung transplant candidates. Results Eighty-two heart transplant candidates (91%) and 77 lung transplant candidates (30%) received an ID consult prior to transplant. More patients completed the pneumococcal series (66.7% vs. 28.6%, P = .045) in the heart transplant group that received an ID consult. In the lung transplant group, patients with an ID consult demonstrated higher rates of immunity to hepatitis A (84.4% vs. 72.9%, P = .047), hepatitis B (75.3% vs. 56.9%, P = .005), and measles (71.4% vs. 52.5%, P = .005) compared to those without. Conclusions Our results demonstrate the value of consulting ID and administering vaccinations in the early evaluation phase, prior to transplant listing. Opportunities remain to better optimize vaccination rates prior to transplant in heart and lung transplant candidates.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ctr.14464
Keywords: heart transplant; infectious diseases; lung transplant; transplant evaluation; vaccination

Coccidioidomycosis in Transplantation - Nokes, Brandon T.; Blair, Janis E. (Emerging Transplant Infections, 2021)
Coccidioidomycosis is an infection due to the fungal species Coccidioides, which is most heavily endemic in the desert southwestern USA. Although early studies of this infection among transplant recipients in the endemic region were complicated by high morbidity and mortality, solid organ and hematologic stem cell transplantation can be a successful undertaking within the Coccidioides-endemic region. Such success has been attributed to careful attention to screening for and treatment of occult infection prior to transplantation. Antifungal prophylaxis is important to prevent new acquisition or reactivation in the first year following transplantation. Prophylaxis strategies have undergone study and revision and should target the prevention of coccidioidomycosis in the first post-transplantation year, after acute organ rejection, and in recipients of Coccidioides-infected donors. Early recognition and treatment of organ recipients with acute coccidioidomycosis is key to minimizing morbidity and mortality. Diagnostic studies early in the course of infection can be insensitive, but sensitivity improves with repeated testing. Prevention and treatment strategies are reviewed and presented herein.

Hospital Epidemiology and Infection Control in the Transplant Center - Patel, Gopi; Hochman, Sarah (Emerging Transplant Infections, 2021)
Both solid organ and hematopoietic stem cell transplant candidates and recipients are at high risk for healthcare-associated infections due to their underlying diseases, comorbid conditions, as well as the receipt of augmented immunosuppression to prevent rejection. Partnership between transplant physicians, institutional leaders, and infection preventionists allows for the accommodation of this growing vulnerable patient population into institutional risk assessments and hazard analyses. In addition, advancements in diagnostics and molecular typing have provided important information regarding sources of transmission of multidrug-resistant or opportunistic pathogens, thus informing strategies for mitigating risk and controlling outbreaks. Here we review common healthcare-associated infections and strategies for source control, prevention, and curbing outbreaks when detected.

Follow-up of human adenovirus viral load in pediatric hematopoietic stem cell transplant recipients - Peker, Bilal Olcay; Tüysüz Kintrup, Gülen; Sağlık, İmran and Can Sarınoğlu, Rabia and Güler, Elif and Mutlu, Derya and Küpesiz, Osman Alphan and Çolak, Dilek (Clinical Transplantation, 2021)
Background The spectrum of human adenovirus (HAdV)–related disease is broad, and the virus acts on many organs and systems in hematopoietic stem cell transplantation (HSCT) recipients. We aimed to evaluate the effect of HAdV-DNA positivity with clinical and laboratory findings 4 months after HSCT. Methods and results We retrospectively investigated HAdV-DNA in 153 HSCT recipients (≤18 years) by quantitative real-time polymerase chain reaction (RealStar; Altona Diagnostics). The results of samples from January 2014 to December 2017 are included. HAdV-DNA was positive for at least one sample type in 50 (32.67%) patients. HAdV-DNA positivity rate was 8.92% (N: 145/1625), 40.25% (N: 64/159), and 25% (N: 2/8) for plasma, stool, and urine samples, respectively. HAdV-DNA was positive in the plasma of 38 (24.83%) patients at a median 16 (range: 1–58 days) days after HSCT. The mortality rate was 23.68% and 6.95% in plasma HAdV-positive and HAdV-negative patients (p = .014). Moreover, HAdV-DNA positivity had an impact on overall survival for allogeneic-HSCT (p = .013), with the cumulative effect including graft-versus-host disease state in multivariate analysis (p = .014). Conclusions Plasma HAdV-DNA positivity is a potential influencer that decreases survival in the early post-transplant period. Due to the high mortality rates, close monitoring is required of HAdV infections after HSCT with sensitive methods, especially at the early stage.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ctr.14209
Keywords: hematopoietic stem cell transplantation; human adenovirus; quantitative polymerase chain reaction; survival

HIV transmission through living donor kidney transplant: An 11-year follow-up on the recipient and donor - Pereira, Marcus R.; Dube, Geoffrey K.; Tatem, Luis; Burack, Daniel; Crew, Russell J.; Cohen, David J.; Ratner, Lloyd E. (Transplant Infectious Disease, 2021)
HIV transmission via solid organ transplant is a rare but serious complication. Here, we describe long-term outcomes in a case of living donor-derived transmission of HIV in a kidney transplant recipient. After 11 years since transplant surgery, the donor shows no evidence of abnormal renal function, while the recipient continues to have a functioning graft. HIV is well controlled in both individuals. This single case report highlights the possibility of acceptable long-term outcomes in living kidney donors with HIV as well as in donor-derived HIV transmission to kidney transplant recipients.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/tid.13691
Keywords: HIV; donor derived infection; kidney transplant; outcomes

Aspergillus in Solid Organ and Stem Cell Transplant Patients: Emerging Options for Diagnosis and Management - Pérez-Cortés Villalobos, Armelle; Husain, Shahid (Emerging Transplant Infections, 2021)
Invasive aspergillosis is a major cause of morbidity and mortality in hematopoietic stem cell transplant and solid organ transplant recipients. The introduction of new noninvasive tests, combined with more effective and better-tolerated antifungal agents, has decreased the mortality rates associated with invasive aspergillosis.

Respiratory Viral Pathogens in Solid Organ and Hematopoietic Stem Cell Transplant Recipients - Pergam, Steven A.; Ison, Michael G. (Emerging Transplant Infections, 2021)
Respiratory viruses are among the most common causes of infection among solid organ and hematopoietic stem cell transplant recipients. Respiratory viruses, such as inﬂuenza and respiratory syncytial virus, can cause a range of disease from asymptomatic shedding, upper respiratory infections, to life threatening pneumonia. In addition, respiratory viruses may be associated with chronic sequelae, including devasting late complications such as chronic rejection in lung transplant recipients and late airﬂow obstruction among hematopoietic stem cell transplant recipients. Currently only inﬂuenza has an available vaccine and licensed antivirals are limited to inﬂuenza and RSV. However, there are a number of novel vaccine candidates, preventative therapies, and antiviral drugs currently in development for the treatment and prevention of other clinically important respiratory viruses. Due to the limitation in currently available treatment options and the increased risk of transmission among high-risk transplant patients, infection prevention and control efforts remain the cornerstone to prevention during respiratory virus season and outbreaks. In this chapter, we will review the epidemiology, clinical presentation, prevention strategies, and management options for respiratory viruses in solid organ and hematopoietic stem cell transplant recipients.

Retrospective-prospective study of safety and efficacy of sofosbuvir-based direct-acting antivirals in HIV/HCV-coinfected participants with decompensated liver disease pre– or post–liver transplant - Peters, Marion G.; Kottilil, Shyam; Terrault, Norah; Amara, Dominic; Husson, Jennifer; Huprikar, Shirish; Florman, Sander; Sulkowski, Mark S.; Durand, Christine M.; Luetkemeyer, Anne F.; Rogers, Rodney; Grab, Joshua; et al. (American Journal of Transplantation, 2021)
Keywords: ALT; APRI; ART; ARV; CPT; Child-Pugh-Turcotte score; DAA; Direct-acting antiviral; ESLD; F; FIB-4; Fibrosis stage; Fibrosis-4 score; HCC; HCV; HIV; Hepatitis C virus; IQR; LLOQ; LT; MELD; Model for End-Stage Liver Disease score; PLWH; SRTR; STOP-CO; SVR; Scientific Registry of Transplant; alanine aminotransferase; antibiotic: antiviral; antiretroviral; antiretroviral therapy; aspartate aminotransferase to platelet ratio; cirrhosis; clinical research / practice; end-stage liver disease; hepatocellular carcinoma; human immunodeficiency virus; infection and infectious agents - viral: hepatitis C; interquartile range; liver transplant; liver transplantation / hepatology; lower limit of quantification; people living with HIV; recurrent disease; stop coinfection; sustained virologic response

Chagas Disease: Coming to a Transplanted Patient Near You - Pierrotti, Lígia Camera; Ibrahim, Karim Yaqub (Emerging Transplant Infections, 2021)
Chagas disease is a vector-borne infection caused by the protozoan Trypanosoma cruzi that is endemic in Latin America. More recently, the geographic distribution of the disease has changed due to immigration of asymptomatic infected individuals from endemic to non-endemic regions. Therefore, Chagas disease involving acute infection among negative recipients receiving a transplant graft from positive donors and reactivation episodes among positive recipients due to posttransplant immunosuppression is a problem that has been recognized worldwide. This chapter aims to highlight the epidemiology, clinical manifestations, diagnosis, management, and outcomes of Chagas disease among transplant recipients.

Neuroinvasive chikungunya in a liver transplant recipient - Pimenta, Eduardo Scarlatelli; Cavalcanti, Marta Guimarães; Cabral-Castro, Mauro Jorge; Lima, Marco Antonio; Peralta, José Mauro; Santoro-Lopes, Guilherme (Transplant Infectious Disease, 2021)
The influence of chronic immunosuppression on the course of chikungunya virus (CHIKV) infection in recipients of solid organ transplantation (SOT) is still unsettled. Scarce data suggest that the course of CHIKV infection is generally benign in this population. In addition, the occurrence of severe atypical manifestations associated with CHIKV has not been well documented among SOT recipients. In this report, we describe a 64-year-old male liver transplant recipient who was admitted with fever, headache, arthralgia, left palpebral ptosis, mydriasis, and right hemiparesis. Cranial magnetic resonance imaging did not reveal any alteration suggestive of acute infection. Nevertheless, CHIKV was detected in the cerebrospinal fluid (CSF) with a real-time reverse transcriptase assay. Other PCR assays carried out in CSF were negative for HSV-1 and 2, cytomegalovirus, dengue virus (DENV), and Zika virus (ZIKV). CHIKV viremia was also detected while PCR assays for ZIKV and DENV in the blood were negative. ZIKV viruria was simultaneously present in this case. All neurologic manifestations waned within 2 weeks after the onset. This report shows that chikungunya must be considered in the differential diagnosis of acute neurologic disease in SOT recipients who live in or have recently traveled to endemic areas.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/tid.13554
Keywords: atypical chikungunya; central nervous system; chikungunya; complication; transplantation

Clostridioides Difficile: Where Should the Management Strategies in Transplant Vary? - Pisano, Jennifer C.; Mullane, Kathleen M. (Emerging Transplant Infections, 2021)
Infectious and noninfectious diarrheas are important complications in immunocompromised host (ICH) populations including hematologic stem cell (HSCT) and solid organ transplant (SOT) recipients. Adverse consequences of diarrhea, including fluid and electrolyte imbalances with resultant malabsorption of nutrition and medications, can lead to prolonged hospital stays or rehospitalizations. Clostridioides (formerly Clostridium) difficile is the most common infectious etiology of infectious diarrhea in hospitalized individuals, and the incidence of C. difficile infections (CDI) has steadily increased since 2000 (Lessa et al, Clin Infect Dis. 55 Suppl 2:S65–70, 2012; Balsells et al, J Glob Health. 9(1):010407, 2019). ICH populations are at increased risk of CDI and of experiencing severe or complicated clinical courses in both initial infection and subsequent recurrences. In addition to CDI risk factors identified in non-ICH populations, there are unique complicating risk factors in ICH patients. These include the use of therapies toxic to the gut mucosa (chemotherapy, mycophenolate, steroids), concurrent infection with cytomegalovirus which may directly damage gut mucosa and additionally alter immune responses to other pathogens, and the frequent need for concomitant antibiotic therapy. Consequences in ICH populations may include graft loss in SOT recipients, graft-versus-host disease (GVHD) in HSCT recipients, malnutrition, bacteremia from translocation of intestinal flora, and death. This chapter focuses on the epidemiology, clinical manifestations, diagnosis, and management of CDI in HSCT and SOT recipients.

Central Nervous System Infections in Immunocompromised Patients - Pruitt, Amy A. (Current Neurology and Neuroscience Reports, 2021)
Purpose of Review This article reviews current epidemiologic trends, clinical presentations, and diagnostic strategies for central nervous system (CNS) infections in human immunodeficiency virus-negative (HIV) patients immunocompromised by their underlying disease or by receipt of immunosuppressive or immunomodulating therapies. Three patient groups are considered: (1) cancer patients; (2) hematopoietic or solid organ transplantation recipients; and (3) patients with autoimmune or inflammatory conditions requiring therapies that alter the host immune response. Recent Findings Clinical presentations, associated neuroimaging, and cerebrospinal fluid (CSF) abnormalities differ between immunocompromised and immunocompetent patients. Infections can trigger the emergence of neurotropic antibodies or inflammatory conditions due to treatment with cancer immunotherapies. Unbiased metagenomic assays to identify obscure pathogens help clinicians navigate the increasing range of conditions affecting the growing population of patients with altered immunity. Summary Awareness of clinical presentations and disease and drug-specific risks is important for early diagnosis and intervention in these often life-threatening infections and their noninfectious mimes.

