Cynthia E. Fisher

The Serum Galactomannan Index Predicts Mortality in Hematopoietic Stem Cell Transplant Recipients With Invasive Aspergillosis

We examined the relationship between serum and bronchoalveolar lavage (BAL) galactomannan index (GMI) values and mortality in allogeneic hematopoietic cell transplant recipients with invasive pulmonary aspergillosis. Using a clinical sign and symptom-initiated approach, we found that the serum but not the BAL GMI level correlated with 42- and 180-day patient mortality.

Symptomatic Respiratory Virus Infection and Chronic Lung Allograft Dysfunction

Our data demonstrate that symptomatic respiratory virus infection is strongly associated with development of chronic lung allograft dysfunction. With multiple new respiratory antivirals currently in clinical trial, this association offers a potentially intervenable risk factor for a highly morbid process.

Independent contribution of bronchoalveolar lavage and serum galactomannan in the diagnosis of invasive pulmonary aspergillosis.

The optimal combination of galactomannan index (GMI) testing for the diagnosis of invasive pulmonary aspergillosis (IPA) remains unclear. For diagnostic approaches that are triggered by clinical signs and symptoms in high‐risk patients, institutional variation remains, with some centers routinely relying on only serum GMI or bronchoalveolar lavage (BAL) GMI testing. In addition, use of mold‐active agents before diagnosis of IPA is becoming increasingly common, and understanding the effect of these drugs on test yield is important when making time‐critical treatment decisions. In a single‐center cohort of 210 allogeneic hematopoietic cell transplant recipients, we found that serum and BAL GMI testing contributed independently to IPA diagnosis, supporting the practice of sending both tests simultaneously to ensure a timely diagnosis of IPA. BAL GMI sensitivity was not affected by receipt of mold‐active therapy in our cohort.

Risk Factors and Outcomes of Ganciclovir-Resistant Cytomegalovirus Infection in Solid Organ Transplant Recipients

Background Ganciclovir-resistant (ganR) cytomegalovirus (CMV) is an emerging and important problem in solid organ transplant (SOT) recipients. Only through direct comparison of ganR- and ganciclovir-sensitive (ganS) CMV infection can risk factors and outcomes attributable specifically to ganciclovir resistance appropriately be determined. Methods We performed a retrospective, case-control (1:3) study of SOT recipients with genotypically confirmed ganR-CMV (n = 37) and ganS-CMV infection (n = 109), matched by donor/recipient CMV serostatus, year and organ transplanted, and clinical manifestation. We used χ2 (categorical) and Mann-Whitney (continuous) tests to determine predisposing factors and morbidity attributable to resistance, and Kaplan-Meier plots to analyze survival differences. Results The rate of ganR-CMV was 1% (37/3467) overall and 4.1% (32/777) among CMV donor-positive, recipient-negative patients, and was stable over the study period. GanR-CMV was associated with increased prior exposure to ganciclovir (median, 153 vs 91 days, P < .001). Eighteen percent (3/17) of lung transplant recipients with ganR-CMV had received <6 weeks of prior ganciclovir (current guideline-recommended resistance testing threshold), and all non-lung recipients had received ≥90 days (median, 160 [range, 90-284 days]) prior to diagnosis of ganR-CMV. GanR-CMV was associated with higher mortality (11% vs 1%, P = .004), fewer days alive and nonhospitalized (73 vs 81, P = .039), and decreased renal function (42% vs 19%, P = .008) by 3 months after diagnosis. Conclusions GanR-CMV is associated with longer prior antiviral duration and higher attributable morbidity and mortality than ganS-CMV. Upcoming revised CMV guidelines should incorporate organ transplant-specific thresholds of prior drug exposure to guide rational ganR-CMV testing in SOT recipients. Improved strategies for prevention and treatment of ganR-CMV are warranted.

Validation of single nucleotide polymorphisms in invasive aspergillosis following hematopoietic cell transplantation

Invasive aspergillosis (IA) is a significant cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Previous studies have reported an association between IA development and single nucleotide polymorphisms (SNPs), but many SNPs have not been replicated in a separate cohort. The presence of a positive serum galactomannan assay (SGM+) has also been associated with a worse prognosis in patients with IA, and genetic determinants in this subset of patients have not been systematically studied. The study cohort included 2609 HCT recipients and their donor pairs: 483 with proven/probable IA (183 SGM+) and 2126 with no IA by standard criteria. Of 25 SNPs previously published, we analyzed 20 in 14 genes that passed quality control. Samples were genotyped via microarray, and SNPs that could not be genotyped were imputed. The primary aim was to replicate SNPs associated with proven/probable IA at 2 years; secondary goals were to explore the associations using an end point of SGM+ IA or proven/probable IA using a different genetic model or time to IA (3 months vs 2 years) compared with the original study. Two SNPs in 2 genes (PTX3, CLEC7a) were replicated. Thirteen SNPs in 9 genes had an association at P ≤ .05 using the secondary aims (PTX3, CLEC7a, CD209, CXCL10, TLR6, S100B, IFNG, PLG, TNFR1), with hazard ratios ranging from 1.2 to 3.29. Underlying genetic differences can influence development of IA following HCT. Identification of genetic predispositions to IA could have important implications in donor screening, risk stratification of recipients, monitoring, and prophylaxis.

