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CAR T-cell therapy has revolutionized the treatment of hematologic malignancies, although its use may be complicated by toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections. Invasive fungal disease (IFD) has been reported after CAR T-cell therapy, but the incidence in the absence of antifungal prophylaxis is unknown. Optimal prophylaxis strategies are widely debated. We performed a single-center retrospective study of 280 adults receiving CD19 CAR T-cell therapy for non-Hodgkin lymphoma (NHL) from December 2017 through September 2021. Patients did not receive routine antiyeast or antimold prophylaxis. IFD was identified between day of cell infusion and last follow-up. Cumulative incidence functions were calculated at 100 days and 18 months based on time to IFD, using dates of IFD-free death, initiation of salvage treatment, and hematopoietic cell transplantation as competing risks. Eight patients (2.9%) developed IFD, including 3 Pneumocystis jirovecii pneumonia, 3 invasive mold infections (IMIs), and 2 invasive yeast infections (IYIs). The 100-day cumulative incidence of IFD accounting for competing risks was 1.8% (95% confidence interval [CI], 0.8% to 4.4%). Among the 280 patients, early toxicities including CRS (85%) and ICANS (55%) and late toxicities after day 30 including grades 3 and 4 neutropenia (41%) and low CD4 T-cell count (20%) were common. IFD was rare among patients who received CD19 CAR T-cell therapy for NHL in the absence of routine antifungal prophylaxis, despite frequent toxicities. These results suggest that, in settings with low institutional rates of IFD, routine antifungal prophylaxis may not be indicated.

Background Individuals who are immunocompromised (IC) are at high risk for severe coronavirus disease 2019 (COVID-19). Methods Post hoc analyses of a double-blind trial conducted prior to Omicron (June 2020–April 2021), in hospitalized patients with COVID-19 assessed viral load, clinical outcomes, and safety of casirivimab plus imdevimab (CAS + IMD) versus placebo in IC versus overall study patients. Results Ninety-nine of 1940 (5.1%) patients were IC. IC versus overall patients were more frequently seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies (68.7% vs 41.2%) and had higher median baseline viral loads (7.21 vs 6.32 log10 copies/mL). On placebo, IC versus overall patients had slower viral load declines. CAS + IMD reduced viral load in IC and overall patients; least-squares mean difference versus placebo in time-weighted average change from baseline viral load at day 7 was −0.69 (95% confidence interval [CI], −1.25 to −.14) log10 copies/mL for IC patients and −0.31 (95% CI, −.42 to −.20) log10 copies/mL for overall patients. For IC patients, the cumulative incidence of death or mechanical ventilation at day 29 was lower with CAS + IMD (11.0%) versus placebo (17.2%), consistent with overall patients (15.7% CAS + IMD vs 18.3% placebo). IC and overall patients receiving CAS + IMD exhibited similar rates of treatment-emergent adverse events (30.4% and 26.6%, respectively), grade ≥2 hypersensitivity or infusion-related reactions (1.4% and 2.5%), and deaths (8.7% and 12.2%). Conclusions IC patients were more likely to exhibit high viral loads and be seronegative at baseline. For susceptible SARS-CoV-2 variants, CAS + IMD reduced viral load and resulted in fewer death or mechanical ventilation events in IC and overall study patients. There were no new safety findings among IC patients. Clinical Trials Registration. NCT04426695.

Background Pseudomonas aeruginosa (PA) readily acquires genomic mutations and exogenous genetic elements that confer antimicrobial resistance (AMR). With the rise in AMR, there are limited antibiotics available to treat multidrug-resistant (MDR) PA. As such, clinicians have returned to previously used antibiotics. Colistin, sidelined for neurotoxicity and nephrotoxicity, has returned to clinical practice as a viable but suboptimal option for MDR-PA treatment. The most common mechanism of resistance to colistin involves modifications of the lipid A moiety within the bacterial lipopolysaccharide (LPS). Following the identification of a MDR PA isolate, BWH047, we experimentally determined its colistin MIC to be > 1,280 µg/mL and used genomic approaches to identify novel genetic mechanisms of extreme colistin resistance. Methods We created a random, saturated transposon (Tn) insertion library in PA BWH047 using the Himar1 mariner system. After exposure of the library to 640 µg/mL colistin for 10 hours, genomic DNA was harvested, and the Tn insertion sites were sequenced. Insertion sequencing (INSeq) analysis was performed. We identified 27 genes conditionally important for BWH047 growth in the presence of colistin. We selected five initial targets arnC, dedA, wapH, speE2, and bchE and tested their impact on colistin resistance using standard microbroth dilution methods. Results Of our deletion mutants, three showed loss of resistance to colistin. ArnC was chosen as a positive control as its role in colistin resistance in PA is well described. Colistin MICs of BWH047 ΔarnC, ΔdedA, ΔwapH, ΔspeE2, and ΔbchE were determined to be 0.5, 0.5, 1, > 1,280 and > 1280 μg/mL, respectively. Conclusion Here, we used INSeq to identify novel genes involved in extreme colistin resistance. Thus far, we have identified two new candidate genes dedA and wapH, critical for colistin resistance in PA BWH047. Neither gene has been associated with colistin resistance in PA; However, dedA orthologs in Burkholderia thailandenesis and Klebsiella pneumoniae have been shown to be important for colistin resistance. The gene wapH is part of the LPS core oligosaccharide biosynthetic pathway and its discovery hints that additional alterations in the bacterial outer membrane may impact colistin resistance. Disclosures All Authors: No reported disclosures.

