A Retrospective, Observational Study of 12 Cases of Expanded-Access Customized Phage Therapy: Production, Characteristics, and Clinical Outcomes.

BACKGROUND: Antimicrobial resistance (AMR) is undermining modern medicine, a problem compounded by bacterial adaptation to antibiotic pressures. Phages are viruses that infect bacteria. Their diversity and evolvability offer the prospect of their use as a therapeutic solution. Reported are outcomes of customized phage therapy for patients with difficult-to-treat antimicrobial resistant infections. METHODS: We retrospectively assessed 12 cases of customized phage therapy from a phage production center. Phages were screened, purified, sequenced, characterized, and Food and Drug Administration-approved via the IND (investigational new drug) compassionate-care route. Outcomes were assessed as favorable or unfavorable by microbiologic and clinical standards. Infections were device-related or systemic. Other experiences such as time to treatment, antibiotic synergy, and immune responses were recorded. RESULTS: Fifty requests for phage therapy were received. Customized phages were generated for 12 patients. After treatment, 42% (5/12) of cases showed bacterial eradication and 58% (7/12) showed clinical improvement, with two-thirds of all cases (66%) showing favorable responses. No major adverse reactions were observed. Antibiotic-phage synergy in vitro was observed in most cases. Immunological neutralization of phages was reported in 5 cases. Several cases were complicated by secondary infections. Complete characterization of the phages (morphology, genomics, and activity) and their production (methods, sterility, and endotoxin tests) are reported. CONCLUSIONS: Customized phage production and therapy was safe and yielded favorable clinical or microbiological outcomes in two-thirds of cases. A center or pipeline dedicated to tailoring the phages against a patient's specific AMR bacterial infection may be a viable option where standard treatment has failed.

Successful restoration of protective immunity against measles, mumps, and rubella following MMR vaccination in adult hematopoietic cell transplant recipients.

BACKGROUND: The optimal number of doses as well as the role for measurement of postvaccination titers after measles, mumps, rubella (MMR) vaccination in adult hematopoietic cell transplantation (HCT) recipients remains unknown. METHODS: In the present study, we assessed humoral immunity against measles, mumps and rubella before and after MMR vaccination in 187 adults who received at least one dose of the MMR vaccine after HCT. RESULTS: Among those with baseline titers, posttransplant prevaccination seroprotection rates were 56%, 30%, and 54% for measles, mumps, and rubella, respectively; and significantly lower in allogeneic versus autologous HCT recipients for measles (39% vs. 80%, p = .0001), mumps (22% vs. 41%; p = .02) and rubella (48% vs. 62%, p = .12). Among those who were seronegative at baseline, seroconversion rates after one dose of MMR were 69%, 56%, and 97% for measles, mumps, and rubella, respectively. Seronegative patients after one dose of MMR (i.e., nonresponders) seroconverted for measles and mumps after a second MMR vaccine dose. CONCLUSION: Our findings demonstrate successful restoration of protective immunity against measles, mumps, and rubella after vaccination in adult HCT recipients; one dose of MMR elicited protective titers in the majority of patients, and a second vaccine dose was immunogenic in nonresponders.

Early administration of SARS-CoV-2 monoclonal antibody reduces the risk of mortality in hematologic malignancy and hematopoietic cell transplant patients with COVID-19.

