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Background In high-resource settings, the survival of children with immunocompromise (IC) has increased and immunosuppressive therapies are increasingly being used. This study aimed to determine the clinical characteristics, performance of diagnostic tools, and outcome of IC children with tuberculosis (TB) in Europe. Methods Multicenter, matched case-control study within the Pediatric Tuberculosis Network European Trials Group, capturing TB cases <18 years diagnosed 2000–2020. Results A total of 417 TB cases were included, comprising 139 children who are IC (human immunodeficiency virus, inborn errors of immunity, drug-induced immunosuppression, and other immunocompromising conditions) and 278 non-IC children as controls. Nonrespiratory TB was more frequent among cases than controls (32.4% vs 21.2%; P =.013). Patients with IC had an increased likelihood of presenting with severe disease (57.6% vs 38.5%; P <.001; odds ratio [95% confidence interval], 2.073 [1.37–3.13]). Children with IC had higher rates of false-negative tuberculin skin test (31.9% vs 6.0%; P <.001) and QuantiFERON-TB Gold assay (30.0% vs 7.3%; P <.001) results at diagnosis. Overall, the microbiological confirmation rate was similar in IC and non-IC cases (58.3% vs 49.3%; P =.083). Although the mortality in children with IC was <1%, the rate of long-term sequelae was significantly higher than in non-IC cases (14.8% vs 6.1%; P =.004). Conclusions Children with IC and TB in Europe have increased rates of nonrespiratory TB, severe disease, and long-term sequelae. Immune-based TB tests have poor sensitivity in those children. Future research should focus on developing improved immunological TB tests that perform better in patients with IC, and determining the reasons for the increased risk of long-term sequelae, with the aim to design preventive management strategies. [ABSTRACT FROM AUTHOR]

Acquired aplastic anemia (AA) is an immune-mediated bone marrow (BM) failure where marrow disruption is driven by a cytotoxic T-cell-mediated autoimmune attack against hematopoietic stem cells. The key diagnostic challenge in children, but also in adults, is to exclude the possible underlying congenital condition and myelodysplasia. The choice of treatment options, either allogeneic hematopoietic cell transplantation (alloHCT) or immunosuppressive therapy (IST), depends on the patient's age, comorbidities, and access to a suitable donor and effective therapeutic agents. Since 2022, horse antithymocyte globulin (hATG) has been available again in Europe and is recommended for IST as a more effective option than rabbit ATG. Therefore, an update on immunosuppressive strategies is warranted. Despite an improved response to the new immunosuppression protocols with hATG and eltrombopag, some patients are not cured or remain at risk of aplasia relapse or clonal evolution and require postponed alloHCT. The transplantation field has evolved, becoming safer and more accessible. Upfront alloHCT from unrelated donors is becoming a tempting option. With the use of posttransplant cyclophosphamide, haploidentical HCT offers promising outcomes also in AA. In this paper, we present the state of the art in the management of severe AA for pediatric and adult patients based on the available guidelines and recently published studies. [ABSTRACT FROM AUTHOR]

Objectives Rituximab has become the cornerstone of induction treatment in ANCA-associated vasculitis (AAV). B-cell depletion may increase the risk of hypogammaglobulinemia, potentially leading to severe infections. This study aims to assess factors associated with hypogammaglobulinemia in AAV patients treated with rituximab. Methods This retrospective cohort study included AAV patients treated with rituximab induction in 14 European centres. Severe adverse events (SAEs) were defined as episodes requiring hospitalization or intravenous antibiotics, malignancies, or death. Linear and logistic regression were used to identify predictors of IgG levels and of the risk of hypogammaglobulinemia, defined as IgG ≤7 g/l at 6 months. Results The study included 227 patients. IgG levels at 6 months were lower than baseline (P  < 0.001). Patients requiring intravenous antibiotics during the first 6 months had lower IgG levels at 6 months (P  = 0.004). Age [β (95% CI): −0.23 (−0.38, −0.08) per 10 years, P  = 0.003], oral glucocorticoid dose at induction [β (95% CI): −0.37 (−0.51, −0.24) per sqrt-transformed mg prednisone, P  < 0.001] and concomitant use of intravenous glucocorticoid pulses [β (95% CI): −0.88 (−1.73, −0.02), P  = 0.044] were associated with IgG levels at 6 months. Hypogammaglobulinemia was identified in 97 (42.7%) patients. In multivariable logistic regression, factors associated with the risk of hypogammaglobulinemia were age [OR (95% CI): 1.46 (1.15, 1.86) per 10 years, P  = 0.002] and oral glucocorticoid dose at induction [OR (95% CI): 1.52 (1.23, 1.89) per 10 mg prednisone, P  < 0.001]. Conclusions In AAV patients treated with rituximab, hypogammaglobulinemia at 6 months after induction is common, and lower IgG levels are associated with serious infections. The risk of hypogammaglobulinemia in these patients increases with age and higher glucocorticoid doses. [ABSTRACT FROM AUTHOR]

Background and Aims: The European Reference Network on Hepatological Diseases (ERN RARE-LIVER) launched the prospective, multicentre, quality-controlled R-LIVER registry on rare liver diseases. The aim of this study was to assess the presentation and outcome of autoimmune hepatitis (AIH) after 1 year of treatment., Methods: Data were prospectively collected at the time of diagnosis and after 6 and 12 months follow-up. Complete biochemical response (CBR) was defined as normalization of alanine aminotransferase (ALT) and immunoglobulin G (IgG) serum levels., Results: A total of 231 patients from six European centres were included in the analysis. After 6 months of treatment 50% (106/212), and after 12 months 63% (131/210) of patients reached CBR with only 27% (56/211) achieving a steroid-free CBR within the first year. Overall, 16 different treatment regimens were administered. Change of treatment, mostly due to intolerance, occurred in 30.4% within the first 6 months. In multivariate analysis, younger age at diagnosis (odds ratio [OR] = 1.03 [95% confidence interval (CI) 1.01-1.05]; p = .007), severe fibrosis (OR .38 [95% .16-.89], p = .026) and change of treatment within the first 6 months (OR .40 [95% CI .2-.86]; p = .018) were associated with a lesser chance of ALT normalization at 12 months follow-up., Conclusion: The landscape of AIH treatment in Europe is highly heterogeneous, even between expert centres. The results from this first European multicentre prospective registry reveal several unmet needs, highlighted by the overall low rates of CBR and the frequent failure to withdraw corticosteroids., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Merkel cell carcinoma (MCC) is a rare skin cancer, accounting for less than 1% of all cutaneous malignancies. It is found predominantly in white populations and risk factors include advanced age, ultraviolet exposure, male sex, immunosuppression, such as AIDS/HIV infection, haematological malignancies or solid organ transplantation, and Merkel cell polyomavirus infection. MCC is an aggressive tumour with 26% of cases presenting lymph node involvement at diagnosis and 8% with distant metastases. Five-year overall survival rates range between 48% and 63%. Two subsets of MCC have been characterised with distinct molecular pathogenetic pathways: ultraviolet-induced MCC versus virus-positive MCC, which carries a better prognosis. In both subtypes, there are alterations in the retinoblastoma protein and p53 gene structure and function. MCC typically manifests as a red nodule or plaque with fast growth, most commonly on sun exposed areas. Histopathology (small-cell neuroendocrine appearance) and immunohistochemistry (CK20 positivity and TTF-1 negativity) confirm the diagnosis. The current staging systems are the American Joint Committee on Cancer/Union for international Cancer control 8th edition. Baseline whole body imaging is encouraged to rule out regional and distant metastasis. For localised MCC, first-line treatment is surgical excision with postoperative margin assessment followed by adjuvant radiation therapy (RT). Sentinel lymph node biopsy is recommended in all patients with MCC without clinically detectable lymph nodes or distant metastasis. Adjuvant RT alone, eventually combined with complete lymph nodes dissection is proposed in case of micrometastatic nodal involvement. In case of macroscopic nodal involvement, the standard of care is complete lymph nodes dissection potentially followed by post-operative RT. Immunotherapy with anti-PD-(L)1 antibodies should be offered as first-line systemic treatment in advanced MCC. Chemotherapy can be used when patients fail to respond or are intolerant for anti-PD-(L)1 immunotherapy or clinical trials. • Major progress in the diagnosis of Merkel cell carcinoma by immunohistochemistry/molecular pathogenesis. • The management of primary tumour was mostly based on retrospective studies. • Breakthrough in advance disease management with the approval of immunotherapy. [ABSTRACT FROM AUTHOR]

