Valganciclovir prophylaxis delays onset of EBV viremia in high-risk pediatric solid organ transplant recipients.

BACKGROUND: The role of antiviral prophylaxis to prevent Epstein-Barr virus (EBV) viremia or posttransplant lymphoproliferative disorder in pediatric solid organ transplant recipients is controversial. We examined whether valganciclovir (VAL) prophylaxis for cytomegalovirus infection was associated with EBV viremia following transplantation in EBV-naive children. METHODS: A single-center, retrospective study was conducted of EBV-naive pediatric heart and renal transplant recipients with an EBV-positive donor from January 1996 to April 2017. VAL was tested for association with EBV viremia-free survival in the first 6 months posttransplantation when immunosuppressant exposure is the highest. Survival models evaluated VAL duration, with adjustment for other baseline confounders. RESULTS: Among the cohort (n = 44), 3 (6.8%) were heart transplants, 25 (56.8%) received VAL, and 22 (50%) developed EBV viremia in the first-year posttransplantation. Mean time-to-viremia was 143 vs. 90 days for the VAL and no-VAL groups, respectively (p = 0.008), in the first 6 months. Only two patients developed viremia while on VAL. Each additional day of VAL was associated with 1.4% increase in viremia-free survival (p < 0.001). Multivariable modeling of VAL with other baseline risk factors did not identify other independent risk factors. CONCLUSION: VAL is independently associated with delayed onset of EBV viremia, with prolongation of delay with each additional day of antiviral prophylaxis.

A vexing case of bone pain in a renal transplant recipient: Voriconazole-induced periostitis.

Immunosuppression increases the risk of opportunistic infections including fungal infections in solid organ transplant recipients. Voriconazole is used to treat invasive aspergillus infections but prolonged usage may rarely lead to periostitis. Increased plasma fluoride concentration leading to osteoblastic upregulation is thought to be the catalyst, and symptom reversal occurs with discontinuation of the offending agent. A renal transplant recipient who was on voriconazole for invasive aspergillosis developed diffuse debilitating symmetrical bone pain. Having ruled out other neurological, metabolic, and drug etiologies, voriconazole-induced periostitis was diagnosed. Increased plasma fluoride level was documented, but bone scan was non-specific. A therapeutic discontinuation of voriconazole and switch to posaconazole provided rapid symptom resolution. The patient accidently restarted voriconazole as an outpatient resulting in the same symptomology, and thus provided further evidence that this was drug related. Voriconazole-induced periostitis is a described entity in immunosuppressed solid organ transplant patients who are treated with a prolonged course of voriconazole. This case study is novel in that it demonstrates drug induced periostitis in a renal transplant recipient who developed debilitating periostitis within a short time after starting voriconazole and equally rapid resolution once it was discontinued. We conclude that patients treated with voriconazole should be routinely monitored for periostitis.

Successful lung transplantation in an HIV seropositive patient with desquamative interstitial pneumonia: a case report.

BACKGROUND: Until recently, lung transplantation was not considered in patients with human immunodeficiency virus (HIV). HIV seropositive patients with suppressed viral loads can now expect long-term survival with the advent of highly active antiretroviral therapies (HAART); however, HIV remains a relative contraindication to lung transplantation. We describe, to our knowledge, the first HIV seropositive lung transplant recipient in Canada. We also review the literature of previously reported cases of solid-organ transplantation in patients with HIV with a focus on immunosuppression considerations. CASE PRESENTATION: A 48-year old man received a bilateral lung transplant for a diagnosis of desquamative interstitial pneumonia (DIP) attributed to cigarette and cannabis smoking. His control of HIV infection pre-transplant was excellent on HAART, and he had no other contraindications to lung transplantation. The patient underwent bilateral lung transplantation using basiliximab, methylprednisolone, and mycophenolate mofetil (MMF) as induction immunosuppression. He was maintained on MMF, prednisone, and tacrolimus thereafter, and restarted his HAART regimen immediately post-operatively. His post-transplant course was complicated by Grade A1 minimal acute cellular rejection, as well as an enterovirus/rhinovirus graft infection. Despite these complications, his functional status and control of HIV infection remain excellent 24 months post-transplant. CONCLUSIONS: Our patient is one of only several HIV seropositive lung transplant recipients reported globally. With growing acceptance of transplantation in this population, there is a need for clarification of prognosis post-transplantation, as well as optimal immunosuppression regimens for these patients. This case report adds to the recent literature that suggests HIV seropositivity should not be considered a contraindication to lung transplantation, and that post-transplant patients with HIV can be managed safely with basiliximab, tacrolimus, MMF and prednisone.