Background Cytomegalovirus (CMV) disease is associated with increased morbidity and mortality following solid organ and hematopoietic cell transplantation. Currently, standard of care CMV treatments often have significant myelosuppressive or renal toxicities. Given letermovir’s favorable safety profile when used prophylactically, it may be a safe and efficacious alternative agent for CMV treatment. Methods A proof-of-concept, open-label trial was conducted in patients who lacked effective therapeutic options or presented with baseline organ dysfunction. Participants were eligible for enrollment if they were ≥12 years old and had documented CMV infection refractory to treatment defined as failure to achieve >1 log reduction in CMV viral load (VL) (when VL > 500 IU/mL) or lack of clinical improvement for CMV end-organ disease after ≥14 days of standard CMV treatment. Alternatively, patients with severe myelosuppression and renal dysfunction at baseline or genotypic antiviral resistance were also eligible. Participants were excluded if their current CMV infection developed while receiving letermovir for CMV prophylaxis. Letermovir was administered daily (480 mg PO/IV) for up to 12 weeks, with optional additional 12 weeks of treatment for secondary prophylaxis if clinically indicated. Results Ten patients met eligibility criteria and were enrolled. Reasons for enrollment included ganciclovir resistance (1/10), refractory CMV infection (6/10), renal dysfunction (7/10), and myelosuppression (7/10). The median baseline CMV VL was 1272 IU/ml [interquartile range (IQR); 925, 2546]. Six patients completed the study, three died due to complications of primary disease, and one discontinued due to diarrhea. Five patients (50%) had documented CMV viremia clearance, with a median time to first unquantifiable/undetectable CMV VL of 13 days [IQR; 9,18] and a median treatment duration of 53 days [IQR; 15,84]. Infections and GI disorders were the most common adverse events (AE), none considered related to study drug. No unexpected AE were observed during letermovir treatment. Conclusion Letermovir may be a safe and tolerable alternative for patients with treatment refractory CMV infection or for patients with severe baseline myelosuppression and renal dysfunction. Disclosures Matthew Cheng, MD, AstraZeneca: Honoraria|Cidara Therapeutics: Grant/Research Support|Scynexis Inc.: Grant/Research Support Sandra Burchett, MD, MSc, merck: Grant/Research Support Sarah P. Hammond, MD, F2G: Advisor/Consultant|F2G: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|pfizer: Advisor/Consultant|Scynexis: Grant/Research Support Nicolas C. Issa, MD, AiCuris: Grant/Research Support|Merck: Grant/Research Support Francisco M. Marty, MD, SM, AlloVir: Advisor/Consultant|Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Ansun: Grant/Research Support|Avir: Advisor/Consultant|Chimerix: Grant/Research Support|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|Kyorin: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Regeneron: Advisor/Consultant|Regeneron: Grant/Research Support|ReViral: Advisor/Consultant|Scynexis: Grant/Research Support|Symbio: Advisor/Consultant|Takeda: Grant/Research Support|United Medical: Advisor/Consultant|WHISCO: Grant/Research Support.

There is limited experience with facial re-transplantation (fRT). We report on the management of facial re-transplantation in a facial vascularized composite allotransplant recipient following irreversible allograft loss 88 months after the first transplant. Chronic antibody mediated rejection and recurrent cellular rejection resulted in a deteriorated first allograft and the patient underwent retransplantation. We summarize the events between the two transplantations, focusing on the final rejection episode. We describe the surgical technique of facial re-transplantation, the immunological and psychosocial management, and the six-month post-operative outcomes. Removal of the old allograft and inset of the new transplant were done in one operation. The donor and recipient were a good immunological match. The procedure was technically complex, requiring more proximal arterial anastomoses and an interposition vein graft. During the first and second transplantation the facial nerve was coapted at the level of the branches. There was no hyperacute rejection in the immediate postoperative phase. Outcomes six months postoperatively are promising. We provide proof-of-concept that facial re-transplantation is a viable option for patients who suffer irreversible facial vascularized composite allograft loss.

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.

Monkeypox 2022 exhibits unprecedented human-to-human transmission and presents with different clinical features than those observed in prior outbreaks. Previously endemic only to West and Central Africa, the monkeypox virus spread rapidly world-wide following confirmation of a case in the United Kingdom on May 7, 2022 of an individual that had traveled to Nigeria. Detection of cases with no travel history confirms on-going community spread. Emergency Medical Services (EMS) professionals will likely encounter patients suspected or confirmed to have monkeypox, previously a rare disease and therefore unfamiliar to most clinicians. Consequently, it is critical for EMS medical directors to immediately implement policies and procedures for EMS teams – including emergency medical dispatchers – to identify potential monkeypox cases. These must include direction on actions EMS professionals should take to protect themselves and others from virus transmission. Monkeypox 2022 may manifest more subtly than it has historically. Presentations include a subclinical prodrome and less dramatic skin lesions – potentially limited to genital or anal body regions – which can be easily confused with dermatologic manifestations of common sexually transmitted infections (STIs). While most readily spread by close contact with infectious skin lesions on a patient, it is also transmissible from fomites, such as bed sheets. Additionally, droplet transmission can occur, and the virus can be spread by aerosolization under certain conditions. The long incubation period could have profound negative consequences on EMS staffing if clinicians are exposed to monkeypox. This report summarizes crucial information needed for EMS professionals to understand and manage the monkeypox 2022 outbreak. It presents an innovative Identify-Isolate-Inform (3I) Tool for use by EMS policymakers, educators, and clinicians on the frontlines who may encounter monkeypox patients. Patients are identified as potentially exposed or infected after an initial assessment of risk factors with associated signs and symptoms. Prehospital workers must immediately don personal protective equipment (PPE) and isolate infectious patients. Also, EMS professionals must report exposures to their agency infection control officer and alert health authorities for non-transported patients. Prehospital professionals play a crucial role in emerging and re-emerging infectious disease mitigation. The monkeypox 2022 3I Tool includes knowledge essential for all clinicians, plus specific information to guide critical actions in the prehospital environment.

Background There are no antiviral therapies for parainfluenza virus (PIV) infections. DAS181, a sialidase fusion protein, has demonstrated activity in in vitro and in animal models of PIV. Methods Adult immunocompromised patients diagnosed with PIV lower respiratory tract infection (LRTI) who required oxygen supplementation were randomized 2:1 to nebulized DAS181 (4.5 mg/day) or matching placebo for up to 10 days. Randomization was stratified by need for mechanical ventilation (MV) or supplemental oxygen (SO). The primary endpoint was the proportion of patients reaching clinical stability survival (CSS) defined as returning to room air (RTRA), normalization of vital signs for at least 24 hours, and survival up to day 45 from enrollment. Results A total of 111 patients were randomized to DAS181 (n = 74) or placebo (n = 37). CSS was achieved by 45.0% DAS181-treated patients in the SO stratum compared with 31.0% for placebo (P = .15), whereas patients on MV had no benefit from DAS181. The proportion of patients achieving RTRA was numerically higher for SO stratum DAS181 patients (51.7%) compared with placebo (34.5%) at day 28 (P = .17). In a post hoc analysis of solid organ transplant, hematopoietic cell transplantation within 1 year, or chemotherapy within 1 year, more SO stratum patients achieved RTRA on DAS181 (51.8%) compared with placebo (15.8%) by day 28 (P = .012). Conclusions The primary endpoint was not met, but post hoc analysis of the RTRA component suggests DAS181 may have clinical activity in improving oxygenation in select severely immunocompromised patients with PIV LRTI who are not on mechanical ventilation. Clinical Trials Registration. NCT01644877., Immunocompromised adults with severe parainfluenza received nebulized DAS181 or placebo for up to 10 days. The primary endpoint was not met, but a subgroup of severely immunocompromised patients experienced a faster return to room air by day 28 (P = .012).

