"Saving lives with nirmatrelvir/ritonavir one transplant patient at a time".

BACKGROUND: Solid organ transplant (SOT) recipients are at risk of complications from COVID-19. Nirmatrelvir/ritonavir (Paxlovid) can reduce mortality from COVID-19 but is contraindicated in patients receiving calcineurin inhibitors (CI), which depend on cytochrome p4503A (CY3PA). In this study, we aim to show the feasibility of nirmatrelvir/ritonavir administration to SOT recipients receiving CI with coordination of medication management and limited tacrolimus trough monitoring. METHODS: We reviewed adult SOT recipients treated with nirmatrelvir/ritonavir from 4/14 to 11/1/2022 and assessed for changes in tacrolimus trough and serum creatinine after therapy. RESULTS: Of 47 patients identified, 28 were receiving tacrolimus and had follow-up laboratory testing. Patients had a mean age of 55 years, 17 (61%) received a kidney transplant and 23 (82%) received three or more doses of SARS-CoV-2 mRNA vaccine. Patients had mild-moderate COVID-19 and started nirmatrelvir/ritonavir within 5 days of symptom onset. Median baseline tacrolimus trough concentration was 5.6 ng/mL (Interquartile range 5.1-6.7), while median follow-up tacrolimus trough concentration was 7.8 ng/mL (Interquartile range 5.7-11.5, p = 0.0017). Median baseline and follow-up serum creatinine levels were 1.21 mg/dL (Interquartile range 1.02-1.39) and 1.21 mg/dL (interquartile range 1.02-1.44, p = 0.3162), respectively. One kidney recipient had a follow up creatinine level >1.5 times baseline. No patients were hospitalized or died from COVID-19 in the follow up period. CONCLUSION: While administration of nirmatrelvir/ritonavir resulted in a significant increase in tacrolimus concentration, this did not result in significant nephrotoxicity. Early oral antiviral treatment in SOT recipients is feasible with medication management, even with limited tacrolimus trough monitoring.

Infectious complications of bronchial stenosis in lung transplant recipients.

BACKGROUND: Bronchial stenosis is a known complication of lung transplantation, but there are limited data regarding whether transplant recipients with bronchial stenosis develop more infectious complications than those without bronchial stenosis. METHODS: We conducted a retrospective single-center observational cohort study between January 1, 2011 and September 29, 2016 of 35 lung transplant recipients diagnosed with bronchial stenosis and a random sample of 35 lung transplant recipients without bronchial stenosis. Data collected included donor/recipient demographic and anatomic information, respiratory cultures, episodes of respiratory infections diagnosed using CDC-NNIS criteria, hospitalizations, and 1-year all-cause mortality. Patients were followed up to 1 year after transplant. RESULTS: Bronchial stenosis occurred at a median of 54 days post-transplant (range 5-365 days). Bronchial stenosis patients spent more time in the hospital (87.4 vs 46.8 days, P = 0.011) and had more total hospitalizations (4.54 vs 2.37, P < 0.01) than their counterparts. The relative risk of pneumonia among cases vs controls was 4.0 (95% CI 2.2-7.3, P < 0.01); for purulent tracheobronchitis the relative risk was 3.1 (95% CI 1.6-6.1, P < 0.01). Patients with bronchial stenosis were significantly more likely to have respiratory cultures growing Staphylococcus aureus (RR 5.0; P = 0.001) and Pseudomonas aeruginosa (RR 2.1, P = 0.026). Mortality within the first year following transplant was equal in both the groups (14.3% vs 14.3%). CONCLUSIONS: There was no significant increase in 1-year mortality for lung transplant patients who developed bronchial stenosis. However, bronchial stenosis patients had significantly higher risks of pneumonia and tracheobronchitis, and spent more days in the hospital than those without bronchial stenosis.

Transmission of yellow fever vaccine virus through blood transfusion and organ transplantation in the USA in 2021: report of an investigation.

