Adjunctive glucocorticoid therapy for Pneumocystis jirovecii pneumonia in solid organ transplant recipients: A multicenter cohort, 2015-2020.

Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jirovecii pneumonia (PJP). This multicenter cohort of SOTRs with PJP admitted to 20 transplant centers in Canada, the United States, Europe, and Australia, was examined for whether AGT was associated with a lower rate of all-cause intensive care unit (ICU) admission, 90-day death, or a composite outcome (ICU admission or death). Of 172 SOTRs with PJP (median [IQR] age: 60 (51.5-67.0) years; 58 female [33.7%]), the ICU admission and death rates were 43.4%, and 20.8%, respectively. AGT was not associated with a reduced risk of ICU admission (adjusted odds ratio [aOR] [95% CI]: 0.49 [0.21-1.12]), death (aOR [95% CI]: 0.80 [0.30-2.17]), or the composite outcome (aOR [95% CI]: 0.97 [0.71-1.31]) in the propensity score-adjusted analysis. AGT was not significantly associated with at least 1 unit of the respiratory portion of the Sequential Organ Failure Assessment score improvement by day 5 (12/37 [32.4%] vs 39/111 [35.1%]; P = .78). We did not observe significant associations between AGT and ICU admission or death in SOTRs with PJP. Our findings should prompt a reevaluation of routine AGT administration in posttransplant PJP treatment and highlight the need for interventional studies.

Noroviral diarrhea in solid organ transplant recipients: An analysis of interventions and outcomes.

INTRODUCTION: Noroviral infection can lead to chronic diarrhea in solid organ transplant (SOT) recipients with significant morbidity and mortality. Existing literature has described a wide spectrum of illness and has not come to a consensus on the optimal management of this condition. METHODS: We undertook a retrospective review of all adult SOT recipients between 1/1/2018 and 12/31/2020 who were diagnosed with their first episode of noroviral diarrhea (NVD). Demographic, clinical interventions, and outcomes within 6 months of diagnosis were recorded. Patients' outcomes were classified as either resolved, improved or persistent at 6 months. RESULTS: Seventy-nine SOT recipients were included. Thirty-eight patients (48%) had chronic diarrhea at baseline (CDB). Thirty-two patients (40%) received nitazoxanide, 28 patients (35%) had their immunosuppression adjusted and seven patients (9%) received intravenous immunoglobulin. Diarrhea improved or resolved in 68 patients (85%). Improvement or resolution of diarrhea was observed in 98% of those who did not have history of chronic diarrhea versus 74% in those who did (p = .002). NVD improved in all 12 patients who had mycophenolate discontinued, although this was not statistically significant (p = .131). CONCLUSION: CDB was associated with worse outcomes regardless of intervention. A low threshold to test for NVD in SOT recipients with chronic diarrhea is prudent to prevent delayed diagnosis.

Recipient and kidney graft outcomes of deceased donors with human immunodeficiency virus in the United States.

BACKGROUND: The HIV Organ Policy Equity (HOPE) act afforded transplantation of organs from donors who have HIV. Herein we compared the long-term outcomes of recipients with HIV by donor HIV testing status. METHODS: Using the Scientific Registry of Transplant Recipients, we identified all primary adult kidney transplant recipients who were HIV-positive between 1/1/16-12/31/21. Recipients were grouped into three cohorts according to the donor HIV status based on antibody (Ab) and nucleic acid testing (NAT): Donor Ab-/NAT- (n = 810), Donor Ab+ /NAT- (n = 98), and Donor Ab+/NAT+ (n = 90). We compared recipient and death-censored graft survival (DCGS) by donor HIV testing status using Kaplan-Meier curves and Cox proportional hazards regression, censored at 3 years posttransplant. Secondary outcomes were delayed graft function (DGF) and the following 1-year outcomes: acute rejection, re-hospitalization, and serum creatinine. RESULTS: In Kaplan-Meier analyses, patient survival and DCGS were similar by donor HIV status (log rank p = .667; log rank p = .388). DGF occurred more frequently in donors with HIV Ab-/NAT- testing compared with Ab+/NAT- or Ab+/NAT+ testing (38.0% vs. 28.6% vs. 26.7%, p = .028). Average dialysis time before transplant was twice as long for recipients who received organs from donors with Ab-/NAT- testing (p < .001). Acute rejection, re-hospitalization and serum creatinine at 12 months did not differ between the groups. CONCLUSIONS: Patient and allograft survival for recipients living with HIV remains comparable irrespective of donor HIV testing status. Utilizing kidneys from deceased donors with HIV Ab+/NAT- or Ab+/NAT+ testing shortens dialysis time prior to transplant.