Celiac disease (CD) is an immune-mediated systemic disorder caused by ingestion of the gluten found in wheat, rye, and barley. The currently estimated prevalence in children is about 1%. CD is a chronic enteropathy with gastrointestinal manifestations including diarrhea, abdominal distension and weight loss, but extra-intestinal features are increasingly being reported. Dental and oral manifestations such as dental enamel defects (ED), delay in dental eruption, and recurrent aphthous stomatitis (RAS) are well-recognized manifestations of CD. The aim of this study was to compare the frequency of oral manifestations (ED, RAS and delay in dental eruption) on deciduous and permanent teeth between children with CD and a control population. An oral examination was performed on 28 CD children and 59 control children. All children were younger than 12 years old and had deciduous or mixed dentition. CD children had significantly more ED and RAS than the control group (67.9% vs. 33.9% P=0.004 and 50.0% vs. 21.8% P=0.011, respectively). No delay in dental eruption was observed in CD children. ED were mainly grade I and II of Aine's classification (color defects and slight structural defects). ED were more often seen on CD children's deciduous teeth than on permanent teeth (57.1% and 13.6%, respectively; P0.001). The main teeth affected by ED are the second molar and canines of the deciduous teeth, and the first molar, central incisor, and lateral incisors of the permanent teeth. RAS and ED that were symmetrical in all quadrants and occurred firstly in teeth that mineralize during the first year of life both seem to be signs of CD. Thus, more information for dentists and pediatricians on these oral manifestations should help improve detection of CD.

Allogeneic hematopoietic cell transplant (allo-HCT) recipients are at increased risk for respiratory viral infections (RVIs), which invoke substantial morbidity and mortality. Limited effective antiviral options and drug resistance often hamper successful RVI treatment, creating additional burden for patients and the health care system.Using an open-source health care claims database, we examined differences in clinical outcomes, health resource utilization, and total reimbursements during the 1-year period following allo-HCT in patients with and without any RVI infection (respiratory syncytial virus, influenza, parainfluenza virus, and human metapneumovirus). RVIs were diagnosed at any time ≤1 year after allo-HCT and identified by International Classification of Disease codes. Analyses were stratified by the presence or absence of acute or chronic graft-versus-host disease (GVHD).The study included 13 363 allo-HCT patients, 1368 (10.2%) of whom had a diagnostic code for any RVI. A higher proportion of patients with any RVI had pneumonia ≤1 year after allo-HCT compared to patients without any RVI, with or without GVHD. Patients with any RVI had higher all-cause mortality risk, longer length of post-allo-HCT hospital stay, higher readmission rate, and higher number of hospital days after allo-HCT compared to patients without the infection (all p .05). Total unadjusted median reimbursements were higher for those with any RVI and each specific RVI assessed than those without the specific infection, with or without GVHD.Allo-HCT patients with RVIs had significantly worse clinical outcomes and increased health resource utilization and reimbursements during the year following allo-HCT, with or without GVHD.

Objective Individuals with systemic lupus erythematosus (SLE) are at high risk for infections and SLE- and medication-related complications. The present study was undertaken to define a set of SLE-specific adverse outcomes that could be prevented, or their complications minimized, if timely, effective ambulatory care had been received. Methods We used a modified Delphi process beginning with a literature review and key informant interviews to select initial SLE-specific potentially preventable conditions. We assembled a panel of 16 nationally recognized US-based experts from 8 subspecialties. Guided by the RAND-UCLA Appropriateness Method, we held 2 survey rounds with controlled feedback and an interactive webinar to reach consensus regarding preventability and importance on a population level for a set of SLE-specific adverse conditions. In a final round, the panelists endorsed the potentially preventable conditions. Results Thirty-five potential conditions were initially proposed; 62 conditions were ultimately considered during the Delphi process. The response rate was 100% for both survey rounds, 88% for the webinar, and 94% for final approval. The 25 SLE-specific conditions meeting consensus as potentially preventable and important on a population level fell into 4 categories: vaccine-preventable illnesses (6 conditions), medication-related complications (8 conditions), reproductive health-related complications (6 conditions), and SLE-related complications (5 conditions). Conclusion We reached consensus on a diverse set of adverse outcomes relevant to SLE patients that may be preventable if patients receive high-quality ambulatory care. This set of outcomes may be studied at the health system level to determine how to best allocate resources and improve quality to reduce avoidable outcomes and disparities among those at highest risk.

It is well known that during ovarian cancer progression, the omentum transforms from a thin lacy organ to a thick tougher tissue. However, the mechanisms regulating this transformation and the implications of the altered microenvironment on ovarian cancer progression remain unclear. To address these questions, the global and local concentrations of collagen I were determined for normal and metastatic human omentum. Collagen I was increased 5.3-fold in omenta from ovarian cancer patients and localized to areas of activated fibroblasts rather than regions with a high density of cancer cells. Transforming growth factor beta 1 (TGFβ1) was detected in ascites from ovarian cancer patients (4 ng/mL), suggesting a potential role for TGFβ1 in the observed increase in collagen. Treatment with TGFβ1 induced fibroblast activation, proliferation, and collagen deposition in mouse omental explants and an in vitro model with human omental fibroblasts. Finally, the impact of increased collagen I on ovarian cancer cells was determined by examining proliferation on collagen I gels formulated to mimic normal and cancerous omenta. While collagen density alone had no impact on proliferation, a synergistic effect was observed with collagen density and heparin-binding epidermal growth factor treatment. These results suggest that TGFβ1 induces collagen deposition from the resident fibroblasts in the omentum and that this altered microenvironment impacts cancer cell response to growth factors found in ascites. IMPACT STATEMENT: Using quantitative analysis of patient samples, in vitro models of the metastatic ovarian cancer microenvironment were designed with pathologically relevant collagen densities and growth factor concentrations. Studies in these models support a mechanism where transforming growth factor β1 in the ascites fluid induces omental fibroblast proliferation, activation, and deposition of collagen I, which then impacts tumor cell proliferation in response to additional ascites growth factors such as heparin-binding epidermal growth factor. This approach can be used to dissect mechanisms involved in microenvironmental modeling in multiple disease applications.