BACKGROUND: Data on severe acute respiratory distress syndrome coronavirus 2 monoclonal antibody (SARS-CoV-2-specific mAb) use in hematologic malignancy and hematopoietic cell transplantation (HM/HCT) patients are limited. Here, we describe our experience with the use of casirivimab-imdevimab or bamlanivimab for the treatment of coronavirus disease 2019 (COVID-19) in HM/HCT patients. METHODS: This was a retrospective chart review at the University of Miami Hospital and Sylvester Comprehensive Cancer Center for HM/HCT patients with COVID-19 who received casirivimab-imdevimab or bamlanivimab from November 21, 2020, to September 30, 2021. Outcomes measured were mortality, hospital admission, and infusion reaction to SARS-CoV-2-specific mAbs. RESULTS: We identified 59 HM/HCT patients with mild to moderate COVID-19 who received casirivimab-imdevimab or bamlanivimab. Median age was 57 years (interquartile range [IQR]: 45-65). Among the 59 patients, 25 (42%) received cellular therapy: 14 (24%) had undergone allogeneic HCT, nine (15%) autologous HCT, and two (3%) received chimeric antigen receptor T-cell therapy. The median time from COVID-19 symptom onset to SARS-CoV-2-specific mAb administration was 4 (IQR: 3-6) days. Forty-six (78%) patients received SARS-CoV-2-specific mAbs as outpatients and 13 (22%) patients received SARS-CoV-2-specific mAbs during hospitalization. Among patients who received SARS-CoV-2-specific mAbs as outpatients, only four (9%) visited the emergency department at days 10, 11, 15, and 35 after SARS-CoV-2-specific mAb administration. None of these four patients required hospital admission. Among the hospitalized patients, five (38%) were admitted to the hospital with neutropenic fever, four (31%) were already hospitalized for transplantation and cellular therapy, three (23%) were admitted for monitoring of COVID-19 symptoms, and one (8%) was admitted with acute kidney injury. Three hospitalized patients (23%) died at 14, 35, and 59 days after SARS-CoV-2-specific mAb administration; two of these three deaths were attributed to COVID-19 infection. One patient developed an immediate infusion reaction to bamlanivimab, and no infusion reactions were reported to casirivimab-imdevimab use. CONCLUSION: During the alpha and delta variant surges, early administration of bamlanivimab or casirivimab-imdevimab prevented hospitalization and death when given in the outpatient setting. Among patients who received mAbs at or after hospital admission, the risk of COVID-19 disease progression and death remains significant. Larger studies of the use of mAb therapy to treat COVID-19 in this population are needed.

Breakthrough invasive fungal infections on isavuconazole prophylaxis in hematologic malignancy & hematopoietic stem cell transplant patients.

BACKGROUND: Isavuconazole (ISA) is a newer antifungal used in patients with history of hematologic malignancies and hematopoietic transplant and cellular therapies (HM/TCT). Although it has a more favorable side-effect profile, breakthrough invasive fungal infections (bIFIs) while on ISA have been reported. METHODS: In this single-center retrospective study evaluating HM/TCT patients who received prophylactic ISA for ≥7 days, we evaluated the incidence and potential risk factors for bIFIs. RESULTS: We evaluated 106 patients who received prophylactic ISA. The patients were predominantly male (60.4%) with median age of 65 (range: 21-91) years. Acute myeloid leukemia (48/106, 45.3%) was the most common HM, with majority having relapsed and/or refractory disease (43/106, 40.6%) or receiving ongoing therapy (38/106, 35.8%). Nineteen patients (17.9%) developed bIFIs-nine proven [Fusarium (3), Candida (2), Mucorales plus Aspergillus (2), Mucorales (1), Colletotrichum (1)], four probable invasive pulmonary Aspergillus, and six possible infections. Twelve patients were neutropenic for a median of 28 (8-253) days prior to bIFI diagnosis. ISA levels checked within 7 days of bIFI diagnosis (median: 3.65 µg/mL) were comparable to industry-sponsored clinical trials. All-cause mortality among the bIFI cases was 47.4% (9/19).We also noted clinically significant cytomegalovirus co-infection in 5.3% (1/19). On univariate analysis, there were no significant differences in baseline comorbidities and potential risk factors between the two groups. CONCLUSION: ISA prophylaxis was associated with a significant cumulative incidence of bIFIs. Despite the appealing side-effect and drug-interaction profile of ISA, clinicians must be vigilant about the potential risk for bIFIs.

