Coronavirus disease 2019 (COVID-19) continues to negatively impact solid organ transplant recipients (SOTr). Data on the use of tixagevimab–cilgavimab (tix-cil) in vaccinated SOTr during circulation of Omicron and its subvariants are limited. Therefore, this single-center review was conducted to evaluate tix-cil efficacy in multiple organ transplant groups during a study period where Omicron B.1.1.529, BA.2.12.1, and BA.5 predominated.
Methods
In this single-center retrospective study, we evaluated the incidence of COVID-19 infection in adult SOTr who did or did not receive pre-exposure prophylaxis (PrEP) with tix-cil. SOTr were included if they were at least 18 years of age and met emergency use authorization criteria for tix-cil use. The primary outcome analyzed was the incidence of COVID-19 infection.
Results
Ninety SOTr met inclusion criteria and comprised of two groups, tix-cil PrEP (n = 45) and no tix-cil PrEP (n = 45). Of SOTr who received tix-cil PrEP, three (6.7%) developed COVID-19 infection, compared to eight (17.8%) in the no tix-cil PrEP group (p = .20). Of the 11 SOTr diagnosed with COVID-19, 15 (82.2%) were fully vaccinated against COVID-19 prior to transplantation. Moreover, 18.2% and 81.8% of the COVID-19 cases observed were asymptomatic and mild-to-moderate, respectively.
Discussion
Our study results, which included months when BA.5 was in increased circulation, suggest no significant difference in COVID-19 infection with or without use of tix-cil PrEP in our solid organ transplant groups. As the COVID-19 pandemic continues to evolve, clinical utility of tix-cil should be evaluated against new, emerging strains.
Abdominal solid organ transplant (SOT) programs have been hit hard by the COVID-19 pandemic, which was officially declared as such on March 11, 2020. Over two years, the tightening and softening of limitations in response to the “waves” of infection and COVID-19 fluctuations have provided distinct issues for waitlisted patients, transplant recipients, and transplant organizations.
Method
We searched Scopus using the terms “transplant” and “transplantation,” and organ-related phrases like “intestin*,” “liver,” “kidney,” “hepatic,” “renal,” and “pancrea*,” as well as COVID-19 terms such as “COVID-19,” “coronavirus,” and “SARS-CoV-2.” We included articles, reviews, conference papers, letters, notes, editorials, brief surveys, book chapters, and errata and studied nations, institutions, authors, journals, keywords, and articles. VOSviewer 1.6.18 and Excel were used to create tables and figures.
Results
We included 1,251 of 1,256 studies. Among them, 289 (23.1%), 489 (39.1%), and 473 (37.8%) papers were published in 2020, 2021, and 2022, with mean (SD) citations of 30.3 (53.3), 14.3 (26.8), and 4.79 (6.38), respectively. Compared to other abdominal organs, the field of kidney transplants had the highest number of articles describing the impact of COVID-19. The United States contributed the most articles, and the American Journal of Transplantation published the most articles.
Conclusion
To our knowledge, this is the first bibliometric investigation of the impact of COVID-19 on SOT. This report provides an overview of the research conducted on SOT and COVID-19. There is potential for this bibliometric analysis to serve as a beneficial and practical resource for ongoing and future research.
Liver transplantation is increasing worldwide with underlying pathologies dominated by metabolic and alcoholic diseases in developed countries.
Methods
We provide a narrative review of invasive aspergillosis (IA) in liver transplant (LT) recipients. We searched PubMed and Google Scholar for references without language and time restrictions.
Results
The incidence of IA in LT recipients is low (1.8%), while mortality is high (∼50%). It occurs mainly early (<3 months) after LT. Some risk factors have been identified before (corticosteroid, renal, and liver failure), during (massive transfusion and duration of surgical procedure), and after transplantation (intensive care unit stay, re-transplantation, re-operation). Diagnosis can be difficult and therefore requires full radiological and clinicobiological collaboration. Accurate identification of Aspergillus species is recommended due to the cryptic species, and susceptibility testing is crucial given the increasing resistance of Aspergillus fumigatus to azoles. It is recommended to reduce the dose of tacrolimus (50%) and to closely monitor the trough level when introducing voriconazole, isavuconazole, and posaconazole. Surgery should be discussed on a case-by-case basis. Antifungal prophylaxis is recommended in high-risk patients. Environmental preventative measures should be implemented to prevent outbreaks of nosocomial aspergillosis in LT recipient units.
