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  • Stier EA
  • Clarke MA
  • Deshmukh AA
  • Wentzensen N
  • Liu Y
  • et al.
Int J Cancer. 2024 May 15;154(10):1694-1702 doi: 10.1002/ijc.34850.

The International Anal Neoplasia Society (IANS) developed consensus guidelines to inform anal cancer screening use among various high-risk groups. Anal cancer incidence estimates by age among risk groups provided the basis to identify risk thresholds to recommend screening. Guided by risk thresholds, screening initiation at age 35 years was recommended for men who have sex with men (MSM) and transgender women (TW) with HIV. For other people with HIV and MSM and TW not with HIV, screening initiation at age 45 years was recommended. For solid organ transplant recipients, screening initiation beginning from 10 years post-transplant was recommended. For persons with a history of vulvar precancer or cancer, screening initiation was recommended starting within 1 year of diagnosis of vulvar precancer or cancer. Persons aged ≥45 years with a history of cervical/vaginal HSIL or cancer, perianal warts, persistent (>1 year) cervical HPV16, or autoimmune conditions could be considered for screening with shared decision-making, provided there is adequate capacity to perform diagnostic procedures (high-resolution anoscopy [HRA]). Anal cytology, high-risk (hr) human papillomavirus (HPV) testing (including genotyping for HPV16), and hrHPV-cytology co-testing are different strategies currently used for anal cancer screening that show acceptable performance. Thresholds for referral for HRA or follow-up screening tests are delineated. These recommendations from IANS provide the basis to inform management of abnormal screening results, considering currently available screening tools. These guidelines provide a pivotal foundation to help generate consensus among providers and inform the introduction and implementation of risk-targeted screening for anal cancer prevention.

  • Fatly ZA
  • Betjes MGH
  • Dik WA
  • Fouchier RAM
  • Reinders MEJ
  • et al.
J Infect. 2024 Mar 2;88(3):106133 doi: 10.1016/j.jinf.2024.106133.
OBJECTIVES:

To study the effect of mycophenolate mofetil (MMF) on various vaccination responses in kidney transplant recipients.

METHODS:

In a randomized controlled trial (EudraCT nr.: 2014-001372-66), low immunologically risk kidney transplant recipients were randomized to TAC/MMF or TAC-monotherapy (TACmono), six months post-transplantation. One year after transplantation, in a pre-specified sub-study, recipients were vaccinated against pneumococcus, tetanus and influenza. Blood was sampled before and 21 days after vaccination. Adequate vaccination responses were defined by international criteria. A post-hoc analysis was conducted on SARS-CoV-2 vaccination responses within the same cohort.

RESULTS:

Seventy-one recipients received pneumococcal and tetanus vaccines (TAC/MMF: n = 37, TACmono: n = 34), with 29 also vaccinated against influenza. When vaccinated, recipients were 60 (54-66) years old, with median eGFR of 54 (44-67) ml/min, tacrolimus trough levels 6.1 (5.4-7.0) ug/L in both groups and TAC/MMF daily MMF dose of 1000 (500-2000) mg. Adequate vaccination responses were: pneumococcal (TAC/MMF 43%, TACmono 74%, p = 0.016), tetanus (TAC/MMF 35%, TACmono 82%, p < 0.0001) and influenza (TAC/MMF 20%, TACmono 71%, p = 0.0092). Only 7% of TAC/MMF responded adequately to all three compared to 36% of TACmono (p = 0.080). Additionally, 40% of TAC/MMF responded inadequately to all three, whereas all TACmono patients responded adequately to at least one vaccination (p = 0.041). Lower SARS-CoV-2 vaccination antibody responses correlated with lower pneumococcal antibody vaccination responses (correlation coefficient: 0.41, p = 0.040).

CONCLUSIONS:

MMF on top of tacrolimus severely hampers antibody responses to a broad range of vaccinations.

