Human polyomaviruses (HPyVs) are a growing challenge in immunocompromised patients in view of the increasing number of now 12 HPyV species and their diverse disease potential. Currently, histological evidence of disease is available for BKPyV causing nephropathy and haemorrhagic cystitis, JCPyV causing progressive multifocal leukoencephalopathy and occasionally nephropathy, MCPyV causing Merkel cell carcinoma and TSPyV causing trichodysplasia spinulosa, the last two being proliferative skin diseases. Here, the current role of HPyV in solid organ transplantation (SOT) was reviewed and recommendations regarding screening, monitoring and intervention were made. Pre-transplant screening of SOT donor or recipient for serostatus or active replication is currently not recommended for any HPyV. Post-transplant, however, regular clinical search for skin lesions, including those associated with MCPyV or TSPyV, is recommended in all SOT recipients. Also, regular screening for BKPyV replication (e.g. by plasma viral load) is recommended in kidney transplant recipients. For SOT patients with probable or proven HPyV disease, reducing immunosuppression should be considered to permit regaining of immune control. Antivirals would be desirable for treating proven HPyV disease, but are solely considered as adjunct local treatment of trichodysplasia spinulosa, whereas surgical resection and chemotherapy are key in Merkel cell carcinoma. Overall, the quality of the clinical evidence and the strength of most recommendations are presently limited, but are expected to improve in the coming years.

Solid organ transplant (SOT) recipients run a high risk for adverse outcomes from COVID‐19, with reported mortality around 19%. We retrospectively reviewed all known Swedish SOT recipients with RT‐PCR confirmed COVID‐19 between March 1 and November 20, 2020 and analyzed patient characteristics, management, and outcome. We identified 230 patients with a median age of 54.0 years (13.2), who were predominantly male (64%). Most patients were hospitalized (64%), but 36% remained outpatients. Age >50 and male sex were among predictors of transition from outpatient to inpatient status. National early warning Score 2 (NEWS2) at presentation was higher in non‐survivors. Thirty‐day all‐cause mortality was 9.6% (15.0% for inpatients), increased with age and BMI, and was higher in men. Renal function decreased during COVID‐19 but recovered in most patients. SARS‐CoV‐2 antibodies were identified in 78% of patients at 1–2 months post‐infection. Nucleocapsid‐specific antibodies decreased to 38% after 6–7 months, while spike‐specific antibody responses were more durable. Seroprevalence in 559 asymptomatic patients was 1.4%. Many patients can be managed on an outpatient basis aided by risk stratification with age, sex, and NEWS2 score. Factors associated with adverse outcomes include older age, male sex, greater BMI, and a higher NEWS2 score.

The authors declare no conflicts of interest. M.F. designed the study, collected data, analyzed results, and reviewed the article. J.M.S. designed the study, collected data, analyzed results, and drafted the article. J.M. collected data, analyzed results, and revised the article. J.E. collected data, analyzed results, and revised the article. K.K. collected data, analyzed results, and drafted the article. A.S. collected data, analyzed results, and revised the article. H.L. collected data, analyzed results, and revised the article. M.O. designed the study, collected data, analyzed results, and drafted the article. V.F. designed the study, collected data, analyzed results, and drafted the article.

ObjectiveDespite long‐standing safe and effective use of immunoglobulin replacement therapy (IgRT) in primary immunodeficiency, clinical data on IgRT in patients with secondary immunodeficiency (SID) due to B‐cell lymphoproliferative diseases are limited. Here, we examine the correlation between approved IgRT indications, treatment recommendations, and clinical practice in SID.MethodsAn international online survey of 230 physicians responsible for the diagnosis of SID and the prescription of IgRT in patients with hematological malignancies was conducted.ResultsSerum immunoglobulin was measured in 83% of patients with multiple myeloma, 76% with chronic lymphocytic leukemia, and 69% with non‐Hodgkin lymphoma. Most physicians (85%) prescribed IgRT after ≥2 severe infections. In Italy, Germany, Spain, and the United States, immunoglobulin use was above average in patients with hypogammaglobulinemia, while in the UK considerably fewer patients received IgRT. The use of subcutaneous immunoglobulin was highest in France (34%) and lowest in Spain (19%). Immunologists measured specific antibody responses, performed test immunization, implemented IgRT, and used subcutaneous immunoglobulin more frequently than physicians overall.ConclusionsThe management of SID in hematological malignancies varied regionally. Clinical practice did not reflect treatment guidelines, highlighting the need for robust clinical studies on IgRT in this population and harmonization between countries and disciplines.