Conclusion
IA remains a very serious disease in LT patients and should be promptly sought and, if possible, prevented by clinicians when risk factors are identified.
Fulminant herpetic hepatitis due to herpes simplex virus (HSV), serotype 1 or 2, is a rare but often fatal complication after solid organ transplantation (SOT). HSV hepatitis in SOT recipients can occur either due to primary infection acquired post transplantation, viral reactivation in a seropositive patient, or as donor-derived infection. Cases of fatal hepatitis have been reported in the liver as well as in other SOT recipients. The fatal outcome is mostly due to delayed diagnosis and treatment, which is explained by the lack of clinical specificity of HSV hepatitis.
Methods
We report two cases of fatal donor-derived HSV hepatitis in liver-transplanted recipients. We reviewed all published cases of donor-derived HSV infections after SOT with an evaluation of the presence of prophylaxis and outcome.
Results
In both liver recipients, the retrospective determination of HSV serostatus was negative, and both cases occurred in the absence of cytomegalovirus or HSV prophylaxis. A review of the literature showed a significant series of cases of severe hepatitis, mostly fatal, as well as the absence of specific preventive therapy guidelines in cases of HSV serology mismatch.
Conclusions
The occurrence of two fatal donor-derived hepatitis made the Swiss Transplant Infectious Diseases working group modify its national recommendations regarding pretransplant serostatus determination and HSV prophylaxis after liver transplantation. Further studies are needed to assess this approach.
Kidney transplant recipients are at risk for a severe course of COVID-19 with a high mortality rate. A considerable number of patients remains without a satisfactory serological response after the baseline and adjuvant SARS-CoV-2 vaccination schedule.
Methods
In this prospective, randomized study, we evaluated the efficacy and safety of one and two booster doses of mRNA vaccines (either mRNA-1273 or BNT162b2) in 125 COVID-19 naive, adult kidney transplant recipients who showed an insufficient humoral response (SARS-CoV-2 IgG <10 AU/ml) to the previous 2-dose vaccination schedule. The primary outcome was the difference in the rate of a positive antibody response (SARS-CoV-2 IgG ≥10 AU/ml) between one and two booster doses at 1 month after the final booster dose.
Results
A positive humoral response was observed in 36 (62%) patients receiving two booster doses and in 28 (44%) patients receiving one booster dose (odds ratio [OR], 2.10, 95% confidence interval [CI], 1.02–4.34, p = .043). Moreover, median SARS-CoV-2 IgG levels were higher with two booster doses (p = .009). The number of patients with positive virus neutralizing antibody (VNA) levels was numerically higher with two booster doses compared to one booster dose, but without statistical significance (66% vs. 50%, p = .084). There was no significant difference in positive seroconversions rate and antibody levels between mRNA-1273 and BNT162b2.
Conclusion
A higher number of kidney transplant recipients achieved a positive antibody response after two booster doses compared to one booster dose.
Management of multidrug-resistant (MDR) and rifampin-resistant (RR) tuberculosis is challenging. Data on transplant recipients is limited. We reviewed published literature to examine treatment choices, outcomes, and adverse effects from MDR-TB/RR-TB treatment in transplant recipients.
Methods
Multiple databases from inception to 12/2022 were reviewed using the keywords “drug-resistant TB” or “drug-resistant tuberculosis” or “multidrug-resistant TB” or “multidrug-resistant tuberculosis”. MDR-TB was defined as resistance to isoniazid (H) and rifampin (R), and RR if resistant to rifampin alone. Cases without patient-level data and reports which did not describe treatment and/or outcomes for MDR-TB were excluded.