  • Huang HJ
  • Schechtman K
  • Askar M
  • Bernadt C
  • Mitter B
  • et al.
Transplantation. 2024 Mar 1;108(3):777-786 doi: 10.1097/TP.0000000000004841.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This pilot study recruited lung transplant recipients at 2 sites, and randomised them to standard immunosuppression (Tac, MMF, Pred) or a belatacept-based regimen (Tac, Belatacept and pred). The hypothesis was that belatacept-based immunosuppression might reduce the incidence of donor-specific antibodies (DSA), leading to a reduction in the risk of chronic lung allograft dysfunction (CLAD). The study was stopped after recruitment of 27 patients due to 3 deaths in the belatacept arm. Causes of death varied – 2 patients died from COVID-19 infection, one from CLAD related to infection, one from PTLD, one from pulmonary embolus and one from haemothorax. The authors ascribe 4 of these deaths to viral infections. No differences were seen in incidence of CLAD or development of DSA. It is very difficult to interpret these results given the small numbers, but clearly the authors were correct in stopping the study and switching patients to standard immunosuppression. The relationship of four of the deaths to viral infection would suggest that the immunosuppressive regimen may have contributed, and in the absence of any detectable clinical benefit, the conclusion that this regimen is unsafe in lung transplant recipients seem justified.
Aims: This study aimed to evaluate the feasibility and inform the design of an RCT investigating the efficacy and safety of belatacept following lung transplantation
Interventions: Participants were randomly assigned to either continue standard-of-care immunosuppression or switch to belatacept.
Participants: 27 lung transplant recipients.
Outcomes: The primary outcome was to assess the feasibility of randomising 80% of eligible patients within 4 hours posttransplantation. The primary outcome was later changed to survival following the cessation of treatment with belatacept.
Follow Up: 1 year posttransplantation.
BACKGROUND:

Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation. The development of donor-specific antibodies (DSA) is a recognized risk factor for CLAD. Based on experience in kidney transplantation, we hypothesized that belatacept, a selective T-cell costimulatory blocker, would reduce the incidence of DSA after lung transplantation, which may ameliorate the risk of CLAD.

METHODS:

We conducted a pilot randomized controlled trial (RCT) at 2 sites to assess the feasibility and inform the design of a large-scale RCT. All participants were treated with rabbit antithymocyte globulin for induction immunosuppression. Participants in the control arm were treated with tacrolimus, mycophenolate mofetil, and prednisone, and participants in the belatacept arm were treated with tacrolimus, belatacept, and prednisone through day 89 after transplant then converted to belatacept, mycophenolate mofetil, and prednisone for the remainder of year 1.

RESULTS:

After randomizing 27 participants, 3 in the belatacept arm died compared with none in the control arm. As a result, we stopped enrollment and treatment with belatacept, and all participants were treated with standard-of-care immunosuppression. Overall, 6 participants in the belatacept arm died compared with none in the control arm (log rank P  = 0.008). We did not observe any differences in the incidence of DSA, acute cellular rejection, antibody-mediated rejection, CLAD, or infections between the 2 groups.

CONCLUSIONS:

We conclude that the investigational regimen used in this pilot RCT is associated with increased mortality after lung transplantation.

  • Lu LY
  • Lee HM
  • Burke A
  • Li Bassi G
  • Torres A
  • et al.
Chest. 2024 Mar;165(3):540-558 doi: 10.1016/j.chest.2023.09.019.
BACKGROUND:

Influenza-associated pulmonary aspergillosis (IAPA) increasingly is being reported in critically ill patients. We conducted this systematic review and meta-analysis to examine the prevalence, risk factors, clinical features, and outcomes of IAPA.

STUDY QUESTION:

What are the prevalence, risk factors, clinical features, and outcomes of IAPA in critically ill patients?

STUDY DESIGN AND METHODS:

Studies reporting IAPA were searched in the following databases: PubMed MEDLINE, CINAHL, Cochrane Library, Embase, Scopus, Cochrane Trials, and ClinicalTrials.gov. We performed one-group meta-analysis on risk factors, clinical features, morbidity, and mortality using random effects models.