Emerging Management of Hepatitis C in Transplant - Puchades, Lorena; Berenguer, Marina (Emerging Transplant Infections, 2021)
Chronic hepatitis C virus (HCV) infection related liver diseases are a leading indication for liver transplantation (LT) worldwide, responsible for about 20% of all LT performed in Europe and the United States. In the context of liver transplantation, treatment of HCV infection has been classically challenging because of therapies’ low efﬁcacy and safety concerns associated with interferon-based regimens, so that patients with decompensated cirrhosis and liver graft recipients have been typically considered as “difﬁcult to treat populations.” The arrival of the new direct-acting antiviral agents (DAAs) has transformed the management of these patients. Treating LT candidates not only prevents viral recurrence, but importantly, leads to functional improvement and potential delisting from the waiting list. Efﬁcacy, safety, and tolerability of DAA treatments worsen as the severity of liver disease increases. In the posttransplant setting, DAA therapies now have excellent efﬁcacy and tolerability, so much so that the transplantation of HCV positive donors into HCV negative recipients in some regions of the world is considered a viable option to increase a limited donor pool. This is especially true in North America, where the opiate epidemic has fueled an availability of viable organs for donation.

Acanthamoeba, Naegleria, and Balamuthia in Transplant Patients: An Emerging Threat - Puius, Yoram A.; Aldrich, Margaret L.; Cope, Jennifer R. (Emerging Transplant Infections, 2021)
Free-living amoebae (FLA) are ubiquitous in the environment. Although they rarely cause infection in humans, when they do so, the infection is often severe and diagnosed late. The three most clinically relevant genera of FLA are Acanthamoeba spp., Naegleria fowleri, and Balamuthia mandrillaris. An increasing body of literature points to these organisms as potential diseasecausing agents in immunocompromised and transplant patients, particularly with regard to donor-derived infections. This chapter will review the salient features, diagnostic modalities, and therapeutic recommendations of these infections in transplant patients.
Keywords: Acanthamoeba; Balamuthia mandirllaris; Donor-derived infection; Granulomatous amebic encephealitis; Naegleria fowleri; Primary amebic meningoencephalitis

Non-Aspergillus Fungal Infections in Transplant Patients - Revankar, Sanjay G. (Emerging Transplant Infections, 2021)
Fungal infections in recipients of solid organ and hematopoietic stem cell transplant recipients are significant causes of morbidity and mortality. Though relatively uncommon compared to other infectious complications, the difficulty in making a timely diagnosis and effectively treating patients presents a daunting challenge. Among the fungi responsible for these infections, there are many that are rarely encountered clinically yet are associated with high mortality in transplant patients. These include the darkly pigmented or dematiaceous fungi causing phaeohyphomycosis, Fusarium spp., Scedosporium spp., and Microsporidia. They have unique clinical presentations not typically seen with other fungal infections and often are not detected by standard diagnostic testing, with culture being the most reliable method to identify these pathogens. Due to the lack of randomized clinical trials, therapy is not standardized, and despite aggressive management strategies, mortality remains high for invasive disease. Further developments in specific diagnostic testing and antifungal drug therapy are needed to improve outcomes for these rare and often refractory infections.

Use of letermovir-valganciclovir combination as a step-down treatment after foscarnet for ganciclovir-resistant CMV infection in kidney transplant recipients - Rho, Elena; Näf, Bettina; Müller, Thomas F; Wüthrich, Rudolf P; Schachter, Thomas; von Moos, Seraina (Clinical Transplantation, 2021)
Background Letermovir (LTV) might be an alternative treatment to nephrotoxic foscarnet (FOS) in Ganciclovir (GCV) resistant cytomegalovirus (CMV) infection. However, its efficacy in controlling active CMV viremia is unclear, as it is only approved for CMV prophylaxis in hematopoietic stem-cell transplantation. Methods This case series describes 14 kidney transplant recipients (KTR) with moderate-level GCV resistant CMV infection, treated by different step-down strategies after initial FOS therapy: (1) Observation without antiviral follow-up or switch to valganciclovir (VGCV) (pre-LTV era), and (2) Switch to LTV±VGCV (LTV era). Results One patient died under FOS. Thirteen patients were followed under step-down regimens. All but two patients had ongoing CMV viremia when stopping FOS. In pre-LTV era, 5/9 (56%) experienced a CMV breakthrough > 10 000 IU/ml calling for another course of FOS, as compared to 1/4 (25%) in the LTV era. Addition of VGCV to LTV at low-level viral breakthrough, addressing a possible developing resistance against LTV, prevented viral surge in two patients. In the pre-LTV era, CMV-related death or graft loss occurred in three of nine (33%), compared to no death or graft loss in the LTV era. Conclusion A step-down strategy combining LTV+VGCV, might allow to safely stop FOS at ongoing low-level viremia.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ctr.14401
Keywords: drug-resistant cytomegalovirus; kidney transplant recipients; letermovir

Post-transplant malignancies in pediatric organ transplant recipients - Robinson, Cal H.; Coughlin, Carrie C.; Chanchlani, Rahul; Dharnidharka, Vikas R. (Pediatric Transplantation, 2021)
The majority of cancer diagnoses in pediatric solid organ transplant recipients (SOTRs) are post-transplantation lymphoproliferative disorders (PTLD) or skin cancers. However, pediatric SOTRs are also at significantly elevated risk for multiple other solid and hematological cancers. The risks of specific cancers vary by transplanted organ, underlying disease, and immunosuppression factors. More than one-quarter of pediatric SOTRs develop cancer within 30 years of transplantation and their risk of solid cancer is 14 times greater than the general population. Pediatric SOTRs are at significantly higher risk of cancer-associated death. Improving patient survival among pediatric SOTRs puts them at risk of adult epithelial cancers associated with environmental carcinogenic exposures. Vaccination against oncogenic viruses and avoidance of excessive immunosuppression may reduce the risk of solid cancers following transplantation. Patient and family education regarding photoprotection is an essential component of skin cancer prevention. There is significant variability in cancer screening recommendations for SOTRs and general population approaches are typically not validated for transplant populations. An individualized approach to cancer screening should be developed based on estimated cancer risk, patient life expectancy, and screening test performance.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/petr.13884
Keywords: cancer; epidemiology; malignancy; pediatric; post-transplantation lymphoproliferative disorder; screening; skin cancer; solid organ transplant; solid tumor

Live virus vaccination of pediatric solid organ transplant candidates within 1 month prior to transplantation: A multicenter experience - Rosenthal, Ayelet; Madigan, Theresa; Chen, Sharon F.; Gans, Hayley; Nadimpalli, Sruti (Transplant Infectious Disease, 2021)
Background: Solid organ transplant (SOT) recipients are at increased risk of vaccine- preventable illness due to the high degree of immunosuppression required following transplantation. The current recommendation is to vaccinate with live attenuated vaccines, including Measles, Mumps, and Rubella (MMR) and Varicella (VAR) vaccines, at least 4 weeks prior to transplant. However, data to support the time interval between vaccine and transplant are limited. Methods: We conduct a literature review of the natural history of the viruses and length of viremia following live-attenuated viral vaccines, and we describe a series of 5 cases from 2 pediatric transplant centers in which live attenuated viral vaccines were administered within 21 days prior to SOT. Results: None of the 5 children who received MMR or VAR 8-21 days prior to liver (2) and heart (3) transplant suffered from vaccine-related viral illness after transplant, even in the presence of significant immunosuppression with T-cell-depleting agents. Conclusion: These cases support that shorter intervals of live vaccine administration prior to transplant may be safe, allowing the vaccination of a larger cohort of SOT candidates. Increasing pretransplant vaccinations is crucial since, in most cases, live viral vaccines are contraindicated posttransplantation, and the most effective vaccine approaches utilize prime-boost strategies, priming before and boosting after transplant.

Pathogenic Intestinal Parasites in Transplant Recipients - Rosser, Joelle I.; Blackburn, Brian G. (Emerging Transplant Infections, 2021)
Although a less common cause of gastrointestinal illness in transplant recipients than bacterial or viral etiologies, intestinal parasitic infections can result in severe and prolonged disease in this population. In the developed world, diagnostic delays stemming from low clinical suspicion for intestinal parasites (and the limitations of standard diagnostics) can worsen outcomes in these patients. As travel becomes more frequent among patients both before and after transplant, and with the increasing availability of transplant services globally, clinicians everywhere should be aware of the risk of intestinal parasitic infections in transplant recipients. In this chapter, we review several intestinal protozoans and the diseases they cause in the transplant population, including Cryptosporidium spp., Cyclospora cayetanensis, Cystoisospora belli, Giardia spp., Blastocystis spp., Entamoeba histolytica, Dientamoeba fragilis, and Balantidium coli. We also review several intestinal helminths and the diseases they cause in transplant recipients, including Ascaris lumbricoides, Trichuris trichiura, Capillaria spp., hookworms, and tapeworms.

Risk Classification for Respiratory Viral Infections in Adult Solid Organ Transplantation Recipients - Samannodi, Mohammed; Vaghefi-Hosseini, Reza; Nigo, Masayuki; Guevara, Eduardo Yepez; Hasbun, Rodrigo (Transplantation Proceedings, 2021)
Introduction. Molecular testing such as nasopharyngeal viral polymerase chain reaction (PCR) (NVP) is available now in most hospitals and widely used to identify respiratory viral infections (RVIs) in solid organ transplantation (SOT) recipients. Materials and Methods. A retrospective multicenter study at 8 hospitals from March 1, 2016, to April 30, 2019. We included all adult SOT recipients who were admitted to the hospitals and had their ﬁrst NVP post transplantation. Results. A total of 102 adult SOT recipients were enrolled. NVP test was positive in 33 (32.4%) SOT recipients and negative in 69 (67.6%). Median age was more than 60 years old with female predominance in both groups. The majority of patients who had positive NVP were hospitalized either in fall or winter seasons (91%). RVI symptoms were documented in about 73% of the positive NVP group. Rhinovirus was the most common identiﬁed virus (48.4%). On logistic regression analysis, clinical presentation in fall or winter seasons, presenting with upper respiratory infection (URI) symptoms and taking prednisone 10 mg/d were signiﬁcantly associated with positive NVP. This model classiﬁed patients into 3 categories of risk for RVIsdlow (none of the variables), 0%; intermediate (1 variable), 6.5%; and high ( 2 variables), 55.4% with P < .001 for all predictors. Conclusion. SOT recipients who are taking prednisone ( 10 mg) and have URI symptoms in fall or winter seasons are more likely to have RVIs

Stem Cell Transplantation: Infection Risk by Transplant Type and Emerging Trends in Infection Management - Satyanarayana, Gowri; Gatwood, Katie S.; Nesbitt, Whitney J. (Emerging Transplant Infections, 2021)
Advances in the ﬁeld of hematopoietic stem cell transplantation (HSCT) provide the opportunity for cure of malignant and nonmalignant diseases. The kinetics of immune reconstitution posttransplant and the immunosuppressive therapies used place HSCT recipients at risk for bacterial, viral, fungal, and other opportunistic infections. Identiﬁcation of new donor sources of hematopoietic cells has improved accessibility to transplant but may lead to signiﬁcant deﬁcits in shortand long-term immune reconstitution as well as an increased risk of graft-versushost disease, which also impacts immune reconstitution. Additionally, new therapies used for the treatment of graft-versus-host disease have increased the risk for development of certain infections posttransplant. Understanding the many risk factors for infection in this patient population has allowed for improvement in infection identiﬁcation and management, including development of new diagnostics and therapeutic modalities, which have decreased morbidity and mortality.

Common and Emerging Infections in Pediatric Transplant Recipients - Schuster, Jennifer E.; Miller-Handley, Hilary; Danziger-Isakov, Lara (Emerging Transplant Infections, 2021)
Practitioners caring for pediatric transplant patients face unique issues compared with adult transplant providers. Distinct challenges to pediatric providers include incomplete or missed primary immunizations, lack of primary immunity to common illnesses, inability to definitively determine infectious serostatus in infants, and recognition of pediatric-specific disease states. Further, the lack of pediatric indications and dosing data for antimicrobials as well as variations in pediatric pharmacokinetics and drug exposure target levels complicates the treatment of infectious diseases in pediatric patients. As the field of pediatric transplantation continues to expand, additional pediatric data will guide best practices in the field, and pediatric-specific recommendations will increase.

Serum procalcitonin as a biomarker for differentiating between infectious and non-infectious fever after pancreas transplantation - Shim, Ye Eun; Shin, Sung; Ko, Youngmin; Kim, Dong Hyun; Lim, Seong Jun; Jung, Joo Hee; Kwon, Hyunwook; Kim, Young Hoon; Kim, Sung-Han; Lee, Sang-Oh; Han, Duck Jong (Clinical Transplantation, 2021)
Laboratory biomarkers that can differentiate non-infectious fever from infectious fever after pancreas transplantation have yet to be discovered. Non-infectious fever was defined as the presence of fever (>38.3°C) in the absence of a documented clinical diagnosis of infection or a positive culture. Among 184 consecutive recipients, a total of 91 recipients developed fever within 1-month post-transplant, of whom 46 had infectious fever and 45 had non-infectious fever at our center between August 2014 and July 2019. The onset of fever was earlier in the non-infectious fever group (14.4 ± 3.7 post-transplant days) compared with the infectious fever group (16.5 ± 5.8 post-transplant days; p = .033). Multivariate analysis showed that serum procalcitonin at the peak of fever could significantly differentiate infectious fever from non-infectious fever (OR 53.378, 95% CI: 6.819-417.802, p < .001). The area under the curve for differentiating between the two groups was 0.853 (95% CI, 0.780-0.926) for procalcitonin and 0.667 (95% CI, 0.549-0.785) for CRP. The best cutoff values of serum procalcitonin and CRP were 0.405 ng/ml (sensitivity, 77.1%; specificity, 80.8%) and 7.355 mg/dl (sensitivity, 66.7%; specificity, 67.3%), respectively. Serum procalcitonin may be useful for differentiating non-infectious fever from infectious fever after pancreas transplantation.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ctr.14224
Keywords: antithymocyte globulin; non-infectious fever; pancreas transplantation; procalcitonin

Pneumocystis jiroveci in Transplant: Recognizing Risk, Understanding Prevention, and Implementing Treatment - Shoham, Shmuel; Dioverti Prono, M. Veronica (Emerging Transplant Infections, 2021)
Pneumocystis pneumonia (PJP) is caused by Pneumocystis jiroveci and is an important infection of chronically immunocompromised patients, especially those receiving higher doses of corticosteroids and those with abnormalities in cell-mediated immunity. Until recently, the vast majority of cases were in HIV patients. This has changed with an increasing proportion occurring in non-HIV patients, including in solid organ and hematopoietic stem cell transplant recipients. The risk factors, clinical presentation, and response to therapy in such patients are different than in HIV. Patients are particularly vulnerable during the initial months after transplant and at times of intensification of immunosuppression for treatment of rejection and graft-versus-host disease (GVHD). Effective prophylaxis for 6–12 months after transplant and during time of treatment for acute rejection (or GVHD) all but eliminates the risk during those periods. PJP now tends to occur in patients not receiving effective prophylaxis during high-risk periods. Reasons include persistence of intense immune compromise beyond the typical prophylaxis periods, failure to prescribe prophylaxis, non-adherence, and occasionally breakthrough infection. Clinical manifestations tend to be more abrupt and severe than in those with HIV, and prompt treatment is imperative. Empiric therapy is often warranted, but establishing the diagnosis is important to limit unnecessary exposure to potentially toxic therapy and potentially lifetime secondary prophylaxis. Traditional tests (staining of induced sputum and bronchoalveolar lavage fluid) continue to be a mainstay of diagnosis, now complemented by nucleic acid testing of respiratory tract specimens and serum beta-D-glucan assays.