Results
A total of 12 patients (10 solid organ transplants and two hematopoietic cell transplants) were included. Of these, 11 were MDR-TB and one was RR-TB. Seven recipients were male. The median age was 41.5 (range 16–60) years. Pre-transplant evaluation for the majority (8/12, 66.7%) did not reveal a prior history of TB or TB treatment, but 9/12 were from TB intermediate or high-burden countries. Seven patients were initially treated with the quadruple first-line anti-TB regimen. Those who had early RR confirmation (5/12) via Xpert MTB/RIF assay were initiated on alternative therapies. Final regimens were individualized based on susceptibility profiles and tolerability. Adverse events were reported in seven recipients, including acute kidney injury (n = 3), cytopenias (n = 3), and jaundice (n = 2). Four recipients died, with two deaths attributable to TB. The remaining eight patients who survived had functioning allografts at the last follow-up.
Conclusions
MDR-TB treatment in transplant recipients is associated with many complications. Xpert MTB/RIF detected RR early and guided early empiric therapy.
Among kidney transplant recipients (KTR) with BK virus associated nephropathy (BKVN), BKV genotypes’ evolution and anti-BKV humoral response are not well established. We aim to analyze BKV replication and genetic evolution following transplantation, and characterize concomitant anti-BKV-VP1 humoral response.
Methods
We retrospectively analyzed 32 cases of biopsy-proven BKVN. Stored plasma and kidney biopsies were tested for BKV viral load, and VP1 sequencing performed on positive samples. BKV–VP1 genotype-specific neutralizing antibodies (NAbs) titers were determined at transplantation and BKVN.
Results
At the time of BKVN diagnosis, BKV viral load was 8.2 log10IU/106 cells and 5.4 log10IU/mL in kidney and plasma, respectively. VP1 sequencing identified the same BKV-subtype in both compartments in 31/32 cases. At the time of transplantation, 8/20 (40%) of biopsies tested positive for BKV detection, whereas concomitant BKV viremia was negative. VP1 sequencing identified a different subtype compared to BKVN in 5/6 of these samples. This was confirmed following transplantation: 8 patients had a BKV+ biopsy before BKV viremia, and VP1 sequencing identified a different subtype compared to BKVN in all of them. After the onset of BKV viremia and prior to BKVN diagnosis, the BKV subtype in BKV+ plasma and kidney biopsy was the same as the one isolated at BKVN. BKV–VP1 NAbs titers were significantly higher at the time of BKVN compared to transplantation (p = .0031), with similar titers across genotypes.
Conclusion
Altogether, our data suggest that among some KTR with BKVN, the BKV genotype from the donor may not be responsible for BKVN pathogenesis.
Norovirus is the second most common cause of diarrhea among solid organ transplant recipients. There are currently no approved therapies for Norovirus, which can substantially impact quality of life, particularly in an immunocompromised patient population. In order to establish clinical efficacy and support any medication claims related to a patient's symptoms or function, the Food and Drug Administration requires that a trial's primary endpoints be derived from patient reported outcome measures- an outcome that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else. In this paper, we describe our study team's approach to the definition, selection, measurement and evaluation of patient reported outcome measures as part of establishing clinical efficacy of Nitazoxanide for acute and chronic Norovirus in solid organ transplant recipients. We specifically describe our approach to measuring the primary efficacy endpoint- days to cessation of vomiting and diarrhea after randomization through 160 days, measured through daily symptom diaries as well as the impact of treatment on exploratory efficacy endpoints, particularly change in the impact of norovirus on psychological function and quality of life.
Culture of bronchoalveolar lavage (BAL) specimens takes time to report. We tested whether a molecular diagnostic test could accelerate donor lung assessment and treatment.
Methods
We compared BioFire Film Array Pneumonia Panel (BFPP) with standard of care (SOC) tests on lung allograft samples at three time points: (1) donor BAL at organ recovery, (2) donor bronchial tissue and airway swab at implantation, and (3) first recipient BAL following lung implantation. Primary outcomes were the difference in time to result (Wilcoxon signed-ranked tests) and the agreement in results between BFPP and SOC assays (Gwet's agreement coefficient).
Results
We enrolled 50 subjects. In donor lung BAL specimens, BFPP detected 52 infections (14 out of 26 pathogens in the panel). Viral and bacterial BFPP results were reported 2.4 h (interquartile range, IQR 2.0–6.4) following BAL versus 4.6 h (IQR 1.9–6.0, p = 0.625) for OPO BAL viral SOC results and 66 h (IQR 47–87, p < .0001) for OPO BAL bacterial SOC results. Although there was high overall agreement of results between BAL–BFPP versus OPO BAL–SOC tests (Gwet's AC p < .001 for all), the level of agreement differed among 26 pathogens designed in BFPP and differed by types of specimens. BFPP could not detect many infections identified by SOC assays.
