Search

Introduction:Identifying genetic factors that influence HIV-pathogenesis is critical for understanding disease pathways. Previous studies have suggested a role for the human gene ten-eleven methylcytosine dioxygenase 2 (TET2) in modulating HIV-pathogenesis.Methods:We assessed whether genetic variation in TET2 was associated with markers of HIV-pathogenesis using both gene level and single nucleotide polymorphism (SNP) level association in 8512 HIV-positive persons across five clinical trial cohorts.Results:Variation at both the gene and SNP-level of TET2 was found to be associated with levels of HIV viral load (HIV-VL) consistently in the two cohorts that recruited antiretroviral-naïve participants. The SNPs occurred in two clusters of high linkage disequilibrium (LD), one associated with high HIV-VL and the other low HIV-VL, and were predominantly found in Black participants.Conclusion:Genetic variation in TET2 was associated with HIV-VL in two large antiretroviral therapy (ART)-naive clinical trial cohorts. The role of TET2 in HIV-pathogenesis warrants further investigation.

Type 2 diabetes mellitus (T2DM) can be multifactorial where both genetics and environmental factors play a role. We aimed to investigate the use of polygenic risk scores (PRS) in the prediction of pre-transplant T2DM and post-transplant diabetes mellitus (PTDM) among solid organ transplant (SOT) patients. Using non-genetic risk scores alone; and the combination with PRS, separate logistic regression models were built and compared using receiver operator curves. Patients were assessed pre-transplant and in three post-transplant periods: 0-45, 46-365 and >365 days. A higher PRS was significantly associated with increased odds of pre-transplant T2DM. However, no improvement was observed for pre-transplant T2DM prediction when comparing PRS combined with non-genetic risk scores to using non-genetic risk scores alone. This was also true for predictions of PTDM in all three post-transplant periods. This study demonstrated that polygenic risk was only associated with the risk of T2DM among SOT recipients prior to transplant and not for PTDM. Combining PRS with a clinical model of non-genetic risk scores did not significantly improve the predictive ability, indicating its limited clinical utility in identifying patients at high risk for T2DM before transplantation, suggesting that non-genetic or different genetic factors may contribute to PTDM.

Vaccination is an evidence-based strategy to prevent or reduce the severity of infectious diseases (ID). Here, we aimed to describe the experience of implementing a vaccination clinic specifically targeting liver, heart, lung, and combined dual organ transplantation at a single transplantation center in Denmark. In this cohort of 242 solid organ transplant (SOT) candidates, we investigated seroprotection and the proportion of recommended vaccinations documented before transplantation. Furthermore, we registered completed vaccinations after ID consultations. The median age in our cohort was 53 years (IQR, 42–60), 60% were males (n = 135), and liver transplants (n = 138; 57%) were the most frequently planned organ transplants. Before the consultation to the vaccination clinic, influenza and pneumococcal vaccines had the highest proportion of documented vaccination (58% and 37%, respectively). Serological protection was more frequently observed for measles, mumps, or rubella (MMR, approximately 90% for each), while only 30% (n = 72) of SOT candidates showed seroprotection against pneumococcal disease. All SOT candidates required at least one of the recommended vaccines, and over 90% required three or more. At least 10% of patients in our cohort needed a live attenuated vaccine for either MMR or yellow fever. The most frequently administered vaccine was the tetanus–diphtheria-acelullar pertussis (Tdap) booster (n = 217; 90%), influenza vaccination was either administered (n = 16; 7%) or recommended (n = 226; 93%), PCV13 was administered (n = 155; 64%) or recommended (n = 27; 11%), and PPSV23 was either administered (n = 18; 7.4%) or recommended (n = 140; 58%). All SOT candidates adhered completely to their vaccination schedules. Based on our findings, we recommend prioritizing vaccination before transplantation by providing ID consultations for SOT candidates., Vaccination is an evidence-based strategy to prevent or reduce the severity of infectious diseases (ID). Here, we aimed to describe the experience of implementing a vaccination clinic specifically targeting liver, heart, lung, and combined dual organ transplantation at a single transplantation center in Denmark. In this cohort of 242 solid organ transplant (SOT) candidates, we investigated seroprotection and the proportion of recommended vaccinations documented before transplantation. Furthermore, we registered completed vaccinations after ID consultations. The median age in our cohort was 53 years (IQR, 42–60), 60% were males (n = 135), and liver transplants (n = 138; 57%) were the most frequently planned organ transplants. Before the consultation to the vaccination clinic, influenza and pneumococcal vaccines had the highest proportion of documented vaccination (58% and 37%, respectively). Serological protection was more frequently observed for measles, mumps, or rubella (MMR, approximately 90% for each), while only 30% (n = 72) of SOT candidates showed seroprotection against pneumococcal disease. All SOT candidates required at least one of the recommended vaccines, and over 90% required three or more. At least 10% of patients in our cohort needed a live attenuated vaccine for either MMR or yellow fever. The most frequently administered vaccine was the tetanus–diphtheria-acelullar pertussis (Tdap) booster (n = 217; 90%), influenza vaccination was either administered (n = 16; 7%) or recommended (n = 226; 93%), PCV13 was administered (n = 155; 64%) or recommended (n = 27; 11%), and PPSV23 was either administered (n = 18; 7.4%) or recommended (n = 140; 58%). All SOT candidates adhered completely to their vaccination schedules. Based on our findings, we recommend prioritizing vaccination before transplantation by providing ID consultations for SOT candidates.