BACKGROUND: In 2021, four patients who had received solid organ transplants in the USA developed encephalitis beginning 2-6 weeks after transplantation from a common organ donor. We describe an investigation into the cause of encephalitis in these patients. METHODS: From Nov 7, 2021, to Feb 24, 2022, we conducted a public health investigation involving 15 agencies and medical centres in the USA. We tested various specimens (blood, cerebrospinal fluid, intraocular fluid, serum, and tissues) from the organ donor and recipients by serology, RT-PCR, immunohistochemistry, metagenomic next-generation sequencing, and host gene expression, and conducted a traceback of blood transfusions received by the organ donor. FINDINGS: We identified one read from yellow fever virus in cerebrospinal fluid from the recipient of a kidney using metagenomic next-generation sequencing. Recent infection with yellow fever virus was confirmed in all four organ recipients by identification of yellow fever virus RNA consistent with the 17D vaccine strain in brain tissue from one recipient and seroconversion after transplantation in three recipients. Two patients recovered and two patients had no neurological recovery and died. 3 days before organ procurement, the organ donor received a blood transfusion from a donor who had received a yellow fever vaccine 6 days before blood donation. INTERPRETATION: This investigation substantiates the use of metagenomic next-generation sequencing for the broad-based detection of rare or unexpected pathogens. Health-care workers providing vaccinations should inform patients of the need to defer blood donation for at least 2 weeks after receiving a yellow fever vaccine. Despite mitigation strategies and safety interventions, a low risk of transfusion-transmitted infections remains. FUNDING: US Centers for Disease Control and Prevention (CDC), the Biomedical Advanced Research and Development Authority, and the CDC Epidemiology and Laboratory Capacity Cooperative Agreement for Infectious Diseases.

Infective endocarditis following heart transplantation: A systematic review.

PURPOSE: Infective endocarditis (IE) is a rare but potentially fatal complication following heart transplantation (HTx). There is a lack of literature regarding the patterns and clinical course of IE development following HTx. We sought to pool the existing data in regards to defining characteristics, management options, and outcomes of IE following HTx. METHODS: An electronic search of Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Ovid Medline, and the Scopus databases were performed to identify all articles in the English literature that report IE following HTx in adult patients. Patient-level data were extracted and analyzed. RESULTS: Systematic search yielded 57 patients from 32 articles. Median patient age was 52 [IQR 43, 59] and 75% of patients (43/57) were male. Median time to IE presentation post-HTx was 8.4 [IQR 3.0, 35.8] months. IE of the mitral valve was observed in 36.8% (21/57) of patients, followed by mural IE in 24.6% (14/57), and tricuspid valve IE in 21.1% (12/57). The most common organisms were Staphylococcus aureus in 26.3% (15/57), Aspergillus fumigatus in 19.3% (11/57), Enterococcus faecalis in 12.3% (7/57), and an undetermined or unspecified organism in 14.0% (8/57) patients. Overall case fatality was 44.6% (25/56). Fungal IE was associated with a significantly higher case fatality 75.0% (9/12) than that of bacterial IE 36.1% (13/36) (p = 0.02). Surgical management of post-HTx IE was observed in 35.1% (20/57) of patients. This included valve surgery for 70.0% (14/20), including the mitral valve in 50.0% (7/14), aortic valve in 35.7% (5/14), and the tricuspid valve in 14.3% (2/14) of patients. CONCLUSION: In addition to bacterial organisms, fungi also represent a frequent cause of IE in post-HTx patients. Overall HTx patient survival in the setting of IE is poor and may be worse if caused by A. fumigatus.

Fever in a returning traveler: A case and literature review of melioidosis.

Burkholderia pseudomallei is an aerobic, motile, non-spore-forming gram-negative bacillus found in tropical endemic environments that causes the disease melioidosis. Melioidosis displays a diversity of clinical presentations ranging from septic shock to chronic latent infection, often with characteristic abscesses in multiple organs. Melioidosis is an opportunistic infection, with risk factors, including diabetes, alcohol use, chronic lung disease, and chronic renal disease, and these risk factors increase the severity of disease (Wiersinga et al., 2006) [1]. In this case report, we illustrate a case of a 32 year old man with several risk factors and recent travel to an endemic region presenting with melioidosis. Our case demonstrates the challenges in obtaining a diagnosis in a non-endemic location, highlights a complex presentation of this disease, and describes the multifaceted clinical management required to care for this patient. As global travel increases, there is an increased need for clinician awareness of this disease in non-endemic regions.