Informative missingness: What can we learn from patterns in missing laboratory data in the electronic health record?

BACKGROUND: In electronic health records, patterns of missing laboratory test results could capture patients' course of disease as well as ​​reflect clinician's concerns or worries for possible conditions. These patterns are often understudied and overlooked. This study aims to identify informative patterns of missingness among laboratory data collected across 15 healthcare system sites in three countries for COVID-19 inpatients. METHODS: We collected and analyzed demographic, diagnosis, and laboratory data for 69,939 patients with positive COVID-19 PCR tests across three countries from 1 January 2020 through 30 September 2021. We analyzed missing laboratory measurements across sites, missingness stratification by demographic variables, temporal trends of missingness, correlations between labs based on missingness indicators over time, and clustering of groups of labs based on their missingness/ordering pattern. RESULTS: With these analyses, we identified mapping issues faced in seven out of 15 sites. We also identified nuances in data collection and variable definition for the various sites. Temporal trend analyses may support the use of laboratory test result missingness patterns in identifying severe COVID-19 patients. Lastly, using missingness patterns, we determined relationships between various labs that reflect clinical behaviors. CONCLUSION: In this work, we use computational approaches to relate missingness patterns to hospital treatment capacity and highlight the heterogeneity of looking at COVID-19 over time and at multiple sites, where there might be different phases, policies, etc. Changes in missingness could suggest a change in a patient's condition, and patterns of missingness among laboratory measurements could potentially identify clinical outcomes. This allows sites to consider missing data as informative to analyses and help researchers identify which sites are better poised to study particular questions.

National Landscape of Human Immunodeficiency Virus-Positive Deceased Organ Donors in the United States.

BACKGROUND: Organ transplantation from donors with human immunodeficiency virus (HIV) to recipients with HIV (HIV D+/R+) presents risks of donor-derived infections. Understanding clinical, immunologic, and virologic characteristics of HIV-positive donors is critical for safety. METHODS: We performed a prospective study of donors with HIV-positive and HIV false-positive (FP) test results within the HIV Organ Policy Equity (HOPE) Act in Action studies of HIV D+/R+ transplantation (ClinicalTrials.gov NCT02602262, NCT03500315, and NCT03734393). We compared clinical characteristics in HIV-positive versus FP donors. We measured CD4 T cells, HIV viral load (VL), drug resistance mutations (DRMs), coreceptor tropism, and serum antiretroviral therapy (ART) detection, using mass spectrometry in HIV-positive donors. RESULTS: Between March 2016 and March 2020, 92 donors (58 HIV positive, 34 FP), representing 98.9% of all US HOPE donors during this period, donated 177 organs (131 kidneys and 46 livers). Each year the number of donors increased. The prevalence of hepatitis B (16% vs 0%), syphilis (16% vs 0%), and cytomegalovirus (CMV; 91% vs 58%) was higher in HIV-positive versus FP donors; the prevalences of hepatitis C viremia were similar (2% vs 6%). Most HIV-positive donors (71%) had a known HIV diagnosis, of whom 90% were prescribed ART and 68% had a VL <400 copies/mL. The median CD4 T-cell count (interquartile range) was 194/µL (77-331/µL), and the median CD4 T-cell percentage was 27.0% (16.8%-36.1%). Major HIV DRMs were detected in 42%, including nonnucleoside reverse-transcriptase inhibitors (33%), integrase strand transfer inhibitors (4%), and multiclass (13%). Serum ART was detected in 46% and matched ART by history. CONCLUSION: The use of HIV-positive donor organs is increasing. HIV DRMs are common, yet resistance that would compromise integrase strand transfer inhibitor-based regimens is rare, which is reassuring regarding safety.

Successful Treatment of Disseminated Disease Due to Highly Resistant Aspergillus calidoustus with a Novel Antifungal Therapy.