Experience With Moxifloxacin for the Treatment of Latent Tuberculosis Infection in Liver Transplantation: A Single‐Center Prospective Study - Silva, Jose Tiago; Fernández‐Ruiz, Mario; Hernández‐Jimenez, Pilar; San Juan, Rafael; Calvo, Jorge; García‐Sesma, Álvaro; Manrique, Alejandro; Justo, Iago; Caso, Oscar; Cambra, Félix; Marcacuzco, Alberto; López‐Medrano, Francisco; et al. (Liver Transplantation, 2021)

Risk of infectious complications in adult patients after allogeneic hematopoietic stem cell transplantation depending on the site of central venous catheter insertion—multicenter prospective observational study, from the IDWP EBMT and Nurses Group of EBMT - Snarski, Emilian; Stringer, Jacqui; Mikulska, Małgorzata; Gil, Lidia; Tridello, Gloria; Bosman, Paul; Lippinkhof, Anne; Hoek, Jennifer; Karas, Michal; Zver, Samo; Lueck, Catherina; Blijlevens, Nicole; et al. (Bone Marrow Transplantation, 2021)

Burkholderia in Transplant: Important to Speciate and Important to Treat - Snell, Gregory; Smibert, Olivia; Tullis, Elizabeth (Emerging Transplant Infections, 2021)
Burkholderia species are found in soil and water and have the ability to cause serious human disease. Infections from these organisms are particularly challenging to manage in the immunocompromised host. Speciation, and identiﬁcation to strain level, has relevance to virulence, prognosis, and therapeutic strategy – particularly in the case of cystic ﬁbrosis – indicated in lung transplantation. B. pseudomallei complex causes melioidosis and needs to be considered in endemic area travelers or residents. If diagnosed, infections are treatable with relatively conventional intravenous antibiotics. B. gladioli is a soil organism often nosocomially acquired and is emerging as a serious pathogen which is challenging to treat with antibiotics. B. cepacia complex (particularly B. cenocepacia) infections are associated with serious morbidity and mortality, particularly in cystic ﬁbrosis patients, and a careful clinical strategy is required if transplantation is being considered or has already been undertaken. Antibiotic therapy for this group of patients in the transplant setting must be aggressive and extensive. Conﬁrming the challenges of current therapeutic approaches, trials of novel anti-infective therapies are ongoing for many Burkholderia species.

Yellow Fever: Prevention in Transplant Candidates and Emerging Treatment Data for Liver Transplant - Song, Alice Tung Wan; Carneiro D’Albuquerque, Luiz Augusto (Emerging Transplant Infections, 2021)
Despite the availability of an efficacious vaccine, yellow fever continues to pose an emerging human health issue, with outbreaks in Africa and South America. Although the majority of cases are oligosymptomatic, severe cases present high mortality, reaching an overall lethality of 50%. The mainstay for yellow fever control remains adequate vaccine coverage. Because the yellow fever vaccine is composed of live, attenuated virus, it is contraindicated in solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients; the vaccine should be preferably administered prior to transplantation. However, transplantation candidates should be evaluated regarding the safety and efficacy of vaccination. In this chapter, we review the current literature on yellow fever vaccination in the population of hematological malignancies, HSCT candidates, kidney transplant recipients, and liver transplant recipients. Traditionally, management of individuals infected with yellow fever consisted of supportive treatment. Recent data have shown that liver transplantation could be a treatment for selected severe cases, and the main indications and contraindications are discussed.

Mucormycosis - Steinbrink, Julie M.; Miceli, Marisa H. (Infectious Disease Clinics of North America, 2021)

Vascular Composite Allografts (VCA): New Transplants, New Infections - Steinbrink, Julie M.; Pruett, Timothy L.; Cendales, Linda C. (Emerging Transplant Infections, 2021)
Vascularized composite allografts, or VCA transplants, are allotransplants that incorporate multiple tissues transplanted as a single functional unit, most commonly hands or face. They are, by deﬁnition, transplants aimed at improving quality of life rather than life sparing. Yet they may also be life-giving in the case of temporary uterine transplants, where the goal is to carry a healthy pregnancy through to term and delivery. Because of the multiple tissue layers involved and the systemic immunosuppression required to prevent rejection, VCA transplants carry unique infection risks, distinct for each tissue in VCA. By understanding the different infectious risks carried by different tissues, this chapter builds a framework to understand and evaluate infection of any vascularized composite allograft.

Mycobacterium tuberculosis in Transplantation - Subramanian, Aruna K. (Emerging Transplant Infections, 2021)
This chapter reviews the epidemiology, clinical impact, diagnosis, prevention, and management of tuberculosis (TB) in solid organ and hematopoietic stem cell transplantation. Given the limitations of screening for latent TB using either the tuberculin skin test or interferon gamma release assays, it is important to also consider exposure history and chest imaging; promising new TB diagnostic strategies are currently under development. The clinical manifestations of active tuberculosis in transplantation are often extrapulmonary or disseminated in nature. Strategies for treatment of latent and active tuberculosis in both solid organ and hematopoietic stem cell transplantation are discussed in this chapter. The optimization of antituberculous drug dosing, treatment duration, and combinations in drug-sensitive and multidrug-resistant TB in transplantation needs further study.

Nosocomial Fungal Infections - Suleyman, Geehan; Alangaden, George J. (Infectious Disease Clinics of North America, 2021)

Impact of pre-transplant carbapenem-resistant Enterobacterales colonization and/or infection on solid organ transplant outcomes - Taimur, Sarah; Pouch, Stephanie M.; Zubizarreta, Nicole; Mazumdar, Madhu; Rana, Meenakshi; Patel, Gopi; Freire, Maristela Pinnheiro; Pellett Madan, Rebecca; Kwak, Eun Jeong; Blumberg, Emily; Satlin, Michael J.; Pisney, Larissa; et al. (Clinical Transplantation, 2021)
The impact of pre-transplant (SOT) carbapenem-resistant Enterobacterales (CRE) colonization or infection on post-SOT outcomes is unclear. We conducted a multi-center, international, cohort study of SOT recipients, with microbiologically diagnosed CRE colonization and/or infection pre-SOT. Sixty adult SOT recipients were included (liver n = 30, hearts n = 17). Klebsiella pneumoniae (n = 47, 78%) was the most common pre-SOT CRE species. Median time from CRE detection to SOT was 2.32 months (IQR 0.33–10.13). Post-SOT CRE infection occurred in 40% (n = 24/60), at a median of 9 days (IQR 7–17), and most commonly due to K pneumoniae (n = 20/24, 83%). Of those infected, 62% had a surgical site infection, and 46% had bloodstream infection. Patients with post-SOT CRE infection more commonly had a liver transplant (16, 67% vs. 14, 39%; p =.0350) or pre-SOT CRE BSI (11, 46% vs. 7, 19%; p =.03). One-year post-SOT survival was 77%, and those with post-SOT CRE infection had a 50% less chance of survival vs. uninfected (0.86, 95% CI, 0.76–0.97 vs. 0.34, 95% CI 0.08–1.0, p =.0204). Pre-SOT CRE infection or colonization is not an absolute contraindication to SOT and is more common among abdominal SOT recipients, those with pre-SOT CRE BSI, and those with early post-SOT medical and surgical complications.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ctr.14239
Keywords: carbapenem-resistant enterobacterales; multidrug-resistant organisms; solid organ transplantation

Donor derived hepatitis B virus infection: Analysis of the Organ Procurement & Transplantation Network/United Network for Organ Sharing Ad Hoc Disease Transmission Advisory Committee - Theodoropoulos, Nicole M.; La Hoz, Ricardo M.; Wolfe, Cameron; Vece, Gabriel; Bag, Remzi; Berry, Gerald J.; Bucio, Jamie; Danziger-Isakov, Lara; Florescu, Diana F.; Goldberg, David; Ho, Chak-Sum; Lilly, Kathleen; et al. (Transplant Infectious Disease, 2021)
Hepatitis B virus (HBV) can be transmitted from organ donor to recipient, but details of transmission events are not widely published. The Disease Transmission Advisory Committee (DTAC) evaluated 105 cases of potential donor derived transmission events of HBV between 2009-2017. Proven, probable or possible transmission of HBV occurred in 25 (23.8%) cases. Recipients of liver grafts were most commonly infected (20 of 21 exposed recipients) compared to 9 of 21 exposed non-hepatic recipients. Eleven of 25 donors were HBV core antibody (HBcAb) positive/HBV surface antigen (HBsAg) negative and infected 8/20 recipients. Of the 10 liver recipients and 1 liver-kidney recipient who received organs from these donors: six were not given antiviral prophylaxis, two developed infection after antiviral prophylaxis was discontinued, two developed HBV while on lamivudine prophylaxis, one was on antiviral prophylaxis and did not develop HBV viremia or antigenemia. One recipient of a HBcAb positive/HBsAg negative kidney developed active HBV infection. Unexpected donor-derived transmission of HBV was a rare event in reports to DTAC, but was often detected in the recipient late post-transplant. Six of 11 recipients (54.5%) of a liver from a HBcAb positive donor did not receive prophylaxis; all of these were potentially preventable with the use of anti-viral prophylaxis.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/tid.13458
Keywords: DTAC; donor-derived transmission; hepatitis B virus; increased risk donors

Ventricular Assist Devices, ECMO, and Cardiac Support Devices: Challenges in the Bridge to Transplant - Tran, Hao; Aslam, Saima (Emerging Transplant Infections, 2021)
We review different types of mechanical circulatory support devices available as a bridge to heart transplantation and then discuss infectious complications in these devices, with a particular focus on ventricular assist devices. We also discuss infection prevention and management strategies, in particular as relevent to transplantation.

Pulmonary Syndromes in Transplantation - Trinh, Sonya; Luk, Alfred (Emerging Transplant Infections, 2021)
Infectious and noninfectious pulmonary syndromes remain significant contributors to morbidity and mortality after solid organ and hematopoietic stem cell transplantation. Multiple factors increase the risk of pulmonary complications including the surgical trauma related to solid organ transplantation, chemotherapy and radiation prior to hematopoietic stem cell transplant, the degree of immunosuppression, and immune factors contributing to rejection and graft-versus-host disease. The first section of the chapter reviews the timeline of infectious and noninfectious pulmonary complications after transplant. The second section provides an approach to evaluating a transplant patient presenting with pulmonary symptoms or infiltrates.

Rapidly Growing Mycobacterial Infections in Transplant: Evolving Epidemiology and Treatment Options - Turner, Nicholas A.; Baker, Arthur W. (Emerging Transplant Infections, 2021)
Rapidly growing mycobacteria (RGM) are environmental microorganisms that thrive in water-associated bioﬁlms and grow more quickly in the laboratory than slow-growing nontuberculous mycobacteria. Prevalence of RGM infection appears to be increasing, and patients with structural lung disease and immunocompromised hosts, especially patients with cystic ﬁbrosis or lung transplant recipients, are at increased risk. Transplant recipients can acquire RGM from the community or from healthcare facilities, and several recent RGM outbreaks have occurred at hospitals with transplant programs. Diagnosis of RGM infection in transplant patients is challenging and often delayed due to indolent, atypical presentations and decreased sensitivity of culture. Treatment requires prolonged combination antimicrobial therapy, and many invasive RGM infections also require surgical debridement. Even with aggressive therapy, however, transplant patients with RGM infections commonly fail to achieve cure, and antibioticrelated toxicities are common. Development of more effective and better-tolerated therapies for both transplant recipients and candidates for transplantation with RGM infection represents an emerging need. In addition, close adherence to infection prevention measures is critical; strategies for prevention should be based upon local RGM and transplant epidemiology.

