Cytomegalovirus infection is associated with thymic dysfunction and chronic graft-versus-host disease after pediatric hematopoietic stem cell transplantation.

Pediatric hematopoietic stem cell transplantation (HSCT) is challenged by chronic graft-versus-host disease (cGvHD) significantly affecting survival and long-term morbidity, but underlying mechanisms including the impact of post-HSCT CMV infection are sparsely studied. We first investigated the impact of CMV infection for development of cGvHD in 322 children undergoing standard myeloablative HSCT between 2000 and 2018. Clinically significant CMV infection (n = 61) was an independent risk factor for chronic GvHD in a multivariable Cox regression analysis (HR = 2.17, 95% CI = 1.18-3.97, P = 0.013). We next explored the underlying mechanisms in a subcohort of 39 children. CMV infection was followed by reduced concentration of recent thymic emigrants (17.5 vs. 51.9 × 106/L, P = 0.048) and naïve CD4+ and CD8+ T cells at 6 months post-HSCT (all P < 0.05). Furthermore, CD25highFOXP3+ Tregs tended to be lower in patients with CMV infection (2.9 vs. 9.6 × 106/L, P = 0.055), including Tregs expressing the naivety markers CD45RA and Helios. CD8+ T-cell numbers rose after CMV infection and was dominated by exhausted PD1-expressing cells (66% vs. 39%, P = 0.023). These findings indicate that post-HSCT CMV infection is a main risk factor for development of chronic GvHD after pediatric HSCT and suggest that this effect is caused by reduced thymic function with a persistently impaired production of naïve and regulatory T cells in combination with increased peripheral T-cell exhaustion.

Differences in toll-like receptor ligand-induced cytokine concentrations before and after solid organ transplantation: A prospective, observational cohort study in a clinical setting.

Reliable methods to assess immune function after solid organ transplantation (SOT) are needed to guide dosing of immunosuppression. We hypothesized that toll-like receptor ligand-induced cytokine concentrations would decrease post-transplantation due to the use of immunosuppressive medication. Furthermore, we hypothesized that induced cytokine concentrations pre-transplantation would be higher in recipients with episodes of acute rejection post-transplantation due to underlying immunological dispositions. We aimed to investigate toll-like receptor ligand-induced cytokine concentrations by TruCulture©, a standardized immunoassay, in SOT recipients before and 3 months after SOT and explored associations with methylprednisolone-treated acute rejections. We conducted a prospective, observational cohort study including 123 participants (67 liver, 32 kidney and 24 lung transplant recipients). Whole blood was stimulated for 22 h with: (A) Lipopolysaccharide (LPS), (B) Resiquimod, (C) Polyinosinic:polycytidylic acid (Poly I:C) and (D) a blank control. Cytokine concentrations (TNF-α, IL-1ß, IL-6, IL-8, IL-10, IL-12p40, IL-17A, IFN-α and IFN-γ) were measured by Luminex. 30 participants developed methylprednisolone-treated acute rejection at a median of 9 days (IQR 5-17) post-SOT. We found that all induced cytokine concentrations decreased post-SOT except from LPS-induced and Poly I:C-induced IL-10. The induced cytokine concentration pre-transplantation did not differ in recipients with or without acute rejection. In conclusion, the induced cytokine concentrations decreased for all stimuli post-SOT, except the anti-inflammatory cytokine IL-10. Importantly, recipients developing early acute rejection did not differ in induced cytokine concentrations pre-SOT. Thus, the use of a standardized assay in SOT is feasible in a clinical setting and may provide important information on the immune function post-SOT.

Waning humoral and cellular immunity after COVID-19 vaccination in patients with psoriasis treated with methotrexate and biologics: a cohort study.