Conclusions
BFPP decreased time to detection of lung pathogens among donated lungs, but it cannot replace SOC tests due to the limited number of pathogens in the panel.
Cytomegalovirus (CMV) is a frequent infectious complication following solid organ transplantation (SOT). Considering significant differences in healthcare systems, a systematic review was conducted to describe the epidemiology, management, and burden of CMV post-SOT in selected countries outside of Europe and North America.
Methods
MEDLINE, Embase, and Cochrane databases were searched for observational studies in SOT recipients across 15 countries in the regions of Asia, Pacific, and Latin America (search period: January 1, 2011 to September 17, 2021). Outcomes included incidence of CMV infection/disease, recurrence, risk factors, CMV-related mortality, treatment patterns and guidelines, refractory and/or resistant CMV, patient-reported outcomes, and economic burden.
Results
Of 2708 studies identified, 49 were eligible (n = 43/49; 87.8% in adults; n = 34/49, 69.4% in kidney recipients). Across studies, selection of CMV preventive strategy was based on CMV serostatus. Overall, rates of CMV infection (within 1 year) and CMV disease post-SOT were respectively, 10.3%–63.2% (9 studies) and 0%–19.0% (17 studies). Recurrence occurred in 35.4%–41.0% cases (3 studies) and up to 5.3% recipients died of CMV-associated causes (11 studies). Conventional treatments for CMV infection/disease included ganciclovir (GCV) or valganciclovir. Up to 4.4% patients were resistant to treatment (3 studies); no studies reported on refractory CMV. Treatment-related adverse events with GCV included neutropenia (2%–29%), anemia (13%–48%), leukopenia (11%–37%), and thrombocytopenia (13%–24%). Data on economic burden were scarce.
The aim of this study is to explore the relationship between ganciclovir exposure and clinical efficacy and/or safety in non-renal solid organ transplant (SOT) recipients receiving preemptive therapy with ganciclovir/valganciclovir and undergoing therapeutic drug monitoring (TDM)-guided dosing optimization.
Methods
Non-renal SOT recipients admitted to IRCCS Azienda Ospedaliero-Universitaria of Bologna receiving preemptive therapy with ganciclovir or valganciclovir for active cytomegalovirus (CMV) infection and who underwent at least one TDM were included. Desired ganciclovir Cmin range was set at 1–3 mg/L, and average ganciclovir trough concentrations (Cmin) were calculated for each patient. Reduced CMV viral load below the lower limit of quantification (LLQ) at 30 days and occurrence of myelotoxicity were selected as the primary outcome. Univariate analysis was performed by comparing patients with average Cmin below or above 1 or 3 mg/L. Receiver operating characteristic (ROC) curve analysis was performed to identify the average ganciclovir Cmin cut-off predictive for clinical efficacy or toxicity.
Results
Twenty-nine out of 89 retrieved patients met the inclusion criteria, with a median (interquartile [IQR]) baseline CMV viral load of 27,163 copies/mL (IQR 13 159.75–151 340.25 copies/mL). Reduced CMV viral load below the LLQ at 30 days was found in 17 patients (58.6%). No difference was found in the primary outcome between patients showing average Cmin below or above 1 mg/L (100.0% vs. 53.8%; p = .25) and/or 3 mg/L (65.2% vs. 33.3%; p = .20). ROC analysis did not allow to identify an average Cmin cut-off predictive of clinical efficacy or toxicity.
Conclusions
No clear relationship between ganciclovir Cmin and neither CMV eradication nor safety issues was identified.
Available data are limited concerning long-term lung function (LF) evolution after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in lung transplant (LT) recipients. The aim of this study is to determine the effect of first SARS-CoV-2 infection on long-term LF in LT recipients. We analyzed spirometry results of LT recipients followed at our institution (March 2020 to July 2022) at 3, 6, and 12 months after first SARS-CoV-2 infection. Overall, 42 LT patients of our cohort (70%) with COVID-19 were included for long-term LF analysis. Forced expiratory volume in 1 s (FEV1) declined significantly at 3 months (−4.5%, −97 mL, 95% CI [−163; −31], p < .01), but not at 6 and 12 months (−3.9%, −65 mL, 95% CI [−168; +39], p = .21). Results were quite similar for the forced vital capacity. Spirometry values declined significantly at 3 months after COVID-19 in LT recipients, presented a mixed decline at 6 months, and no significant decline at 12 months.