European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults - Van Prehn, Joffrey; Reigadas, Elena; Vogelzang, Erik H.; Bouza, Emilio; Hristea, Adriana; Guery, Benoit; Krutova, Marcela; Norén, Torbjorn; Allerberger, Franz; Coia, John E.; Goorhuis, Abraham; Van Rossen, Tessel M.; et al. (Clinical Microbiology and Infection, 2021)

Letermovir in lung transplant recipients with cytomegalovirus infection: A retrospective observational study - Veit, Tobias; Munker, Dieter; Barton, Jürgen; Milger, Katrin; Kauke, Teresa; Meiser, Bruno; Michel, Sebastian; Zoller, Michael; Nitschko, Hans; Keppler, Oliver T.; Behr, Jürgen; Kneidinger, Nikolaus (American Journal of Transplantation, 2021)
Letermovir is a new antiviral drug approved for the prophylaxis of CMV infection in allogeneic stem cell transplants. The aim of the study was to assess the therapeutic efficacy of letermovir in difficult to treat CMV infections in lung transplant recipients. All lung transplant recipients between March 2018 and August 2020, who have been treated with letermovir for ganciclovir-resistant or refractory CMV infection were included in the study and analysed retrospectively. In total, 28 patients were identified. CMV disease was present in 15 patients (53.6%). In 23 patients (82.1%), rapid response was noticed, and CMV-viral load could be significantly decreased (>1 log10) after a median of 17 [14–27] days and cleared subsequently in all of these patients. Five patients (17.9%) were classified as non-responder. Thereof, development of a mutation of the CMV UL56 terminase (UL-56-Gen: C325Y) conferring letermovir resistance could be observed in three patients (60%). Common side effects were mild and mostly of gastrointestinal nature. Mild adjustments of the immunosuppressive drugs were mandatory upon treatment initiation with letermovir. In addition to other interventions, letermovir was effective in difficult to treat CMV infections in lung transplant recipients. However, in patients with treatment failure mutation conferring letermovir, resistance should be taken into account.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ajt.16718
Keywords: antibiotic drug resistance; antibiotic: antiviral; clinical research/practice; infection and infectious agents - viral: Cytomegalovirus (CMV); infectious disease; lung disease: infectious; lung transplantation/pulmonology; pharmacology

Association of CMV-specific T-cell immunity and risk of CMV infection in lung transplant recipients - Veit, Tobias; Pan, Ming; Munker, Dieter; Arnold, Paola; Dick, Andrea; Kunze, Susanne; Meiser, Bruno; Schneider, Christian; Michel, Sebastian; Zoller, Michael; Böhm, Stephan; Walter, Julia; et al. (Clinical Transplantation, 2021)
Background Protecting against CMV infection and maintaining CMV in latent state are largely provided by CMV-specific T-cells in lung transplant recipients. The aim of the study was to assess whether a specific T-cell response is associated with the risk for CMV infection in seronegative patients who are at high risk for delayed CMV infection. Methods All CMV-seronegative recipients (R−) from CMV-seropositive donors (D+) between January 2018 and April 2019 were included and retrospectively screened for CMV infection before and after assessment of CMV-specific cell-mediated immunity. Results Thirty-one of the 50 patients (62%) developed early-onset CMV infection. Lower absolute neutrophil counts were significantly associated with early-onset CMV infection. Antiviral prophylaxis was ceased after 137.2 ± 42.8 days. CMV-CMI were measured at a median of 5.5 months after LTx. 19 patients experienced early and late-onset CMV infection after prophylaxis withdrawal within 15 months post transplantation. Positive CMV-CMI was significantly associated with lower risk of late-onset CMV infection after transplantation in logistic and cox-regression analysis (OR=0.05, p = .01; OR=2,369, p = .026). Conclusion D+/R− lung transplant recipients are at high risk of developing early and late-onset CMV infection. Measurement of CMV-CMI soon after transplantation might further define the CMV infection prediction risk in LTx recipients being at high risk for CMV viremia.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ctr.14294
Keywords: CMV-specific immunity; cytomegalovirus; infection; lung transplantation

Clinical prediction tool for extended-spectrum beta-lactamase-producing enterobacterales as the etiology of a bloodstream infection in solid organ transplant recipients - Wang, Rebecca; Han, Jennifer H.; Lautenbach, Ebbing; Tamma, Pranita D.; Thom, Kerri A.; Alby, Kevin; Blumberg, Emily A.; Bilker, Warren B.; Werzen, Alissa; Omorogbe, Jacqueline; Tolomeo, Pam; Anesi, Judith A. (Transplant Infectious Disease, 2021)
Background Multidrug-resistant Gram-negative bacterial infections are increasingly common among solid organ transplant (SOT) recipients, leading to challenges in the selection of empiric antimicrobial therapy. We sought to develop a clinical tool to predict which SOT recipients are at high risk for extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales (EB) bloodstream infection (BSI). Methods A multicenter case-control study was performed. The source population included SOT recipients with an EB BSI between 2005 and 2018. Cases were those with ESBL-EB BSI; controls were those with non-ESBL EB BSI. The population was subdivided into derivation and validation cohorts based on study site. The predictive tool was developed in the derivation cohort through iterative multivariable logistic regression analyses that maximized the area under the receiver-operating curve (AUC). External validity was assessed using the validation cohort. Results A total of 897 SOT recipients with an EB BSI were included, of which 539 were assigned to the derivation cohort (135, 25% ESBL-EB) and 358 to the validation cohort (221, 62% ESBL-EB). Using multivariable analyses, the most parsimonious model that was predictive of ESBL-EB BSI consisted of 10 variables, which fell into four clinical categories: prior colonization or infection with EB organisms, recent antimicrobial exposures, severity of preceding illness, and immunosuppressive regimen. This model achieved an AUC of 0.81 in the derivation cohort and 0.68 in the validation cohort. Conclusions Though further refinements are needed in additional populations, this tool shows promise for guiding empiric therapy for SOT recipients with EB BSI.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/tid.13599
Keywords: bloodstream infection; enterobacterales; extended-spectrum beta-lactamase; predictive tool; transplant

Rashes to Recognize in the Immunocompromised Transplant Patient: Focus on the Solid Organ Transplant Recipient - Whitley, Melodi Javid; Cardones, Adela R.; Myers, Sarah A. (Emerging Transplant Infections, 2021)

Low CD4 count may be a risk factor for non-tuberculous mycobacteria infection in pediatric hematopoietic cell transplant recipients - Wobma, Holly; Chang, Alicia K.; Jin, Zhezhen; Baker, Courtney; Garvin, James; George, Diane; Satwani, Prakash; Foca, Marc; Bhatia, Monica (Pediatric Transplantation, 2021)
Background HCT leaves patients in a relative state of immune deficiency both during their initial transplant admission and for several years following discharge. NTM are generally harmless colonizers of the outside environment, but for immunocompromised patients, they can cause significant disease due to a paucity of T-cell defense. While routine prophylaxis against NTM is recommended for patients with low CD4 counts in certain clinical settings (eg, AIDS), this is not yet established for HCT patients despite their higher risk. Methods Here we build upon our prior work to determine risk factors for NTM in pediatric HCT patients by comparing NTM patient characteristics to matched HCT controls. Results We followed 272 patients across a 13-year time period, with 11 cases of NTM. Patients with NTM had a significantly lower CD4 count at Day 365 than matched HCT controls (105.5 ± 97.0 cells/µl vs. 856.2 ± 446.1 cells/µl, respectively; p = .001). No other potential risk factors (eg, CMV, GvHD, disease type) were found to be statistically significant, including use of T-cell depleting agents. This is consistent with an average diagnosis of NTM at Day +323 (ie, outside immediate post-transplant period). All-cause mortality was similar between NTM and control HCT groups, with an NTM attributable mortality of <10%. Conclusion Since reduced CD4 counts are associated with NTM, and cost and morbidity are high, azithromycin prophylaxis for CD4 count <200 cells/µl in high-risk patients should be considered.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/petr.13994
Keywords: bone marrow transplantation; mycobacterium avium complex; non-tuberculous mycobacteria; pediatric

Introduction to Immunosuppression, Tolerance, and Infection Risk - Wolfe, Cameron R. (Emerging Transplant Infections, 2021)
Over the last half a century, there have been innumerable advances in our understanding of the human immune system. We now have a better understanding not only of the ways our innate and adaptive immune pathways interact to seek out and control infection and malignancy, but we are closer to understanding some of the control mechanisms behind tissue rejection. Organ allograft rejection, with consequent loss of graft function, remains one of the most challenging problems facing solid organ allotransplantation. Developments in therapeutic immunosuppression have enabled us to minimize rejection risk and improve the life expectancy and graft survival for many of our patients, but at a cost: the more intense the immunosuppression, typically the greater the infection risk. Ultimately, the field continues to work towards ways of achieving organ tolerance whereby both rejection risk and the threats of infection are minimized.

Respiratory Syncytial Virus in Transplant: Stopping the Short-Term Spread, Solving the Longer-Term Problems - Wright, A. J.; Mah, A. (Emerging Transplant Infections, 2021)
Respiratory syncytial virus (RSV) causes signiﬁcant morbidity and mortality in immunocompromised hosts with particular burden among allogeneic hematopoietic stem cell transplant and lung transplant recipients. Affected patients have a substantial risk of secondary infection, ICU admission, or death. Improved diagnostic testing with better sensitivity has given new insights into the epidemiology of disease. In particular, it has highlighted the issue of nosocomial transmission and hospital outbreaks. These can be challenging to manage. Currently, treatment options include ribavirin and immunoglobulin replacement.

Epstein-Barr Virus and Posttransplant Lymphoproliferative Disorders - Yamada, Masaki; Nowalk, Andrew; Green, Michael (Emerging Transplant Infections, 2021)
Epstein-Barr virus (EBV) is an important potential cause of morbidity and mortality in children and adults undergoing solid organ (SOT) and hematopoietic stem cell transplantation (HSCT). The EBV virus is associated with a range of clinical symptoms and syndromes in both immunocompetent and immunocompromised patients based upon the virus’ ability to transform and immortalize B lymphocytes leading to viral-driven proliferation of infected B cells. In the immunocompetent host, this proliferation is primarily controlled by EBV-speciﬁc cytotoxic T lymphocytes (CTL). However, in the immunosuppressed SOT and HSCT recipient, impairment of the function of CTL can lead to unchecked proliferation and the development of EBV-associated posttransplant lymphoproliferative disorder (PTLD). In SOT recipients, the major risk factor for EBV-associated is being seronegative to the virus prior to and developing primary infection after the transplant, while in general SOT recipients who are EBV seropositive prior to transplant are at little risk for disease. For HSCT, the major risk factor relates to the EBV status and the potential T-cell depletion of the donor in an effort to minimize the risk of graftversus-host disease (GVHD). In both SOT and HSCT, adverse outcomes relating to EBV infection led to efforts to optimize treatment and to develop preventive strategies to mitigate the impact of this pathogen. This chapter will review epidemiology, diagnosis, treatment, and prevention of EBV disease including PTLD in SOT and HSCT recipients.

Recurrent nocardiosis in solid organ transplant recipients: An evaluation of secondary prophylaxis - Yetmar, Zachary A.; Wilson, John W.; Beam, Elena (Transplant Infectious Disease, 2021)
Background: Immunocompromised individuals are at risk for Nocardia infection, with a recurrence rate of approximately 5%. Solid organ transplant (SOT) recipients often receive secondary prophylaxis due to their requirement of lifelong immunosuppression. However, data supporting this practice is sparse. We sought to evaluate Nocardia recurrence in SOT recipients, specifically evaluating secondary prophylaxis. Methods: We conducted a retrospective cohort study of SOT recipients diagnosed with nocardiosis from 2000 through 2020. We included adult SOT recipients who completed their course of Nocardia therapy and had at least 6 months of posttherapy follow-up. The primary outcome was Nocardia recurrence, which included relapse and reinfection. Results: One hundred two patients met inclusion criteria. Sixty-six (64.7%) were male and mean age was 58.6 ± 11.7 years. Most common SOT types were kidney (46.1%), heart (18.6%), kidney-pancreas (11.8%), and lung (10.8%). Most common sites of infection were lung (85.3%), skin (17.6%), and brain (14.7%). Secondary prophylaxis was utilized in 53 (52.0%) patients. Trimethoprim-sulfamethoxazole (TMP-SMX) singlestrength daily was the most common prophylaxis agent and dose. Five patients (4.9%) experienced Nocardia recurrence, three of which were receiving secondary prophylaxis at time of recurrence. Two recurrences were with the same Nocardia species. Factors associated with recurrence were lung transplantation (p = .011), chronic lung disease (p = .032), and treatment ≤120 days (p = .006). Time from treatment completion to recurrence ranged from 107 to 875 days. Conclusions: Nocardia recurrence in SOT recipients is an uncommon event. TMP-SMX secondary prophylaxis is incompletely protective and recurrence may be dependent upon other factors. Further study of secondary prophylaxis is warranted.

The impact of antibiotic allergy testing in transplant patients - Ying, Amy; Chua, Kyra Y. L.; Rose, Morgan; Vogrin, Sara; Trubiano, Jason A. (Transplant Infectious Disease, 2021)
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/tid.13411
Keywords: antibiotic allergy label; antibiotic allergy testing; transplant patients

American Society for Transplantation and Cellular Therapy Series: #4 - Cytomegalovirus treatment and management of resistant or refractory infections after hematopoietic cell transplantation - Yong, Michelle K.; Shigle, Terri Lynn; Kim, Yae-Jean; Carpenter, Paul A.; Chemaly, Roy F.; Papanicolaou, Genovefa A. (Transplantation and Cellular Therapy, 2021)
The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy (ASTCT) partnered with its Transpl. Infect. Dis. Special Interest Group (TID-SIG) to update its 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). A new approach was employed with the goal of better serving clinical providers by publishing each standalone topic in the infectious diseases series as a concise format of frequently asked questions (FAQ), tables, and ﬁgures. Adult and pediatric infectious diseases and HCT content experts developed and answered FAQs. Topics were ﬁnalized with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. The fourth topic in the series focuses on the management and treatment of cytomegalovirus (CMV) resistant and refractory infections. The diagnosis, deﬁnitions of resistant and refractory CMV, risk factors, virological genotypes and treatment algorithms are reviewed.