The burden of COVID-19 remains unchanged for immunocompromised patients who do not respond to vaccines. Unfortunately, Omicron sublineages are resistant to monoclonal antibodies authorized in Europe so far, and small chemical antivirals have contraindications and toxicities that have not been studied in these patients. We report here the successful treatment of COVID-19 pneumonia lasting for 4 months after the transfusion of COVID-19 convalescent plasma (CCP) in a patient with severe immunosuppression due to both chronic lymphocytic leukemia and venetoclax treatment. The patient achieved a complete clinical, radiological and virological response after six transfusions (600 mL each) of high-titer CCP collected from triple-vaccinated and convalescent donors. This dramatic case adds to the mounting evidence of CCP efficacy in immunocompromised patients, provided that high-titer and large volumes are infused. [ABSTRACT FROM AUTHOR]

Strongyloidiasis has been estimated to affect over 600 million people worldwide. It is caused by Strongyloides stercoralis, a roundworm endemic to the tropics and subtropics, especially areas where sanitation is suboptimal Autochthonous transmission has been documented in rural areas of the USA and Europe. Humans are infected when larvae penetrate the skin or are ingested. Autoinfection, in which larvae generated in the host go on to re-infect the host, leads to a state of chronic asymptomatic infection often with eosinophilia. Hyperinfection syndrome may develop when patients develop immune suppression, due to medications such as corticosteroids or following solid-organ transplantation. Hyperinfection is characterized by exponential increase in parasitic burden, leading to tissue invasion and life-threatening disease and associated bloodstream infections due to enteric organisms. Cases following use of corticosteroids for COVID-19 pneumonia have been described. Strongyloidiasis can be diagnosed by direct visualization of larvae in stool or other body fluids, or by serology. Ivermectin is highly effective in treating the disease. Patients with exposure to endemic areas and those expected to become immune suppressed should be screened and treated before starting immune suppressive agents. Empiric treatment should be considered when timely testing is not readily available. [ABSTRACT FROM AUTHOR]

Background and Aims: Contemporary multicentre data on clinical and diagnostic spectrum and outcome in myocarditis are limited. Study aims were to describe baseline features, 1-year follow-up, and baseline predictors of outcome in clinically suspected or biopsy-proven myocarditis (2013 European Society of Cardiology criteria) in adult and paediatric patients from the EURObservational Research Programme Cardiomyopathy and Myocarditis Long-Term Registry., Methods: Five hundred eighty-one (68.0% male) patients, 493 adults, median age 38 (27-52) years, and 88 children, aged 8 (3-13) years, were divided into 3 groups: Group 1 (n = 233), clinically suspected myocarditis with abnormal cardiac magnetic resonance; Group 2 (n = 222), biopsy-proven myocarditis; and Group 3 (n = 126) clinically suspected myocarditis with normal or inconclusive or no cardiac magnetic resonance. Baseline features were analysed overall, in adults vs. children, and among groups. One-year outcome events included death/heart transplantation, ventricular assist device (VAD) or implantable cardioverter defibrillator (ICD) implantation, and hospitalization for cardiac causes., Results: Endomyocardial biopsy, mainly right ventricular, had a similarly low complication rate in children and adults (4.7% vs. 4.9%, P = NS), with no procedure-related death. A classical myocarditis pattern on cardiac magnetic resonance was found in 31.3% of children and in 57.9% of adults with biopsy-proven myocarditis (P < .001). At 1-year follow-up, 11/410 patients (2.7%) died, 7 (1.7%) received a heart transplant, 3 underwent VAD (0.7%), and 16 (3.9%) underwent ICD implantation. Independent predictors at diagnosis of death or heart transplantation or hospitalization or VAD implantation or ICD implantation at 1-year follow-up were lower left ventricular ejection fraction and the need for immunosuppressants for new myocarditis diagnosis refractory to non-aetiology-driven therapy., Conclusions: Endomyocardial biopsy was safe, and cardiac magnetic resonance using Lake Louise criteria was less sensitive, particularly in children. Virus-negative lymphocytic myocarditis was predominant both in children and adults, and use of immunosuppressive treatments was low. Lower left ventricular ejection fraction and the need for immunosuppressants at diagnosis were independent predictors of unfavourable outcome events at 1 year., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Solid organ transplant recipients (SOTRs) are believed to have an increased risk of metastatic cutaneous squamous cell carcinoma (cSCC), but reliable data are lacking regarding the precise incidence and associated risk factors., Methods: In a prospective cohort study, including 19 specialist dermatology outpatient clinics in 15 countries, patient and tumor characteristics were collected using standardized questionnaires when SOTRs presented with a new cSCC. After a minimum of 2 years of follow-up, relevant data for all SOTRs were collected. Cumulative incidence of metastases was calculated by the Aalen-Johansen estimator. Fine and Gray models were used to assess multiple risk factors for metastases., Results: Of 514 SOTRs who presented with 623 primary cSCCs, metastases developed in 37 with a 2-year patient-based cumulative incidence of 6.2%. Risk factors for metastases included location in the head and neck area, local recurrence, size > 2 cm, clinical ulceration, poor differentiation grade, perineural invasion, and deep invasion. A high-stage tumor that is also ulcerated showed the highest risk of metastasis, with a 2-year cumulative incidence of 46.2% (31.9%-68.4%)., Conclusions: SOTRs have a high risk of cSCC metastases and well-established clinical and histologic risk factors have been confirmed. High-stage, ulcerated cSCCs have the highest risk of metastasis., Competing Interests: Conflicts of interest This study was partly sponsored by the European Academy of Dermatology and Venerology (EADV), however this did not affect the content of the manuscript. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Genetic variation in the CYP3A4 and CYP3A5 (CYP3A4/5) genes, which encode the key enzymes in tacrolimus metabolism, is associated with tacrolimus clearance and dose requirements. Tacrolimus has a narrow therapeutic index with high intra‐ and intersubject variability, in part because of genetic variation. High tacrolimus clearance and low trough concentration are associated with a greater risk for rejection, whereas high troughs are associated with calcineurin‐induced toxicity. The objective of this study was to develop a model of tacrolimus clearance with a dosing equation accounting for genotypes and clinical factors in adult kidney transplant recipients of European ancestry that could preemptively guide dosing. Recipients receiving immediate‐release tacrolimus for maintenance immunosuppression from 2 multicenter studies were included. Participants in the GEN03 study were used for tacrolimus model development (n = 608 recipients) and was validated by prediction performance in the DeKAF Genomics study (n = 1361 recipients). Nonlinear mixed‐effects modeling was used to develop the apparent oral tacrolimus clearance (CL/F) model. CYP3A4/5 genotypes and clinical covariates were tested for their influence on CL/F. The predictive performance of the model was determined by assessing the bias (median prediction error [ME] and median percentage error [MPE]) and the precision (root median squared error [RMSE]) of the model. CYP3A5*3, CYP3A4*22, corticosteroids, calcium channel blocker and antiviral drug use, age, and diabetes significantly contributed to the interindividual variability of oral tacrolimus apparent clearance. The bias (ME, MPE) and precision (RMSE) of the final model was good, 0.49 ng/mL, 6.5%, and 3.09 ng/mL, respectively. Prospective testing of this equation is warranted. [ABSTRACT FROM AUTHOR]

