"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.

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.

Cladophialophora bantiana brain abscess and concurrent pulmonary cryptococcus neoformans infection in a patient twenty years after renal transplantation.

Recipients of solid organ transplants are at risk for a variety of infections due to their immunocompromised status. The types of infections are often correlated to the timing from their transplant. After about six to twelve months, transplant recipients remain at risk for typical community acquired pathogens, late viral infections, and fungal infections including atypical molds such as Cladophialophora bantiana. C. bantiana is a dematiaceous fungus that has a predilection for infecting the brain and is the most common cause of cerebral phaeohyphomycosis - a term used to describe infections caused by molds that produce dark cell walls. Patients with cerebral abscesses due to C. bantiana infections have an estimated mortality of about 70%. Improved outcomes have been seen in patients who receive both surgical and antifungal therapy. While there are no clear guidelines on antifungal therapy, most cases have been treated with combination amphotericin B, a triazole (itraconazole, voriconazole, or posaconazole) with flucytosine sometimes in conjunction as well. This case describes a patient with C. bantiana brain abscess and concurrent Cryptococcus neoformans pulmonary infection that occurred twenty years after his kidney transplantation. He was treated successfully with two craniotomies for cerebral abscess debridement and liposomal amphotericin B followed by planned lifelong voriconazole.

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.

A rare fatal case of adenovirus serotype 4 associated acute disseminated encephalomyelitis in an adult: A case report.

Acute disseminated encephalomyelitis (ADEM) is an autoimmune demyelinating disease directed against the myelin sheath of the central nervous system that typically presents 1-4 weeks after an infection or vaccination, most commonly in children. We describe a case of a young female who presented with rapidly progressive mental deterioration and died secondary to ADEM following an adenovirus upper respiratory tract infection.

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.

Gene duplication and functional divergence of the zebrafish insulin-like growth factor 1 receptors.

Insulin-like growth factor (IGF) 1 receptor (IGF1R)-mediated signaling plays key roles in growth, development, and physiology. Recent studies have shown that there are two distinct ig f1r genes in zebrafish, termed ig f1ra and ig f1rb. In this study, we tested the hypothesis that zebrafish ig f1ra and ig f1rb resulted from a gene duplication event at the ig f1r locus and that this has led to their functional divergence. The genomic structures of zebrafish ig f1ra and ig f1rb were determined and their loci mapped. While zebrafish ig f1ra has 21 exons and is located on linkage group (LG) 18, zebrafish ig f1rb has 22 exons and mapped to LG 7. There is a strong syntenic relationship between the two zebrafish genes and the human IG F1R gene. Using a MO-based loss-of-function approach, we show that both Igf1ra and Igf1rb are required for zebrafish embryo viability and proper growth and development. Although Igf1ra and Igf1rb demonstrated a large degree of functional overlap with regard to cell differentiation in the developing eye, inner ear, heart, and muscle, they also exhibited functional distinction involving a greater requirement for Igf1rb in spontaneous muscle contractility. These findings suggest that the duplicated zebrafish ig f1r genes play largely overlapping but not identical functional roles in early development and provide novel insight into the functional evolution of the IGF1R/insulin receptor gene family.