Strategies to prevent BK virus infection in kidney transplant recipients.

PURPOSE OF REVIEW: Despite improvements in posttransplant care, BK virus (BKV) remains one of the most challenging posttransplant infections in kidney transplant recipients with high rates of allograft failure. In the absence of well tolerated and efficacious viral specific therapeutics, treatment is primarily focused on reduction of immunosuppression, which poses a risk of rejection and fails to lead to viral clearance in a number of patients. RECENT FINDINGS: Recent work has turned toward preventive therapies analogous to those used for other infections like cytomegalovirus. These efforts have focused on the use of quinolone antibiotic prophylaxis to prevent BKV infection and pretransplant vaccination to boost humoral and cellular immunity. SUMMARY: Despite promising in-vitro and observational data, quinolone antibiotic prophylaxis has not been effective in preventing BKV infection in prospective studies. However, prophylaxis with newer less toxic viral specific agents such as brincidofovir - the lipid oral formulation of cidofovir - may yet prove effective. Strategies focused on eliciting a humoral immune response to recombinant virus-like particles or using adoptive transfer of BKV-specific T cells have also shown significant potential to prevent BKV infection in organ transplant recipients.

Successful long-term management of invasive cerebral fungal infection following liver transplantation.

Central nervous system (CNS) infections after liver transplantation may be fungal in aetiology, with involvement from either common organisms such as Cryptococcus neoformans and Aspergillus spp. as well as less common organisms, such as the Mucorales and Scedosporium spp. Although the mortality of CNS fungal infections was nearly 100% in early series, more recent data has suggested that good outcomes can be achieved. This may be due to both improved diagnostic capabilities, such as the ability to obtain fungal susceptibilities and therapeutic drug levels, and improved therapeutic options, such as the newer triazoles- voriconazole and posaconazole. Due to improved outcomes, issues have now arisen around the long-term tolerability of these agents. The following two cases of invasive cerebral fungal infections following liver transplantation, one with Aspergillus flavus, and the other with Scedosporium boydii/apiospermum highlight the success that can be seen with the modern management of a previously fatal diagnosis. In particular, we highlight the issues around therapeutic monitoring and discontinuation of therapy.

Central nervous system syndromes in solid organ transplant recipients.

Solid organ transplant recipients have a high incidence of central nervous system (CNS) complications, including both focal and diffuse neurologic deficits. In the immunocompromised host, the initial clinical evaluation must focus on both life-threatening CNS infections and vascular or anatomic lesions. The clinical signs and symptoms of CNS processes are modified by the immunosuppression required to prevent graft rejection. In this population, these etiologies often coexist with drug toxicities and metabolic abnormalities that complicate the development of a specific approach to clinical management. This review assesses the multiple risk factors for CNS processes in solid organ transplant recipients and establishes a timeline to assist in the evaluation and management of these complex patients.

Increased moxifloxacin utilization associated with an unrestricted addition to a drug reimbursement formulary: A population-based analysis.