Influence of donor and recipient hepatitis B virus infection on long-term outcomes after kidney transplantation - Yuan, Qing; Haque, Omar; Hong, Shanjuan; Ortiz, Andric; Bethea, Emily D.; Sise, Meghan E.; Markmann, James F.; Elias, Nahel (Clinical Transplantation, 2021)
Background The demand for transplantable kidneys continues to outstrip supply, and the risk of donor-derived infection limits utilization. The effect of donor or recipient HBV status, defined by surface antigen (HBsAg) positivity, on long-term survival outcomes of kidney transplant (KT) is unknown. Methods We conducted a retrospective cohort study based on Organ Procurement and Transplantation Network (OPTN) data from 2000 to 2019. We identified three cohorts based on donor (D) or recipient (R) HBsAg status: D–R, D–R+, and D+R–. Pairwise comparisons of patient survival (PS) and all-cause graft survival (GS) after propensity score matching were performed to assess the effect of HBV infection in KT recipients. Results Our findings showed that there were no statistically significant differences in PS and GS among D–R, D–R+, and D+R–groups, nor was the patient or GS different between donor and recipient HBsAg+ status. Finally, in 2019 kidney discard rates were 15% higher for HBsAg+ deceased donors compared to HBsAg– donors. Conclusions HBsAg+ status was not associated with worse PS or GS after KT. Prior to broadly advocating utilization of HbsAg+ kidneys, further studies assessing KT recipient morbidity and safety are necessary.
_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ctr.14466
Keywords: graft survival; hepatitis B virus; kidney transplant; organ allocation; patient survival

Evolving Epidemiology of Transplant Infections: Impact of Population Shifts and Climate Change - Zangeneh, Tirdad T.; Al-Obaidi, Mohanad (Emerging Transplant Infections, 2021)
Humanity is facing many challenges associated with population growth and shift in the setting of predicted climate change and global warming. These changes are expected to impose economic, political, and sociological challenges. Such changes will further introduce significant impediments to the functioning of global public health systems through the increasing risk of emerging infectious diseases. These issues are of utmost importance for investigation, in order to understand the future epidemiological map and predict disease outbreaks. The current chapter will address these challenges within the field of emerging infectious diseases and the impact on transplant donors and recipients, including the spread of vector-borne diseases, antimicrobial resistance, and emerging fungal infections. Solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients are at risk for various infectious diseases including but not limited to donor-derived infections, reactivation of latent infections, or de novo infections. Therefore, understanding the effect of climate change and population shift on the future epidemiology of infectious diseases is imperative to the field of transplant infectious diseases.

Herpes Simplex and Varicella Zoster in Transplant Candidates and Recipients - Zuckerman, Richard A. (Emerging Transplant Infections, 2021)
Herpes Simplex Virus (HSV) 1 and 2 and Varicella Zoster Virus (VZV) are ubiquitous alpha-herpes viruses that establish lifelong latency in nerve root ganglia. They are characterized by clinical and subclinical reactivation which can lead to signiﬁcant morbidity in the transplant population. Primary infection after transplant can also be highly morbid, potentially fatal. Despite signiﬁcant advances in screening, diagnosis, treatment and prevention, there are further gains to be made in managing these infections in transplant recipients. Thankfully, there are novel modalities on the horizon such that these viral infections could become signiﬁcantly less morbid in the future.

Mucormycosis in Hematopoietic cell Transplant Recipients and in patients with Hematological Malignancies in the Era of New Antifungal Agents - Miller, Matthew A; Molina, Kyle C; Gutman, Jonathan A; Scherger, Sias; Lum, Jessica M; Mossad, Sherif B; Burgess, Mary; Cheng, Matthew P; Chuang, Sally T; Jacobs, Samantha E; Melendez, Dante P; Shah, Dimpy P; et al. (Open Forum Infectious Diseases, 2020)
The survival benefit of combination antifungal therapy for Invasive mucormycosis (IM) in patients with hematologic malignancy (HM) and hematopoietic cell transplant (HCT) is not well defined.This multicenter, retrospective study included HM and HCT recipients with proven or probable IM between Jan 1, 2007-Dec 31, 2017 from ten transplant centers across North America.Sixty-four patients with proven (n = 47) or probable (n = 17) IM defined by 2008 EORTC/MSG consensus definitions were included. Thirty-nine (61%) were HCT recipients (95% allogeneic). Sites of infection included rhino-orbital-cerebral (33), pulmonary (30%), disseminated (19%), gastrointestinal (3%) and cutaneous (3%). Surgical debridement was performed in 66%. Initial antifungal treatment consisted of: AmB alone (44%), AmB + posaconazole (25%), AmB + echinocandin (13%), AmB + isavuconazole (8%), posaconazole alone (5%), and isavuconazole alone (3%). All-cause mortality at 30-days and 1-year were 38% and 66%, respectively. Initial treatment with AmB plus posaconazole or isavuconazole (n=28) was associated with a trend toward lower treatment failure compared to AmB (n=21) (42% vs. 64%, p=0.136)Long-term survival with IM among HM and HCT populations remains poor. However, initial use of AmB + azole in conjunction with surgery may result in less treatment failure. More evidence from prospective controlled studies is needed to confirm this observation.

New evidence shows it is time to stop unnecessary use of antibiotics in kidney transplant recipients with asymptomatic bacteriuria - Coussement, Julien; Kamar, Nassim; Abramowicz, Daniel (Nephrology Dialysis Transplantation, 2020)

Comparison of Transplantation Outcomes after Foscarnet and Ganciclovir Administration as First-Line Anti-Cytomegalovirus Preemptive Therapy - Miyao, Kotaro; Terakura, Seitaro; Ozawa, Yukiyasu; Sawa, Masashi; Kohno, Akio; Kasahara, Senji; Iida, Hiroatsu; Ino, Kazuko; Kusumoto, Shigeru; Kasai, Masanobu; Takami, Akiyoshi; Kurahashi, Shingo; et al. (Transplantation and Cellular Therapy, 2020)
Ganciclovir (GCV) and foscarnet (FCN) are effective anti-cytomegalovirus (CMV) preemptive therapies; however, the impact of the 2 agents on various clinical outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) remains unclear. We retrospectively analyzed data on 532 patients undergoing allogeneic HSCT from unrelated donors and administered FCN (n = 86) or GCV (n = 446) as first-line anti-CMV preemptive therapy. Overall survival, relapse, and nonrelapse mortality (NRM) did not differ between the FCN and GCV groups, whereas the GCV group had a higher risk of chronic graft-versus-host disease (cGVHD) (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.28 to 4.39; P = .006) and extensive cGVHD (HR, 3.94; 95% CI, 1.43 to 10.9; P = .008). All 13 patients with cGVHD in the FCN group survived. Switching to the other agent was done mainly due to hematologic adverse events in the GCV group and mainly due to insufficient efficacy in the FCN group. The incidence of end-organ CMV disease was similar in the 2 groups. Selection of FCN or GCV as first-line preemptive anti-CMV therapy did not affect survival, relapse, or NRM. Physicians can select either of the agents, depending on the clinical situation; however, the selection may influence the cGVHD-related clinical course in HSCT recipients.
Keywords: Anti-cytomegalovirus preemptive therapy; Foscarnet; Ganciclovir

Human Herpesviruses 6A and 6B in Brain Diseases: Association versus Causation - Komaroff, Anthony L.; Pellett, Philip E.; Jacobson, Steven (Clinical Microbiology Reviews, 2020)
Human herpesvirus 6A (HHV-6A) and human herpesvirus 6B (HHV-6B), collectively termed HHV-6A/B, are neurotropic viruses that permanently infect most humans from an early age. Although most people infected with these viruses appear to suffer no ill effects, the viruses are a well-established cause of encephalitis in immunocompromised patients. In this review, we summarize the evidence that the viruses may also be one trigger for febrile seizures (including febrile status epilepticus) in immunocompetent infants and children, mesial temporal lobe epilepsy, multiple sclerosis (MS), and, possibly, Alzheimer’s disease. We propose criteria for linking ubiquitous infectious agents capable of producing lifelong infection to any neurologic disease, and then we examine to what extent these criteria have been met for these viruses and these diseases.
Publisher: American Society for Microbiology Journals Section: Review

Progress and Challenges in the Prevention, Diagnosis, and Management of Cytomegalovirus Infection in Transplantation - Limaye, Ajit P.; Babu, Tara M.; Boeckh, Michael (Clinical Microbiology Reviews, 2020)
Hosts with compromised or naive immune systems, such as individuals living with HIV/AIDS, transplant recipients, and fetuses, are at the highest risk for complications from cytomegalovirus (CMV) infection. Despite substantial progress in prevention, diagnostics, and treatment, CMV continues to negatively impact both solid-organ transplant (SOT) and hematologic cell transplant (HCT) recipients. In this article, we summarize important developments in the field over the past 10 years and highlight new approaches and remaining challenges to the optimal control of CMV infection and disease in transplant settings.
Publisher: American Society for Microbiology Journals Section: Review

How I perform hematopoietic stem cell transplantation on patients with a history of invasive fungal disease - Puerta-Alcalde, Pedro; Champlin, Richard E.; Kontoyiannis, Dimitrios P. (Blood, 2020)
Hematopoietic transplantation is the preferred treatment for many patients with hematologic malignancies. Some patients may develop invasive fungal diseases (IFDs) during initial chemotherapy, which need to be considered when assessing patients for transplantation and treatment posttransplantation. Given the associated high risk of relapse and mortality in the post–hematopoietic stem cell transplantation (HSCT) period, IFDs, especially invasive mold diseases, were historically considered a contraindication for HSCT. Over the last 3 decades, advances in antifungal drugs and early diagnosis have improved IFD outcomes, and HSCT in patients with a recent IFD has become increasingly common. However, an organized approach for performing transplantation in patients with a prior IFD is scarce, and decisions are highly individualized. Patient-, malignancy-, transplantation procedure–, antifungal treatment–, and fungus-specific issues affect the risk of IFD relapse. Effective surveillance to detect IFD relapse post-HSCT and careful drug selection for antifungal prophylaxis are of paramount importance. Antifungal drugs have their own toxicities and interact with immunosuppressive drugs such as calcineurin inhibitors. Immune adjunct cytokine or cellular therapy and surgery can be considered in selected cases. In this review, we critically evaluate these factors and provide guidance for the complex decision making involved in the peri-HSCT management of these patients.

Cytomegalovirus (CMV) Cell-Mediated Immunity and CMV Infection After Allogeneic Hematopoietic Cell Transplantation: The REACT Study - Chemaly, Roy F; El Haddad, Lynn; Winston, Drew J; Rowley, Scott D; Mulane, Kathleen M; Chandrasekar, Pranatharthi; Avery, Robin K; Hari, Parameswaran; Peggs, Karl S; Kumar, Deepali; Nath, Rajneesh; Ljungman, Per; et al. (Clinical Infectious Diseases, 2020)
Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality in allogeneic hematopoietic cell transplant (allo-HCT) recipients. CMV cell-mediated immunity (CMV-CMI) as determined by a peptide-based enzyme-linked immunospot (ELISPOT) CMV assay may identify patients at risk for clinically significant CMV infection (CS-CMVi).The CS-CMVi was defined as CMV viremia and/or disease necessitating antiviral therapy. CMV-CMI was characterized as high when the intermediate-early 1 (IE-1) antigen spot counts (SPCs) were >100 (cutoff 1) or when the IE-1 and phosphoprotein 65 antigen SPCs were both >100 SPCs per 250 000 cells (cutoff 2), and a low CMV-CMI when SPCs were below these thresholds. In this prospective multicenter study, we evaluated CMV-CMI every 2 weeks from the pretransplant period until 6 months posttransplantation in 241 allo-HCT recipients with positive CMV serostatus. The primary endpoint was CS-CMVi occurring within 2 weeks of the last measurement of CMV-CMI.CS-CMVi occurred in 70 allo-HCT recipients (29%). CMV-CMI was low in patients who experienced CS-CMVi (94%), whereas those who had a high CMV-CMI were less likely to have CS-CMVi (P < .0001). Patients with CS-CMVi had higher all-cause mortality (P = .007), especially those with low CMV-CMI (P = .035). On multivariable analysis, CMV-CMI, sex, race, antithymocyte globulin, and steroid use were independent predictors of CS-CMVi, and the time from transplant to engraftment was the only predictor of mortality.Measurement of CMV-CMI using a novel ELISPOT assay would be useful clinically to monitor allo-HCT recipients and distinguish between those at risk of developing CS-CMVi and requiring antiviral prophylaxis or therapy and those who are protected.

Emerging Issues in Antifungal Resistance - Perfect, John R.; Ghannoum, Mahmoud (Infectious Disease Clinics of North America, 2020)
The increasing emergence and spread of drug resistant Candida albicans represent a serious challenge for effective treatment and call for the development of new therapeutic options. To address this need, we synthesized a series of polypyridyl iridium(III) complexes and studied their antimicrobial activities. Herein, one lead iridium(III) complex Ir-3 [(ptpy)2Ir(dppz)]PF6, with ptpy = 2-(p-tolyl)pyridine and dppz = dipyrido[3,2-a:2′,3′-c]phenazine, exhibited potent and broad-spectrum antifungal activities against drug-resistant pathogens and low hemolytic activity toward mammalian cells. Furthermore, Ir-3 showed low tendency to induce resistance, displayed biofilm inhibition and eradication activities. Significantly, Ir-3 exhibited potent in vivo antifungal activity in a murine model of disseminated candidiasis. This study may pave the way for the development of novel antifungal agent based upon polypyridyl iridium(III) complex to combat antifungal resistance. To monitor trends in the distribution of yeast species and the susceptibilities of these species to commonly prescribed antifungal drugs, we conduct the Taiwan Surveillance of Antimicrobial Resistance of Yeasts (TSARY) every 4 years. We found that 25 of 294 Candida tropicalis isolates from TSARY 2014 and 31 of 314 C. tropicalis isolates from TSARY 2018 were resistant to fluconazole. We determined the genetic relatedness among fluconazole-resistant C. tropicalis isolates by multilocus sequence typing (MLST). Among 174 C. tropicalis isolates, including all 56 fluconazole-resistant, all 26 susceptible-dose dependent and 92 selected fluconazole-susceptible isolates, 59 diploid sequence types (DSTs) were identified. We found that 22 of the 25 fluconazole-resistant C. tropicalis from TSARY 2014 and 29 of the 31 fluconazole-resistant C. tropicalis from TSARY 2018 were genetically related and belonged to the same cluster (clade 4). A combination of mutation and overexpression of ERG11, encoding the target of azole drugs, was the major mechanism contributing to drug resistance. Approximately two-thirds of reviewed patients infected or colonised by fluconazole-resistant C. tropicalis were azole-naïve. Furthermore, there was no evidence of patient-to-patient transmission. Because the clade 4 fluconazole-resistant C. tropicalis strain persists in Taiwan, it is important to identify the source of azole-resistant C. tropicalis to prevent the spread of this resistant strain.
Keywords: Antifungal agents; Drug resistance; Fungi; Invasive fungal disease

Late Onset Invasive Pulmonary Aspergillosis in Lung Transplant Recipients in the Setting of a Targeted Prophylaxis/Preemptive Antifungal Therapy Strategy - Herrera, Sabina; Davoudi, Setareh; Farooq, Ali; Tikkanen, Jussi; Foroutan, Farid; Kumar, Deepali; Humar, Atul; Rotstein, Coleman; Singer, Lianne G.; Keshavjee, Shaf; Husain, Shahid (Transplantation, 2020)
Background. Invasive pulmonary aspergillosis (IPA) is a significant cause of morbidity and mortality in lung transplant recipients (LTRs). It is unclear how a targeted prophylaxis/ preemptive antifungal therapy strategy impacts the incidence of IPA beyond the first-year posttransplant. Methods. This is a retrospective cohort of LTRs from January 2010 to December 2014. We included all LTRs who survived beyond the first year and followed them until death or 4 years postoperatively. Incidence of probable/proven IPA and Aspergillus colonization were assessed as per International Society for Heart and Lung Transplantation (ISHLT) criteria. Patients with risk factors, positive Aspergillus cultures, or galactomannan (GM) received targeted prophylaxis/preemptive therapy within the first-year posttransplant. Results. During the study period, 350 consecutive LTRs underwent 1078 bronchoscopies. Positive bronchoalveolar lavage for GM or Aspergillus cultures was reported for 15% (52/350) of LTRs between 2 and 4 years after transplantation. Among them, the median time to positive Aspergillus culture or GM positivity was 703 days (interquartile range, 529–754 d). The incidence rate of IPA and Aspergillus colonization was 30 of 1000 patient-y, and 63 of 1000 patient-y, respectively. The mortality rate was significantly higher in patients with IPA than without IPA (107/1000 patient-years versus 18/1000 patient-years; P < 0.0001). Rate of first-year colonization and IPA was 33% and 9%, respectively. Among the 201 patients who had a negative bronchoscopy during the first year posttransplant, only 6 (3%) developed IPA during the follow-up. Conclusions. A targeted prophylaxis/preemptive therapy strategy within the first-year posttransplant resulted in 4% incidence of IPA at 4-years after transplantation. However, IPA was associated with higher mortality.