Background: Hepatic Actinomycosis (HA) is one of the infections that causes disorders in patients when diagnosed untimely and inappropriately.Methods: Case reports on HA in patients published between 2000 and April 2020 were gathered by carrying out a structured search through PubMed/Medline.Results: Through a survey of the Medline database, 130 studies were identified and then, 64 cases with HA were included in the final analysis. Asia had the largest share of cases with 37.5% (24 reports), followed by Europe and the Americas. Affected patients were predominantly males (64%) and the overall mortality rate was 1% with only one male patient in his 50 s dying. Nearly all patients (92%) were immunocompetent. However, in four patients, the use of immunosuppressive medication led to depression of the immune system. Most of the patients (80%) experienced complications. In terms of the complications, the most frequent ones were previous history of abdominal surgery (32%) and foreign bodies in the abdominopelvic region (20%). Actinomyces israelii was the most common pathogen isolated from patients. Abdominal pain (66%), fever (62%), weight loss (48%), night sweat, malaise, and anorexia (14%) over about 3.1 months were the most frequently reported clinical symptoms. Extension to one or more surrounding organs was evident in 18 patients (28%). Histopathologic examination confirmed infection in 67% of the patients and samples obtained from liver puncture biopsy (32%) were most frequently used in diagnosis. Surgery or puncture drainage + anti-infection was the most common method to treat patients and penicillin, Amoxicillin, Doxycycline, and ampicillin were the most frequently used drugs to control infection.Conclusion: HA should be considered in patients with a subacute or chronic inflammatory process of the liver. With accurate and timely diagnosis of infection, extensive surgery can be prevented. [ABSTRACT FROM AUTHOR]

Background In human immunodeficiency virus (HIV)–positive adults, low CD4 cell counts despite fully suppressed HIV-1 RNA on antiretroviral therapy (ART) have been associated with increased risk of morbidity and mortality. We assessed the prevalence and outcomes of poor immune response (PIR) in children receiving suppressive ART. Methods Sixteen cohorts from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) contributed data. Children <18 years at ART initiation, with sustained viral suppression (VS) (≤400 copies/mL) for ≥1 year were included. The prevalence of PIR (defined as World Health Organization advanced/severe immunosuppression for age) at 1 year of VS was described. Factors associated with PIR were assessed using logistic regression. Rates of acquired immunodeficiency syndrome (AIDS) or death on suppressive ART were calculated by PIR status. Results Of 2318 children included, median age was 6.4 years and 68% had advanced/severe immunosuppression at ART initiation. At 1 year of VS, 12% had PIR. In multivariable analysis, PIR was associated with older age and worse immunological stage at ART start, hepatitis B coinfection, and residing in Thailand (all P ≤.03). Rates of AIDS/death (95% confidence interval) per 100 000 person-years were 1052 (547, 2022) among PIR versus 261 (166, 409) among immune responders; rate ratio of 4.04 (1.83, 8.92; P <.001). Conclusions One in eight children in our cohort experienced PIR despite sustained VS. While the overall rate of AIDS/death was low, children with PIR had a 4-fold increase in risk of event as compared with immune responders. [ABSTRACT FROM AUTHOR]

Myocarditis remains an unknown disease with varying clinical manifestations, often leading to heart failure. The latest 2021 and 2022 guidelines of the European Society of Cardiology (ESC) are the first official European documents updating knowledge on the diagnosis and treatment of myocarditis since the 2013 ESC expert consensus statement. These guidelines and new studies allow standardization and improvements to the management of myocarditis. In this review, we discuss the most important aspects of myocarditis diagnosis, therapies and follow-up based on current knowledge.

Tick-borne encephalitis (TBE) is an infectious illness of the central nervous system caused by the TBE virus, which is commonly transmitted through a tick-bite. TBE is endemic in Europe and mid-Asia. In this study, we report a case of a 36-year-old woman, living in Northeastern Poland, with a history of double corneal transplantation and post-transplant immunosuppressive therapy who was admitted to hospital because of progressive weakness, acute headache, nausea, vertigo, vomiting, and fever. The patient was diagnosed with TBE. However, the diagnosis was challenging as the initial serological tests for antibodies against the TBE virus were negative. We want to raise the awareness among the clinicians that the course of TBE is often unpredictable and that it tends to be more severe in immunocompromised individuals.. Delayed production of antibodies against TBE virus, which might inhibit the diagnosis of the disease, is observed in some immunocompromised patients., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background and Aims: Sporadic hepatitis E is an emerging indigenous disease in Europe induced by genotype 3 of the virus. While the disease takes an acute self‐limited course in immunocompetent individuals, under immunocompromised conditions chronic hepatitis E might develop. The histology of chronic hepatitis E has not been described in detail systematically. Methods: Liver biopsies from 19 immunosuppressed patients with chronic hepatitis E were collected: 17 were organ transplant recipients, one had a CD4‐deficiency and one had received steroid therapy because of ulcerative colitis. Biopsies were processed with standard stains. Evaluation of histologic activity and fibrosis was performed according to Ishak. Additionally, immunohistochemistry with antibodies directed against open reading frame 2 and 3 of the virus was performed and liver biopsies were tested for hepatitis E virus RNA. Results: Biochemical data showed an increase in alanine transaminase, aspartate transaminase, gamma‐glutamyl transferase and total bilirubin. Histopathology displayed typical features of chronic hepatitis with mild to moderate activity. The number of polymorphonuclear leucocytes was considerably increased and all patients had a florid cholangitis that presented as a destructive form in five of them. Hepatocytes and bile duct epithelia stained positive for hepatitis E virus by immunohistochemistry. Conclusions: Chronic hepatitis E in immunocompromised individuals runs a similar course as hepatitis B and C and shows similar histopathology. However, the presence of destructive cholangitis in some cases accompanied by an increased number of polymorphonuclear leucocytes is markedly different. Immunohistochemically the virus is present in bile duct epithelia, seemingly the cause for cholangitis. [ABSTRACT FROM AUTHOR]