OBJECTIVES: To determine whether utilization of moxifloxacin, a broad-spectrum fluoroquinolone antibiotic, has changed since its addition to the British Columbia provincial formulary in 2009 and to determine whether utilization was guideline concordant. METHODS: BC PharmaNet prescriptions for moxifloxacin from 2001 to 2010 were anonymously linked to associated Medical Services Plan fee-for-service practitioner claims for indication-specific analysis. Prescribing trends for adults ≥18 years of age were described using defined daily dose (DDD) per 1000 person-years. Monthly utilization rates were fit to a linear regression model that controlled for seasonal variation to examine the effect of the formulary addition. RESULTS: Utilization rose more than sevenfold throughout the study period, from 21.3 DDD per 1000 person-years in 2001 to 163.3 DDD per 1000 person-years in 2010. Although the formulary addition was not associated with an immediate increase in utilization (7.5% [95% CI -4.4% to 20.9%]; P=0.226), it was associated with an overall increase in utilization of 2.1% (95% CI 1.3% to 3.0%; P<0.001) for every month after 2009. Overall, only 29% of moxifloxacin prescriptions could be linked to a diagnostic code that was considered to be guideline concordant. In more than one-half of moxifloxacin prescriptions, the patient had not used another antibiotic in the previous 90 days. Among moxifloxacin prescriptions in which another antibiotic had been used in the previous 90 days, 41.5% were prescriptions for an alternative fluoroquinolone. CONCLUSIONS: The formulary addition was associated with a sustained increase in moxifloxacin utilization over time. Moxifloxacin is often prescribed to patients for indications that are not guideline concordant or to patients who have not previously received first-line antibiotics.

OBJECTIFS: Déterminer si l'utilisation de moxifloxacine, un antibiotique de la famille des fluoriquonolones à large spectre, a changé depuis son ajout au formulaire provincial de la Colombie-Britannique en 2009 et établir si cette utilisation concorde avec les lignes directrices. MÉTHODOLOGIE: Les chercheurs ont lié de manière anonyme les prescriptions de moxifloxacine figurant dans BC PharmaNet de 2001 à 2010 aux réclamations des médecins rémunérés à l'acte auprès du régime d'assurance-maladie connexe en vue d'une analyse propre aux indications. Ils ont décrit les tendances de prescription aux adultes de 18 ans ou plus au moyen de la dose quotidienne déterminée (DQD) sur 1 000 années-personne. Les taux d'utilisation mensuels respectaient un modèle de régression linéaire de variation saisonnière afin d'examiner l'effet de l'ajout au formulaire. RÉSULTATS: L'utilisation a plus que septuplé pendant la période de l'étude, passant de 21,3 DQD sur 1 000 années-personnes en 2001 à 163,3 DQD sur 1 000 années-personne en 2010. Même si l'ajout au formulaire ne s'associait pas à une augmentation immédiate de l'utilisation (7,5 % [95 % IC −4,4 % à 20,9 %]; P=0,226), il s'associait à une augmentation globale d'utilisation de 2,1 % (95 % IC 1,3 % à 3,0 %; P<0,001) chaque mois après 2009. Dans l'ensemble, seulement 29 % des prescriptions de moxifloxacine pouvaient être liées à un code diagnostique considéré comme correspondant à des lignes directrices. Dans plus de la moitié des prescriptions de moxifloxacine, le patient n'avait pas utilisé d'autre antibiotique au cours des 90 jours précédents. Parmi les prescriptions de moxifloxacine associées à l'utilisation d'un autre antibiotique au cours de 90 jours précédents, 41,5 % étaient des prescriptions pour une autre fluoroquinolone. CONCLUSIONS: L'ajout au formulaire s'est associé à une augmentation soutenue de l'utilisation de moxifloxacine au fil du temps. La moxifloxacine est souvent prescrite aux patients pour des indications qui ne correspondent pas aux lignes directrices ou à des patients qui n'ont pas reçu d'antibiotiques de première ligne auparavant.

Severe hypercalcemia as a result of disseminated Candida krusei infection.

Candida krusei disseminated infection is a rare complication of protracted neutropenia. Herein, we report a case of a 31-year-old male with relapsed acute myeloid leukemia who developed Candida krusei fungemia with cutaneous, ocular, splenic, renal, bone marrow and osseous involvement leading to severe hypercalcemia, treated with parenteral antifungals followed by oral ibrexafungerp.