Invasive aspergillosis is the most common invasive mold infection following a hematopoietic cell transplant. Widespread use of antifungal prophylaxis has led to the increasing incidence of cryptic Aspergillus species. Aspergillus calidoustus is one of those emerging species and is notorious for multidrug resistance to antifungals. Here, we report a case of disseminated A. calidoustus infection in a hematopoietic stem cell transplant recipient who was successfully treated with combination therapy that included a novel antifungal.

SurvMaximin: Robust federated approach to transporting survival risk prediction models.

OBJECTIVE: For multi-center heterogeneous Real-World Data (RWD) with time-to-event outcomes and high-dimensional features, we propose the SurvMaximin algorithm to estimate Cox model feature coefficients for a target population by borrowing summary information from a set of health care centers without sharing patient-level information. MATERIALS AND METHODS: For each of the centers from which we want to borrow information to improve the prediction performance for the target population, a penalized Cox model is fitted to estimate feature coefficients for the center. Using estimated feature coefficients and the covariance matrix of the target population, we then obtain a SurvMaximin estimated set of feature coefficients for the target population. The target population can be an entire cohort comprised of all centers, corresponding to federated learning, or a single center, corresponding to transfer learning. RESULTS: Simulation studies and a real-world international electronic health records application study, with 15 participating health care centers across three countries (France, Germany, and the U.S.), show that the proposed SurvMaximin algorithm achieves comparable or higher accuracy compared with the estimator using only the information of the target site and other existing methods. The SurvMaximin estimator is robust to variations in sample sizes and estimated feature coefficients between centers, which amounts to significantly improved estimates for target sites with fewer observations. CONCLUSIONS: The SurvMaximin method is well suited for both federated and transfer learning in the high-dimensional survival analysis setting. SurvMaximin only requires a one-time summary information exchange from participating centers. Estimated regression vectors can be very heterogeneous. SurvMaximin provides robust Cox feature coefficient estimates without outcome information in the target population and is privacy-preserving.

Distinguishing Admissions Specifically for COVID-19 From Incidental SARS-CoV-2 Admissions: National Retrospective Electronic Health Record Study.

BACKGROUND: Admissions are generally classified as COVID-19 hospitalizations if the patient has a positive SARS-CoV-2 polymerase chain reaction (PCR) test. However, because 35% of SARS-CoV-2 infections are asymptomatic, patients admitted for unrelated indications with an incidentally positive test could be misclassified as a COVID-19 hospitalization. Electronic health record (EHR)-based studies have been unable to distinguish between a hospitalization specifically for COVID-19 versus an incidental SARS-CoV-2 hospitalization. Although the need to improve classification of COVID-19 versus incidental SARS-CoV-2 is well understood, the magnitude of the problems has only been characterized in small, single-center studies. Furthermore, there have been no peer-reviewed studies evaluating methods for improving classification. OBJECTIVE: The aims of this study are to, first, quantify the frequency of incidental hospitalizations over the first 15 months of the pandemic in multiple hospital systems in the United States and, second, to apply electronic phenotyping techniques to automatically improve COVID-19 hospitalization classification. METHODS: From a retrospective EHR-based cohort in 4 US health care systems in Massachusetts, Pennsylvania, and Illinois, a random sample of 1123 SARS-CoV-2 PCR-positive patients hospitalized from March 2020 to August 2021 was manually chart-reviewed and classified as "admitted with COVID-19" (incidental) versus specifically admitted for COVID-19 ("for COVID-19"). EHR-based phenotyping was used to find feature sets to filter out incidental admissions. RESULTS: EHR-based phenotyped feature sets filtered out incidental admissions, which occurred in an average of 26% of hospitalizations (although this varied widely over time, from 0% to 75%). The top site-specific feature sets had 79%-99% specificity with 62%-75% sensitivity, while the best-performing across-site feature sets had 71%-94% specificity with 69%-81% sensitivity. CONCLUSIONS: A large proportion of SARS-CoV-2 PCR-positive admissions were incidental. Straightforward EHR-based phenotypes differentiated admissions, which is important to assure accurate public health reporting and research.

SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories can discover the viral composition and study health outcomes. The small ∼30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread while enabling a robust understanding of all of the proteins the viral genome encodes. We have employed protein modeling, molecular dynamics simulations, evolutionary mapping, and 3D printing to gain a full proteome- and dynamicome-level understanding of SARS-CoV-2. We established the Viral Integrated Structural Evolution Dynamic Database (VIStEDD at RRID:SCR_018793) to facilitate future discoveries and educational use. Here, we highlight the use of VIStEDD for nsp6, nucleocapsid (N), and spike (S) surface glycoprotein. For both nsp6 and N, we found highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we developed a quantitative dynamics cross-correlation matrix to gain insights into its interactions with the angiotensin I-converting enzyme 2 (ACE2)-solute carrier family 6 member 19 (SLC6A19) dimer. Using this quantitative matrix, we elucidated 47 potential functional missense variants from genomic databases within ACE2/SLC6A19/transmembrane serine protease 2 (TMPRSS2), warranting genomic enrichment analyses in SARS-CoV-2 patients. These variants had ultralow frequency but existed in males hemizygous for ACE2. Two ACE2 noncoding variants (rs4646118 and rs143185769) present in ∼9% of individuals of African descent may regulate ACE2 expression and may be associated with increased susceptibility of African Americans to SARS-CoV-2. We propose that this SARS-CoV-2 database may aid research into the ongoing pandemic.

Genomic, transcriptomic, and protein landscape profile of CFTR and cystic fibrosis.

Cystic Fibrosis (CF) is caused most often by removal of amino acid 508 (Phe508del, deltaF508) within CFTR, yet dozens of additional CFTR variants are known to give rise to CF and many variants in the genome are known to contribute to CF pathology. To address CFTR coding variants, we developed a sequence-to-structure-to-dynamic matrix for all amino acids of CFTR using 233 vertebrate species, CFTR structure within a lipid membrane, and 20 ns of molecular dynamic simulation to assess known variants from the CFTR1, CFTR2, ClinVar, TOPmed, gnomAD, and COSMIC databases. Surprisingly, we identify 18 variants of uncertain significance within CFTR from diverse populations that are heritable and a likely cause of CF that have been understudied due to nonexistence in Caucasian populations. In addition, 15 sites within the genome are known to modulate CF pathology, where we have identified one genome region (chr11:34754985-34836401) that contributes to CF through modulation of expression of a noncoding RNA in epithelial cells. These 15 sites are just the beginning of understanding comodifiers of CF, where utilization of eQTLs suggests many additional genomics of CFTR expressing cells that can be influenced by genomic background of CFTR variants. This work highlights that many additional insights of CF genetics are needed, particularly as pharmaceutical interventions increase in the coming years.

Viral kinetics and outcomes of adenovirus viremia following allogeneic hematopoietic cell transplantation.

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

International Changes in COVID-19 Clinical Trajectories Across 315 Hospitals and 6 Countries: Retrospective Cohort Study.