Ciprofloxacin prophylaxis is associated with a lower incidence of gram-negative bacteremia in patients undergoing allogeneic hematopoietic cell transplantation - Maurer, A. Katie; Li, Shuli; Hunter, Bradley D.; Luk, Samantha O.; O’Donnell, Susan E.; Dey, Bimalangshu R.; El-Jawahri, Areej; Frigault, Matthew J.; McAfee, Steven; O’Donnell, Paul V.; Spitzer, Thomas R.; Chen, Yi-Bin; et al. (Bone Marrow Transplantation, 2020)
Number: 12 Publisher: Nature Publishing Group

Asymptomatic bacteriuria in kidney transplant recipients: to treat, or not to treat, that is the question - Sabé, Núria; Cruzado, Josep M.; Carratalà, Jordi (Clinical Microbiology and Infection, 2020)
Abstract In this article we comment on the few interventional studies that have addressed the question of how asymptomatic bacteriuria should be managed in kidney transplant (KT) recipients. The findings from the studies reported to date support recent guidelines arguing against systematic screening and treatment of asymptomatic bacteriuria in KT recipients. However, these studies present significant limitations and should be interpreted with caution.
Publisher: Elsevier

Direct-Acting Antivirals and Organ Transplantation: Is There Anything We Can’t Do? - Kappus, Matthew R; Wolfe, Cameron R; Muir, Andrew J (The Journal of Infectious Diseases, 2020)
The opioid epidemic has resulted in an increase in organ donors with hepatitis C virus (HCV) infection in the United States. With the development of direct-acting antiviral regimens that offer high sustained virologic response rates even in the setting of immunosuppression after transplantation, these HCV-viremic organs are now being offered to transplant candidates with or without preexisting HCV infection. Strategies for HCV treatment with HCV-viremic organs have included delayed and preemptive approaches. This review will discuss key studies in the different solid organ transplants, recent reports of adverse events, and ethical and regulatory considerations. The efficacy of current HCV therapies has created this important opportunity to improve survival for patients with end-organ failure through greater access to organ transplantation and decreased waitlist mortality rate.

Gallium-67 Single-Photon Emission Computed Tomography Affects Management of Infections of Left Ventricular Assist Devices - Puius, Yoram A.; Parkar, Fauziya; Tlamsa, Aileen P.; Nistico, Justin A.; Muggia, Victoria A.; Minamoto, Grace Y.; Jorde, Ulrich P.; Goldstein, Daniel J.; Moadel, Renée M. (ASAIO journal (American Society for Artificial Internal Organs: 1992), 2020)
Our institution employs gallium-67 single-photon emission computed tomography low-dose CT (Ga-SPECT-CT) to determine the presence and extent of left ventricular assist device (LVAD) infections. We present a retrospective single-center study of 41 LVAD recipients who underwent Ga-SPECT-CT from January 2011 to June 2018 to determine whether Ga-SPECT-CT led to changes in antimicrobial therapy, LVAD revision or exchange, or application for 1A exception. The average age was 56.6 years, predominantly male (80.5%) and diabetic (68.3%), divided between ischemic (48.8%) and nonischemic (51.2%) cardiomyopathy. The majority had HeartMate II devices (82.9%). Device-related infections were classified as possible (12.2%), probable (36.6%), proven (36.6%), or rejected (14.6%). Sensitivity was 68.6% and specificity was 100%. Most VAD-specific infections were percutaneous deep driveline infections (DRIs) (34.1%), and VAD-related infections were primarily bloodstream infections (31.7%). Staphylococcus aureus was the major pathogen isolated. Gallium-67 single-photon emission computed tomography low-dose CT resulted in changes in management in more than half (53.7%) of patients: starting (24.4%) or stopping (17.1%) antimicrobial therapy, LVAD revision (22.0%) or exchange (12.2%), and the application for 1A exception for transplant listing (17.1%). We conclude that Ga-SPECT-CT is an effective modality for determining the presence and extent of LVAD DRIs, and contributed to a change in management in more than half of cases.

Latest Thoughts on Treating Pediatric Mucormycosis - Steinbach, William J. (Journal of the Pediatric Infectious Diseases Society, 2020)
Abstract. Mucormycosis is one of the most complicated to diagnose and treat invasive fungal diseases. Diagnostic techniques have not significantly advanced in y

Increased early acute cellular rejection events in hepatitis C-positive heart transplantation - Gidea, Claudia G.; Narula, Navneet; Reyentovich, Alex; Fargnoli, Anthony; Smith, Deane; Pavone, Jennifer; Lewis, Tyler; Karpe, Hannah; Stachel, Maxine; Rao, Shaline; Moreira, Andre; Saraon, Tajinderpal; et al. (The Journal of Heart and Lung Transplantation, 2020)
BACKGROUND Increased utilization of hepatitis C virus (HCV)-positive donors has increased transplantation rates. However, high levels of viremia have been documented in recipients of viremic donors. There is a knowledge gap in how transient viremia may impact acute cellular rejections (ACRs). METHODS In this study, 50 subjects received hearts from either viremic or non-viremic donors. The recipients of viremic donors were classified as nucleic acid amplification testing (NAT)+ group, and the remaining were classified as NAT-. All patients were monitored for viremia levels. Endomyocardial biopsies were performed through 180 days, evaluating the incidence of ACRs. RESULTS A total of 50 HCV-naive recipients received hearts between 2018 and 2019. A total of 22 patients (44%) who received transplants from viremic donors developed viremia at a mean period of 7.2 ± 0.2 days. At that time, glecaprevir/pibrentasvir was initiated. In the viremia period (<56 days), 14 of 22 NAT+ recipients (64%) had ACR vs 5 of 28 NAT- group (18%) (p = 0.001). Through 180 days, 17 of 22 NAT+ recipients (77%) had a repeat rejection biopsy vs 12 of 28 NAT– recipients (43%) (p = 0.02). NAT+ biopsies demonstrated disparity of ACR distribution: negative, low-grade, and high-grade ACR in 84%, 12%, and 4%, respectively, vs 96%, 3%, and 1%, respectively, in the NAT– group (p = 0.03). The median time to first event was 26 (interquartile range [IQR]: 8–45) in the NAT+ group vs 65 (IQR: 44–84) days in the NAT–. Time to first event risk model revealed that NAT+ recipients had a significantly higher rate of ACR occurrences, adjusting for demographics (p = 0.004). CONCLUSIONS Transient levels of viremia contributed to higher rates and severity of ACRs. Further investigation into the mechanisms of early immune activation in NAT+ recipients is required.
Publisher: Elsevier

Cellular Immunity to Predict the Risk of Cytomegalovirus Infection in Kidney Transplantation: A Prospective, Interventional, Multicenter Clinical Trial - Jarque, Marta; Crespo, Elena; Melilli, Edoardo; Gutiérrez, Alex; Moreso, Francesc; Guirado, Lluís; Revuelta, Ignacio; Montero, Nuria; Torras, Joan; Riera, Lluís; Meneghini, Maria; Taco, Omar; et al. (Clinical Infectious Diseases, 2020)
Improving cytomegalovirus (CMV) immune-risk stratification in kidney transplantation is highly needed to establish guided preventive strategies.This prospective, interventional, multicenter clinical trial assessed the value of monitoring pretransplant CMV-specific cell-mediated immunity (CMI) using an interferon-γ release assay to predict CMV infection in kidney transplantation. One hundred sixty donor/recipient CMV-seropositive (D+/R+) patients, stratified by their baseline CMV (immediate-early protein 1)–specific CMI risk, were randomized to receive either preemptive or 3-month antiviral prophylaxis. Also, 15-day posttransplant CMI risk stratification and CMI specific to the 65 kDa phosphoprotein (pp65) CMV antigen were investigated. Immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil, and corticosteroids in 80% of patients, whereas 20% received thymoglobulin induction therapy. Patients at high risk for CMV based on pretransplant CMI developed significantly higher CMV infection rates than those deemed to be at low risk with both preemptive (73.3% vs 44.4%; odds ratio [OR], 3.44 [95% confidence interval {CI}, 1.30–9.08]) and prophylaxis (33.3% vs 4.1%; OR, 11.75 [95% CI, 2.31–59.71]) approaches. The predictive capacity for CMV-specific CMI was only found in basiliximab-treated patients for both preemptive and prophylaxis therapy. Fifteen-day CMI risk stratification better predicted CMV infection (81.3% vs 9.1%; OR, 43.33 [95% CI, 7.89–237.96]).Pretransplant CMV-specific CMI identifies D+/R+ kidney recipients at high risk of developing CMV infection if not receiving T-cell–depleting antibodies. Monitoring CMV-specific CMI soon after transplantation further defines the CMV infection prediction risk. Monitoring CMV-specific CMI may guide decision making regarding the type of CMV preventive strategy in kidney transplantation.NCT02550639.

International Society for Heart and Lung Transplantation consensus statement for the standardization of bronchoalveolar lavage in lung transplantation - Martinu, Tereza; Koutsokera, Angela; Benden, Christian; Cantu, Edward; Chambers, Daniel; Cypel, Marcelo; Edelman, Jeffrey; Emtiazjoo, Amir; Fisher, Andrew J.; Greenland, John R.; Hayes, Don; Hwang, David; et al. (The Journal of Heart and Lung Transplantation, 2020)
Publisher: Elsevier
Keywords: bronchial wash; bronchoalveolar lavage; donor bronchoscopy; lung transplantation; methodology; pediatric bronchoscopy; standardization

BK Polyomavirus-specific T Cells as a Diagnostic and Prognostic Marker for BK Polyomavirus Infections After Pediatric Kidney Transplantation - Ahlenstiel-Grunow, Thurid; Sester, Martina; Sester, Urban; Hirsch, Hans H.; Pape, Lars (Transplantation, 2020)
Background. After kidney transplantation, uncontrolled BK polyomavirus (BKPyV) replication causes kidney graft failure through BKPyV-associated nephropathy (BKPyVAN), but markers predicting outcome are missing. BKPyV-specific T cells may serve as a predictive marker to identify patients at risk of persistent DNAemia and BKPyVAN. Methods. Out of a total of 114 pediatric kidney recipients transplanted between 2008 and 2018, 36 children with posttransplant BKPyV-DNAemia were identified. In a prospective noninterventional study, BKPyV-specific CD4 and CD8 T cells were measured in 32 of 36 viremic pediatric kidney recipients using intracellular cytokine staining and flow cytometry. The course of the BKPyV replication was monitored with regard to duration of BKPyV-DNAemia and need of therapeutic intervention and diagnosis of proven BKPyVAN. Results. Levels of BKPyV-specific T cells negatively correlated with subsequent duration of BKPyV-DNAemia. Patients with BKPyV-specific CD4 T cells ≥0.5 cells/µL and/or BKPyV-specific CD8 T cells ≥0.1 cells/µL had transient, self-limiting DNAemia (PPV 1.0, NPV 0.86). BKPyV-specific CD4 and CD8 T cells below these thresholds were found in children with persistent BKPyV-DNAemia and biopsy-proven BKPyVAN with need for therapeutic intervention. After reducing immunosuppressive therapy, levels of BKPyV-specific CD4 T cells increased while plasma BKPyV-DNAemia declined. Conclusions. This study found that BKPyV-specific T cell levels may help to distinguish patients with transient, self-limiting BKPyV-DNAemia from those with persisting BKPyV-DNAemia and biopsy-proven BKPyVAN, who would benefit from individualized therapeutic interventions such as reduced immunosuppression. Thereby the risk for rejection because of unnecessary reduction of immunosuppression in case of self-limiting BKPyV-DNAemia can be minimized.