COVID-19 in Solid Organ Transplantation: Disease Severity and Clinical Update.

BACKGROUND: Solid organ transplant (SOT) recipients are a complex, immunocompromised population in whom greater coronavirus disease 2019 (COVID-19) mortality has been reported compared with the general population. METHODS: We examined a retrospective cohort of 58 SOT recipients with first-wave COVID-19, comparing patients with severe and nonsevere illness. Additionally, SOT recipients are compared with general patients with first-wave COVID-19. RESULTS: Organs transplanted included 38 kidneys, 8 livers, 5 hearts, and 3 pancreases. Average SOT recipient age was 57.4 years; 62% were male; 46.6% were African American 36.2% were white. Comorbidities included hypertension (86%), chronic kidney disease (86%), diabetes mellitus (50%), coronary artery disease (26%), and chronic obstructive pulmonary disease (14%). Twenty patients had severe COVID-19 (34.5%) and 38 had nonsevere disease (65.5%). Severe disease was more common in older SOT recipients with comorbidities and was associated with cough, dyspnea, pneumonia, C-reactive protein >10 mg/L, and platelet count <150/µL. Sex, race, body mass index, time from transplant, baseline immunosuppression, and diagnosis month did not differ among those with severe and nonsevere COVID-19. Seventy percent of SOT recipients were hospitalized vs 27.2% of general patients with COVID-19 and inpatient SOT recipients had a higher mechanical ventilation rate. Though a trend toward longer length of stay, higher intensive care unit admission, and greater inpatient mortality was observed (19.5% vs 14.8%), these differences were not significant. CONCLUSIONS: The severe acute respiratory syndrome coronavirus 2 has greatly impacted SOT recipients. One-third of our SOT recipients seen during the first wave had severe illness with associated standard risk factors for poor outcome. Compared with general first-wave patients, more SOT recipients were hospitalized, although inpatient COVID-19 mortality did not significantly differ.

What's Hot in Clinical Infectious Diseases? 2019 IDWeek Summary.

The year 2019 brought about a multitude of innovations in clinical infectious diseases. With the continued rise of antimicrobial resistance (AMR), advances in diagnostics and newly available antibiotics offer additional strategies for combating this threat, but the broken antibiotic market serves as an impediment to further developments. The IDSA and other stakeholders are working to create novel pull incentives to stabilize the pipeline. Ongoing needs include developing optimal stewardship practices, including by using narrow-spectrum antibiotics and shorter durations of therapy. In the area of solid organ transplantation, early data from transplanting Hepatitis C virus (HCV)-infected organs are encouraging and the American Society of Transplantation (AST) released new guidelines addressing several key issues. Lastly, 2019 saw a resurgence in Measles emphasizing the importance of vaccination.

Characterization of the interplay between DNA repair and CRISPR/Cas9-induced DNA lesions at an endogenous locus.

The CRISPR-Cas9 system provides a versatile toolkit for genome engineering that can introduce various DNA lesions at specific genomic locations. However, a better understanding of the nature of these lesions and the repair pathways engaged is critical to realizing the full potential of this technology. Here we characterize the different lesions arising from each Cas9 variant and the resulting repair pathway engagement. We demonstrate that the presence and polarity of the overhang structure is a critical determinant of double-strand break repair pathway choice. Similarly, single nicks deriving from different Cas9 variants differentially activate repair: D10A but not N863A-induced nicks are repaired by homologous recombination. Finally, we demonstrate that homologous recombination is required for repairing lesions using double-stranded, but not single-stranded DNA as a template. This detailed characterization of repair pathway choice in response to CRISPR-Cas9 enables a more deterministic approach for designing research and therapeutic genome engineering strategies.