Letermovir, a cytomegalovirus (CMV) terminase-complex inhibitor, is indicated for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of allogeneic hematopoietic cell transplantation (HCT). In a phase III, double-blind, randomized trial, letermovir significantly reduced the risk of clinically significant CMV infection (CS-CMVi) vs placebo through Week 24 post-HCT. This analysis investigated outcomes in participants with detectable CMV DNA at randomization, who were excluded from the primary efficacy analysis. In total, 70 of 565 randomized participants had detectable CMV DNA at randomization (letermovir 48; placebo 22). Study treatment completion rates were greater in letermovir-treated participants compared with placebo (52.1% vs 9.1%). The incidence of CS-CMVi or imputed primary endpoint events through Week 24 were 64.6% and 90.9% in the letermovir and placebo groups, respectively (treatment difference -26.1%; P = .010). Kaplan-Meier event rates for CS-CMVi onset through Week 14 (end-of-treatment period) were 33.1% for letermovir and 86.6% for placebo (P < .001). Median viral loads at the CS-CMVi events was similar in both treatment arms. All-cause mortality through Week 24 posttransplant was 15.0% for letermovir and 18.2% for placebo; through Week 48, mortality rates were 26.5% and 40.9%, respectively (P = .268). Overall, clinical outcomes were similar to those reported for participants with undetectable CMV DNA at randomization.

Missing the Target A 58-year-old man presented to the emergency department with a 2-week history of pelvic pain on the left side, with subsequent development of severe pain in the abdomen, lower ba...

Invasive aspergillosis (IA) is an acute infection affecting patients who are immunocompromised, as a result of receiving chemotherapy for malignancy, or immunosuppressant agents for transplantation or autoimmune disease. Whilst criteria exist to define the probability of infection for clinical trials, there is little evidence in the literature or clinical guidelines on when to change antifungal treatment in patients who are receiving prophylaxis or treatment for IA. To try and address this significant gap, an advisory board of experts was convened to develop criteria for the management of IA for use in designing clinical trials, which could also be used in clinical practice. For primary treatment failure, a change in antifungal therapy should be made: (i) when mycological susceptibility testing identifies an organism from a confirmed site of infection, which is resistant to the antifungal given for primary therapy, or a resistance mutation is identified by molecular testing; (ii) at, or after, 8 days of primary antifungal treatment if there is increasing serum galactomannan, or galactomannan positivity in serum, or bronchoalveolar lavage fluid when the antigen was previously undetectable, or there is sudden clinical deterioration, or a new clearly distinct site of infection is detected; and (iii) at, or after, 15 days of primary antifungal treatment if the patient is clinically stable but with ≥2 serum galactomannan measurements persistently elevated compared with baseline or increasing, or if the original lesions on CT or other imaging, show progression by >25% in size in the context of no apparent change in immune status. F2G Ltd funded the advisory board, provided travel and accommodation costs, as well as providing an honorarium according to global, national and local regulations for the time spent at the workshop and for completing the pre- and post-meeting questionnaires. None of the authors was paid for writing or reviewing this paper. Sí

Clarithromycin (CYP inhibitor) can be used instead of azithromycin for nontuberculous mycobacteria therapy in patients requiring CYP substrates to mitigate rifampin’s CYP induction. We found no differences in adverse events (10/13 vs 14/17; P = .73), drug intolerability (1/5 vs 4/11; P = 1), or 90-day mortality (0/13 vs 1/17; P = 1) in patients receiving clarithromycin vs azithromycin.

Significance Hematopoietic cell transplantation is the gold standard treatment for many blood disorders, including blood cancers. Nonetheless, frequent post-transplant complications limit the long-term benefit of HCT. Here, we find that circulating cell-free DNA is a highly versatile analyte for monitoring of the most important complications of HCT: Graft-Versus-Host Disease, infection, graft failure and disease relapse. We show that these different therapeutic complications can be informed from a single cell-free DNA sequencing assay followed by disease-specific bioinformatic analyses. This test requires only low coverage DNA sequencing and is compatible with small volumes of blood. Cell-free DNA may improve the care of allogeneic HCT recipients by enabling earlier detection and better prediction of the complex array of complications that occur after HCT.

Hox genes encode transcription factors that are critical for embryonic skeletal patterning and organogenesis. The Hoxa5, Hoxb5, and Hoxc5 paralogs are expressed in the lung mesenchyme and function redundantly during embryonic lung development. Conditional loss-of-function of these genes during postnatal stages leads to severe defects in alveologenesis, specifically in the generation of the elastin network, and animals display bronchopulmonary dysplasia (BPD) or BPD-like phenotype. Here we show the surprising results that mesenchyme-specific loss of Hox5 function at adult stages leads to rapid disruption of the mature elastin matrix, alveolar enlargement, and an emphysema-like phenotype. As the elastin matrix of the lung is considered highly stable, adult disruption of the matrix was not predicted. Just 2 weeks after deletion, adult Hox5 mutant animals show significant increases in alveolar space and changes in pulmonary function, including reduced elastance and increased compliance. Examination of the extracellular matrix (ECM) of adult Tbx4rtTA; TetOCre; Hox5afafbbcc lungs demonstrates a disruption of the elastin network although the underlying fibronectin, interstitial collagen and basement membrane appear unaffected. An influx of macrophages and increased matrix metalloproteinase 12 (MMP12) are observed in the distal lung 3 days after Hox5 deletion. In culture, fibroblasts from Hox5 mutant lungs exhibit reduced adhesion. These findings establish a novel role for Hox5 transcription factors as critical regulators of lung fibroblasts at adult homeostasis.

Invasive aspergillosis (IA) remains a common cause of mortality in pediatric immunocompromised populations. Much of our knowledge of IA stems from adult literature. We conducted a retrospective evaluation of cases of proven or probable IA, defined according to the 2019 EORTC/MSG criteria, in patients with underlying immunocompromising conditions at Boston Children's Hospital from January 1, 2007 to January 1, 2019. We estimated survival curves over 12 weeks using the Kaplan-Meier method for all-cause mortality, and we used univariate Cox proportional hazards modeling to evaluate for mortality risk factors. We identified 59 cases, 29% with proven and 71% with probable IA. Pulmonary IA was the most common presentation (78%). The median age at diagnosis was 11 years (range, 0.5–28). Hematopoietic cell transplantation (HCT) was the most frequent predisposing underlying condition (41%). Among affected patients, 44.8% were neutropenic and 59.3% were lymphopenic at diagnosis. The 12-week all-cause mortality rate was 25.4%; HCT recipients comprised the majority of deaths (9/15) with a hazard ratio of 2.47 [95% CI, 0.87–6.95]. No patients with congenital immunodeficiencies (n = 8) died within 12 weeks of IA diagnosis. Other risk factors that were significantly associated with mortality included mechanical ventilation at diagnosis, intensive care unit stay, and lymphopenia; treatment with an Aspergillus-active azole was associated with decreased mortality. In conclusion, our study found that in pediatric immunocompromised hosts, IA is associated with a high 12-week all-cause mortality rate, with a particular impact on the HCT population. Lay abstract This study explores the epidemiology, outcomes and predictors of mortality of invasive aspergillosis (IA) at a high-volume pediatric center for immunocompromised hosts. Much of our understanding of pediatric IA is extrapolated from the adult literature. Our study found that IA is associated with a high 12-week all-cause mortality rate, with a particular impact on the hematopoietic cell transplantation study cohort.