Candida auris: Epidemiology, biology, antifungal resistance, and virulence - Du, Han; Bing, Jian; Hu, Tianren; Ennis, Craig L.; Nobile, Clarissa J.; Huang, Guanghua (PLOS Pathogens, 2020)
First described in 2009 in Japan, the emerging multidrug-resistant fungal pathogen Candida auris is becoming a worldwide public health threat that has been attracting considerable attention due to its rapid and widespread emergence over the past decade. The reasons behind the recent emergence of this fungus remain a mystery to date. Genetic analyses indicate that this fungal pathogen emerged simultaneously in several different continents, where 5 genetically distinct clades of C. auris were isolated from distinct geographical locations. Although C. auris belongs to the CTG clade (its constituent species translate the CTG codon as serine instead of leucine, as in the standard code), C. auris is a haploid fungal species that is more closely related to the haploid and often multidrug-resistant species Candida haemulonii and Candida lusitaniae and is distantly related to the diploid and clinically common fungal pathogens Candida albicans and Candida tropicalis. Infections and outbreaks caused by C. auris in hospitals settings have been rising over the past several years. Difficulty in its identification, multidrug resistance properties, evolution of virulence factors, associated high mortality rates in patients, and long-term survival on surfaces in the environment make C. auris particularly problematic in clinical settings. Here, we review progress made over the past decade on the biological and clinical aspects of C. auris. Future efforts should be directed toward understanding the mechanistic details of its biology, epidemiology, antifungal resistance, and pathogenesis with a goal of developing novel tools and methods for the prevention, diagnosis, and treatment of C. auris infections.
Publisher: Public Library of Science
Keywords: Antifungals; Antimicrobial resistance; Biofilms; Candida; Candida albicans; Fungal pathogens; Yeast; Yeast infections

Voriconazole versus Itraconazole for the Initial and Step-Down Treatment of Histoplasmosis: A Retrospective Cohort - Hendrix, Michael Joshua; Larson, Lindsey; Rauseo, Adriana M.; Rutjanawech, Sasinuch; Franklin, Alexander D.; Powderly, William G.; Spec, Andrej (Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 2020)
BACKGROUND: Itraconazole is the preferred azole for histoplasmosis in the current Infectious Diseases Society of America guidelines. Voriconazole is increasingly used as treatment for histoplasmosis; it has in-vitro activity against Histoplasma capsulatum and has shown success in case reports and small case series but may have a lower barrier to resistance. No comparative studies have been published. METHODS: We constructed a single-center retrospective cohort of adult patients diagnosed with histoplasmosis from 2002 to 2017. Individual charts were reviewed to gather clinical information including demographics, clinical features, immune status, treatments, and mortality. Patients were categorized based on initial choice of azole, either as initial treatment or as step-down therapy from amphotericin B. Initial therapies with other azoles were excluded. Mortality was compared using a multivariable Cox proportional hazards with Heaviside function at 42 days. RESULTS: We identified 261 cases of histoplasmosis from 2002 to 2017. After excluding patients not treated with itraconazole or voriconazole, 194 patients remained. 175 (90%) patients received itraconazole and 19 (10%) received voriconazole. There were no significant demographic differences between patient populations receiving either azole as their initial azole treatment. Death at 180 days occurred in 41 patients (23.4%) in the itraconazole group and 6 patients (31.6%) in the voriconazole group. Patients on voriconazole had a statistically significant increase in mortality during the first 42 days after initiation of treatment when compared to patients receiving itraconazole (HR 4.30 [95% CI 1.3-13.9, p 0.015]) when controlled for other risk factors. CONCLUSION: Voriconazole in histoplasmosis was associated with increased mortality in the first 42 days compared to itraconazole.
Keywords: histoplasmosis; inferior; itraconazole; mortality; voriconazole

Drug Resistance Assessment Following Administration of Respiratory Syncytial Virus (RSV) Fusion Inhibitor Presatovir to Participants Experimentally Infected With RSV - Stray, Kirsten; Perron, Michel; Porter, Danielle P; Anderson, Francisco; Lewis, Sandra A; Perry, Jason; Miller, Michael; Cihlar, Tomas; DeVincenzo, John; Chien, Jason W; Jordan, Robert (The Journal of Infectious Diseases, 2020)
Presatovir is an oral respiratory syncytial virus (RSV) fusion inhibitor targeting RSV F protein. In a double-blind, placebo-controlled study in healthy adults experimentally infected with RSV (Memphis-37b), presatovir significantly reduced viral load and clinical disease severity in a dose-dependent manner.Viral RNA from nasal wash samples was amplified and the F gene sequenced to monitor presatovir resistance. Effects of identified amino acid substitutions on in vitro susceptibility to presatovir, viral fitness, and clinical outcome were assessed.Twenty-eight treatment-emergent F substitutions were identified. Of these, 26 were tested in vitro; 2 were not due to lack of recombinant virus recovery. Ten substitutions did not affect presatovir susceptibility, and 16 substitutions reduced RSV susceptibility to presatovir (2.9- to 410-fold). No substitutions altered RSV susceptibility to palivizumab or ribavirin. Frequency of phenotypically resistant substitutions was higher with regimens containing lower presatovir dose and shorter treatment duration. Participants with phenotypic presatovir resistance had significantly higher nasal viral load area under the curve relative to those without, but substitutions did not significantly affect peak viral load or clinical manifestations of RSV disease.Emergence of presatovir-resistant RSV occurred during therapy but did not significantly affect clinical efficacy in participants with experimental RSV infection.

Letermovir Prophylaxis Decreases Burden of Cytomegalovirus (CMV) in Patients at High Risk for CMV Disease Following Hematopoietic Cell Transplant - Johnsrud, Joyce J.; Nguyen, Isabelle T.; Domingo, Walter; Narasimhan, Balasubramanian; Efron, Bradley; Brown, Janice Wes (Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation, 2020)
Despite effective therapies, cytomegalovirus (CMV) continues to have a significant impact on morbidity and mortality in hematopoietic cell transplant recipients. At particular risk are recipients of alternative grafts such as umbilical cord blood (UCB), haploidentical transplants (haplo), or patients conditioned with T-cell depleting regimens such as anti-thymocyte globulin (ATG). With the approval of letermovir, its impact on high-risk patients is of particular interest. To evaluate the impact of letermovir prophylaxis at our center, we performed a retrospective analysis of 114 high-risk patients who received letermovir as prophylaxis (LET PPX) between January 2018 through December 2019, including 30 UCB and 22 haplo recipients, compared with 637 historical controls with comparable risk between January 2013 and December 2019. By post-transplant day 100 (D+100), letermovir prophylaxis significantly decreased the incidence of both CMV DNAemia compared with controls (45.37% versus 74.1%; P < .001) and clinically significant CMV infection (12.04% versus 48.82%; P < .001). The impact of LET PPX was even more profound on the incidence of clinically significant CMV infection (CSI), defined as the administration of antiviral therapy as preemptive therapy for CMV DNAemia or treatment for CMV disease. CSI was significantly lower in haplo recipients on LET PPX compared with controls (13.64% versus 73.33%; P= .02) and UCB recipients on LET PPX compared with controls (3.45% versus 37.5%; P < .001). No patients on LET primary PPX developed CMV disease in any treatment group by D+100 compared with controls (0% versus 5.34%, respectively; P = .006). Patients on LET PPX had fewer hospitalizations involving initiation of anti-CMV therapy compared with controls (0.93% versus 15.23%, respectively). Our analysis of the largest cohort of patients at high risk for CMV reactivation published to date demonstrates that letermovir prophylaxis significantly reduces the number of patients who receive CMV-active antiviral therapy for either DNAemia or disease due to CMV.
Keywords: Alternative donors; Cytomegalovirus; Hematopoietic cell transplant

Recalls, Market Withdrawals, & Safety Alerts - Affairs, Office of Regulatory (FDA, 2020)
FDA and industry press releases regarding product recalls
Publisher: FDA

Phase I EnACT Trial of the Safety and Tolerability of a Novel Oral Formulation of Amphotericin B - Skipper, Caleb P.; Atukunda, Mucunguzi; Stadelman, Anna; Engen, Nicole W.; Bangdiwala, Ananta S.; Hullsiek, Katherine H.; Abassi, Mahsa; Rhein, Joshua; Nicol, Melanie R.; Laker, Eva; Williams, Darlisha A.; Mannino, Raphael; et al. (Antimicrobial Agents and Chemotherapy, 2020)
Amphotericin B deoxycholate (AMB) has substantial toxicities. A novel encochleated amphotericin B deoxycholate (cAMB) formulation has oral bioavailability, efficacy in an animal model, and minimal toxicity due to targeted drug delivery into macrophages, where intracellular fungi reside. We conducted a phase I, ascending-dose trial of cAMB administered at 1.0 g, 1.5 g, or 2.0 g per day in 4 to 6 divided doses among HIV-positive survivors of cryptococcosis (n = 9 per cohort). We assessed the tolerability of cAMB and the adverse events (AEs) associated with cAMB treatment over 3 days. A second trial (n = 9) assessed the tolerability of 1.5 g/day given for 7 days. In the single-ascending-dose study, all subjects received their full daily dose without vomiting (100% tolerability). The cohort receiving 1.0 g had 4 transient clinical AEs in 2 subjects within 48 h and 8 laboratory AEs (n = 6 grade 2, n = 2 grade 1). The cohort receiving 1.5 g had 7 clinical AEs in 1 subject attributed to acute gastroenteritis (n = 4 grade 2) and 5 laboratory AEs (n = 1 grade 2). The cohort receiving 2.0 g had 20 clinical AEs among 5 subjects within 48 h (n = 3 grade 2) and 11 laboratory AEs (n = 2 grade 2, n = 1 grade 3). From a qualitative survey, 26 of 27 subjects (96%) preferred their experience with oral cAMB over their prior experience with intravenous (i.v.) AMB. The second, multiple-dose cohort received 1.5 g/day for 1 week, with 98.4% (248/252) of the doses being taken. Overall, 5 clinical AEs (n = 5 grade 1) and 6 laboratory AEs (n = 6 grade 1) occurred without kidney toxicity. Oral cAMB was well tolerated when given in 4 to 6 divided daily doses without the toxicities commonly seen with i.v. AMB. (This study has been registered at ClinicalTrials.gov under registration no. NCT04031833.).
Keywords: Amphotericin B; Animals; Antifungal Agents; Cryptococcosis; Cryptococcus; Fungi; HIV; amphotericin B; antifungal agents; cryptococcal meningitis; human immunodeficiency virus; pharmacokinetics

Rezafungin Versus Caspofungin in a Phase 2, Randomized, Double-blind Study for the Treatment of Candidemia and Invasive Candidiasis: The STRIVE Trial - Thompson, III, George R; Soriano, Alex; Skoutelis, Athanasios; Vazquez, Jose A; Honore, Patrick M; Horcajada, Juan P; Spapen, Herbert; Bassetti, Matteo; Ostrosky-Zeichner, Luis; Das, Anita F; Viani, Rolando M; Sandison, Taylor; et al. (Clinical Infectious Diseases, 2020)
Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to compare the safety and efficacy of RZF once weekly (QWk) to caspofungin (CAS) once daily for treatment of candidemia and/or invasive candidiasis (IC).Adults with systemic signs and mycological confirmation of candidemia and/or IC were randomized to RZF 400 mg QWk (400 mg), RZF 400 mg on week 1 then 200 mg QWk (400/200 mg), or CAS 70 mg as a loading dose followed by 50 mg daily for ≤4 weeks. Efficacy assessments included overall cure (resolution of signs of candidemia/IC + mycological eradication) at day 14 (primary endpoint), investigator-assessed clinical response at day 14, and 30-day all-cause mortality (ACM) (secondary endpoints), and time to negative blood culture. Safety was evaluated by adverse events and ACM through follow-up.Of 207 patients enrolled, 183 were in the microbiological intent-to-treat population (~21% IC). Overall cure rates were 60.5% (46/76) for RZF 400 mg, 76.1% (35/46) for RZF 400/200 mg, and 67.2% (41/61) for CAS; investigator-assessed clinical cure rates were 69.7% (53/76), 80.4% (37/46), and 70.5% (43/61), respectively. In total, 30-day ACM was 15.8% for RZF 400 mg, 4.4% for RZF 400/200 mg, and 13.1% for CAS. Candidemia was cleared in 19.5 and 22.8 hours in RZF and CAS patients, respectively. No concerning safety trends were observed; ACM through follow-up was 15.2% (21/138) for RZF and 18.8% (13/69) for CAS.RZF was safe and efficacious in the treatment of candidemia and/or IC.