RESULTS:

We included 10 observational studies with 1,720 critically ill patients with influenza, resulting in an IAPA prevalence of 19.2% (331 of 1,720). Patients who had undergone organ transplantation (OR, 4.8; 95% CI, 1.7-13.8; I2 = 45%), harbored a hematogenous malignancy (OR, 2.5; 95% CI, 1.5-4.1; I2 = 0%), were immunocompromised (OR, 2.2; 95% CI, 1.6-3.1; I2 = 0%), and underwent prolonged corticosteroid use before admission (OR, 2.4; 95% CI, 1.4-4.3; I2 = 51%) were found to be at a higher risk of IAPA developing. Commonly reported clinical and imaging features were not particularly associated with IAPA. However, IAPA was associated with more severe disease progression, a higher complication rate, and longer ICU stays and required more organ supports. Overall, IAPA was associated with a significantly elevated ICU mortality rate (OR, 2.6; 95% CI, 1.8-3.8; I2 = 0%).

INTERPRETATION:

IAPA is a common complication of severe influenza and is associated with increased mortality. Early diagnosis of IAPA and initiation of antifungal treatment are essential, and future research should focus on developing a clinical algorithm.

TRIAL REGISTRY:

International Prospective Register of Systematic Reviews; No.: CRD42022284536; URL: https://www.crd.york.ac.uk/prospero/.

  • Manuel O
  • Laager M
  • Hirzel C
  • Neofytos D
  • Walti LN
  • et al.
Clin Infect Dis. 2024 Feb 17;78(2):312-323 doi: 10.1093/cid/ciad575.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This multicentre trial enrolled kidney and liver transplant recipients receiving organs from CMV-positive donors, and randomised them to either fixed-duration prophylaxis, or guided by immune monitoring. In the study group, CMV ELISpot was used to monitor, and prophylaxis stopped if positive (indicating immune reactivity). The study failed to confirm non-inferiority of the immune monitoring strategy, although the overall rates of CMV infection were similar, with earlier CMV infection seen in the study group. However, duration of prophylaxis was shorter in the study arm. The failure to demonstrate non-inferiority is due to a lack of statistical power – in reality, the infection rates were very similar between groups. The study also fails to stratify randomisation by recipient serostatus, leading to an imbalance between the two arms of the study. This is important, as the risk of CMV infection is likely different between the two subgroups. Despite these limitations, it does appear that immune monitoring-guided prophylaxis is a reasonable strategy, resulting in a shorter duration of prophylaxis and a relatively low risk of clinically relevant CMV disease.
Aims: The aim of this study was to compare the effect of an immune monitoring–guided approach versus the current standard for tailoring the duration of antiviral prophylaxis to measure cytomegalovirus (CMV)-specific immunity in solid-organ transplant recipients.
Interventions: Participants were randomised to receive a duration of antiviral prophylaxis according to immune–guided monitoring or a fixed duration (control).
Participants: 193 kidney and liver transplant recipients CMV-seronegative with seropositive donors or CMV-seropositive receiving antithymocyte globulins.
Outcomes: The two primary endpoints were proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. The secondary endpoints were the incidence of all CMV events including untreated CMV replication, high-level CMV-DNAemia, patient survival, graft survival and incidence of acute rejection.
Follow Up: 1 year
BACKGROUND:

The use of assays detecting cytomegalovirus (CMV)-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation.

METHODS:

In this randomized trial, kidney and liver transplant recipients from 6 centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving antithymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV ELISpot assay (T-Track CMV); prophylaxis in the intervention group was stopped if the assay was positive. The co-primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus.