BACKGROUND: Many countries have experienced 2 predominant waves of COVID-19-related hospitalizations. Comparing the clinical trajectories of patients hospitalized in separate waves of the pandemic enables further understanding of the evolving epidemiology, pathophysiology, and health care dynamics of the COVID-19 pandemic. OBJECTIVE: In this retrospective cohort study, we analyzed electronic health record (EHR) data from patients with SARS-CoV-2 infections hospitalized in participating health care systems representing 315 hospitals across 6 countries. We compared hospitalization rates, severe COVID-19 risk, and mean laboratory values between patients hospitalized during the first and second waves of the pandemic. METHODS: Using a federated approach, each participating health care system extracted patient-level clinical data on their first and second wave cohorts and submitted aggregated data to the central site. Data quality control steps were adopted at the central site to correct for implausible values and harmonize units. Statistical analyses were performed by computing individual health care system effect sizes and synthesizing these using random effect meta-analyses to account for heterogeneity. We focused the laboratory analysis on C-reactive protein (CRP), ferritin, fibrinogen, procalcitonin, D-dimer, and creatinine based on their reported associations with severe COVID-19. RESULTS: Data were available for 79,613 patients, of which 32,467 were hospitalized in the first wave and 47,146 in the second wave. The prevalence of male patients and patients aged 50 to 69 years decreased significantly between the first and second waves. Patients hospitalized in the second wave had a 9.9% reduction in the risk of severe COVID-19 compared to patients hospitalized in the first wave (95% CI 8.5%-11.3%). Demographic subgroup analyses indicated that patients aged 26 to 49 years and 50 to 69 years; male and female patients; and black patients had significantly lower risk for severe disease in the second wave than in the first wave. At admission, the mean values of CRP were significantly lower in the second wave than in the first wave. On the seventh hospital day, the mean values of CRP, ferritin, fibrinogen, and procalcitonin were significantly lower in the second wave than in the first wave. In general, countries exhibited variable changes in laboratory testing rates from the first to the second wave. At admission, there was a significantly higher testing rate for D-dimer in France, Germany, and Spain. CONCLUSIONS: Patients hospitalized in the second wave were at significantly lower risk for severe COVID-19. This corresponded to mean laboratory values in the second wave that were more likely to be in typical physiological ranges on the seventh hospital day compared to the first wave. Our federated approach demonstrated the feasibility and power of harmonizing heterogeneous EHR data from multiple international health care systems to rapidly conduct large-scale studies to characterize how COVID-19 clinical trajectories evolve.

Authorship Correction: International Changes in COVID-19 Clinical Trajectories Across 315 Hospitals and 6 Countries: Retrospective Cohort Study.

[This corrects the article DOI: 10.2196/31400.].

Prevalence of colorectal cancer and advanced adenoma in patients with acute diverticulitis: implications for follow-up colonoscopy.

BACKGROUND AND AIMS: Guidelines recommend colonoscopy after an episode of diverticulitis to exclude neoplasia but the effectiveness of testing is uncertain. Patients with complicated diverticulitis may be at higher risk for neoplasia, but most patients have uncomplicated disease. We examined the incidence of colorectal cancer (CRC) and advanced adenoma (AA) in patients with diverticulitis compared with patients undergoing screening colonoscopy. METHODS: CT scans from January 1, 2008, to May 1, 2013, at the University of Pittsburgh Medical Center (UPMC) were reviewed to identify those with confirmed acute diverticulitis. Subsequent surgical, colonoscopy, and pathology reports were abstracted to identify those with a diagnosis of AA and CRC. The incidence of neoplasia was compared with that reported for screening colonoscopy from a meta-analysis (n = 68,324), and from colonoscopy examinations at UPMC between 2013 and 2015 (n = 28,573). RESULTS: A total of 5167 abdominal/pelvic CT scan reports identified 978 patients with acute diverticulitis, among which 474 (48.5%) patients had undergone at least 1 colonoscopy or gastrointestinal surgery to April 2015. The CRC rate in patients with diverticulitis (13/474, 2.7%) was significantly higher (P < .0001) compared with both the meta-analysis (0.8%) and UPMC (0.3%). The AA rate (19/474, 4.0%) was similar to the rate in the meta-analysis (5.0%, P = .39) but significantly lower than at UPMC (7.7%, P = .003). The incidence of AA or CRC in complicated diverticulitis (10/141, 7.1%) did not differ significantly (P = .85) from the incidence of AA or CRC in uncomplicated diverticulitis (22/332, 6.6%). CONCLUSIONS: CRC after diverticulitis was significantly higher than that observed at screening colonoscopy and was not limited to complicated disease. Colonoscopy is advisable after the diagnosis of diverticulitis.