BACKGROUND: mRNA-based COVID-19 vaccines have short- and long-term efficacy in healthy individuals, but their efficacy in patients with psoriasis receiving immunomodulatory therapy is less studied. OBJECTIVES: To investigate long-term immunity after COVID-19 vaccination in patients with psoriasis receiving immunomodulatory therapy. METHODS: A prospective cohort study including patients (n = 123) with psoriasis receiving methotrexate (MTX) or biologics and controls (n = 226). Only mRNA-based COVID-19 vaccines administered with standard intervals between doses were investigated. Markers of immunity included SARS-CoV-2 spike glycoprotein-specific IgG and IgA, neutralizing capacity, and interferon-γ release from T cells stimulated with peptides of the SARS-CoV-2 spike glycoprotein. RESULTS: The proportion of IgG responders was lower 6 months after vaccination in patients receiving anti-tumour necrosis factor (TNF) treatment compared with controls. Anti-TNF treatment was associated with lower IgG levels (ß = -0.82, 95% confidence interval -1.38 to -0.25; P = 0.001). The median neutralizing index was lower in the anti-TNF group [50% inhibition (interquartile range [IQR] 37-89)] compared with controls [98% inhibition (IQR 96-99)]; P < 0.001. Cellular responses were numerically lowest in the anti-TNF group. CONCLUSIONS: Treatment with anti-TNF has an impact on the immunity elicited by mRNA-based COVID-19 vaccination in patients with psoriasis, resulting in a faster waning of humoral and cellular markers of immunity; however, the clinical implications are unknown.

Humoral and cellular immune responses after three or four doses of BNT162b2 in patients with hematological malignancies.

OBJECTIVES: Initial responses to coronavirus disease 2019 vaccination are impaired in patients with hematological malignancies. We investigated immune responses after three or four doses of BNT162b2 in patients with myeloid and lymphoid malignancies compared to controls, and identified risk factors for humoral and cellular nonresponse 1 year after first vaccination. METHODS: In 407 hematological patients (45 myeloid, 362 lymphoid) and 98 matched controls, we measured immunoglobulin G (IgG) and neutralizing antibodies specific for the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at baseline, 3 weeks, 2, 6, and 12 months, and interferon-γ release at 12 months. RESULTS: In patients with lymphoid malignancies, SARS-CoV-2 receptor-binding domain IgG concentration and mean neutralizing capacity was lower than in controls at all time points. A diagnosis of chronic lymphocytic B-cell leukemia (CLL) or lymphoma was associated with humoral nonresponse at 12 months compared to having multiple myeloma/amyloidosis (p < .001 and p = .013). Compared to controls, patients with lymphoid malignancies had increased risk of cellular nonresponse. A lymphoma diagnosis was associated with lower risk of cellular nonresponse compared to patients with multiple myeloma/amyloidosis, while patients with CLL had comparable response rates to patients with multiple myeloma/amyloidosis (p = .037 and p = .280). CONCLUSIONS: In conclusion, long-term humoral and cellular immune responses to BNT162b2 were impaired in patients with lymphoid malignancies.

Incidence, Risk Factors, and Consequences of Human Alphaherpesvirus Infections in Patients With Psoriasis Who Initiate Methotrexate or Biologic Agents.

BACKGROUND: Immunosuppressive agents may increase the risk of infections with human alphaherpesviruses. METHODS: We included all adult patients with moderate to severe psoriasis who initiated methotrexate (MTX) or biologic agents in a retrospective cohort study. An episode of alphaherpesviruses infection was defined as filling a prescription for systemic acyclovir, valacyclovir, or famciclovir. Using nationwide registries, we determined the incidence, risk factors, 180-day hospital contacts, and 30-day mortality following infection. RESULTS: We included 7294 patients; 4978 (68%) received MTX, and 2316 (32%) biologic agents. The incidence rates (95% confidence intervals) of alphaherpesviruses were 23 (20-27), 26 (19-35), 17 (11-27), and 6.7 (1.3-21) per 1000 person-years of follow-up in patients on MTX, tumor necrosis factor alpha (TNF-α) inhibitors, interleukin 12/23 (IL-12/23) inhibitors, and interleukin 17 (IL-17) inhibitors, respectively. Males had an unadjusted hazard ratio (HR) of 0.47 (P < .001) for alphaherpesvirus infection. Patients on IL-17 inhibitors had an adjusted HR of 0.24 (P = .048) compared to TNF-α inhibitors. Within 180 days after infection, 13%, 7.5%, and <0.5% of patients on MTX, TNF-α inhibitors, and IL-12/23 or IL-17 inhibitors, respectively, had hospital contacts, and the 30-day mortality for all groups was <0.5%. CONCLUSIONS: The incidence and risk of alphaherpesvirus infections were comparable between patients on MTX and TNF-α inhibitors, whereas use of IL-17 inhibitors was associated with a lower risk.