Objective The ABCB1 gene encodes P-glycoprotein (P-gp), a cellular membrane pump. One functional mutation that leads to expression of a less functional form of P-gp, ABCB1-1Δ, has been described in dogs. Individuals with this mutation can have severe adverse reactions to common veterinary pharmaceuticals that are known substrates of this pump. We investigated the detection of this mutation in samples submitted to two Australian diagnostic laboratories. Methods A total of 4842 dogs across 27 breeds were tested for the ABCB1-1Δ mutation from buccal swabs or EDTA blood using standard PCR, multiplex PCR, or genotyping chip. Statistical analysis was applied to determine the proportions and odds ratios of the ABCB1-1Δ mutation in herding breeds compared with non-herding breeds. Results The ABCB1-1Δ mutation was detected in nine breeds. The most commonly affected breeds were collies, Australian shepherds, white Swiss shepherds, and Shetland sheepdogs. Of 32 dogs in 18 non-herding breeds tested, one cocker spaniel and one labradoodle were positive for the mutation, both heterozygous. Conclusion The most frequently affected breeds for ABCB1-1Δ mutation are the collie, Australian shepherd, white Swiss shepherd and Shetland sheepdog. As the mutation is associated with an increased incidence of adverse reactions to commonly used pharmaceuticals, veterinarians need to be aware of the breeds at most risk of carrying this mutation and consider testing these individuals prior to administering these medications.

In a 3-year cohort study of adult patients with proven or probable IA, fewer patients initially treated with isavuconazole experienced adverse events compared with voriconazole, but more patients required a change in therapy due to lack of clinical efficacy.

BackgroundAntimicrobial resistance (AMR) is a major challenge in the treatment of infections caused by Pseudomonas aeruginosa. Highly drug-resistant infections are disproportionally caused by a small subset of globally distributed P. aeruginosa sequence types (STs), termed “high-risk clones.” We noted that clonal complex (CC) 446 (which includes STs 298 and 446) isolates were repeatedly cultured at 1 medical center and asked whether this lineage might constitute an emerging high-risk clone.MethodsWe searched P. aeruginosa genomes from collections available from several institutions and from a public database for the presence of CC446 isolates. We determined antibacterial susceptibility using microbroth dilution and examined genome sequences to characterize the population structure of CC446 and investigate the genetic basis of AMR.ResultsCC446 was globally distributed over 5 continents. CC446 isolates demonstrated high rates of AMR, with 51.9% (28/54) being multidrug-resistant (MDR) and 53.6% of these (15/28) being extensively drug-resistant (XDR). Phylogenetic analysis revealed that most MDR/XDR isolates belonged to a subclade of ST298 (designated ST298*) of which 100% (21/21) were MDR and 61.9% (13/21) were XDR. XDR ST298* was identified repeatedly and consistently at a single academic medical center from 2001 through 2017. These isolates harbored a large plasmid that carries a novel antibiotic resistance integron.ConclusionsCC446 isolates are globally distributed with multiple occurrences of high AMR. The subclade ST298* is responsible for a prolonged epidemic (≥16 years) of XDR infections at an academic medical center. These findings indicate that CC446 is an emerging high-risk clone deserving further surveillance.

Background Liver tumours observed in rats exposed to micafungin led to a black box warning upon approval in Europe in 2008. Micafungin’s risk for liver carcinogenicity in humans has not been investigated. We sought to describe the risk of fatal hepatocellular carcinoma (HCC) among persons who received micafungin and other parenteral antifungals (PAFs) with up to 12 years of follow-up. Methods We assembled a US multicentre cohort of hospitalized patients who received micafungin or other PAFs between 2005 and 2012. We used propensity score (PS) matching on patient characteristics from electronic medical records to compare rates of HCC mortality identified through the National Death Index though to the end of December 2016. We computed HRs and 95% CIs. Results A total of 40110 patients who received a PAF were identified; 6903 micafungin recipients (87% of those identified) were successfully matched to 16317 comparator PAF users. Ten incident HCC deaths, one in the micafungin-exposed group and nine among comparator PAF users, occurred in 71285 person-years of follow-up. The HCC mortality rate was 0.05 per 1000 person-years in micafungin patients and 0.17 per 1000 person-years in comparator PAF patients. The PS-matched HR for micafungin versus comparator PAF was 0.29 (95% CI 0.04–2.24). Conclusions Both micafungin and comparator PAFs were associated with HCC mortality rates of

BK virus (BKV), a human polyomavirus that remains latent in renal epithelial cells, can be reactivated after hematopoietic stem cell transplantation (HSCT) leading to hemorrhagic cystitis. The incidence of BK viremia is higher after Umbilical cord blood transplantation (UCBT) than HSCT from adult donors. Data regarding the role of immune recovery after UCBT in BKV reactivation is lacking. We examined the correlation between the development of BK viremia and immune reconstitution in 27 adult recipients of UCBT. The incidence of BK viremia was 52% and developed most frequently within the first 8 weeks after the transplantation, but persisted in seven patients at 6 months, and three patients at 1-year post UCBT. Detection of BK viremia 1 year after transplant was negatively associated with the number of CD8+ cells (p = 0.03) and CD8+CD45RO+ cells (p = 0.05) at 6 months, and the number of CD4+ (p = 0.03) and CD4+CD45RO+ cells (p = 0.03) at 12 months after UCBT. Conversely, BK viremia at 6 and 12 months was positively correlated with the number of T regulatory (Treg) cells at 1 month (p = 0.005 and p = 0.016, respectively). Because UCB Treg have highly potent immunosuppressive function, our findings indicate that sustained BK viremia in UCBT recipients might be associated with the increase of Treg cells early after transplantation, which mediate impaired and delayed reconstitution of CD4+ and CD8+ T effector cells.