Infectious bursal disease virus (IBDV) is the causative agent of a highly contagious immunosuppressive disease affecting young chickens. The recently described "distinct IBDV" (dIBDV) genetic lineage encompasses a group of worldwide distributed strains that share conserved genetic characteristics in both genome segments making them unique within IBDV strains. Phenotypic characterization of these strains is scarce and limited to Asiatic and European strains collected more than 15 years ago. The present study aimed to assess the complete and comprehensive phenotypic characterization of a recently collected South American dIBDV strain (1/chicken/URY/1302/16). Genetic analyses of both partial genome segments confirmed that this strain belongs to the dIBDV genetic lineage and that it is not a reassortant. Antigenic analysis with monoclonal antibodies indicated that this strain has a particular antigenic profile, similar to that obtained in a dIBDV strain from Europe (80/GA), which differs from those previously found in the traditional classic, variant and very virulent strains. Chickens infected with the South American dIBDV strain showed subclinical infections but had a marked bursal atrophy. Further analysis using Newcastle disease virus-immunized chickens, previously infected with the South American and European dIBDV strains, demonstrated their severe immunosuppressive effect. These results indicate that dIBDV strains currently circulating in South America can severely impair the immune system of chickens, consequently affecting the local poultry industry. Our study provides new insights into the characteristics and variability of this global genetic lineage and is valuable to determine whether specific control measures are required for the dIBDV lineage. Research Highlights A South American strain of the dIBDV lineage was phenotypically characterized. The strain produced subclinical infections with a marked bursal atrophy. Infected chickens were severely immunosuppressed. The dIBDV strains are antigenically divergent from other IBDV lineages. [ABSTRACT FROM AUTHOR]

Eltrombopag (ELT), an oral thrombopoietin receptor agonist, has recently emerged as a promising new drug for the treatment of aplastic anemia (AA). How ELT is used outside of clinical trials in the real-world setting and results of this treatment are not known. We conducted therefore a retrospective survey on the use of ELT in AA among EBMT member centers. We analyzed the 134 patients reported in our survey together with 46 patients recently published by Lengline et al. The median follow-up from start of ELT treatment was 15.3 months, with 85.6% patients alive at last follow-up. Importantly, only 28.9% of our patients received ELT according to the FDA/EMA label as monotherapy in the relapsed/refractory setting, whereas 16.7% received ELT upfront. The overall response rate in our cohort was 62%, very similar to the results of the pivotal ELT trial. In multivariate analysis, combination therapy with ELT/cyclosporine/ATG and response to previous therapy were associated with response. Overall survival was favorable with a 1-year survival from ELT start of 87.4%. We identified age, AA severity before ELT start and response to ELT as variables significantly associated with OS. Two patients transformed to MDS; other adverse events were mostly benign. In sum, ELT is used widely in Europe to treat AA patients, mostly in the relapsed/refractory setting. Response to ELT is similar to the clinical trial data across different age groups, treatment lines, and treatment combinations and results in favorable survival. [ABSTRACT FROM AUTHOR]

Background: T cell-replete haploidentical stem cell transplantation (haplo-SCT) is a valid therapeutic option for adult patients with high-risk acute myeloid leukemia (AML) lacking an HLA-matched sibling or unrelated donor.Method: We retrospectively analyzed the outcomes of 912 AML patients ≥45 years of age who had undergone haplo-SCT with either myeloablative conditioning (MAC; n = 373) or reduced intensity conditioning (RIC; n = 539) regimens.Results: The median follow-up was 31.1 and 25.7 months for MAC and RIC, respectively. The incidence of relapse and nonrelapse mortality (NRM) were 25.1% versus 28.7% and 31.0% versus 30.3% for MAC and RIC, respectively; 2-year leukemia-free survival (LFS) was 43.9% for MAC versus 41.0% for RIC. In multivariate analysis, the use of MAC versus RIC was not associated with a difference in the outcomes. Results were confirmed in the propensity score-weighted analysis. Disease status and performance status at transplantation were associated with outcomes. Notably, the use of posttransplantation cyclophosphamide was associated with reduced acute graft-versus-host disease (aGVHD) stage III-IV, and NRM and increased overall survival, LFS, and GVHD-free, relapse-free survival. The use of mobilized peripheral blood stem cells was associated with an increased risk of stage II-IV aGVHD.Conclusion: No differences were found between MAC and RIC regimens for haplo-SCT in adults with AML who were ≥45 years of age. The type of GVHD prophylaxis, disease status, and performance status were the major predictors of transplantation outcome. These results may serve as the background for randomized study comparing RIC versus MAC for haplo-SCT in adults with AML. [ABSTRACT FROM AUTHOR]

Invasive cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in white populations, accounting for 20% of all cutaneous malignancies. Overall, cSCC mostly has very good prognosis after treatment, with 5-year cure rates greater than 90%. Despite the overall favourable prognosis and the proportionally rare deaths, cSCC is associated with a high total number of deaths due to its high incidence. A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), the European Society for Radiotherapy and Oncology (ESTRO), the European Union of Medical Specialists (UEMS), the European Academy of Dermatology and Venereology (EADV) and the European Organization of Research and Treatment of Cancer (EORTC), was formed to update recommendations on cSCC, based on current literature and expert consensus. Part 1 of the guidelines addresses the updates on classification, epidemiology, diagnosis, risk stratification, staging and prevention in immunocompetent as well as immunosuppressed patients. • Diagnosing, staging and classifying cSCC as high-risk, e.g. without locoregional or distant metastasis and with high-risk features, or as locally advanced, e.g. not amenable to curative surgery or radiotherapy, or as metastatic, e.g. with in transit, regional or distant metastasis, is fundamental as it affects further management decisions. • If invasive cSCC is suspected, a histopathological diagnosis shall be made. • Immunocompromised patients require special considerations regarding prevention strategies. [ABSTRACT FROM AUTHOR]

Background: Avoidance of vaccine-preventable infections in paediatric renal allograft recipients is of utmost importance. However, the development and maintenance of protective vaccination titres may be impaired in this patient population owing to their need for immunosuppressive medication.Methods: In the framework of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN), we therefore performed a multi-centre, multi-national study and analysed vaccination titres pre- and post-transplant in 155 patients with serial titre measurements in comparison with published data in healthy children.Results: The percentage of patients with positive vaccination titres before renal transplantation (RTx) was low, especially for diphtheria (38.5%, control 75%) and pertussis (21.3%, control 96.3%). As few as 58.1% of patients had a hepatitis B antibody (HBsAb) titre >100 IU/L before RTx. 38.1% of patients showed a vaccination titre loss post-transplant. Patients with an HBsAb titre between 10 and 100 IU/L before RTx experienced a significantly (p < 0.05) more frequent hepatitis B vaccination titre loss post-transplant than patients with an HBsAb titre >100 IU/L. The revaccination rate post-transplant was low and revaccination failed to induce positive titres in a considerable number of patients (27.3 to 83.3%). Treatment with rituximab was associated with a significantly increased risk of a vaccination titre loss post-transplant (odds ratio 4.26, p = 0.033).Conclusions: These data show a low percentage of patients with positive vaccination titres pre-transplant, a low revaccination rate post-transplant with limited antibody response, and a high rate of vaccination titre losses. [ABSTRACT FROM AUTHOR]

Background. Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods. Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥ 1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results. Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions. One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch. [ABSTRACT FROM AUTHOR]