Isavuconazole Prophylaxis in Patients With Hematologic Malignancies and Hematopoietic Cell Transplant Recipients.

BACKGROUND: Isavuconazole (ISA) is an attractive candidate for primary mold-active prophylaxis in high-risk patients with hematologic malignancies or hematopoietic cell transplant (HCT) recipients. However, data supporting the use of ISA for primary prophylaxis in these patients are lacking. METHODS: We conducted a retrospective review of breakthrough invasive fungal infections (bIFIs) among adult hematologic malignancy patients and HCT recipients who received ≥7 days of ISA primary prophylaxis between 1 September 2016 and 30 September 2018. The incidence of bIFIs in patients receiving ISA was compared to those receiving posaconazole (POS) and voriconazole (VOR) during the same time period. RESULTS: One hundred forty-five patients received 197 courses of ISA prophylaxis. Twelve bIFIs (Aspergillus fumigatus [5], Aspergillus species [2], Mucorales [2], Fusarium species [2], and Candida glabrata [1]) occurred, representing 8.3% of patients and 6.1% of courses, after a median duration of 14 days of ISA prophylaxis. All bIFIs occurred during periods of neutropenia. Seven patients (58.3%) died within 42 days of onset of bIFI. In addition, bIFIs complicated 10.2% of ISA, 4.1% of POS, and 1.1% of VOR courses among patients with de novo or relapsed/refractory acute myeloid leukemia during the study period, with invasive pulmonary aspergillosis (IPA) complicating 6.8% of ISA, 1.3% of POS, and zero VOR courses. CONCLUSIONS: Although ISA has been approved for treatment of invasive Aspergillus and mucormycosis, we observed an increased rate of bIFI, notably IPA, using ISA for primary prophylaxis. These results support the need for further study to determine the role of ISA as primary prophylaxis.

Progressive multifocal leukoencephalopathy in a lung transplant recipient.

Progressive multifocal leukoencephalopathy (PML) is a rare and fatal demyelinating disease of the central nervous system (CNS). The case we describe highlights the importance of considering a diagnosis of PML early (<1 year) after lung transplant.

The impact of an intervention to reduce dispersal from wastewater drain sites on carbapenem-resistant Pseudomonas aeruginosa colonization and bloodstream infection on a hematopoietic cell transplant and hematologic malignancy unit.

OBJECTIVE: To evaluate the impact of an intervention to limit dispersal from wastewater drain (WWD) sites on meropenem-nonsusceptible Pseudomonas aeruginosa patient and environmental colonization and bloodstream infection (BSI) on a hematopoietic cell transplant (HCT) and hematologic malignancy (HM) unit. DESIGN: This quasi-experimental study included pre/postintervention point-prevalence surveys in July 2019 and June 2020, respectively. The retrospective cohort included HCT/HM patients with P. aeruginosa BSI between 2012 and 2022. SETTING: Adult HCT/HM unit at an academic center. PARTICIPANTS: This study included consenting HCT/HM patients on the unit at the time of the point-prevalence surveys. HCT/HM patients with P. aeruginosa BSI between 2012 and 2022. METHODS: A quality improvement intervention targeting WWD sites was conceived and implemented on a HCT/HM unit. Pre and postintervention colonization samples were obtained from patients and environmental sites, cultivated on selective media, then characterized by susceptibility testing. Whole-genome sequencing and phylogenetic analysis were performed on select isolates. The impact of the intervention on colonization and BSI was evaluated, as was relatedness among isolates. RESULTS: Although colonization of WWD sites with meropenem-nonsusceptible P. aeruginosa was widespread before and after this intervention, we observed a substantial decline in patient colonization (prevalence rate ratio, 0.35; 95% confidence interval [CI], 0.04-3.12) and BSI (incidence rate ratio, 0.67; 95% CI, 0.31-1.42) after the intervention. Among 3 predominant sequence types (ST-111, ST-446, and ST-308), there was striking genetic conservation within groups and among environmental colonization, patient colonization, and BSI isolates. CONCLUSIONS: An intervention targeting WWD sites on a HCT/HM unit had a meaningful impact on meropenem-nonsusceptible P. aeruginosa patient colonization and BSI.

Demystifying Fogging in Lyophilized Products: Impact of Pharmaceutical Processing.