Incidence and severity of SARS-CoV-2 infections in liver and kidney transplant recipients in the post-vaccination era: Real-life data from Denmark.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has been associated with a high risk of adverse outcomes in solid organ transplant (SOT) recipients in the pre-vaccination era. In this retrospective cohort study, we examined the incidence and severity of COVID-19 in kidney and liver transplant recipients in Denmark in the post-vaccination era, from December 27, 2020, to December 27, 2021. We included 1428 SOT recipients with 143 cases of first-positive SARS-CoV-2 PCR test. The cumulative incidence of first-positive SARS-CoV-2 PCR test 1 year after initiation of vaccination was 10.4% (95% CI: 8.8-12.0), and the incidence was higher in kidney than in liver transplant recipients (11.6% [95% CI: 9.4-13.8] vs. 7.4% [95% CI: 5.1-9.8], p = .009). After the first-positive SARS-CoV-2 PCR test, the hospitalization rate was 31.5% (95% CI: 23.9-39.1), and 30-day all-cause mortality was 3.7% (95% CI: 0.5-6.8). Hospitalization was lower in vaccinated than in unvaccinated SOT recipients (26.4% [95% CI: 18.1-34.6] vs. 48.5% [95% CI: 31.4-65.5], p = .011), as was mortality (1.8% [95% CI: 0.0-4.3] vs. 9.1% [95% CI: 0.0-18.9], p = .047). In conclusion, SOT recipients remain at high risk of adverse outcomes after SARS-CoV-2 infections, with a lower risk observed in vaccinated than in unvaccinated SOT recipients.

Humoral response to two doses of BNT162b2 vaccination in people with HIV.

BACKGROUND: People with HIV (PWH) are at increased risk of severe COVID-19. We aimed to determine humoral responses in PWH and controls who received two doses of BNT162b2. METHODS: In 269 PWH and 538 age-matched controls, we measured IgG and neutralizing antibodies specific for the receptor-binding domain of SARS-CoV-2 at baseline, 3 weeks and 2 months after the first dose of BNT162b2. RESULTS: IgG antibodies increased from baseline to 3 weeks and from 3 weeks to 2 months in both groups, but the concentrations of IgG antibodies were lower in PWH than that in controls at 3 weeks and 2 months (p = 0.025 and <0.001), respectively. The IgG titres in PWH with a humoral response at 2 months were 77.9% (95% confidence interval [62.5%-97.0%], age- and sex-adjusted p = 0.027) of controls. CONCLUSIONS: Reduced IgG antibody response to vaccination with BNT162b2 was found in PWH, and thus increased awareness of breakthrough infections in PWH is needed.

Impact of methotrexate and adalimumab on immune function of patients with psoriasis.

Patients with psoriasis are commonly treated with methotrexate or biologics. We examined the immune response in a whole blood assay (TruCulture®) to assess the effect of methotrexate and adalimumab. Twenty patients with psoriasis were included and cytokine levels following stimulation with LPS, R848, HKCA, PolyIC, or a blank were investigated before and after 3-6 months of treatment with methotrexate or adalimumab and in patients who had received adalimumab >5 years. Methotrexate only induced minor changes in the cytokine responses, whereas adalimumab affected a wide range of cytokines important for the immune defense towards microorganisms. In the long-term adalimumab treated group, the cytokine levels were almost equivalent to the short-term adalimumab-treated group. Overall, methotrexate was not associated with cytokine suppression. Short and long-term treatment with adalimumab lowered multiple cytokines involved in the immune defense equally emphasizing the need to continuously be aware of the risk of infections in these patients.