Epidemiology of cytomegalovirus antiviral resistance testing for solid organ and bone marrow transplant patients from 2011 - 2019.

BACKGROUND: CMV reactivation post-transplantation is common, with need for prompt identification of patients most at-risk for CMV antiviral drug resistance (AVDR). OBJECTIVES: This study describes CMV AVDR frequencies, antiviral prescribing practices, and AVDR risk factors in patients from 2011 to 2019 in British Columbia, Canada. STUDY DESIGN: Retrospective review of demographics, transplant type, viral loads, antiviral exposure duration, and 12-month mortality was conducted for all patients with samples submitted for CMV AVDR testing from 2011 to 2019. Genotyping of AVDR mutations occurred at the national reference laboratory. Mann-Whitney U, T-test or Fisher's exact tests examined differences between patients with and without AVDR. RESULTS: Fifty-three plasma and three tissue/fluid specimens successfully underwent CMV AVDR testing; of these samples, 27/56 (48%) had AVDR mutations detected. The commonest AVDR mutations were at UL97 loci A594 (20%), H596 (12%) and L595 (12%). Mutations occurred more frequently in requests from solid organ than hematopoietic stem cell transplant patients (58% vs. 27%, p = 0.05). Previous resistance testing was a significant risk factor for AVDR (p < 0.001). Patients with AVDR had approximately 51 more days of antiviral therapy (p = 0.007) and took 9 days longer to clear viremia (p = 0.23). The median turnaround time from sample send-out to reporting was nine days. However, empiric use of second-line antivirals occurred in most cases (39/53, 74%) before results were available. DISCUSSION: Laboratories should strive to provide timely CMV AVDR testing for transplant patients, to minimize unnecessary exposure to second-line antiviral agents. The findings of this study may help guide clinicians when selecting empiric antiviral therapy.

The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers.

BACKGROUND: The macrolide antibiotics clarithromycin and erythromycin may potentiate calcium-channel blockers by inhibiting cytochrome P450 isoenzyme 3A4. However, this potential drug interaction is widely underappreciated and its clinical consequences have not been well characterized. We explored the risk of hypotension or shock requiring hospital admission following the simultaneous use of calcium-channel blockers and macrolide antibiotics. METHODS: We conducted a population-based, nested, case-crossover study involving people aged 66 years and older who had been prescribed a calcium-channel blocker between Apr. 1, 1994, and Mar. 31, 2009. Of these patients, we included those who had been admitted to hospital for the treatment of hypotension or shock. For each antibiotic, we estimated the risk of hypotension or shock associated with the use of a calcium blocker using a pair-matched analytic approach to contrast each patient's exposure to each macrolide antibiotic (erythromycin, clarithromycin or azithromycin) in a seven-day risk interval immediately before admission to hospital and in a seven-day control interval one month earlier. RESULTS: Of the 7100 patients admitted to hospital because of hypotension while receiving a calcium-channel blocker, 176 had been prescribed a macrolide antibiotic during either the risk or control intervals. Erythromycin (the strongest inhibitor of cytochrome P450 3A4) was most strongly associated with hypotension (odds ratio [OR] 5.8, 95% confidence interval [CI] 2.3-15.0), followed by clarithromycin (OR 3.7, 95% CI 2.3-6.1). Azithromycin, which does not inhibit cytochrome P450 3A4, was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). We found similar results in a stratified analysis of patients who received only dihydropyridine calcium-channel blockers. INTERPRETATION: In older patients receiving a calcium-channel blocker, use of erythromycin or clarithromycin was associated with an increased risk of hypotension or shock requiring admission to hospital. Preferential use of azithromycin should be considered when a macrolide antibiotic is required for patients already receiving a calcium-channel blocker.

Successful Liver Transplantation in a Patient With Acute COVID-19 Infection and Acute Liver Failure: A Case Report.