A commonly encountered challenge with freeze-dried drug products is glass vial fogging. Fogging is characterized by a thin layer of product deposited upon the inner surface of the vial above the lyophilized cake. While considered to be a routine cosmetic defect in many instances, fogging around the shoulder and neck of the vial may potentially impact container closure integrity and reject rates during inspection. In this work, the influence of processing conditions i.e. vial pre-treatment, lyophilization cycle modifications and filling conditions on fogging was evaluated. A battery of analytical techniques was employed to investigate factors affecting glass vial fogging. A fogging score was used to quantify its severity in freeze-dried products. Additionally, a dye-based method was used to study solution upcreep (Marangoni flow) following product filling. Our lab-scale results indicate measurable improvement in fogging following the addition of an annealing step in the lyophilization cycle. Pre-freeze isothermal holding of the vials (at 5°C on the lyophilizer shelf) for an extended duration indicated a reduction in fogging whereas an increase in the freezing time exhibited no effect on fogging. Vial pre-treatment conditions were critical determinants of fogging for Type 1 vials whereas they had no impact on fogging in TopLyo® vials. The headspace relative humidity (RH) investigation also indicated sufficient increase in the water vapor pressure inside the vial to be conducive to the formulation of a hydration film - the precursor to Marangoni flow.

Evaluation of a Raman Chemometric Method for Detecting Protein Structural Conformational Changes in Solution.

Raman scattering shows promise as a powerful routine tool, to determine both secondary and the smaller tertiary structural changes that precede aggregation in both solutions and solids. A method was developed utilizing principal component analysis (PCA) of Raman spectra for detection of small, but meaningful, pH induced changes in tertiary protein structure linked to aggregate formation using α-lactalbumin solutions as a model. The sample preparation and spectral parameters, were optimized for a bulk Raman probe. Analysis of large regions (600-1850 cm-1) yielded principal component (PC) scores useful for semi-quantitative comparison of protein conformation between formulations. PC loadings corresponded to specific structural peaks known to change with solution pH. PCA of circular dichroism (CD) spectra of dilute solutions yielded similar results. Sucrose is a common formulation excipient with a Raman spectrum that overlaps many protein peaks. With sucrose in the protein solution, the ability of PCA to discern protein structural changes from the Raman spectra was somewhat reduced. Analysis of a more limited spectral region (1530-1780 cm-1) with negligible sucrose spectral contribution improved the discrimination of protein conformational states. The new Raman method accurately distinguished differences in protein structure in concentrated solutions. The long-term goal is to explore Raman characterization as a routine monitoring tool of protein stability in both solution and solid states.

Importance of Kv Distribution in Freeze Drying Part I: A Holistic Model to Predict Changes in Kv Bimodal Distribution as a Function of Pressure.

Measurement of heat transfer coefficients (Kv) is an important part of freeze-dryers characterization and as well a necessary step for executing any modelling. In most cases only an average value of Kv is calculated, or an average value of center and edge vials is provided. Our aim is to go a step further and to describe the overall Kv distribution various vial/ freeze drier combinations, whatever the pressure. From an experimental point of view, in this article we propose three methods to calculate the Kv value for individual vials based on the ice sublimation gravimetric method. The first method we use is the most usual one, where the Kv value is calculated based on the mass of sublimated ice and the product temperature measured in selected vias. In the second method, the average product temperature is estimated for each vial, based on the mass difference before and after sublimation and the Kv value is calculated accordingly. In the third method, the Kv is estimated by comparison to sublimation results from a simulation. Results from methods 2 and 3 are very similar results and are slightly different from those of method 1. Method 1 was shown to exhibit a systematic bias due to the fact that it is based on the temperature of recording of selected vials only, which are not representative for all positions. Once the individual values of Kv have been calculated, it is possible to establish a distribution for each method. It was observed that an overlay of two normal distributions describing the center and the edge vials provides a good representation of the empirical distribution. Furthermore, we propose a holistic model aiming to calculate the Kv distribution for any specified pressure.

Emergence of non-susceptibility during persistent Pseudomonas aeruginosa bacteraemia in haematopoietic cell transplant recipients and haematological malignancy patients.