Thymic stromal lymphopoietin levels after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is an immunoregulatory, Th2-polarizing cytokine produced by epithelial cells. We hypothesized that TSLP affects immune reconstitution after hematopoietic stem cell transplantation (HSCT) leading to increased alloreactivity. METHODS: We measured plasma TSLP by ELISA in 38 patients and assessed the immune reconstitution by flow cytometry. RESULTS: TSLP levels rose after initiation of the conditioning to peak at day +21 after HSCT (p = .03), where TSLP levels correlated with counts of neutrophils (rho = 0.36, p = .04), monocytes (rho = 0.58, p = .006), and lymphocytes (rho = 0.59, p = .02). Overall absolute TSLP levels were not associated with acute or chronic graft-vs-host disease (a/cGvHD). However, patients mounting a sustained increase in TSLP levels at day +90 had a higher risk of cGvHD compared to patients who had returned to pre-conditioning levels at that stage (cumulative incidence: 77% vs. 38%, p = .01). CONCLUSION: In conclusion, this study suggests a role of TSLP in immune reconstitution and alloreactivity post-HSCT. lymphopoietin (TSLP) is an immunoregulatory, Th2-polarizing cytokine produced by epithelial cells. We hypothesized that TSLP affects immune reconstitution after hematopoietic stem cell transplantation (HSCT) leading to increased alloreactivity. We measured plasma TSLP by ELISA in 38 patients and assessed the immune reconstitution by flow cytometry.

Incidence and Impact of Parvovirus B19 Infection in Seronegative Solid Organ Transplant Recipients.

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.

Measles, Mumps, Rubella, and Varicella Zoster Virus Serology and Infections in Solid Organ Transplant Recipients During the First Year Posttransplantation.

BACKGROUND: Mumps, measles, rubella, and varicella zoster (MMRV) viruses 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 1 year after transplantation as well as evidence of MMRV infections in a large, prospective cohort of SOT recipients. METHODS: This was 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 1-year follow-up. Systematic monitoring of MMRV serology was performed prior to transplantation and 1 year posttransplantation. Polymerase chain reaction (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 varicella zoster virus (VZV), respectively, and 165 (14%) were seronegative for at least 1 of the MMRV viruses. One year posttransplantation, 29 of 823 (3.5%) of seropositive SOT recipients had seroreverted, and 63 of 111 (57%) of seronegative SOT recipients seroconverted for at least 1 MMRV virus. No evidence of measles, mumps, or rubella infection 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 1 of the MMRV viruses. MMRV infections in SOT recipients may disseminate and become fatal, and although only a few cases of VZV infection were detected, results from this study suggest increase attention toward vaccination of patients waiting for SOT.

Bacterial and fungal bloodstream infections in pediatric liver and kidney transplant recipients.

BACKGROUND: Bacterial and fungal bloodstream infections (BSI) are common after pediatric liver and kidney transplantations and associated with morbidity and mortality. However, knowledge about incidence rates, pathogen composition, and resistance patterns is limited. We aimed to describe the pattern of bacterial and fungal BSI in a cohort of pediatric liver and kidney transplant recipients. METHODS: A prospective study of 85 pediatric liver and kidney transplant recipients transplanted from 2010 to 2017 with a total of 390 person-years of follow-up. Clinical characteristics and BSI were retrieved from national registries assuring nationwide follow-up for at least 1 year. BSI incidence rates and pathogen composition were investigated and stratified by the time post-transplantation and type of transplanted organ. RESULTS: A total of 29 BSI were observed within the first 5 years post-transplantation with 16 different pathogens. The overall incidence rate of first BSI was 1.91 per 100 recipients per month (95% CI, 1.1-3.1) in the first year post-transplantation. The most common pathogens were Enterococcus faecium, Candida albicans, Escherichia coli, and Klebsiella pneumoniae. The pathogen composition depended on the transplanted organ with a higher proportion of BSI with Enterobacterales in kidney transplant recipients than in liver transplant recipients (67% vs. 20%, p = 0.03), while multiple pathogens were detected in the liver transplant recipients. CONCLUSIONS: BSI were common in pediatric liver and kidney transplant recipients and the pathogen composition differed between liver and kidney transplant recipients. Guidelines for empiric antibiotic therapy should consider the type of transplanted organ as well as the local resistance patterns.