Current liver transplantation societies recommend recipients with active coronavirus disease 2019 (COVID-19) be deferred from transplantation for at least 2 wks, have symptom resolution and at least 1 negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test.1 This approach does not address patients who require urgent transplantation and will otherwise die from liver failure. We report a successful orthotopic liver transplant (OLT) in a patient with active COVID-19 infection. This is only the second to be reported worldwide and the first in Canada.

Clinical Practice Guideline for Solid Organ Donation and Transplantation During the COVID-19 Pandemic.

The coronavirus 2019 (COVID-19) pandemic has disrupted health systems worldwide, including solid organ donation and transplantation programs. Guidance on how best to screen patients who are potential organ donors to minimize the risks of COVID-19 as well as how best to manage immunosuppression and reduce the risk of COVID-19 and manage infection in solid organ transplant recipients (SOTr) is needed. METHODS: Iterative literature searches were conducted, the last being January 2021, by a team of 3 information specialists. Stakeholders representing key groups undertook the systematic reviews and generation of recommendations using a rapid response approach that respected the Appraisal of Guidelines for Research and Evaluation II and Grading of Recommendations, Assessment, Development and Evaluations frameworks. RESULTS: The systematic reviews addressed multiple questions of interest. In this guidance document, we make 4 strong recommendations, 7 weak recommendations, 3 good practice statements, and 3 statements of "no recommendation." CONCLUSIONS: SOTr and patients on the waitlist are populations of interest in the COVID-19 pandemic. Currently, there is a paucity of high-quality evidence to guide decisions around deceased donation assessments and the management of SOTr and waitlist patients. Inclusion of these populations in clinical trials of therapeutic interventions, including vaccine candidates, is essential to guide best practices.

The Impact of Left Ventricular Assist Device Infections on Postcardiac Transplant Outcomes: A Systematic Review and Meta-Analysis.

Left ventricular assist devices (LVADs) are associated with numerous short- and long-term complications, including infection. The impact LVAD infections have on clinical outcomes after transplantation is not well established. We sought to determine whether the presence of infection while on LVAD support negatively influences outcomes after cardiac transplantation. We searched electronic databases and bibliographies for full text studies that identified LVAD infections during support and also reported on posttransplant outcomes. A meta-analysis of posttransplant survival was conducted using a random effects model. Of 2,373 records, 13 bridge to transplant (BTT) cohort studies were selected (n = 6,631, 82% male, mean age 50.7 ± 2.7 years). A total of 6,067 records (91.5%) received transplant. There were 3,718 (56.1%) continuous-flow LVADs (CF-LVADs), 1,752 (26.4%) pulsatile LVADs, and 1,161 (17.5%) unknown type records. A total of 2,586 records (39.0%) developed LVAD infections. Patients with LVAD infections were younger (50.5 ± 1.5 vs. 51.3 ± 1.5, p = 0.02), had higher body mass indeices (BMIs) (28.4 ± 0.7 vs. 26.8 ± 0.4, p < 0.01), and longer LVAD support times (347.0 ± 157.6 days vs. 180.2 ± 106.0 days, p < 0.01). Meta-analysis demonstrated increased posttransplant mortality in those patients who had an LVAD infection (hazard ratio [HR] 1.30, 95% CI: 1.16-1.46, p < 0.001). Subgroup meta-analyses by continuous-flow and pulsatile device type demonstrated significant increased risk of death for both types of devices (HR 1.47, 95% CI: 1.22-1.76, p < 0.001 and 1.71, 95% CI: 1.19-2.45, p = 0.004, respectively). Patients who develop LVAD infections are younger, have higher BMIs and longer LVAD support times. Our data suggests that LVAD-related infections result in a 30% increase in postcardiac transplantation mortality. Strategies to prevent LVAD infections should be implemented to improve posttransplant outcomes in this high-risk population.

Transplantation of a Liver Allograft From a Hepatitis C Virus Seropositive Donor With Previous Sustained Virologic Response to an Uninfected Recipient Suffering Steroid Refractory Acute Graft Rejection With No Evidence of HCV Transmission.