Monitoring specific underlying causes of death in solid organ transplant (SOT) recipients is important in order to identify emerging trends and health challenges. This retrospective cohort study includes all SOT recipients transplanted at Rigshospitalet between January 1st, 2010 and December 31st, 2019. The underlying cause of death was determined using the newly developed Classification of Death Causes after Transplantation (CLASS) method. Cox regression analyses assessed risk factors for all-cause and cause-specific mortality. Of the 1774 SOT recipients included, 299 patients died during a total of 7511 person-years of follow-up (PYFU) with cancer (N = 57, 19%), graft rejection (N = 55, 18%) and infections (N = 52, 17%) being the most frequent causes of death. We observed a lower risk of all-cause death with increasing transplant calendar year (HR 0.91, 95% CI 0.86–0.96 per 1-year increase), alongside death from graft rejection (HR 0.84 per year, 95% CI 0.74–0.95) and death from infections (HR 0.86 per year, 95% CI 0.77–0.97). Further, there was a trend towards lower cumulative incidence of death from cardiovascular disease, graft failure and cancer in more recent years, while death from other organ specific and non-organ specific causes did not decrease. All-cause mortality among SOT recipients has decreased over the past decade, mainly due to a decrease in graft rejection- and infection-related deaths. Conversely, deaths from a broad range of other causes have remained unchanged, suggesting that cause of death among SOT recipients is increasingly diverse and warrants a multidisciplinary effort and attention in the future.

Background: Understanding the genetic interplay between human hosts and infectious pathogens is crucial for how we interpret virulence factors. Here, we tested for associations between HIV and host genetics, and interactive genetic effects on viral load (VL) in HIV-positive antiretroviral treatment-naive clinical trial participants. Methods: HIV genomes were sequenced and the encoded amino acid (AA) variants were associated with VL, human single nucleotide polymorphisms (SNPs), and imputed HLA alleles using generalized linear models with Bonferroni correction. Results: Human (388 501 SNPs) and HIV (3010 variants) genetic data were available for 2122 persons. Four HIV variants were associated with VL (P < 1.66 × 10-5). Twelve HIV variants were associated with a range of 1-512 human SNPs (P < 4.28 × 10-11). We found 46 associations between HLA alleles and HIV variants (P < 1.29 × 10-7). HIV variants and immunotypes when analyzed separately were associated with lower VL, whereas the opposite was true when analyzed in concert. Epitope binding predictions supported our observations. Conclusions: Our results show the importance of immunotype specificity on viral antigenic determinants, and the identified genetic interplay emphasizes that viral and human genetics should be studied in the context of each other. Clinical Trials Registration: NCT00867048.

Routine monitoring of parvovirus B19 (B19V) the first 6 months posttransplantation was performed in 241 seronegative solid organ transplant (SOT) recipients. Incidence rates during the first month and the second to sixth months posttransplantation were 1.2 (95% confidence interval [CI],. 33-3.2) and 0.21 (95% CI,. 06-.57) per 100 recipients per month, respectively. Of the 6 SOT recipients with positive B19V polymerase chain reaction, 3 (50%) were admitted to hospital and 2 (33%) were treated with intravenous immunoglobulin. Thus, routine monitoring of B19V in seronegative SOT recipients may not be necessary. Targeted screening 1 month posttransplantation and screening upon clinical suspicion could be an alternative strategy.