Clinical "real-world" experience with letermovir for prevention of cytomegalovirus infection in allogeneic hematopoietic cell transplant recipients.

BACKGROUND: Letermovir was approved in 2017 for prevention of cytomegalovirus (CMV) infection in seropositive (R+) allogeneic hematopoietic cell transplantation (HCT) patients. Post-marketing data with this new agent are scarce. METHODS: We compared the incidence of both CMV reactivation (any viremia) and clinically significant CMV infection (CS-CMVi; CMV DNAemia leading to preemptive treatment or presence of CMV tissue invasive disease) at days +100 and +200 post-HCT in 25 adult allogeneic HCT patients who received letermovir prophylaxis (until day 100) and a historical control group of 106 CMV R+ allogeneic HCT recipients who underwent CMV preemptive therapy. RESULTS: CMV reactivation within 100 days post-HCT was lower in the letermovir group vs control group (20% vs 72% respectively, P < .001). The 100-day cumulative incidence of CS-CMVi was significantly lower in the letermovir group vs control group (4% vs 59% respectively, P < .001). Significantly reduced incidence of CMV reactivation and CS-CMVi was also observed at 200 days in the letermovir group. No difference in mortality was observed between the two groups. CONCLUSION: This study confirms the efficacy of letermovir in preventing CMV reactivation in CMV R+ allogeneic HCT recipients in first 100 days post-HCT and suggests sustained efficacy after discontinuation of prophylaxis.

Treatment of latent tuberculosis infection with short-course regimens in potential living kidney donors.

BACKGROUND: Treatment data for latent tuberculosis infection (LTBI) among potential living kidney donors are scarce. METHODS: This retrospective study was performed to evaluate the prevalence of positive QuantiFERON-TB Gold In-Tube (QFT-GIT) among potential living kidney donors that were screened from 2009 to 2017. We investigated if there was any difference in the time to donation between QFT-GIT-positive and QFT-GIT-negative donors. We assessed the regimens used to treat LTBI and whether the recipients of QFT-GIT-positive donors developed active tuberculosis (TB). RESULTS: Forty out of 427 (9%) potential living kidney donors had a positive QFT-GIT. QFT-GIT-positive donors were as likely as negative donors to undergo donation (30 [75%] vs 315 [81%], P = .33). The time from QFT-GIT testing to donation was longer among QFT-GIT-positive donors (median 221 days [range: 4-1139] vs 86 days [range: 3-1887], P = .001). Twelve-week rifapentine (RPT)/Isoniazid (INH) was the most common treatment used and was not associated with significant adverse reactions. There was a trend toward longer time to donation among QFT-GIT-positive donors who were treated for LTBI compared with QFT-GIT-positive donors who were not (252 days [range: 88-1139] vs 95 days [range: 4-802], P = .05). Twenty-nine recipients of QFT-GIT-positive living kidney donors were evaluated. Eleven of these recipients received kidneys from donors that were not treated for LTBI. Two of these recipients were treated with INH post-transplantation. CONCLUSIONS: The time from QFT-GIT testing to donation was longer among QFT-GIT-positive donors. The short-course regimens appear to be excellent options for LTBI treatment among living kidney donors and avoid delaying organ donation further.

Kidney transplantation during coronavirus 2019 pandemic at a large hospital in Miami.