BACKGROUND: The goal of treating chronic hepatitis C virus (HCV) infection is sustained virologic response (SVR). There is concern that despite achieving SVR, replication-competent HCV may be sequestered at low levels within the liver and could theoretically reactivate with immunosuppression. We report transplantation of a HCV-seropositive liver donor, who achieved SVR, into a seronegative patient without HCV reactivation despite profound immunosuppression. METHOD: Retrospective chart review. RESULTS: We present a 21-year-old male who was HCV seronegative and received a liver transplant from a donor who had been treated for HCV and achieved SVR. The liver recipient, despite developing severe acute graft rejection and undergoing intense immunosuppression with T cell-depleting antibodies, did not become HCV RNA-positive with a follow up period of 8 months. The recipient was HCV seronegative before transplant, but became HCV seropositive immediately posttransplant. The antibodies were undetectable after 97 days, in keeping with a passive antibody transmission or B lymphocyte transmission with the graft. CONCLUSIONS: To the best of our knowledge, this is the first reported case of an HCV seropositive liver allograft transplanted into an HCV-negative recipient who subsequently received intense immunosuppression. This case, therefore, is an encouraging and novel step in liver transplantation, and demonstrates that SVR may be closer to a true "cure" of HCV in the donor population and that, even in circumstances of very potent immunosuppression in the recipient, this SVR is sustained.

Recommendations for Management of Endemic Diseases and Travel Medicine in Solid-Organ Transplant Recipients and Donors: Latin America.

The Recommendations for Management of Endemic Diseases and Travel Medicine in Solid-Organ Transplant Recipients and Donors: Latin America clinical practice guideline is intended to guide clinicians caring for solid-organ transplant (SOT) donors, candidates and recipients regarding infectious diseases (ID) issues related to this geographical region, mostly located in the tropics. These recommendations are based on both systematic reviews of relevant literature and expert opinion from both transplant ID and travel medicine specialists. The guidelines provide recommendations for risk evaluation and laboratory investigation, as well as management and prevention of infection of the most relevant endemic diseases of Latin America. This summary includes a brief description of the guideline recommendations but does not include the complete rationale and references for each recommendation, which is available in the online version of the article, published in this journal as a supplement. The supplement contains 10 reviews referring to endemic or travel diseases (eg, tuberculosis, Chagas disease [ChD], leishmaniasis, malaria, strongyloidiasis and schistosomiasis, travelers diarrhea, arboviruses, endemic fungal infections, viral hepatitis, and vaccines) and an illustrative section with maps (http://www.pmourao.com/map/). Contributors included experts from 13 countries (Brazil, Canada, Chile, Denmark, France, Italy, Peru, Spain, Switzerland, Turkey, United Kingdom, United States, and Uruguay) representing four continents (Asia, the Americas and Europe), along with scientific and medical societies.

Attentional control and reflexive orienting to gaze and arrow cues.

A wealth of data indicate that central spatially nonpredictive eyes and arrows trigger very similar reflexive spatial orienting, although the effects of eyes may be more strongly reflexive (e.g., Friesen, Ristic, & Kingstone, 2004). Pratt and Hommel (2003) recently reported that the orienting effect for arrows is sensitive to arbitrary cue-target color contingencies; for example, an attentional orienting effect for blue colored arrows is evident only for blue targets. We reasoned that if the orienting effect elicited by eye direction is more strongly reflexive than the orienting effect elicited by arrow direction, it follows that eyes, unlike arrows, may trigger orienting effects that generalize across congruent and incongruent cue-target color contingencies. Replicating Pratt and Hommel (2003), we found that the reflexive attention effect elicited by arrows is specific to color-congruent target stimuli. The attention effect triggered by eyes, however, generalizes across color-congruent and color-incongruent target stimuli. These data support the hypothesis that eye direction and arrow direction trigger similar reflexive shifts in spatial attention, but that the attention effect triggered by eye direction is more strongly reflexive.