BACKGROUND: Systematic studies pertaining to the emergence of resistance during therapy of Pseudomonas aeruginosa bloodstream infections (BSIs) in haematopoietic cell transplant (HCT) recipients and haematological malignancy (HM) patients are lacking. OBJECTIVES: To determine how frequently non-susceptibility emerges during therapy of P. aeruginosa BSIs and to compare these findings with non-HCT/HM patients. PATIENTS AND METHODS: P. aeruginosa BSIs that occurred at our institution between 1 July 2012 and 31 October 2019 in HCT/HM patients and non-HCT/HM patients were identified. Episodes in which bacteraemia persisted while on appropriate therapy ('persistent BSI') were evaluated for emergence of non-susceptibility during therapy. RESULTS: In total, 96 BSI episodes among 86 HCT/HM patients were analysed. Eight persistent BSI episodes (8.3%) occurred in eight patients (9.3%). Repeat susceptibility testing was performed in seven (87.5%) of these episodes. Non-susceptibility to the treatment agent emerged in five (71.4%) episodes and to any antipseudomonal agent in seven (100%) episodes. The 21 day mortality rate associated with persistent BSI was 87.5% (seven of eight), and it was 80% (four of five) among persistent BSI episodes in which non-susceptibility to the treatment agent emerged on therapy. Non-susceptibility to any antipseudomonal agent during persistent BSI emerged significantly more frequently in HCT/HM patients compared with non-HCT/HM patients. CONCLUSIONS: Non-susceptibility emerges frequently during persistent P. aeruginosa BSIs in HCT/HM patients, and this is associated with a high mortality rate. Our findings have implications for the management of persistent P. aeruginosa BSIs in these patients. Larger studies are needed to confirm and expand on our findings.

Understanding viral shedding of severe acute respiratory coronavirus virus 2 (SARS-CoV-2): Review of current literature.

OBJECTIVE: Transmission of SARS-CoV-2 has significant implications for hospital infection prevention and control, discharge management, and public health. We reviewed available literature to reach an evidenced-based consensus on the expected duration of viral shedding. DESIGN: We queried 4 scholarly repositories and search engines for studies reporting SARS-CoV-2 viral shedding dynamics by PCR and/or culture available through September 8, 2020. We calculated the pooled median duration of viral RNA shedding from respiratory and fecal sources. RESULTS: The review included 77 studies on SARS-CoV-2. All studies reported PCR-based testing and 12 also included viral culture data. Among 28 studies, the overall pooled median duration of RNA shedding from respiratory sources was 18.4 days (95% CI, 15.5-21.3; I2 = 98.87%; P < .01). When stratified by disease severity, the pooled median duration of viral RNA shedding from respiratory sources was 19.8 days (95% CI, 16.2-23.5; I2 = 96.42%; P < .01) among severely ill patients and 17.2 days (95% CI, 14.0-20.5; I2 = 95.64%; P < .01) in mild-to-moderate illness. Viral RNA was detected up to 92 days after symptom onset. Viable virus was isolated by culture from -6 to 20 days relative to symptom onset. CONCLUSIONS: SARS-COV-2 RNA shedding can be prolonged, yet high heterogeneity exists. Detection of viral RNA may not correlate with infectivity since available viral culture data suggests shorter durations of shedding of viable virus. Additional data are needed to determine the duration of shedding of viable virus and the implications for risk of transmission.

Respiratory Virus Infections of the Stem Cell Transplant Recipient and the Hematologic Malignancy Patient.

Respiratory virus infections in hematologic stem cell transplant recipients and patients with hematologic malignancies are increasingly recognized as a cause of significant morbidity and mortality. The often overlapping clinical presentation makes molecular diagnostic strategies imperative for rapid diagnosis and to inform understanding of the changing epidemiology of each of the respiratory viruses. Most respiratory virus infections are managed with supportive therapy, although there is effective antiviral therapy for influenza. The primary focus should remain on primary prevention infection control procedures and isolation precautions, avoidance of ill contacts, and vaccination for influenza.

Quantification of Moisture-Induced Cohesion in Pharmaceutical Mixtures.

Moisture-induced flow variabilities in pharmaceutical blends lead to multiple impediments during manufacturing of solid dosage formulations. Processing and storage humidity conditions both govern the moisture contents of the pharmaceutical mixtures and bear significant impact on the final product quality. In this study, experimentally validated discrete element method-based computational models along with statistical formalism have been implemented to develop a predictive tool for moisture-induced cohesion in binary and tertiary mixtures. V-blending was applied to prepare the pharmaceutical blends, and mixing characterization was performed using a Raman PhAT probe. Optimum fill volume was established for the mixing conditions to minimize static charging due to blender wall interactions on the pharmaceutical powders. A simplex-centroid (augmented) design for 3-component system was implemented to predict and quantify the nonlinear behavior of moisture-induced cohesion between the pharmaceutical powders based on their systematic hopper discharge studies (experiments and simulations). A methodical implementation of these quantification tools was hence performed to validate a design space that enables an approach to the appropriate selection of blend concentrations that achieve minimum mixture flow variability across different humidity conditions.