RESULTS:

Overall, 193 patients were randomized (92 in the immune-monitoring group and 101 in the control group), of whom 185 had evaluation of the primary outcome (87 and 98 patients). CMV infection occurred in 26 of 87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32 of 98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference, -0.1; 95% confidence interval [CI], -13.0% to 12.7%; P = .064). The duration of prophylaxis was shorter in the immune-monitoring group (adjusted difference, -26.0 days; 95%, CI, -41.1 to -10.8 days; P < .001).

CONCLUSIONS:

Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary outcome of CMV infection.

CLINICAL TRIALS REGISTRATION:

NCT02538172.

  • Eeuwijk J
  • Ferreira G
  • Yarzabal JP
  • Robert-Du Ry van Beest Holle M
Infect Dis Ther. 2024 Feb;13(2):273-298 doi: 10.1007/s40121-024-00919-0.
INTRODUCTION:

Clostridioides difficile infection (CDI) is a major public health threat. Up to 40% of patients with CDI experience recurrent CDI (rCDI), which is associated with increased morbidity. This study aimed to define an at-risk population by obtaining a detailed understanding of the different factors leading to CDI, rCDI, and CDI-related morbidity and of time to CDI.

METHODS:

We conducted a systematic literature review (SLR) of MEDLINE (using PubMed) and EMBASE for relevant articles published between January 1, 2016, and November 11, 2022, covering the US population.

RESULTS:

Of the 1324 articles identified, 151 met prespecified inclusion criteria. Advanced patient age was a likely risk factor for primary CDI within a general population, with significant risk estimates identified in nine of 10 studies. Older age was less important in specific populations with comorbidities usually diagnosed at earlier age, such as bowel disease and cancer. In terms of comorbidities, the established factors of infection, kidney disease, liver disease, cardiovascular disease, and bowel disease along with several new factors (including anemia, fluid and electrolyte disorders, and coagulation disorders) were likely risk factors for primary CDI. Data on diabetes, cancer, and obesity were mixed. Other primary CDI risk factors were antibiotics, proton pump inhibitors, female sex, prior hospitalization, and the length of stay in hospital. Similar factors were identified for rCDI, but evidence was limited. Older age was a likely risk factor for mortality. Timing of primary CDI varied depending on the population: 2-3 weeks in patients receiving stem cell transplants, within 3 weeks for patients undergoing surgery, and generally more than 3 weeks following solid organ transplant.

CONCLUSION:

This SLR uses recent evidence to define the most important factors associated with CDI, confirming those that are well established and highlighting new ones that could help to identify patient populations at high risk.

  • Li JM
  • Cosler LE
  • Harausz EP
  • Myers CE
  • Kufel WD
Pharmacotherapy. 2024 Feb;44(2):197-206 doi: 10.1002/phar.2895.

Urinary tract infections (UTIs) commonly affect many patient populations. Recurrent UTIs (rUTIs) can be particularly problematic and lead to potential hospitalizations, multiple antibiotic courses, and have a potential negative impact on quality of life. To prevent UTIs, antibiotics are frequently used for prophylaxis; however, antibiotic prophylaxis has notable untoward consequences including but not limited to potential adverse effects and development of antibiotic resistance. Methenamine, an antiseptic agent initially available in 1967, has re-emerged as a potential option for UTI prophylaxis in various populations, including older adults and renal transplant recipients. The objective of this systematic review was to evaluate the clinical effectiveness and safety of methenamine for UTI prophylaxis. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance was performed. A PubMed, Embase, and Cochrane library search was conducted to identify relevant English-language studies evaluating methenamine for UTI prophylaxis including randomized controlled trials, case-control studies, and meta-analyses through June 2023. Articles were excluded if the studies did not primarily describe or evaluate methenamine for UTI prophylaxis, were commentaries/viewpoints articles, point prevalence studies, review articles, studies that evaluated methenamine used with another agent, and any duplicate publications from searched databases. A total of 11 articles were identified for inclusion. This systematic review suggests methenamine generally appears to be an effective and well-tolerated antibiotic-sparing option for UTI prophylaxis. Furthermore, the pharmacology, dosage and formulation, warnings, precautions, and safety considerations of methenamine that provide potential clinical considerations regarding its use for UTI prophylaxis are described. Further studies are needed to evaluate the clinical utility of methenamine for UTI prophylaxis.