BACKGROUND: Coronavirus 2019 (COVID-19) pandemic has resulted in more than 350 000 deaths worldwide. The number of kidney transplants has declined during the pandemic. We describe our deceased donor kidney transplantation (DDKT) experience during the pandemic. METHODS: A retrospective study was conducted to evaluate the safety of DDKT during the COVID-19 pandemic. Multiple preventive measures were implemented. Adult patients that underwent DDKT from 3/1/20 to 4/30/20 were included. COVID-19 clinical manifestations from donors and recipients, and post-transplant outcomes (COVID-19 infections, readmissions, allograft rejection, and mortality) were obtained. The kidney transplant (KT) recipients were followed until 5/31/20. RESULTS: Seventy-six patients received kidneys from 57 donors. Fever, dyspnea, and cough were reported in 1, 2, and 1 donor, respectively. Thirty-eight (66.6%) donors were tested for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) prior to donation (mainly by nasopharyngeal or bronchoalveolar lavage polymerase chain reaction [PCR]) and 36 (47.3%) KT recipients were tested at the time of DDKT by nasopharyngeal PCR; all of these were negative. Our recipients were followed for a median of 63 (range: 33-91) days. A total of 42 (55.3%) recipients were tested post-transplant for SARS-CoV2 by nasopharyngeal PCR including 12 patients that became symptomatic; all tests were negative except for one that was inconclusive, but it was repeated and came back negative. Forty (52.6%) KT recipients were readmitted, and 7 (9.2%) had biopsy-proven rejection during the follow-up. None of the KT recipients transplanted during this period died. CONCLUSIONS: Our cohort demonstrated that DDKT can be safely performed during the COVID-19 pandemic when preventive measures are implemented.

Antimicrobial resistance and recurrent bacterial urinary tract infections in hospitalized patients following kidney transplantation: A single-center experience.

PURPOSE: The burden of urinary tract infections (UTIs) and risk factors for developing infections with multidrug resistant organisms (MDROs) post-kidney transplantation (KT) are poorly understood. METHODS: Single-center retrospective cohort study (January 2015-December 2017) evaluating first and recurrent episodes of bacteriuria and subsequent analysis of episodes caused by MDROs up to 6 months post-KT. Donor and recipient variables were reviewed. RESULTS: A total of 743 adults underwent single KT during the study period, and 106 patients were hospitalized with bacteriuria. 45% were asymptomatic in their first episode. 73.6% had a single episode, and 26.4% had 2 or more episodes. A total of 28 patients had recurrent episodes; 64.3% had an MDRO on the first episode and 78.6% on the second episode. Escherichia coli was the most common organism isolated, 88.5% were resistant to trimethoprim-sulfamethoxazole (TMP-SMX), 9.3% were extended-spectrum beta-lactamase (ESBL) producers, and 38.1% were MDROs. Body mass index ≥30 was significantly associated with the presence of MDROs in both univariate and multivariate analyses (RR 1.37, 95% CI 1.01-1.88; OR 3.26, CI 1.29-8.25). A total of 12 donors had bacteremia or bacteriuria and 6 (50%) with E coli. A total of 10 KT recipients received antibiotic prophylaxis to prevent donor-derived infections. CONCLUSIONS: Our results suggest that a significant proportion of patients develop recurrent bacteriuria post-transplantation; of those, more than half caused by MDROs. There is a possible association between obesity and MDROs in KT recipients that merits further investigation. With the global crisis in antimicrobial resistance, innovative strategies are needed to prevent and treat UTIs in KT patients.

Successful Treatment of Invasive Fungal Infection Due to Highly Resistant Aspergillus calidoustus in an Allogeneic Hematopoietic Cell Transplant Recipient.

Invasive aspergillosis (IA) is the most common invasive fungal infection following a hematopoietic cell transplant, with emerging cryptic species exhibiting resistance to commonly used antifungals such as azoles. These species have been increasingly found after the introduction of anti-mold prophylaxis. We report a case of a 56-year-old female with primary myelofibrosis whose allogeneic hematopoietic cell transplant was complicated by disseminated fungal infection (skin, lung) due to Aspergillus calidoustus, a cryptic specie. Treatment of Aspergillus species remains challenging as these cryptic species are usually resistant to azoles including voriconazole which is the first line of treatment of IA. Infection was successfully treated with surgical excision and combination antifungal therapy based on in vitro susceptibility and synergy testing. Therapy included isavuconazole, a drug that has been shown to be non-inferior to voriconazole in the treatment of invasive mold infections.