BACKGROUND: Mumps, measles, rubella, and varicella-zoster viruses (MMRV) may cause severe infections in seronegative adult solid organ transplant (SOT) recipients but can be prevented by vaccination. We aimed to determine MMRV serostatus in adult SOT recipients before and one-year post-transplantation as well as evidence of MMRV infections in a large, prospective cohort of SOT recipients.METHODS: A prospective study of 1182 adult SOT recipients included in the Management of Posttransplant Infections in Collaborating Hospitals (MATCH) cohort from 2011 to 2017 with a one-year follow-up. Systematic monitoring of MMRV serology was performed prior to transplantation and one-year post-transplantation. PCR was used to confirm viral replication in SOT-recipients presenting with clinical evidence of infection.RESULTS: Among 1182 adult SOT recipients, 28 (2.4%), 77 (6.5%), 65 (5.5%), and 22 (1.9%) were seronegative for measles, mumps, rubella, and VZV, respectively, and 165 (14%) were seronegative for at least one of the MMRV viruses. One-year post-transplantation, 29/823 (3.5%) of seropositive SOT recipients had seroreverted, and 63/111 (57%) of seronegative SOT recipients seroconverted for at least one MMRV virus. No evidence of MMR infections was found, but 8 (0.7%) SOT recipients developed symptoms and had a positive VZV PCR.CONCLUSIONS: A large proportion of SOT recipients were seronegative for at least one of the MMRV viruses. MMRV infections in SOT recipients may disseminate and become fatal, and although only few cases of VZV infection were detected, results from this study suggest increase attention towards vaccination of patients waiting for SOT.

Background Solid organ transplant (SOT) recipients are at a high risk of developing cytomegalovirus (CMV) post-transplant (tx) with many experiencing a recurrence shortly after clearing the first episode. We aimed to identify risk factors associated with CMV infection and recurrence. Methods SOT recipients (≥ 18 years) transplanted between 2011-2016 were investigated for factors associated with CMV infection within 1 year from baseline and recurrent CMV within 6 months of stopping CMV treatment for the first infection using cumulative incidence curves and Cox proportional hazards models. Baseline was defined as either tx date or date of stopping CMV prophylaxis for those initiating CMV prophylaxis within 7 days of tx. Individuals with breakthrough CMV while on prophylaxis were excluded (n=29). Results We included 755 SOT recipients, 173(23%) developed CMV infection within one year of baseline with CMV disease present at diagnosis in 17% of the cases. The risk of CMV infection was lower in patients with low (aHR 0.19, 95%CI 0.12-0.29) and intermediate (aHR 0.26, 95%CI 0.18-0.36) risk CMV IgG serostatus compared to high risk (Figure1). Liver and lung tx, female sex, older age and year of tx were also associated with an increased risk of CMV infection (Figure 2). Among the 470 (62%) patients who received CMV prophylaxis those who received < 85 days had a higher risk of CMV infection than those receiving ≥ 85 days (aHR 1.80, 95%CI 1.19-2.72). 99 recipients were investigated for recurrent CMV; 40 (40%) experienced relapse within 6 months of stopping treatment for their first infection. The risk of recurrent CMV was significantly lower in those with low (aHR 0.20, 95%CI 0.06-0.74) and intermediate risk serostatus (aHR 0.40, 95%CI 0.19-0.84) (Figure 3). Older age (aHR 1.23 per 5 years older, 95%CI 1.06-1.44) was also significantly associated with recurrent CMV infection (Figure 4). Conclusion Recurrent CMV infection remains a signif, Background Solid organ transplant (SOT) recipients are at a high risk of developing cytomegalovirus (CMV) post-transplant (tx) with many experiencing a recurrence shortly after clearing the first episode. We aimed to identify risk factors associated with CMV infection and recurrence. Methods SOT recipients (≥ 18 years) transplanted between 2011-2016 were investigated for factors associated with CMV infection within 1 year from baseline and recurrent CMV within 6 months of stopping CMV treatment for the first infection using cumulative incidence curves and Cox proportional hazards models. Baseline was defined as either tx date or date of stopping CMV prophylaxis for those initiating CMV prophylaxis within 7 days of tx. Individuals with breakthrough CMV while on prophylaxis were excluded (n=29). Results We included 755 SOT recipients, 173(23%) developed CMV infection within one year of baseline with CMV disease present at diagnosis in 17% of the cases. The risk of CMV infection was lower in patients with low (aHR 0.19, 95%CI 0.12-0.29) and intermediate (aHR 0.26, 95%CI 0.18-0.36) risk CMV IgG serostatus compared to high risk (Figure1). Liver and lung tx, female sex, older age and year of tx were also associated with an increased risk of CMV infection (Figure 2). Among the 470 (62%) patients who received CMV prophylaxis those who received < 85 days had a higher risk of CMV infection than those receiving ≥ 85 days (aHR 1.80, 95%CI 1.19-2.72). 99 recipients were investigated for recurrent CMV; 40 (40%) experienced relapse within 6 months of stopping treatment for their first infection. The risk of recurrent CMV was significantly lower in those with low (aHR 0.20, 95%CI 0.06-0.74) and intermediate risk serostatus (aHR 0.40, 95%CI 0.19-0.84) (Figure 3). Older age (aHR 1.23 per 5 years older, 95%CI 1.06-1.44) was also significantly associated with recurrent CMV infection (Figure 4). Figure 3 Risk of recurrent CMV infection in th