Epidermolysis bullosa (EB) is a group of rare skin diseases that can strongly affect the oral mucosa. The aim of the study was to describe the perception of oral health– related quality of life (OHRQoL) in children living with EB. A quantitative and qualitive study was conducted. First, a quantitative analysis was used to compare the Child Oral Health Impact Profile (COHIP) scores of 23 patients living with EB to normative values. Second, a qualitative approach was taken to help understand the oral health experience of 10 children (aged 5–17 y) living with EB until thematic saturation was reached. For every COHIP domain, the scores were significantly lower in patients living with EB than in healthy patients (P = 0.001). The thematic analysis provided several themes: young patients suffer from EB oral complications, with which they deal in different ways; they experience functional disorders, mainly in eating and speaking; and they also require esthetic dental care. The results of this mixed-method study show that, from the perspective of affected children, that EB affects OHRQoL. Using the children’s own words makes it possible to understand both the difficulties they face and their ability to adapt to these difficulties. Their words also show us what they want from the treatment and help us to identify means of improving practices. Knowledge Transfer Statement: The results of this study confirm the difficulties experienced by patients in the oral sphere. They also show that patients are able to adapt and that their demands go beyond functional rehabilitation. This work should encourage dental practitioners to be part of the overall management of the disease, involving regular checkups, preventive dental measures, and oral hygiene education. Therefore, more effective communication is required, not only between the dental and dermatological teams but also with the parents and caregivers.

Background Consensus definitions for the diagnosis of invasive fungal diseases (IFDs) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cutoff limits to define positivity. To date, there is a paucity of data as to the impact of the revised definitions on clinical trials. Methods In this study, we sought to determine the impact of the new definitions on classifying invasive aspergillosis (IA), the most common invasive mold disease in immunocompromised patients. We reclassified 226 proven and probable IA cases plus 139 possible IFD cases in the Aspergillus Technology Consortium (AsTeC) and in an antifungal prophylaxis trial (BMT CTN 0101) using the new criteria. Results Fewer cases met the more stringent diagnostic 2020 criteria after applying the reclassification criteria to define probable IA. Of 188 evaluable probable cases, 41 (22%) were reclassified to 40 possible IA and 1 probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% of hematopoietic cell transplant (HCT) patients, and in no lung transplant (LT) patients. Date of diagnosis was established a median (range) of 3 (1–105) days later in 15% of probable IA cases using the new criteria. Applying the new definitions to the BMT CTN 0101 trial, the power to detect the same odds ratio decreased substantially. Conclusions The updated IA consensus definitions may impact future trial designs, especially for antifungal prophylaxis studies., Using more stringent consensus diagnostic definitions for Invasive Aspergillosis, more than 20% of cases in hematopoietic cell transplant and hematologic malignancies patients that met earlier definitions no longer meet diagnostic criteria. This has important implications for antifungal prevention trials.

Coronavirus Disease 2019 (COVID-19) has posed unique challenges to nephrology. COVID-19–associated acute kidney injury occurs in as high as 36.6% of patients,S1 with the most common etiology being acute tubular injury due to hemodynamic changes and a proinflammatory milieu. In addition to acute tubular injury, patients with COVID-19 can also develop a variety of glomerular pathologies, including primary podocytopathies and immune-mediated glomerular diseases (membranous nephropathy, lupus nephritis, anti–glomerular basement membrane disease).1 Here, we report another pattern of tubular pathology related to COVID-19, osmotic injury associated with antiviral therapy.

Background Candida species are a major cause of invasive and mucocutaneouls infections. There are limited oral treatment options available for patients with Candida infections who are unresponsive to or who are intolerant of currently available antifungals. Oral ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida and Aspergillus species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of or with fungal disease refractory to standard antifungal therapy. We present an analysis of patient outcomes from the FURI study by fungal disease type. Table 1: FURI Outcomes by Fungal Disease Methods FURI patients were eligible for enrollment if they have proven or probable, severe mucocutaneous candidiasis, invasive candidiasis or invasive aspergillosis,other fungal diseases and evidence of failure to, intolerance to, or toxicity related to a currently approved standard-of-care antifungal treatment or can not receive approved oral antifungal options (e.g., susceptibility of the organism) and a continued IV antifungal therapy is clinically undesirable or unfeasible. Results An independent Data Review Committee (DRC) provided an assessment of treatment response for 74 patients enrolled in the FURI study from 22 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016- 2020. A total of 39 (52.7%) patients had invasive candidiasis, 32 (43.2%) had mucocutaneous candidiasis and 3 (4.5%) patients had invasive aspergillosis. The percent of patients who were determined to have a complete response (CR), partial response (PR), clinical improvement (CI) was 63.5%, stable disease (SD) was 23.0%, patients with progression of disease 6.8% and 4 patients were indeterminate. Additionally, there was 1 death in the FURI study that was not related to fungal disease. Table 1 shows outcomes by fungal disease type as determined by the DRC. Conclusion Analysis of 74 patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging fungal disease and limited treatment options. Disclosures Peter G. Pappas, MD, Astellas (Research Grant or Support)Cidara (Research Grant or Support)F2G (Consultant)Matinas (Consultant, Scientific Research Study Investigator)Mayne Pharma (Research Grant or Support)Scynexis (Research Grant or Support) Oliver Cornely, Prof., Actelion (Consultant, Grant/Research Support)Al-Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant)Amplyx (Consultant, Grant/Research Support)Astellas (Consultant, Grant/Research Support)Basilea (Consultant, Grant/Research Support)Biocon (Consultant)Biosys (Consultant)Cidara (Consultant, Grant/Research Support)CoRe Consulting (Consultant)Da Volterra (Consultant, Grant/Research Support)DFG (German Research Foundation) (Grant/Research Support)Entasis (Consultant)F2G (Consultant, Grant/Research Support)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Grant/Research Support)Grupo Biotoscana (Consultant)Immunic (Grant/Research Support)IQVIA (Consultant)Janssen (Grant/Research Support)Matinas (Consultant)Medicines Company (Grant/Research Support)MedPace (Consultant, Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini (Consultant)Merck/MSD (Consultant, Grant/Research Support)Molecular Partners (Consultant)MSG-ERC (Consultant)Mylan (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant)Paratek (Consultant)Pfizer (Consultant, Grant/Research Support)PSI (Consultant)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support)Seres (Consultant)Shionogi (Consultant)Wiley (Blackwell) (Other Financial or Material Support) Philipp Koehler, MD, Ambu GmbH (Consultant, Speaker's Bureau)Astellas Pharma (Speaker's Bureau)Euopean Confederation of Medical Mycology (Speaker's Bureau)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Speaker's Bureau)MSD (Speaker's Bureau)Noxxon N.V. (Consultant)Pfizer (Speaker's Bureau)State of North Rhine-Westphalia, Germany (Grant/Research Support) Todd P. McCarty, MD, Cidara (Grant/Research Support)GenMark (Grant/Research Support, Other Financial or Material Support, Honoraria for Research Presentation)T2 Biosystems (Consultant) Barbara D. Alexander, MD, MHS, SCYNEXIS, Inc. (Consultant) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Caryn Morse, MD, Chimerix (Scientific Research Study Investigator)Covis Pharma (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator)Ridgeback Biotherapeutics (Scientific Research Study Investigator)Roche (Scientific Research Study Investigator)SCYNEXIS, Inc. (Scientific Research Study Investigator)Theratechnologies (Advisor or Review Panel member)Viiv (Advisor or Review Panel member) Luis Ostrosky-Zeichner, MD, Amplyx (Consultant)Cidara (Consultant)F2G (Consultant)Gilead (Grant/Research Support, Speaker's Bureau)Pfizer (Scientific Research Study Investigator, Speaker's Bureau)Scynexis (Grant/Research Support, Scientific Research Study Investigator)Viracor (Consultant) Jürgen Prattes, Dr, AbbVie Inc. (Shareholder)Gilead (Speaker's Bureau)MSD (Grant/Research Support)Novo Nordisk (Shareholder)Pfizer (Advisor or Review Panel member)Stryker (Shareholder) Andrej Spec, MD, MSCI, Mayne Pharma (Grant/Research Support) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support) Francisco M. Marty, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Marisa Miceli, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Martin Hoenigl, MD, Astellas (Grant/Research Support)Gilead (Grant/Research Support)Pfizer (Grant/Research Support) Martin Hoenigl, MD, Astellas (Individual(s) Involved: Self): Grant/Research Support; F2G (Individual(s) Involved: Self): Grant/Research Support; Gilead (Individual(s) Involved: Self): Grant/Research Support; Pfiyer (Individual(s) Involved: Self): Grant/Research Support; Scýnexis (Individual(s) Involved: Self): Grant/Research Support Thomas F. Patterson, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)