Background: BK polyomavirus (BKPyV)-associated nephropathy remains a challenge to the success of kidney transplantation, but its impact varies in different transplant programmes. Methods: We investigated current practice through a webbased questionnaire made available by the European Society for Paediatric Nephrology (ESPN). Results: A total of 90 physicians (23% of 391 active members) from 27 countries participated in the study. BKPyV-associated nephropathy is seen in 1-5% of patients annually with treatment success in 30-60%, and graft loss in 10%. Quantitative BKPyV load testing is available to >90% of physicians. Screening is performed in urine alone in 26%, in urine and blood in 37% and in blood alone in 37%. Most physicians (47%) screen at month 1, 2, 3, 6, 9 and 12 post-transplant. For patients with baseline renal function and plasma BKPyV loads of 10 000-1 000 000 copies/mL, 50% report performing renal biopsies prior to intervention. Intervention consists of reducing immunosuppression first with mycophenolate (Myc) in 40%, first with calcineurin inhibitors (CNI) in 29% or with both in 31%. Changing immunosuppressive drugs is considered mainly for biopsy-proven nephropathy consisting of discontinuation of Myc in 75%, and switching from CNI to mTOR inhibitors (52%). Cidofovir, intravenous immunoglobulin G, leflunomide and fluoroquinolones are used in less than one-third of this group. Furthermore, 66% of participants see a need for new antiviral drugs and new immmunosuppressive strategies, and almost 90% are willing to participate in future observational and interventional trials. Conclusion: This ESPN survey suggests that prompt translation of a positive screening test into reducing immunosuppression could improve outcomes. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the presence of circoviruses in wild bird populations, in Poland. Circoviruses possess immuno-suppressive properties and might interfere with the health of wild birds. Method: 83 birds, which belonged to 23 species, were tested with broad-range, nested PCR. The obtained PCR products were sequenced and new primers designed, to analyse the full-length, viral genome. A phylogenetic analysis was conducted, to find any relationship to known circoviruses. Results: The circovirus DNA sequence was found in 4 birds. All samples originated from the velvet scoter (Melanitta fusca) a marine duck from the Merginae sub-family. Birds which tested positive for the circovirus were found dead in fishing nets, off the Baltic coast. During post-mortem examination, carcasses of two of the scoters showed only light emaciation, while the two other birds appeared healthy. The obtained, full-length, circovirus sequence revealed 1,988 nucleotides and the presence of typical features (i.e. Cap, Rep and ORF3). Nucleotide similarity to other duck circoviruses was 84 to 86 %. Phylogenetic analysis of the complete genome and cap gene, indicated that the new circovirus is related to known duck circoviruses, especially to sub-types sometimes referred to as duck circovirus genotype 1, but not genotype 2. Conclusions: In this study, we have reported a new duck circovirus sequence detected in the velvet scoter, a species of marine duck. Sequence comparison and phylogenetic analysis of the new virus sequence support previous reports that duck circovirus (DuCV) is a species with a high degree of diversity. The viral sequence obtained from the velvet scoter suggests that DuCV may infect birds from the Anatinae sub-family. More studies are needed to prove if the velvet scoter and other marine ducks act as a reservoir for DuCV. [ABSTRACT FROM AUTHOR]

At present, transient asymptomatic hepatitis E virus (HEV) infection is common among healthy adults in Western Europe, as reported by blood transfusion services. In immune-suppressed patients HEV infection is often without clinical symptoms, but without therapeutic intervention it may become chronic and lead to cirrhosis. This report describes the course of chronic HEV infection after kidney transplantation in 2 children, who cleared the virus after reduction in immunosuppressive therapy. If aminotransferase levels continue to be moderately elevated after transplantation, HEV infection should be excluded. [ABSTRACT FROM AUTHOR]

Aim This article describes the rationale, design and methodology of the Building research initiative group: chronic illness management and ad herence in transplantation ( BRIGHT) study. This study of heart transplant patients will: (1) describe practice patterns relating to chronic illness management; (2) assess prevalence and variability of non-adherence to the treatment regimen; (3) determine the multi-level factors related to immunosuppressive medication non-adherence. Background The unaltered long-term prognosis after heart transplantation underscores an urgent need to identify and improve factors related to survival outcomes. The healthcare system (e.g. level of chronic illness management implemented) and patient self-management are major drivers of outcome improvement. Design The study uses a survey design in 40 heart transplant centres covering 11 countries in four continents. Methods Theoretical frameworks informed variable selection, which are measured by established and investigator-developed instruments. Heart transplant recipients, outpatient clinicians and programme's directors complete a survey. A staged convenience sampling strategy is implemented in heart transplant centres, countries and continents. Depending on the centre's size, a random sample of 25-60 patients is selected (N estimated 1680 heart transplant recipients). Five randomly selected clinicians and the medical director from each centre will be invited to participate. Conclusion This is the first multi-centre, multi-continental study examining healthcare system and heart transplant centres chronic illness management practice patterns and potential correlates of immunosuppressive medication non-adherence. The knowledge gained will inform clinicians, researchers and healthcare policy makers at which level(s) interventions need to be implemented to improve long-term outcomes for transplant recipients. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a vector-born chronic infectious disease caused by a group of protozoan parasites of the genus Leishmania. Whereas most immunocompetent individuals will not develop disease after Leishmania infection, immunosuppression is a well-established risk factor for disease. The most severe form is visceral leishmaniasis ( VL), which is typically fatal if untreated. Whereas human immunodeficiency virus ( HIV) co-infection ( VL- HIV) was initially mainly reported from southern Europe, it is now emerging in other regions, including East Africa, India, and Brazil. VL has also been found in a wide range of non- HIV-related immunosuppressive states, mainly falling under the realm of transplantation medicine, rheumatology, haematology, and oncology. Clinical presentation can be atypical in immunosuppressed individuals, being easily misdiagnosed or mistaken as a flare-up of the underlying disease. The best diagnostic approach is the combination of parasitological and serological or molecular methods. Liposomal amphotericin B is the drug of choice. Treatment failure and relapse rates are particularly high in cases of HIV co-infection, despite initiation of antiretroviral treatment. Primary prophylaxis is not recommended, but secondary prophylaxis is recommended when the patient is immunosuppressed. Cutaneous leishmaniasis can have a number of particular features in individuals with immunosuppression, especially if severe, including parasite dissemination , clinical polymorphism with atypical and often more severe clinical forms, and even visceralization. Mucosal leishmaniasis is more common. Treatment of cutaneous and mucosal leishmaniasis can be challenging, and systemic treatment is more often indicated. With globally increased travel and access to advanced medical care in developing countries, the leishmaniasis burden in immunosuppressed individuals will probably continue to rise, warranting increased awareness and enhanced surveillance systems. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Heartsease (Viola tricolor L.), a member of the Violaceae family, has a long history as a medicinal plant and has been documented in the Pharmacopoeia of Europe. Due to its anti-inflammatory properties it is regarded as a traditional remedy against skin diseases, for example for the treatment of scabs, itching, ulcers, eczema or psoriasis, and it is also used in the treatment of inflammation of the lungs and chest such as bronchitis or asthma. Because T-cells play an important role in the pathological process of inflammatory diseases we investigated the effect of an aqueous Viola extract on lymphocyte functions and explored the ‘active’ principle of the extract using bioactivity-guided fractionation. Material and Methods: An aqueous Viola extract was prepared by C18 solid-phase extraction. Effects on proliferation of activated lymphocytes (using the cell membrane permeable fluorescein dye CFSE), apoptosis and necrosis (using annexin V and propidium iodide staining), interleukin-2 (IL-2) receptor expression (using fluorochrome-conjugated antibodies) and IL-2 cytokine secretion (using an ELISA-based bead array system) were measured by flow cytometry. Influence on lymphocyte polyfunctionality was characterized by Viola extract-induced production of IFN-γ and TNF-α, as well as its influence on lymphocyte degranulation activity. Fractionation and phytochemical analysis of the extract were performed by RP-HPLC and mass spectrometry. Results: The aqueous Viola extract inhibited proliferation of activated lymphocytes by reducing IL-2 cytokine secretion without affecting IL-2 receptor expression. Similarly, effector functions were affected as indicated by the reduction of IFN-γ and TNF-α production; degranulation capacity of activated lymphocytes remained unaffected. Bioassay-guided fractionation and phytochemical analysis of the extract led to identification of circular plant peptides, so called cyclotides, as bioactive components. Conclusion: An aqueous Viola extract contains bioactive cyclotides, which inhibit proliferation of activated lymphocytes in an IL-2 dependent manner. The findings provide a rationale for use of herbal Viola preparations in the therapy of disorders related to an overactive immune system. However, further studies to evaluate its clinical potency and potential risks have to be performed. [ABSTRACT FROM AUTHOR]