Background: The risk of active TB among solid organ transplant (SOT) recipients and patients initiating chronic dialysis in a country with low incidence of TB is not well elucidated.Methods: Patients aged >18 years who were transplanted with a solid organ or initiated chronic dialysis at Copenhagen University Hospital in the period 2004-2017 were followed from date of transplantation or initiation of dialysis. Data on demographics and outcomes were obtained from nationwide registries.Results: We included 1,989 SOT recipients and 1,305 patients initiating chronic dialysis, who were followed for a total of 9,785 and 4,196 person-years (PY), respectively. Only a minority of patients had been screened for latent TB prior to SOT or initiation of dialysis. The incidence rates (IRs)/100,000 PY of TB among patients from medium/high TB endemic areas were 358 (95% CI 115-1,110) and 1,266 (95% CI 681-2354) for SOT and dialysis patients, respectively, whereas IRs among patients of Danish origin were 11 (95% CI 2-81) and 31 (95% CI 4-218).Conclusion: The incidence of TB among immunosuppressed immigrants from medium/high TB endemic countries was very high, while the risk of TB among patients from low-endemic countries was minimal.

BACKGROUND: Cytomegalovirus (CMV) infection is common among solid organ transplant (SOT) recipients and may cause CMV disease. To optimize the implementation of existing prevention strategies, the Management of Post-transplant Infections in Collaborating Hospitals (MATCH) program was developed. Two key performances of MATCH (diagnosing CMV infection at low viral load (VL) and before the onset of CMV disease) were assessed prior to, during and after the implementation of MATCH.METHODS: The MATCH program included a personalized surveillance plan, prophylaxis and preemptive therapy determined by the recipient's risk of CMV infection. The plan was composed through predefined algorithms and implemented through harvesting of real-time data from medical records. Risk of CMV disease was compared for recipients transplanted during and after vs prior to the implementation of MATCH. Lung and non-lung transplants were analyzed separately.RESULTS: A total of 593, 349, 520, and 360 SOT recipients were transplanted before (2007-2010), during (2011-2012), early after (2013-2015), and late after (2016-2017) implementation of MATCH with an observed reduction of diagnostic VL (P < .001) over time. Risk of CMV disease was reduced among non-lung transplant recipients transplanted during (adjusted hazard ratios [95% CI] 0.15 [0.04-0.54], P = .003), early after (aHR 0.27 [0.11-0.63], P = .003), and late after (aHR 0.17 [0.06-0.52], P = .002) compared with prior to MATCH. No significant change was observed among lung transplants.CONCLUSION: Implementation of CMV preventive strategies through MATCH was associated with a reduced risk of CMV disease among non-lung transplant recipients. Furthermore, the limitations of VL as a sole indicator for CMV disease in lung transplants were emphasized.

Correct classification of death causes is an important component of transplant trials.We aimed to develop and validate a system to classify causes of death in hematopoietic stem cell (HSCT) and solid organ (SOT) transplant recipients.Case record forms (CRF) of fatal cases were completed, including investigator-designated cause of death. Deaths occurring in 2010 to 2013 were used for derivation; and were validated by deaths occurring in 2013 to 2015. Underlying cause of death (referred to as recorded underlying cause) was determined through a central adjudication process involving 2 external reviewers, and subsequently compared with the Danish National Death Cause Registry.Three hundred eighty-eight recipients died 2010 to 2015 (196 [51%] SOT and 192 [49%] HSCT). The main recorded underlying causes of death among SOT and HSCT were classified as cancer (20%, 48%), graft rejection/failure/graft-versus-host-disease (35%, 28%), and infections (20%, 11%). Kappa between the investigator-designated and the recorded underlying cause of death was 0.74 (95% CI 0.69-0.80) in derivation and comparable in the validation cohort. Death causes were concordant with the Danish National Death Cause Registry in 37.2% (95% CI 31.5-42.9) and 38.4% (95% CI 28.8-48.0) in the derivation and validation cohorts, respectively.We developed and validated a method to systematically and reliably classify the underlying cause of death among transplant recipients. There was a high degree of discordance between this classification and that in the Danish National Death Cause Registry.