Self-reported symptom occurrence and distress, and psychological well-being after liver transplantation - a descriptive cross-sectional study of Danish recipients.

Introduction: Symptom distress and impaired psychological well-being after liver transplantation may lead to limitations in everyday activities and lowered health-related quality of life. The aim of this nationwide, descriptive, and cross-sectional study was to explore self-reported symptom occurrence and distress, among Danish liver transplant recipients, and their association with self-reported psychological well-being as well as demographic, and clinical characteristics. Methods: Liver transplant recipients transplanted from 1990 to 2022 were included. All recipients were asked to complete the Organ Transplant Symptom and Wellbeing instruments consisting of two instruments measuring self-reported symptom occurrence and distress, respectively, as well as self-reported psychological well-being by the Psychological General well-being instrument. Results: Of 511 invited recipients 238 responded: 116 women and 122 men with a median post-transplant follow-up of 7.5 years (IQR 3.6-14.2 years). The most common single symptoms reported were decreased libido (18%), diarrhea (10%), and headache (8%). Sleep problems were the most common transplant-specific domain. 41% of the recipients reported poor psychological well-being, especially those who had undergone transplantation within the last 5 years, women, and younger recipients. Discussion: In the interest of equity, the fact that women reported a higher level of symptom distress than men requires attention. Research on symptom management support is warranted with interventions focusing on how to alleviate symptom distress, which might increase long-term survival, which has not improved in recent decades.

Early Results of a Screening Program for Skin Cancer in Liver Transplant Recipients: A Cohort Study.

(1) Background: Skin cancer is the most common cancer in transplant recipients. Timely and regular screening may reduce advanced disease. The study aimed to determine referral rates to screening, the incidence, and risk factors of skin cancer in a Danish liver transplant recipient cohort. (2) Methods: All first-time liver transplant recipients, >18 years old, attending outpatient care between January 2018 and December 2021 were included. The referral rates and incidence of skin cancer/preneoplastic lesions were calculated. Risk factors were assessed using Cox regression analyses. (3) Results: Of the 246 included recipients, 219 (89.0%) were referred to screening, and 102 skin cancer/preneoplastic lesions were diagnosed in 32 (15.6%) recipients. The IR of any skin cancer/preneoplastic lesion was 103.2 per 1000 person-years. BCC was the most frequent skin cancer followed by SCC, IR: 51.3 vs. 27.1 per 1000 person-years, respectively. No cases of MM were observed. The IR of actinic keratosis and Bowen's Disease were 48.1 vs. 13.2 per 1000 person-years, respectively. Time since transplantation was independently associated with skin cancer/preneoplastic lesions, HR (95%CI) 2.81 (1.64-4.80). (4) Conclusions: The study determined the incidence and risk factors of skin cancer/preneoplastic lesions in liver transplant recipients enrolled in a screening program, while demonstrating a high screening referral rate.

Anemia in liver transplant recipients: prevalence, severity, risk factors, and survival.