Abstract: Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically important diseases of swine worldwide. Since its first emergence in 1987 the PRRS virus (PRRSV) has become particularly divergent with highly pathogenic strains appearing in both Europe and Asia. However, the underlying mechanisms of PRRSV pathogenesis are still unclear. This study sets out to determine the differences in pathogenesis between subtype 1 and 3 strains of European PRRSV (PRRSV-I), and compare the immune responses mounted against these strains. Piglets were infected with 3 strains of PRRSV-I: Lelystad virus, 215-06 a British field strain and SU1-bel from Belarus. Post-mortem examinations were performed at 3 and 7 days post-infection (dpi), and half of the remaining animals in each group were inoculated with an Aujeszky''s disease (ADV) vaccine to investigate possible immune suppression resulting from PRRSV infection. The subtype 3 SU1-bel strain displayed greater clinical signs and lung gross pathology scores compared with the subtype 1 strains. This difference did not appear to be caused by higher virus replication, as viraemia and viral load in broncho-alveolar lavage fluid (BALF) were lower in the SU1-bel group. Infection with SU1-bel induced an enhanced adaptive immune response with greater interferon (IFN)-γ responses and an earlier PRRSV-specific antibody response. Infection with PRRSV did not affect the response to vaccination against ADV. Our results indicate that the increased clinical and pathological effect of the SU1-bel strain is more likely to be caused by an enhanced inflammatory immune response rather than higher levels of virus replication. [Copyright &y& Elsevier]

Abstract: Organ transplant recipients (OTR) are at increased risk of cutaneous squamous cell carcinoma, which may be related to reactivation of human papillomavirus (HPV) infections. Measurement of change in HPV antibodies after transplantation would help to explore this hypothesis. We measured antibodies to 34 HPV types on up to six occasions over 18 months in 441 OTRs from five European countries. At baseline (mean 24 days after transplantation), 80% of all OTRs were seropositive to at least one HPV type. The beta HPV genus had the highest seroprevalence (45%). For most HPV genera baseline seroprevalence peaked between 40 and 59 years old. Most OTRs retained their serostatus over time and antibody levels were stable. Seroprevalence in immunosuppressed OTRs is stable in the 18 months immediately after transplantation. Thus there is no short-term evidence that immunosuppression leads to new or reactivated skin infection with HPV sufficient to induce antibodies. [Copyright &y& Elsevier]

The goal of research in transplant therapeutics is to achieve safe and effective immunosuppression strategies that allow durable engraftment free of toxicities. The calcineurin inhibitors (CNIs) regimens, because of their inherent toxicities (including nephrotoxicity), have been unable to meet these promises. Over the past decade acute cellular rejection decreased dramatically with a concomitant robust increase in 1-year graft survival; however, long-term graft outcome showed only modest improvement. This is due in part to the toxicities of the immunosuppressive drugs. The quest for a toxicity-free-CNI-free regimen has been both intense and frustrating. A turning point in CNIs-free therapy may have occurred with the recent approval of belatacept, which represents a new paradigm in immunosuppression: biological therapy for chronic immunosuppression devoid of the usual toxicities associated with the CNIs. Belatacept, a fusion receptor protein, blocks costimulation signals necessary for the activation of T cells. Although costimulation blockade has not been shown to induce tolerance, it can provide safe and effective immunosuppression without renal or cardiovascular toxicities. The approval of belatacept in both the United States and Europe for use in renal transplantation will finally push CNI-free regimens into prime time. Novel biologics such as ASKP1240 (a human anti-CD40 monoclonal antibody) and one small molecule, tofacitinib, may advance further the use of CNI-free regimens in organ transplantation. [ABSTRACT FROM AUTHOR]

Hepatitis E virus (HEV), the main etiologic agent of enterically transmitted acute hepatitis in developing countries, is now recognized as an emerging agent of autochthonous disease and chronic hepatitis E in immunocompromised patients in Europe where HEV infection is probably zoonotically acquired. We describe the first human case of acute HEV infection with two genotype 3 viruses in a French kidney transplant recipient, probably acquired through consumption of uncooked pig liver sausage (figatellu). The patient presented two viral sequences nearly identical to sequences recovered from figatelli. Autochthonous co-infections with different genotype 3 HEV strains can occur in our geographical area. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Study Type - Therapy (prospective cohort) Level of Evidence 2a What's known on the subject? and What does the study add? In the West, transitional cell carcinoma (TCC) in renal transplant patients is uncommon, but aggressive. Conversely, it appears to be frequent in the Far East, necessitating aggressive surgical approaches such as prophylactic nephroureterectomy. There are few European case series to date. TCC in the present population was predominantly low-grade and superficial, with no progression in patients with those tumours. Endoscopic management was sufficient for most patients. The behaviour of TCC in the present population was much less aggressive than that described in the Far East. Altering immunosuppression regimes may have a role to play in managing bladder cancer in renal transplant patients. OBJECTIVE To examine the clinical characteristics, management and long-term outcomes of patients with transitional cell carcinoma (TCC) who also have had renal transplantation., PATIENTS AND METHODS A retrospective case note review was performed for the 15-year period 1995-2009., Searches from three different urological centres in the UK, using multiple sources, yielded 1647 patients with renal transplants, 12 of whom had TCC., Eight cases were identified who developed de novo TCC after transplantation (0.48%). Four patients had pre-existing TCC who then had renal transplantation. The current literature was reviewed., RESULTS In the eight de novo TCC cases, the bladder was the site in all with no upper tract TCC; seven were superficial (pTa/T1) and five were low grade (G1/2). The mean time to development of TCC after transplant was 5 years, with a mean follow-up of 11 years. There was no progression in low-grade superficial disease that was managed endoscopically. The 5- and 10-year overall survival was 83% and 72%, respectively., In patients with pre-existing TCC prophylactic bilateral nephroureterectomy before transplantation was performed once. There was progression of superficial disease whilst on immunosuppression in one patient., Sirolimus was used in patients with TCC and reports suggest this may have a role to play in modifying malignancy in this setting., The number of patients involved in studies particularly focusing on TCC in renal transplantation is small (136 patients), with 60% from China/Taiwan where there is a high incidence of upper tract TCC and high-grade muscle-invasive disease., CONCLUSIONS Although this is one of the largest European case series of renal transplant patients with TCC, the numbers are small making clear conclusions difficult., The frequency of TCC in our renal transplant population is low, consistent with previous studies. However, contrary to prior studies, TCC after renal transplantation in this European population was predominantly superficial, low-grade, non-progressive and confined to the bladder. Altering immunosuppression regimes in patients with TCC may have a role to play, although further work is required to clarify and substantiate this. [ABSTRACT FROM AUTHOR]

Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIM more than 70 lU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P< .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level. [ABSTRACT FROM AUTHOR]

Abstract: Background: Human HEV infections reported in Europe without previous travel to endemic regions are linked to exposure to genotype 3 Hepatitis E virus (HEV).Genotype 3 is widely distributed through human cases and zoonotic reservoir. The geographical distribution of genotype 4 is limited to Asian countries. Objectives: The first human case of autochthonous genotype 4 hepatitis E infectionwasreported in France. Study design: The HEV infection was described in an immunosuppressed patient, presenting an acute myeloblastic leukemia. Investigation of the case was performed on detection of HEV markers in the patient and in the environment. Results: Hepatitis E infection was diagnosed on the basis of HEV RNA viremia, and detection of anti-HEV IgM. The prognostic of leukemia was favorable and HEV was cleared without relapsing. HEV isolate was classified into genotype 4. Conclusions: The recent characterization of genotype 4 HEV through swine surveillance in Europe and the description of the first human case in France open interesting questions about the circulation of this genotype: health risks in human population, transmission patterns, and zoonotic reservoir. [Copyright &y& Elsevier]

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Abstract: Hibernation is a unique natural model to study large and specific modulation in numbers of leukocytes and thrombocytes, with potential relevance for medical application. Hibernating animals cycle through cold (torpor) and warm (arousal) phases. Previous research demonstrated clearance of leukocytes and thrombocytes from the circulation during torpor, but did not provide information regarding the timing during torpor or the subtype of leukocytes affected. To study the influence of torpor-bout duration on clearance of circulating cells, we measured blood cell dynamics in the European Ground Squirrel. Numbers of leukocytes and thrombocytes decreased within 24h of torpor by 90% and remained unchanged during the remainder of the torpor-bout. Differential counts demonstrated that granulocytes, lymphocytes and monocytes are all affected by torpor. Although a decreased production might explain the reduced number of thrombocytes, granulocytes and monocytes, this cannot explain the observed lymphopenia since lymphocytes have a much lower turnover rate than thrombocytes, granulocytes and monocytes. In conclusion, although underlying biochemical signaling pathways need to be unraveled, our data show that the leukocyte count drops dramatically after entrance into torpor and that euthermic cell counts are restored within 1.5h after onset of arousal, even before body temperature is fully normalized. [Copyright &y& Elsevier]

The SPREAD Programme investigated prospectively the time trend from September 2002 through December 2005 of transmitted drug resistance (TDR) among 2793 patients in 20 European countries and in Israel with newly diagnosed human immunodeficiency virus type 1 (HIV-1) infection. The overall prevalence of TDR was 8.4% (225 of 2687 patients; 95% confidence interval [CI], 7.4%-9.5%), the prevalence of nucleoside reverse-transcriptase inhibitor (NRTI) resistance was 4.7% (125 of 2687 patients; 95% CI, 3.9%-5.5%), the prevalence of nonucleoside reverse-transcriptase inhibitor (NNRTI) resistance was 2.3% (62 of 2687 patients; 95% CI, 1.8%-2.9%), and the prevalence of protease inhibitor (PI) resistance was 2.9% (79 of 2687 patients; 95% CI, 2.4%- 3.6%). There was no time trend in the overall TDR or in NRTI resistance, but there was a statistically significant decrease in PI resistance (Pp.04) and in NNRTI resistance after an initial increase (Pp.02). We found that TDR appears to be stabilizing in Europe, consistent with recent reports of decreasing drug resistance and improved viral suppression in patients treated for HIV-1 infection. [ABSTRACT FROM AUTHOR]

The HLA-B*5701 allele is predictive of hypersensitivity reaction to abacavir, a response herein termed "ABC-HSR." This study of 1103 individuals infected with human immunodeficiency virus assessed the usefulness of genotyping a HCP5 single-nucleotide polymorphism (SNP), rs2395029, in relation to ABC-HSR. In populations with European ancestry, rs2395029 is in linkage disequilibrium with HLA-B*5701. The HCP5SNPwas present in all 98 HLA-B*5701-positive individuals and was absent in 999 of 1005 HLA-B*5701-negative individuals. rs2395029 was overrepresented in 25 individuals with clinically likely ABC-HSR, compared with its frequency in 175 ABC-tolerant individuals (80% vs. 2%, respectively; P<.0001). Therefore, HCP5 genotyping could serve as a simple screening tool for ABC-HSR, particularly in settings where sequence-based HLA typing is not available. [ABSTRACT FROM AUTHOR]

Recent developments in basic and translational immunology open new exciting perspectives for clinical cell and organ transplantation, including the development of novel immunosuppressive agents, new diagnostic tools and validation of biomarkers for the prediction of rejection as well as the induction of tolerance. With respect to tolerance, a number of hurdles still need to be overcome before immunosuppressive drugs can be safely minimized or withdrawn in solid organ transplant recipients. Indeed, the human immune system appears more resistant to tolerance induction than expected from experimental studies in animals. Furthermore, the basic ethical principle ‘ primum non-nocere’ prevents the implementation of clinical protocols endowed with a significant risk for graft and/or patient survival. With this background, the European Commission recently launched several initiatives to tackle unmet needs in transplantation medicine. Herein, we focus attention on the ongoing collaborative effort across the European Union aiming at identifying the current priorities requiring better integration of resources dedicated to transplantation research. [ABSTRACT FROM AUTHOR]

Routine immune function testing in preclinical drug development was established as a regulatory requirement in June of 2000 under the Committee of Proprietary Medicinal Products (CPMP) Note for Guidance on Repeated Dose Toxicity (CPMP/SWP/1042/99). The purpose of the more stringent approach to immunotoxicology testing was to better identify unintended immunosuppression; however, the requirement was met with much discussion and debate. At the center of the discussion was an attempt to reconcile opposing regulatory directives from agencies outside of Europe that adhere to a more selective, weight-of-evidence approach to functional evaluations. Uncertainty over the predictive value of the recommended immune function tests relative to conventional toxicology parameters prompted an investigation by the International Committee on Harmonization (ICH). The results of a preliminary, industry-wide survey indicated that only a low percentage of pharmaceuticals adversely affect immune function without alterations to standard toxicology parameters. Expected ICH guidelines will ultimately determine to what extent and for what purpose immune function tests will be conducted. In the meantime, optimization of the recommended immune function tests is ongoing. The T-cell dependent antibody response (TDAR) by either conventional Sheep Red Blood Cell (SRBC) plaque assay or by the modified ELISA method using either SRBC or keyhole limpet hemocyanin (KLH) as antigen is being extensively evaluated to determine best practices and procedures for preclinical immunotoxicity evaluations. This review addresses some aspects of the debate concerning the appropriateness of immune function tests for hazard identification, along with recommendations for optimizing TDAR methodology to ensure adequate sensitivity and predictability in risk assessments for immunotoxicity. [ABSTRACT FROM AUTHOR]

Immunocompromise is a common condition in cats, especially due to widespread infections with immunosuppressive viruses, such as feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV), but also due to chronic non-infectious diseases, such as tumours, diabetes mellitus, and chronic kidney disease, as well as treatment with immunosuppressive drugs, such as glucocorticoids, cyclosporins, or tumour chemotherapy. In this review, the European Advisory Board on Cat Diseases (ABCD), a scientifically independent board of experts in feline medicine from eleven European countries, discusses the current knowledge and rationale for vaccination of immunocompromised cats. So far, there are few data available on vaccination of immunocompromised cats, and sometimes studies produce controversial results. Thus, this guideline summarizes the available scientific studies and fills in the gaps with expert opinion, where scientific studies are missing. Ultimately, this review aims to help veterinarians with their decision-making in how best to vaccinate immunocompromised cats.