Delayed graft function (DGF) increases the renal allograft failure risk. Late-onset Cytomegalovirus (CMV) infection's effect on the association between DGF and allograft failure has not been determined.
Methods
In this retrospective cohort, we included all renal allograft recipients at London Health Sciences Centre from January 1, 2014 to December 30, 2017, and continued clinical follow-up until February 28, 2020. We determined whether late-onset CMV infection affects the association between DGF and allograft failure in stratified and Cox proportional hazard analyses.
Results
Of 384 patients (median age [interquartile range]: 55 [43.3–63]; 38.7% female), 57 recipients (14.8%) were diagnosed with DGF. Patients with DGF were at a greater risk of CMV infection than patients without DGF (22.8% vs. 11.3%, p = .017). Late-onset CMV infection (odds ratio [OR]: 4.7, 95% CI: 2.07–10.68) and rejection (OR: 9.59, 95% CI: 4.15–22.16) significantly increased the risk of allograft failure in recipients with DGF. Patients with DGF had a significantly greater risk of graft failure than those without DGF (17.5% vs. 6.1%, p = .007). In the adjusted Cox hazard model, CMV infection significantly increased the risk of allograft failure (aHR: 3.19, 95% CI: 1.49–6.84).
Conclusion
Late-onset CMV infection considerably increased the risk of graft failure in patients with DGF. A hybrid preventive model including prophylaxis followed by CMV-specific cell-mediated immunity monitoring may decrease the risk of allograft failure in recipients with DGF.
Perfusion fluid (PRF) is employed in liver transplantation (LTx) to maintain graft viability. Still, it represents a new potential way of infection transmission in LTx recipients (LTRs). Currently, no systematic research has investigated this topic.
Methods
Five-year single-center retrospective study conducted on LTRs from January 2017 to December 2021. We analyzed the incidence of positive PRF culture (PRF+) and perfusion fluid-related infections (PRF-RI) and their associated factors. We also assessed 1-year mortality, both overall and infection-related.
Results
Overall, 234 LTx were included. PRF+ were found in 31/234 (13.2%) LTx for a total of 37 isolates, with >1 isolate identified in 5 (2.1%) cases. High-risk microorganisms (Enterobacterales 13/37, Enterococcus spp. 4/37, S. aureus 3/37, P. aeruginosa 2/37) were isolated in 25/37 (67.6%) LTRs, the remaining being coagulase-negative staphylococci (12/37, 32.4%). Antimicrobial prophylaxis was administered to all LTRs, always active against the isolate even if suboptimal in 19 cases (61.3%). PRF-RI developed in 4/234 LTx (1.7%), and prophylaxis was considered suboptimal in 2/4 of them. The isolation of >1 microorganism in PRF culture was associated with an increased risk of developing PRF-RI (OR 37.5 [95%CI 2.6–548.4], p = .01). PRF-RI were associated with longer ICU stays (p = .005) and higher 1-year mortality, both overall and related to infections (p = .001).
Conclusion
Despite PRF+ being infrequent, only a minority of patients develops PRF-RI. Nonetheless, once occurred, PRF-RI seems to increase morbidity and mortality rates.
Among lung transplant recipients, serial bronchoscopies are performed frequently. Often, serial galactomannan (GM), 1,3-β-d-glucan (BDG), and Pneumocystis jirovecii (PJ) testing is performed with these broncho-alveolar lavages (BALs) as standard of care with limited data to support their routine use.
Methods
After Institutional Review Board approval, we retrospectively collected all blood and BAL GM, BDG, and PJ test results from January 2015 to July 20, 2022. Primary data collection from the Northwestern Medicine EDW was supplemented by manual chart review.