A patient self-collection method for longitudinal monitoring of respiratory virus infection in solid organ transplant recipients

Abstract Background Methods for the longitudinal study of respiratory virus infections are cumbersome and limit our understanding of the natural history of these infections in solid organ transplant (SOT) recipients. Objectives To assess the feasibility and patient acceptability of self-collected foam nasal swabs for detection of respiratory viruses in SOT recipients and to define the virologic and clinical course. Study design We prospectively monitored the course of symptomatic respiratory virus infection in 18 SOT patients (14 lung, 3 liver, and 1 kidney) using patient self-collected swabs. Results The initial study sample was positive in 15 patients with the following respiratory viruses: rhinovirus (6), metapneumovirus (1), coronavirus (2), respiratory syncytial virus (2), parainfluenza virus (2), and influenza A virus (2). One hundred four weekly self-collected nasal swabs were obtained, with a median of 4 samples per patient (range 1–17). Median duration of viral detection was 21 days (range 4–77 days). Additional new respiratory viruses detected during follow-up of these 15 patients included rhinovirus (3), metapneumovirus (2), coronavirus (1), respiratory syncytial virus (1), parainfluenza virus (1), and adenovirus (1). Specimen collection compliance was good; 16/18 (89%) patients collected all required specimens and 79/86 (92%) follow-up specimens were obtained within the 7±3 day protocol-defined window. All participants agreed or strongly agreed that the procedure was comfortable, simple, and 13/14 (93%) were willing to participate in future studies using this procedure. Conclusion Self-collected nasal swabs provide a convenient, feasible, and patient-acceptable methodology for longitudinal monitoring of upper respiratory virus infection in SOT recipients.

A Prospective Study Comparing Self-Collected Nasal Swabs to Oral Washes for Monitoring Viral Load Kinetics in Lung Transplant Recipients With Respiratory Virus Infection

Washes for Monitoring Viral Load Kinetics in Lung Transplant Recipients With Respiratory Virus Infection Cynthia Fisher, MD, MPH; Rebecca Bornstein, BS; Jane Kuypers, PhD; Michael Boeckh, MD; Ajit Limaye, MD, FIDSA; Keith Jerome, MD, PhD; Department of Medicine, University of Washington, Seattle, Washington; Medicine, University of Washington, Seattle, Washington; Laboratory Medicine, University of Washington, Seattle, Washington; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington

Clinical characteristics and outcomes of late-onset BK virus nephropathy in kidney and kidney-pancreas transplant recipients

BK virus nephropathy (BKPyVAN) is a major complication in kidney transplant recipients (KTR) and typically occurs within 1 year of transplant. Guidelines vary in recommendations for BKPyV screening beyond 1 year. A systematic characterization of risk factors and outcomes of late‐onset (>1 year) BKPyVAN has not previously been reported.

Reply to King and Stover

To the Editor—We appreciate the response of King and Stover [1] to our recent article [2]. The authors bring up the important issue of piperacillin-tazobactam and its association with positive serum galactomannan index assays due to the presence of antigenic epitopes in many branded preparations. In our report, we did not comment on the use of branded or generic piperacillin-tazobactam in our patient cohort. At our institution, ceftazidime is administered as the first-line empiric treatment for fever and neutropenia in allogeneic hematopoietic stem cell transplant (HSCT) recipients. In contrast, branded or generic piperacillin-tazobactam formulations are not routinely used for prophylaxis or treatment purposes in allogeneic HSCT patients at our institution. In our cohort, only 2 patients (of 210) received piperacillin-tazobactam within 7 days leading up to serum and bronchoalveolar lavage galactomannan index testing. One of the patients had a negative serum galactomannan index, and the other had a positive serum galactomannan index (0.685, confirmed); the latter patient had both a chest computed tomography scan and a clinical course compatible with invasive aspergillosis. Due to the small number of patients (1%) receiving this drug in our study, piperacillin-tazobactam administration was not included in our multivariate analysis and does not impact our study conclusions. We agree with King and Stover that it is important to be cognizant of piperacillin-tazobactam use and of its potential to cause false-positive test results. Although piperacillin-tazobactam was not a factor in our study due to lack of usage of this antibiotic, we appreciate the opportunity to clarify this important issue.