Canine non-infectious inflammatory meningoencephalomyelitis is termed meningoencephalomyelitis of unknown origin (MUO) and may affect dogs of every breed at any age. Treatment with immunosuppressive medication, the survival time based on MRI, and cerebrospinal fluid (CSF) findings has been widely reported; however, these studies only included a small number of patients, or they are summaries from the literature. Therefore, the aim of this study was to compare the clinical presentation, diagnostic findings, treatment protocol and long-term survival time in many dogs diagnosed with MUO in one clinic with previously published studies. One hundred eighty-two dogs met the inclusion criteria. Age, sex, duration of clinical signs before diagnosis, presence of neurological signs, MRI and CSF analysis were similar to those in previous reports. Our study revealed that dogs with a brainstem lesion have a 60% lower chance of death before 1 year than dogs with multifocal brain lesions. A total of 55.56% of treated dogs survived for more than 1 year, and 10.55% survived for more than 5 years since diagnosis. The median survival time for all dogs was 540 days. Our findings support glucocorticosteroid monotherapy as a viable treatment option for dogs with MUO., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The risk of Burkitt lymphoma (BL) is increased in HIV-infected patients as compared to general population in Europe and in the US. This effect might be due to immune suppression and low CD4-cell counts associated with the development of AIDS. However, there is also evidence of a direct effect of HIV on B cell proliferation and differentiation, which may account for the development of B cell malignancies. We shall discuss possible mechanisms of implication of HIV in BL with a focus on the role of different viral components (Tat, Nef and gp120 proteins, viral envelope) in the c-myc/IgH translocation characteristic of BL. [ABSTRACT FROM AUTHOR]

Rocha MJ, Ferreira S, Martins LS, Almeida M, Dias L, Pedroso S, Henriques AC, Almeida R, Cabrita A. Cost analysis of renal replacement therapy by transplant in a system of bundled payment of dialysis. Abstract: Renal replacement therapies (RRT) for patients with end-stage renal failure represent a high burden on European countries' healthcare budget. Our purpose was to report and compare the costs of RRT by hemodialysis (HD) or peritoneal dialysis (PD) and renal transplantation (RT) after introduction of a bundled payment system of dialysis. We analyzed average annual cost of RT in a public national health system hospital - surgical/anesthesiologist team and material, induction and maintenance immunosuppression therapy, hospital stay, diagnostic examinations (DE), and post-transplant office visits (including DE). Incentives paid to hospitals performing RT were included. Annual cost of HD or PD was estimated by bundled payment established in a recently revised law - 537.25 €/wk. Total first year cost or RT is 61 658.14 € and from the second year forth 543.86 €/month. Dialysis costs 28 033.71 €/yr. Break-even point for cost is at 32 months, and from there on, RT is less expensive. Strategies aimed at increasing RT are needed as it confers better survival than RRT by dialysis with lower costs to Portuguese health system. [ABSTRACT FROM AUTHOR]

Black yeasts are a rare cause of infections especially in Europe, yet their pathological significance is increasing, particularly in cases of immunosuppression. We report a 53-year-old immunocompetent woman with an extensive skin infection due to Aureobasidium pullulans, who responded well to treatment with liposomal amphotericin B. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To describe the demographics, clinical features, etiology, imaging findings, bacteriologic profile, treatment and outcome in patients presenting splenic abscess in a European tertiary hospital. Methods: Review of the medical charts of patients in whom splenic abscess was diagnosed at a tertiary hospital in Madrid (Spain) within a nine-year period. Results: Twenty-two cases (13 males, 9 females) were found. Mycobacterium tuberculosis was the most frequent causative microorganism, accounting for 8 cases, and immunosuppression the main predisposing factor (in 63.6% of the patients). Symptoms were quite unspecific, leading to a long, median time until diagnosis (17 days). The overall mortality rate was 18.2% and it was 25% in patients with tuberculosis and 14.28% in patients with other causes of splenic abscesses (p =0.6). Conclusions: Immunosuppressed states are the predisposing condition for splenic abscess in almost two thirds of the patients. We found a higher percentage of M. tuberculosis than that previously reported in the English literature. [Copyright &y& Elsevier]

COVID-19 might potentially give rise to a more severe infection in solid organ transplant recipients due to their chronic immunosuppression. These patients are at a higher risk of developing concurrent or secondary bacterial and fungal infections. Co-infections can increase systemic inflammation influencing the prognosis and the severity of the disease, and can in turn lead to an increased need of mechanical ventilation, antibiotic therapy and to a higher mortality. Here we describe, for the first time in Europe, a fatal case of co-infection between SARS-CoV-2 and Pneumocystis jirevocii in a kidney transplant recipient. [ABSTRACT FROM AUTHOR]

Little is known regarding the travel practices of thoracic organ transplant recipients and their potential associated morbidity. A questionnaire was distributed to thoracic organ transplant recipients in the transplant clinic at a single French center between October, 2015, and October, 2018. Questions addressed demographics, transplant history, current immune suppression, knowledge regarding vaccination status, past history of travel (any destination outside metropolitan France), including pre-travel advice, health issues during travels outside Europe, and travel intentions during the following year. 117 patients completed the survey (82 lung, 14 heart and 21 heart-lung transplant recipients). Mean age was 49.4 years, 61.5% were female. 19 patients (17%) were born outside metropolitan France. At the time of survey completion, 70%, 68%, 96% and 12% of patients were receiving steroids, mycophenolate, calcineurin inhibitors, and mTOR inhibitors, respectively. 36%, 16%, and 10% of respondents considered that being a transplant recipient increased their risk of travel-related health issues mildly, moderately, and greatly, respectively. 58 patients (50%) had traveled outside metropolitan France after transplant (mean number of travels=7; mean number of destinations=3.3). Among 34 subjects who had traveled outside Europe in the last 5 years, 23 had received pre-travel advice, predominantly by their transplant physician. Among 41 respondents having traveled outside metropolitan France, 6 (15%) had experienced health issues (all outside Europe), which led to consultation and hospitalization in 3 and 1 cases, respectively. No immunosuppressives shortage was reported. Among 102 respondents, 61 (60%) intended to travel within the following year, and 50 (82%) to sought medical advice before departure, predominantly from their transplant physician (50 patients, including 17 in combination with a general practitioner or a travel medicine center). These data highlight the significant number of international travels undertaken by thoracic transplant recipients, and a relatively low travel-associated morbidity. As very few patients intend to seek advice from travel medicine specialists, transplant physicians are expected to be the major players of pre-travel counselling in this specific population. [ABSTRACT FROM AUTHOR]