  • Passerini M
  • Nayfeh T
  • Yetmar ZA
  • Coussement J
  • Goodlet KJ
  • et al.
Clin Microbiol Infect. 2024 Feb;30(2):170-177 doi: 10.1016/j.cmi.2023.10.008.
BACKGROUND:

Whether trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis prevents nocardiosis in solid organ transplant (SOT) recipients is controversial.

OBJECTIVES:

To assess the effect of TMP-SMX in the prevention of nocardiosis after SOT, its dose-response relationship, its effect on preventing disseminated nocardiosis, and the risk of TMP-SMX resistance in case of breakthrough infection.

METHODS:

A systematic review and individual patient data meta-analysis.

DATA SOURCES:

MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science Core Collection, and Scopus up to 19 September 2023.

STUDY ELIGIBILITY CRITERIA:

(a) Risk of nocardiosis between SOT recipients with and without TMP-SMX prophylaxis, or (b) sufficient details to determine the rate of TMP-SMX resistance in breakthrough nocardiosis.

PARTICIPANTS:

SOT recipients.

INTERVENTION:

TMP-SMX prophylaxis versus no prophylaxis.

ASSESSMENT OF RISK OF BIAS:

Risk Of Bias In Non-randomized Studies-of Exposure (ROBINS-E) for comparative studies; dedicated tool for non-comparative studies.

METHODS OF DATA SYNTHESIS:

For our primary outcome (i.e. to determine the effect of TMP-SMX on the risk of nocardiosis), a one-step mixed-effects regression model was used to estimate the association between the outcome and the exposure. Univariate and multivariable unconditional regression models were used to adjust for the potential confounding effects. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

RESULTS:

Individual data from three case-control studies were obtained (260 SOT recipients with nocardiosis and 519 uninfected controls). TMP-SMX prophylaxis was independently associated with a significantly decreased risk of nocardiosis (adjusted OR = 0.3, 95% CI 0.18-0.52, moderate certainty of evidence). Variables independently associated with an increased risk of nocardiosis were older age, current use of corticosteroids, high calcineurin inhibitor concentration, recent acute rejection, lower lymphocyte count, and heart transplant. Breakthrough infections (66/260, 25%) were generally susceptible to TMP-SMX (pooled proportion 98%, 95% CI 92-100).

CONCLUSIONS:

In SOT recipients, TMP-SMX prophylaxis likely reduces the risk of nocardiosis. Resistance appears uncommon in case of breakthrough infection.

  • Preiksaitis J
  • Allen U
  • Bollard CM
  • Dharnidharka VR
  • Dulek DE
  • et al.
Pediatr Transplant. 2024 Feb;28(1):e14471 doi: 10.1111/petr.14471.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein-Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of "viremia" to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre-emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre-emptive interventions in patients who are EBV seronegative pre-transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre-transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre-emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority.

  • Green M
  • Squires JE
  • Chinnock RE
  • Comoli P
  • Danziger-Isakov L
  • et al.
Pediatr Transplant. 2024 Feb;28(1):e14350 doi: 10.1111/petr.14350.

The International Pediatric Transplant Association (IPTA) convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorder after solid organ transplantation in children. In this report from the Prevention Working Group, we reviewed the existing literature regarding immunoprophylaxis and chemoprophylaxis, and pre-emptive strategies. While the group made a strong recommendation for pre-emptive reduction of immunosuppression at the time of EBV DNAemia (low to moderate evidence), no recommendations for use could be made for any prophylactic strategy or alternate pre-emptive strategy, largely due to insufficient or conflicting evidence. Current gaps and future research priorities are highlighted.