Results
During the study period, 236 lung transplant recipients were cared for by our center. Of these patients, 217 (91.9%) had 1418 GM tests performed; 61 (4.3%) were positive (index ≥1). Fungal cultures were requested for most BAL-GM (90.7%). Out of duplicates in same BAL, results discrepancy was minimal (3.4%). 172 (72.9%) had BDG tests were performed; 25.6% were positive. Thirteen patients had multiple BDG during one hospitalization (mean 2.3 tests); none of the negative test repeated became positive. Eleven negative BDG were seen in patients with invasive aspergillosis (IA). Note that, 577 PJ testing were performed (direct fluorescent antibody [n = 494] or polymerase chain reaction [PCR] [n = 80], or both [n = 3]) in 174 different patients. None were positive.
Conclusion
Despite supplemental GM, BDG, and Pneumocystis jirovecii pneumonia PCR being performed routinely on lung transplant recipients undergoing BAL at our center, the data suggests a more tailored approach may be appropriate. There is no role for routine serial testing with these assays during a single hospitalization. BDG confers no added-value over GM with cultures for IA diagnosis.
There is increased interest in bacteriophage (phage) therapy to treat infections caused by antibiotic-resistant bacteria. A lung transplant recipient with cystic fibrosis and Burkholderia multivorans infection was treated with inhaled phage therapy for 7 days before she died.
Methods
Phages were given via nebulization through the mechanical ventilation circuit. Remnant respiratory specimens and serum were collected. We quantified phage and bacterial deoxyribonucleic acid (DNA) using quantitative polymerase chain reaction, and tested phage neutralization in the presence of patient serum. We performed whole genome sequencing and antibiotic and phage susceptibility testing on 15 B. multivorans isolates. Finally, we extracted lipopolysaccharide (LPS) from two isolates and visualized their LPS using gel electrophoresis.
Results
Phage therapy was temporally followed by a temporary improvement in leukocytosis and hemodynamics, followed by worsening leukocytosis on day 5, deterioration on day 7, and death on day 8. We detected phage DNA in respiratory samples after 6 days of nebulized phage therapy. Bacterial DNA in respiratory samples decreased over time, and no serum neutralization was detected. Isolates collected between 2001 and 2020 were closely related but differed in their antibiotic and phage susceptibility profiles. Early isolates were not susceptible to the phage used for therapy, while later isolates, including two isolates collected during phage therapy, were susceptible. Susceptibility to the phage used for therapy was correlated with differences in O-antigen profiles of an early versus a late isolate.
Conclusions
This case of clinical failure of nebulized phage therapy highlights the limitations, unknowns, and challenges of phage therapy for resistant infections.
The cover image is based on the Original Article Cannabinoid-1 receptor regulates mitochondrial dynamics and function in renal proximal tubular cells by Adi Drori et al., 10.1111/dom.13497 .
Measles, mumps, rubella, and even poliomyelitis outbreaks have recently perplexed infectious disease clinicians and epidemiologists globally due to the decline in vaccination coverage rates in children and adults. Measles and yellow fever (YF) have represented an increasing burden on the Brazilian public health system in recent decades. Both diseases are preventable by live-attenuated viral vaccines (LAVV), which have restricted use in hematopoietic cell transplant (HCT) recipients.
Methods
Autologous and allogeneic HCT recipients returning for regular appointments at the outpatient clinic were invited to participate in the study. Patients transplanted for at least 2 years and with a printed copy of the vaccination record were included.
Results
We assessed the vaccination records of 273 HCT recipients after the second year of HCT (193 allogeneic and 80 autologous) and observed lower compliance with the YF vaccine (58 patients, 21.2%) than with the measles vaccine (138 patients, 50.5%, p ≤ .0001). This is the largest published series of YF vaccination in HCT recipients so far. No severe adverse events occurred. Although expected, chronic graft-versus-host disease (GVHD) did not affect the compliance with measles (p = .08) or YF vaccination (p = .7). Indeed, more allogeneic recipients received measles vaccine in comparison with autologous patients (p < .0001), suggesting that chronic GVHD was not the main reason for not being vaccinated. Children and allogeneic HCT were more likely to receive measles vaccine. Time elapsed from HCT >5 years favored both measles and YF vaccination.
Conclusion
A better understanding of the reasons for low compliance with LAVV is necessary to overcome this problem.