Beyond Cytomegalovirus and Epstein-Barr Virus: a Review of Viruses Composing the Blood Virome of Solid Organ Transplant and Hematopoietic Stem Cell Transplant Recipients - Zanella, Marie-Céline; Cordey, Samuel; Kaiser, Laurent (Clinical Microbiology Reviews, 2020)
Viral primary infections and reactivations are common complications in patients after solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT) and are associated with high morbidity and mortality. Among these patients, viral infections are frequently associated with viremia. Beyond the usual well-known viruses that are part of the routine clinical management of transplant recipients, numerous other viral signatures or genomes can be identified in the blood of these patients. The identification of novel viral species and variants by metagenomic next-generation sequencing has opened up a new field of investigation and new paradigms. Thus, there is a need to thoroughly describe the state of knowledge in this field with a review of all viral infections that should be scrutinized in high-risk populations. Here, we review the eukaryotic DNA and RNA viruses identified in blood, plasma, or serum samples of pediatric and adult SOT/HSCT recipients and the prevalence of their detection, with a particular focus on recently identified viruses and those for which their potential association with disease remains to be investigated, such as members of the Polyomaviridae, Anelloviridae, Flaviviridae, and Astroviridae families. Current knowledge of the clinical significance of these viral infections with associated viremia among transplant recipients is also discussed. To ensure a comprehensive description in these two populations, individuals described as healthy (mostly blood donors) are considered for comparative purposes. The list of viruses that should be on the clinicians’ radar is certainly incomplete and will expand, but the challenge is to identify those of possible clinical significance.
Publisher: American Society for Microbiology Journals Section: Review

Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium - Donnelly, J Peter; Chen, Sharon C; Kauffman, Carol A; Steinbach, William J; Baddley, John W; Verweij, Paul E; Clancy, Cornelius J; Wingard, John R; Lockhart, Shawn R; Groll, Andreas H; Sorrell, Tania C; Bassetti, Matteo; et al. (Clinical Infectious Diseases, 2020)
Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential.To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups’ findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved.There is no change in the classifications of “proven,” “probable,” and “possible” IFD, although the definition of “probable” has been expanded and the scope of the category “possible” has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses.These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

A living WHO guideline on drugs for covid-19 - Agarwal, Arnav; Rochwerg, Bram; Lamontagne, François; Siemieniuk, Reed AC; Agoritsas, Thomas; Askie, Lisa; Lytvyn, Lyubov; Leo, Yee-Sin; Macdonald, Helen; Zeng, Linan; Amin, Wagdy; Barragan, Fabian AJ; et al. (BMJ, 2020)
Updates This is the ninth version (eighth update) of the living guideline, replacing earlier versions, available as data supplements. New recommendations will be published as updates to this guideline. Clinical question What is the role of drugs in the treatment of patients with covid-19? Context The evidence base for therapeutics for covid-19 is evolving with numerous recently completed randomised controlled trials (RCTs). This update adds a new recommendation on molnupiravir in patients with non-severe illness, informed by data from 6 RCTs with 4796 patients. The omicron variant has resulted in an update to the recommendations for casirivimab-imdevimab. Concerning remdesivir, new trial data is currently being reviewed. New recommendation The Guideline Development Group (GDG) suggests administering molnupiravir in patients with non-severe illness, for those at highest risk of hospitalisation and combined with implementation of mitigation strategies to reduce potential harms. No recommendation was made in patients with severe or critical illness as there are no trial data on molnupiravir for this population. Understanding the new recommendation In patients with non-severe illness, molnupiravir reduces hospitalisation risk and time to symptom resolution and may have a small effect on mortality. Only patients at the highest risk of being hospitalised are likely to derive important benefits and would want to receive molnupiravir. This is especially true given the potential long term harms associated with molnupiravir (such as theoretical risk of malignancy). The conditional recommendation reflects the challenge to accurately identify those at the highest risk, the limited availability of the drug, and concerns about long term individual and population-level harms such as drug resistance and/or emergence of new variants Updates to prior recommendations • The conditional recommendations for casirivimab-imdevimab in patients with both non-severe (for those at highest risk of hospitalisation) and severe or critical covid-19 (for those with seronegative status) are now restricted to cases where rapid viral genotyping is available and confirms infection with a susceptible SARS-CoV-2 variant (such as delta). This change follows pre-clinical evidence that casirivimab-imdevimab lacks efficacy against the omicron BA1 variant.• Regarding the conditional recommendation against remdesivir in patients with covid-19, new trial data have resulted in an ongoing evidence review by the GDG with an anticipated update of the recommendation in the next iteration of this guideline. Prior recommendations • Recommended for patients with severe or critical covid-19—a strong recommendation for systemic corticosteroids; a strong recommendation for IL-6 receptor blockers (tocilizumab or sarilumab), in combination with corticosteroids; and a strong recommendation for baricitinib as an alternative to IL-6 receptor blockers, in combination with corticosteroids.• Recommended for patients with non-severe covid-19—a conditional recommendation for sotrovimab, for those at highest risk of hospitalisation. • Not recommended for patients with non-severe covid-19—a conditional recommendation against systemic corticosteroids; and a strong recommendation against convalescent plasma.• Not recommended for patients with severe or critical covid-19—a recommendation against convalescent plasma, except in the context of a clinical trial; and a conditional recommendation against ruxolitinib and tofacitinib.• Not recommended, regardless of covid-19 disease severity—a strong recommendation against hydroxychloroquine; a strong recommendation against lopinavir/ritonavir; and a recommendation against ivermectin, except in the context of a clinical trial. About this guideline This living guideline from the World Health Organization (WHO) incorporates a new recommendation on molnupiravir for covid-19 and updates existing recommendations. The GDG typically evaluates a therapy when WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF, with a summary version here in The BMJ.
Publisher: British Medical Journal Publishing Group Section: Practice

Diagnostic accuracy of serum (1-3)-β-D-glucan for Pneumocystis jirovecii pneumonia: a systematic review and meta-analysis - Corpo, Olivier Del; Butler-Laporte, Guillaume; Sheppard, Donald C.; Cheng, Matthew P.; McDonald, Emily G.; Lee, Todd C. (Clinical Microbiology and Infection, 2020)
Abstract Background Pneumocystis jirovecii pneumonia (PJP) can be a life-threatening opportunistic infection in immunocompromised hosts. The diagnosis can be challenging, often requiring semi-invasive respiratory sampling. The serum 1,3-β-D-glucan (BDG) assay has been proposed as a minimally invasive test for the presumptive diagnosis of PJP. Method We carried out a systematic review and meta-analysis using articles in the English language published between January 1960 and September 2019. We estimated the pooled sensitivity and specificity of BDG testing using a bivariate random effects approach and compared test performance in human immunodeficiency virus (HIV) and non-HIV subgroups with meta-regression. Data from the pooled sensitivity and specificity were transformed to generate pre- and post-test probability curves. Results Twenty-three studies were included. The pooled sensitivity and specificity of serum BDG testing for PJP were 91% (95%CI 87–94%) and 79% (95%CI 72–84%) respectively. The sensitivity in patients with HIV was better than in patients without (94%, 95%CI 91–96%) versus 86% (95%CI 78–91%) (p 0.02), with comparable specificity (83%, 95%CI 69–92% versus 83%, 95%CI 72–90%) (p 0.10). A negative BDG was only associated with a low post-test probability of PJP (≤5%) when the pre-test probability was low to intermediate (≤20% in non-HIV and ≤50% in HIV). Conclusions Among patients with a higher likelihood of PJP, the pooled sensitivity of BDG is insufficient to exclude infection. Similarly, for most cases, the pooled specificity is inadequate to diagnose PJP. Understanding the performance of BDG in the population being investigated is therefore essential to optimal clinical decision-making.
Publisher: Elsevier

Core Recommendations for Antifungal Stewardship: A Statement of the Mycoses Study Group Education and Research Consortium - Johnson, Melissa D; Lewis, Russell E; Dodds Ashley, Elizabeth S; Ostrosky-Zeichner, Luis; Zaoutis, Theoklis; Thompson, George R; Andes, David R; Walsh, Thomas J; Pappas, Peter G; Cornely, Oliver A; Perfect, John R; Kontoyiannis, Dimitrios P (The Journal of Infectious Diseases, 2020)
In recent years, the global public health community has increasingly recognized the importance of antimicrobial stewardship (AMS) in the fight to improve outcomes, decrease costs, and curb increases in antimicrobial resistance around the world. However, the subject of antifungal stewardship (AFS) has received less attention. While the principles of AMS guidelines likely apply to stewarding of antifungal agents, there are additional considerations unique to AFS and the complex field of fungal infections that require specific recommendations. In this article, we review the literature on AMS best practices and discuss AFS through the lens of the global core elements of AMS. We offer recommendations for best practices in AFS based on a synthesis of this evidence by an interdisciplinary expert panel of members of the Mycoses Study Group Education and Research Consortium. We also discuss research directions in this rapidly evolving field. AFS is an emerging and important component of AMS, yet requires special considerations in certain areas such as expertise, education, interventions to optimize utilization, therapeutic drug monitoring, and data analysis and reporting.
Keywords: Antifungal Agents; Antimicrobial Stewardship; Clinical Competence; Drug Monitoring; Drug Prescriptions; Drug Resistance; Fungal; Evidence-Based Medicine; Humans; Inappropriate Prescribing; Mycoses; Practice Guidelines as Topic; antifungal; aspergillosis; candidiasis; diagnostics; guidelines; stewardship

Outcomes of donor-derived superinfection screening in HIV-positive to HIV-positive kidney and liver transplantation: a multicentre, prospective, observational study - Bonny, Tania S; Kirby, Charles; Martens, Craig; Rose, Rebecca; Desai, Niraj; Seisa, Michael; Petropoulos, Christos; Florman, Sander; Friedman-Moraco, Rachel J; Turgeon, Nicole A; Brown, Diane; Segev, Dorry L; et al. (The lancet. HIV, 2020)
Background One of the primary risks of HIV-positive to HIV-positive organ transplantation is loss of virological control because of donor-derived HIV superinfection, which occurs when an HIV-positive individual becomes infected with a new distinct HIV strain. In this study, as part of the larger HIV Organ Policy Equity pilot study, HIV-positive to HIV-positive kidney and liver transplant recipients in the USA were examined for evidence of sustained donor-derived HIV superinfection. Methods In this multicentre, prospective, observational study, HIV-positive to HIV-positive kidney and liver transplant recipients were followed in three hospitals in the USA. Candidates with well controlled HIV infection on ART, no active opportunistic infections, and minimum CD4 T-cell counts (>100 cells per μL for liver and >200 cells per μL for kidney per federal guidelines) were eligible to receive a kidney or liver from deceased HIV-positive donors without active infections or neoplasm. Peripheral blood mononuclear cells were collected from donor–recipient pairs at the time of transplantation, and from recipients at several timepoints up to 3 years after transplantation. Donor samples were assessed for HIV RNA viral load, CD4 cell count, and antiretroviral drug-resistant mutations. Donor and recipient HIV proviral DNA, and viral RNA from the viraemic timepoint were sequenced using a site-directed next-generation sequencing assay for the reverse transcriptase and gp41 genes. Neighbour-joining phylogenetic trees and direct sequence comparison were used to detect the presence of HIV superinfection. This study is registered with ClinicalTrials.gov, NCT02602262. Findings 14 HIV-positive to HIV-positive kidney and eight liver transplant recipients were followed from March, 2016, to July, 2019. 17 recipients had adequate viral sequences allowing for HIV superinfection assessment. Eight donors were suppressed (viral load <400 copies per mL), and none had multiclass drug-resistant mutations detected. None of the recipients examined had evidence of HIV superinfection. One recipient had a viraemic episode (viral load of 2 080 000 copies per mL) 3 years after transplantation as a result of non-adherence to ART. Only recipient viral sequences were detected during the viraemic episode, suggesting that the donor virus, if present, was not reactivated despite temporary withdrawal of ART. Interpretation These findings suggest that loss of HIV suppression due to donor-derived HIV superinfection might not be a significant clinical concern in carefully monitored ART suppressed HIV-positive organ recipients. Funding US National Institute of Allergy and Infectious Diseases and National Cancer Institute.

How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor T cells for B-cell malignancies - Hill, Joshua A.; Seo, Susan K. (Blood, 2020)
Adoptive immunotherapy using B-cell–targeted chimeric antigen receptor (CAR)-modified T cells to treat hematologic malignancies is transforming cancer care for patients with refractory or relapsed diseases. Recent and anticipated regulatory approval for products targeting acute lymphoblastic leukemia, lymphomas, and multiple myeloma have led to global implementation of these novel treatments. The rapidity of commercial utilization of CAR–T-cell therapy has created a largely unexplored gap in patient supportive-care approaches. Such approaches are critical in these complex patients given their high net state of immunosuppression prior to CAR–T-cell infusion coupled with unique acute and persistent insults to their immune function after CAR–T-cell infusion. In this “How I Treat” article, we focus on key questions that arise during 3 phases of management for patients receiving CD19-targeted CAR-T cells: pre CAR–T-cell infusion, immediate post CAR–T-cell infusion, and long-term follow-up. A longitudinal patient case is presented for each phase to highlight fundamental issues including infectious diseases screening, antimicrobial prophylaxis, immunoglobulin supplementation, risk factors for infection, and vaccination. We hope this discussion will provide a framework for institutions and health care providers to formulate their own approach to preventing infections in light of the paucity of data specific to this treatment modality.

Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline - Daley, Charles L.; Iaccarino, Jonathan M.; Lange, Christoph; Cambau, Emmanuelle; Wallace, Richard J.; Andrejak, Claire; Böttger, Erik C.; Brozek, Jan; Griffith, David E.; Guglielmetti, Lorenzo; Huitt, Gwen A.; Knight, Shandra L.; et al. (Clinical Infectious Diseases, 2020)
Abstract. Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect bo
Publisher: Oxford Academic

Fecal microbiota transplantation for norovirus infection: a clinical and microbiological success - Barberio, Brigida; Massimi, Davide; Bonfante, Luciana; Facchin, Sonia; Calò, Lorenzo; Trevenzoli, Marco; Savarino, Edoardo Vincenzo; Cattelan, Anna Maria (Therapeutic Advances in Gastroenterology, 2020)

Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma - Wudhikarn, Kitsada; Palomba, M. Lia; Pennisi, Martina; Garcia-Recio, Marta; Flynn, Jessica R.; Devlin, Sean M.; Afuye, Aishat; Silverberg, Mari Lynne; Maloy, Molly A.; Shah, Gunjan L.; Scordo, Michael; Dahi, Parastoo B.; et al. (Blood Cancer Journal, 2020)
CD19-targeted chimeric antigen receptor (CAR) T cell therapy is an effective treatment for diffuse large B cell lymphoma (DLBCL). In addition to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), B cell aplasia and hypogammaglobulinemia are common toxicities predisposing these patients to infections. We analyzed 60 patients with DLBCL treated with FDA-approved CD19 CAR T cells and report the incidence, risk factors, and management of infections during the first year after treatment. A total of 101 infectious events were observed, including 25 mild, 51 moderate, 23 severe, 1 life-threatening, and 1 fatal infection. Bacteria were the most common causative pathogens. The cumulative incidence of overall, bacterial, severe bacterial, viral, and fungal infection at 1 year were 63.3%, 57.2%, 29.6%, 44.7%, and 4%, respectively. In multivariate analyses, the use of systemic corticosteroids for the management of CRS or ICANS was associated with an increased risk of infections and prolonged admission. Impaired performance status and history of infections within 30 days before CAR T cell therapy was a risk factor for severe bacterial infection. In conclusion, infections were common within the first 60 days after CAR T cell therapy, however, they were not associated with an increased risk of death.
Bandiera_abtest: a Cc_license_type: cc_by Cg_type: Nature Research Journals Number: 8 Primary_atype: Research Publisher: Nature Publishing Group Subject_term: B-cell lymphoma;Infectious diseases Subject_term_id: b-cell-lymphoma;infectious-diseases
Keywords: B-cell lymphoma; Infectious diseases