Information about anemia in liver transplant (LTx) recipients is scarce. We investigated the prevalence and severity of anemia before and within the first-year post-LTx, risk factors for having anemia before LTx, and 1-year survival according to anemia status before LTx. This retrospective cohort study received data from The Knowledge Center for Transplantation database at Rigshospitalet, Copenhagen, Denmark. Uni- and multivariate logistic regression were used to investigate factors associated with anemia and a Kaplan-Meier plot to illustrate the probability of survival. We included 346 first-time adult LTx recipients. The median age was 50 years (IQR: 42-57), and 203 (59%) were male. The prevalence of anemia before and 1-year post-LTx were 69 and 45%, respectively. Male sex (aOR 4.0 [95% CI: 2.2-7.2]; p < 0.001) and each unit increase in MELD score (aOR 1.2 [95% CI: 1.1-1.2]; p < 0.001) were positively associated with anemia before LTx. Compared to autoimmune liver diseases, LTx recipients with fulminant hepatic failure (aOR 0.03 [0.00-0.17]; p = 0.001) had lower odds for anemia. The 1-year survival in LTx recipients who had and did not have anemia before transplantation were 93 and 91% (p = 0.47). Anemia was frequent among LTx recipients, and anemia before LTx did not affect 1-year survival.

Incidence of bacterial respiratory infection and pneumonia in people with HIV with and without airflow limitation.

OBJECTIVES: We aimed to determine the incidence rate, pathogen composition, and risk factors, particularly airflow limitation, associated with bacterial respiratory infection and pneumonia in a prospective cohort of well-treated people with HIV (PWH) between 2015-2021. METHODS: We included 1007 PWH from the Copenhagen Comorbidity in HIV infection (COCOMO) study. Spirometry was performed at inclusion. Microbiology samples were collected prospectively. Cumulative incidence was determined by the Aalen-Johansen estimator. Cox proportional hazard models were used to calculate risk factors, adjusted for traditional and HIV-specific variables. RESULTS: The incidence rates of first bacterial respiratory infection and pneumonia were 12.4 (95% CI 9.7-15.5) and 5.5 (95% CI: 3.8-7.7) per 1000 person-years, respectively. The cumulative incidence of pneumonia was four times higher in PWH with airflow limitation (11.8% vs 3.2%, P <0.001). Risk factors for bacterial respiratory infection were airflow limitation (hazard ratio [HR] 2.9, [95% CI: 1.7-5.1], P <0.001), smoking (HR 2.3, [95% CI: 1.4-3.8], P <0.001), and previous AIDS-defining event (HR 2.0, [95% CI: 1.2-3.3], P = 0.009). For pneumonia, airflow limitation (HR 2.7, [95% CI: 1.2-6.3], P = 0.016), smoking (HR 2.5, [95% CI: 1.2-5.4], P = 0.016), and older age (HR 1.5, [95% CI: 1.1-2.1], P = 0.015) were identified as risk factors. CONCLUSIONS: Increased emphasis on airflow limitation prevention, including smoking cessation, may reduce the burden of bacterial respiratory infection and pneumonia in PWH.

The Impact of Time between Booster Doses on Humoral Immune Response in Solid Organ Transplant Recipients Vaccinated with BNT162b2 Vaccines.

As solid organ transplant (SOT) recipients remain at risk of severe outcomes after SARS-CoV-2 infections, vaccination continues to be an important preventive measure. In SOT recipients previously vaccinated with at least three doses of BNT162b2, we investigated humoral responses to BNT162b2 booster doses. Anti-SARS-CoV-2 receptor binding domain (RBD) immunoglobulin G (IgG) was measured using an in-house ELISA. Linear mixed models were fitted to investigate the change in the geometric mean concentration (GMC) of anti-SARS-CoV-2 RBD IgG after vaccination in participants with intervals of more or less than six months between the last two doses of vaccine. We included 107 SOT recipients vaccinated with a BNT162b2 vaccine. In participants with an interval of more than six months between the last two vaccine doses, we found a 1.34-fold change in GMC per month (95% CI 1.25-1.44), while we found a 1.09-fold change in GMC per month (95% CI 0.89-1.34) in participants with an interval of less than six months between the last two vaccine doses, resulting in a rate ratio of 0.82 (95% CI 0.66 to 1.01, p = 0.063). In conclusion, the administration of identical COVID-19 mRNA vaccine boosters within six months to SOT recipients may result in limited humoral immunogenicity of the last dose.

Influenza in Liver and Kidney Transplant Recipients: Incidence and Outcomes.