Background Histoplasmosis is a common endemic fungal infection in the Americas, causing significant morbidity and mortality, particularly in immunocompromised patients. Existing diagnostic methods are limited in their sensitivity (especially in pulmonary histoplasmosis) and turnaround time. Methods We examined prospectively collected breath samples from 84 patients with suspected histoplasmosis 3/2019 - 2/2020 at Hospital Roosevelt (HR; Guatemala City, Guatemala, n = 56) and suspected invasive fungal disease 1/2018 - 10/2019 at Brigham and Women’s Hospital (BWH; Boston, MA, USA, n = 28) using thermal desorption gas chromatography-tandem mass spectrometry (TDU-GC-MS/MS). Patients were evaluated for histoplasmosis and other infections according to the local standard of care – of note, 18/56 patients at HR did not have Histoplasma urine antigen testing. Results Median age was 44 years, 60 (71%) were male, 23 (27%) had HIV, 15 (18%) had hematologic malignancy. 7 patients were diagnosed with histoplasmosis over the study period (4 at HR, 5 at BWH), with a clinical syndrome + positive Histoplasma urine or serum antigen test, with some patients also having yeast forms on tissue biopsy. 3 patients had disseminated and 4 pulmonary histoplasmosis. 4 patients with histoplasmosis had co-infections – 2 tuberculosis (TB), 1 influenza, and 1 Pneumocystis jirovecii (PJP) pneumonia. 4 patients were receiving antifungal therapy active against Histoplasma at the time of their first breath sample. We found 3 sesquiterpenes: (A) cyperene, (B) 1R,4aR,8aR)-2,5,5,8a-Tetramethyl-4,5,6,7,8,8a-hexahydro-1H-1,4a-methanonaphthalene, and (C) viridiflorol in patients with histoplasmosis, that distinguished these patients from those with other pneumonia (TB, coccidioidomycosis, invasive aspergillosis, mucormycosis, PJP, bacterial pneumonia) with 100% sensitivity and 70% (95% CI 59, 80) specificity. Figure 1. TDU GC-MS/MS spectral comparison in histoplasmosis vs. the other invasive mycoses aspergillosis or mucormycosis. A: Cyperene; B: (1R,4aR,8aR)-2,5,5,8a Tetramethyl-4,5,6,7,8,8a-hexahydro-1H-1,4a-methanonaphthalene; C: viridiflorol; D: 1H-Indene, 2,3,3a,4-tetrahydro-3,3a,6-trimethyl-1-(1-methylethyl)-; E: β-funebrene; F: trans-α-bergamotene; G: eremophilene; H: spathulenol; I: cedrene; J: cedranoxide, 8,14- Conclusion Conclusion: Patients with histoplasmosis have a unique secondary metabolite breath signature that can be used for the noninvasive diagnosis of pulmonary and disseminated histoplasmosis. Many patients in this cohort did not undergo urine antigen testing or other diagnostic workup for histoplasmosis, which may have affected our specificity estimates. Disclosures Francisco M. Marty, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator)

Background Candida albicans is the predominant organism causing esophageal candidiasis (EC) and oropharyngel candidiasis (OPC). These infections may arise from subjects colonized with Candida who are predisposed due to illness, debility or a local reduction in host resistance to an overgrowth of their own indigenous flora. Patients with mucocutaneous Candida infections can be treated in the outpatient setting, yet there are limited oral treatment options available for patients who are unresponsive to or who are intolerant to currently available antifungals. Oral ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of or with fungal disease refractory to standard antifungal therapy. Table 1. FURI Outcomes in OPC and EC Methods FURI subjects were eligible for enrollment if they had proven or probable severe mucocutaneous candidiasis, invasive candidiasis, invasive aspergillosis, or other fungal diseases with evidence of treatment failure, intolerance, or toxicity related to a currently approved standard-of-care antifungal treatment or if they were unable to receive an approved oral antifungal option (e.g., susceptibility of the organism) and a continued IV antifungal therapy was clinically undesirable or unfeasible. Results An independent Data Review Committee (DRC) provided an assessment of treatment response for 74 subjects enrolled in the FURI study from 22 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016- 2020. A total 32 subjects (43.2%) had mucocutaneous candidiasis and 24 subjects were diagnosed with OPC or EC. The percent of patients who were determined to have a complete response (CR) or partial response (PR) was 62.5%, stable disease (SD), 20.8%, and progression of disease, 16.7%. Table 1 shows outcomes by EC and OPC as determined by the DRC. Conclusion Analysis of 24 EC and OPC patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging mucocutaneous fungal disease and limited treatment options. Disclosures Oliver Cornely, Prof., Actelion (Consultant, Grant/Research Support)Al-Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant)Amplyx (Consultant, Grant/Research Support)Astellas (Consultant, Grant/Research Support)Basilea (Consultant, Grant/Research Support)Biocon (Consultant)Biosys (Consultant)Cidara (Consultant, Grant/Research Support)CoRe Consulting (Consultant)Da Volterra (Consultant, Grant/Research Support)DFG (German Research Foundation) (Grant/Research Support)Entasis (Consultant)F2G (Consultant, Grant/Research Support)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Grant/Research Support)Grupo Biotoscana (Consultant)Immunic (Grant/Research Support)IQVIA (Consultant)Janssen (Grant/Research Support)Matinas (Consultant)Medicines Company (Grant/Research Support)MedPace (Consultant, Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini (Consultant)Merck/MSD (Consultant, Grant/Research Support)Molecular Partners (Consultant)MSG-ERC (Consultant)Mylan (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant)Paratek (Consultant)Pfizer (Consultant, Grant/Research Support)PSI (Consultant)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support)Seres (Consultant)Shionogi (Consultant)Wiley (Blackwell) (Other Financial or Material Support) Philipp Koehler, MD, Ambu GmbH (Consultant, Speaker’s Bureau)Astellas Pharma (Speaker’s Bureau)Euopean Confederation of Medical Mycology (Speaker’s Bureau)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Speaker’s Bureau)MSD (Speaker’s Bureau)Noxxon N.V. (Consultant)Pfizer (Speaker’s Bureau)State of North Rhine-Westphalia, Germany (Grant/Research Support) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) G. Marshall Lyon, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Francisco M. Marty, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support) Peter Pappas, MD, Astellas (Grant/Research Support)Cidara (Grant/Research Support, Advisor or Review Panel member)Mayne (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support)SCYNEXIS, Inc. (Consultant, Grant/Research Support) Todd P. McCarty, MD, Cidara (Grant/Research Support)GenMark (Grant/Research Support, Other Financial or Material Support, Honoraria for Research Presentation)T2 Biosystems (Consultant) Caryn Morse, MD, Chimerix (Scientific Research Study Investigator)Covis Pharma (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator)Ridgeback Biotherapeutics (Scientific Research Study Investigator)Roche (Scientific Research Study Investigator)SCYNEXIS, Inc. (Scientific Research Study Investigator)Theratechnologies (Advisor or Review Panel member)Viiv (Advisor or Review Panel member) Luis Ostrosky-Zeichner, MD, Amplyx (Consultant)Cidara (Consultant)F2G (Consultant)Gilead (Grant/Research Support, Speaker’s Bureau)Pfizer (Scientific Research Study Investigator, Speaker’s Bureau)Scynexis (Grant/Research Support, Scientific Research Study Investigator)Viracor (Consultant) Jürgen Prattes, Dr, AbbVie Inc. (Shareholder)Gilead (Speaker’s Bureau)MSD (Grant/Research Support)Novo Nordisk (Shareholder)Pfizer (Advisor or Review Panel member)Stryker (Shareholder) Andrej Spec, MD, MSCI, SCYNEXIS, Inc. (Consultant, Scientific Research Study Investigator) David Andes, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Oliver Witzke, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)

Letermovir is approved for the prevention of cytomegalovirus (CMV) reactivation and clinical disease in patients undergoing allogeneic hematopoietic-cell transplantation (HCT). However, there is uncertainty about letermovir's ability to prevent clinical events during the period of prophylaxis as well as after the discontinuation of prophylaxis in the post-transplant setting. We performed a retrospective cohort study in CMV-seropositive allogeneic HCT recipients at high risk of CMV events, who received letermovir for primary prophylaxis from November 2017 through December 2019. We analyzed CMV outcomes for these patients during and after prophylaxis was discontinued. Patient outcomes were followed through June 2020. Sixty patients received letermovir for a median of 13 weeks (range, 1-72 weeks). Thirteen (22%) patients had quantifiable CMV DNAemia (reactivation) during letermovir prophylaxis a median of 9 days (range, 1-59 days) after starting letermovir. Five (8%) of these patients discontinued prophylaxis and received preemptive therapy (PET) with valganciclovir; eight (13%) continued letermovir as prophylaxis and CMV DNAemia resolved without PET. Thirteen patients (22%) had post-prophylaxis CMV reactivation a median of 33 days (range, 14-109 days) after letermovir discontinuation. In four (7%) of these patients, CMV DNAemia resolved without PET, and nine (15%) received PET. No patient developed CMV disease. Patients who developed CMV reactivation during prophylaxis did so shortly after initiation of letermovir, and most patients who developed CMV reactivation post-prophylaxis did so within 60 days after discontinuation of letermovir. Letermovir prophylaxis has changed the presentation of CMV infection in high-risk HCT patients.

Summary Background Coronavirus disease 2019 (COVID-19) primarily affects the lungs, but evidence of systemic disease with multi-organ involvement is emerging. Here, we developed a blood test to broadly quantify cell-, tissue-, and organ-specific injury due to COVID-19. Methods Our test leverages genome-wide methylation profiling of circulating cell-free DNA in plasma. We assessed the utility of this test to identify subjects with severe disease in two independent, longitudinal cohorts of hospitalized patients. Cell-free DNA profiling was performed on 104 plasma samples from 33 COVID-19 patients and compared to samples from patients with other viral infections and healthy controls. Findings We found evidence of injury to the lung and liver and involvement of red blood cell progenitors associated with severe COVID-19. The concentration of cell-free DNA correlated with the World Health Organization (WHO) ordinal scale for disease progression and was significantly increased in patients requiring intubation. Conclusions This study points to the utility of cell-free DNA as an analyte to monitor and study COVID-19. Funding This work was supported by NIH grants 1DP2AI138242 (to I.D.V.), R01AI146165 (to I.D.V., M.P.C., F.M.M., and J.R.), 1R01AI151059 (to I.D.V.), K08-CA230156 (to W.G.), and R33-AI129455 to C.Y.C., a Synergy award from the Rainin Foundation (to I.D.V.), a SARS-CoV-2 seed grant at Cornell (to I.D.V.), a National Sciences and Engineering Research Council of Canada fellowship PGS-D3 (to A.P.C.), and a Burroughs-Wellcome CAMS Award (to W.G.). D.C.V. is supported by a Fonds de la Recherche en Sante du Quebec Clinical Research Scholar Junior 2 award . C.Y.C. is supported by the California Initiative to Advance Precision Medicine , and the Charles and Helen Schwab Foundation .

This post hoc analysis of international phase III isavuconazole trials identified 50 patients (90% immunocompromised or diabetic) with invasive fungal sinusitis (88% mucormycetes, Aspergillus) who received isavuconazole as primary (n = 33) or salvage (n = 17) therapy for a median of 82 days (range, 2–882). Overall survival was 82% at day 42 and 70% at day 84.