Influenza is a common respiratory tract infection in solid organ transplant (SOT) recipients. We aimed to investigate the incidence, risk factors, and complications of influenza in a large cohort of kidney and liver transplant recipients over 10 consecutive seasons. We conducted a retrospective study, including 378 liver and 683 kidney transplant recipients who were transplanted from January 1, 2010, to October 1, 2019. The data on influenza were retrieved from MiBa, which is a nationwide database that contains all of the microbiology results in Denmark. Clinical data were retrieved from patient records. Incidence rates and cumulative incidences were calculated, and risk factors were investigated using time-updated Cox proportional hazards models. The cumulative incidence of influenza in the first 5 years posttransplantation was 6.3% (95% CI: 4.7 to 7.9%). Of the 84 influenza positive recipients, 63.1% had influenza A, 65.5% were treated with oseltamivir, 65.5% were hospitalized, and 16.7% developed pneumonia. There were no significant differences in outcomes when comparing patients with influenza A and B. We found no significant effect of same-season influenza vaccination, sex, age, or comorbidities on the risk of acquiring influenza. The incidence of influenza in kidney and liver recipients is high, and 65.5% of infected transplant recipients required hospitalization. We were not able to confirm a reduction in influenza incidence or in the risk of complications associated with vaccination. IMPORTANCE Influenza is a common respiratory virus in solid organ transplant recipients that may have severe complications, including pneumonia and hospitalization. This study investigates the incidence, risk factors, and complications of influenza in a Danish cohort of kidney and liver transplant recipients over 10 consecutive influenza seasons. The study shows a high incidence of influenza and a high frequency of both pneumonia and hospitalization. This emphasizes the importance of continuous focus on influenza in this vulnerable group. During the COVID-19 pandemic, the incidence of influenza has been low due to COVID-related restrictions, and immunity may have waned. However, as most countries have now opened up, the incidence of influenza is expected to be high this season.

Prediction of herpes virus infections after solid organ transplantation: a prospective study of immune function.

Introduction: Herpes virus infections are a major concern after solid organ transplantation and linked to the immune function of the recipient. We aimed to determine the incidence of positive herpes virus (cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus type 1/2 (HSV-1/2), and varicella zoster virus (VZV)) PCR tests during the first year post-transplantation and assess whether a model including immune function pre-transplantation and three months post-transplantation could predict a subsequent positive herpes virus PCR. Methods: All participants were preemptively screened for CMV, and EBV IgG-negative participants were screened for EBV during the first year post-transplantation. Herpes virus PCR tests for all included herpes viruses (CMV, EBV, HSV-1/2, and VZV) were retrieved from the Danish Microbiology database containing nationwide PCR results from both hospitals and outpatient clinics. Immune function was assessed by whole blood stimulation with A) LPS, B) R848, C) Poly I:C, and D) a blank control. Cytokine concentrations (TNF-α, IL-1ß, IL-6, IL-8, IL-10, IL-12p40, IL-17A, IFN-α, and IFN-γ) were measured using Luminex. Results: We included 123 liver (54%), kidney (26%), and lung (20%) transplant recipients. The cumulative incidence of positive herpes virus PCR tests was 36.6% (95% CI: 28.1-45.1) during the first year post-transplantation. The final prediction model included recipient age, type of transplantation, CMV serostatus, and change in Poly I:C-induced IL-12p40 from pre-transplantation to three months post-transplantation. The prediction model had an AUC of 77% (95% CI: 61-92). Risk scores were extracted from the prediction model, and the participants were divided into three risk groups. Participants with a risk score <5 (28% of the cohort), 5-10 (45% of the cohort), and >10 (27% of the cohort) had a cumulative incidence of having a positive herpes virus PCR test at 5.8%, 25%, and 73%, respectively (p < 0.001). Conclusion: In conclusion, the incidence of positive herpes virus PCR tests was high, and a risk model including immune function allowed the prediction of positive herpes virus PCR and may be used to identify recipients at higher risk.