Secondary immunodeficiencies occur as a consequence of various diseases, including hematological malignancies, and the use of pharmacological therapies, such as immunosuppressive, anti-inflammatory, and biological drugs. Infections are the main cause of morbidity and mortality in multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients. Recent advances in treatment have prolonged the duration of remission and the time between relapse phases in MM and CLL patients. However, managing multiple relapses and the use of salvage therapies can lead to cumulative immunosuppression and a higher risk of infections. The pathogenesis of immune deficiency secondary to lymphoproliferative malignancy is multifactorial including disease- and treatment-related factors. Supportive treatment, including early vaccination, anti-infective prophylaxis, and replacement immunoglobulin, plays a key role in preventing infections in MM and CLL. This article provides an overview of the basic immunology necessary to understand the pathogenesis of secondary immunodeficiency and the infectious complications in MM and CLL. We also discuss the evidence supporting the role of prophylactic replacement immunoglobulin treatment in patients with antibody failure secondary to MM and CLL and the indications for its use. Copyright © 2016 John Wiley & Sons, Ltd.

Our results indicate that intake of L. plantarum could have a preventive effect on milder gastrointestinal symptoms during treatment with antibiotics.

BackgroundCytomegalovirus (CMV) is associated with an increased risk of cardiac allograft vasculopathy (CAV), the major limiting factor for long-term survival after heart transplantation (HTx). The purpose of this study was to evaluate the impact of CMV infection during long-term follow-up after HTx.MethodsA retrospective, single-centre study analyzed 226 HTx recipients (mean age 45 ± 13 years, 78 % men) who underwent transplantation between January 1988 and December 2000. The incidence and risk factors for CMV infection during the first year after transplantation were studied. Risk factors for CAV were included in an analyses of CAV-free survival within 10 years post-transplant. The effect of CMV infection on the grade of CAV was analyzed.ResultsSurvival to 10 years post-transplant was higher in patients with no CMV infection (69 %) compared with patients with CMV disease (55 %; p = 0.018) or asymptomatic CMV infection (54 %; p = 0.053). CAV-free survival time was higher in patients with no CMV infection (6.7 years; 95 % CI, 6.0–7.4) compared with CMV disease (4.2 years; CI, 3.2–5.2; p < 0.001) or asymptomatic CMV infection (5.4 years; CI, 4.3–6.4; p = 0.013). In univariate analysis, recipient age, donor age, coronary artery disease (CAD), asymptomatic CMV infection and CMV disease were significantly associated with CAV-free survival. In multivariate regression analysis, CMV disease, asymptomatic CMV infection, CAD and donor age remained independent predictors of CAV-free survival at 10 years post-transplant.ConclusionsCAV-free survival was significantly reduced in patients with CMV disease and asymptomatic CMV infection compared to patients without CMV infection. These findings highlight the importance of close monitoring of CMV viral load and appropriate therapeutic strategies for preventing asymptomatic CMV infection.

Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europeans. Our GWAS meta-analysis of 1,635 IgAD patients and 4,852 controls identified four new significant (P < 5x10 −8 ) loci and association with a rare IFIH1 variant (Ile923Val). Peak novel variants (PVT1 P = 4.3x10 −11 , ATG13-AMBRA1 P = 6.7x10 −10 , AHI1 P = 8.4x10 −10 and CLEC16A P = 1.4x10 −9 ) overlapped with autoimmune markers (3/4) and correlated with 21 putative regulatory variants, including eQTLs for AHI1 and DEXI and DNase hypersensitivity in FOXP3+ T regulatory cells. A pathway analysis of the meta-analysis results showed a striking association with the KEGG pathway for IgA production (pathway P < 0.0001): where 22 of 30 annotated pathway genes contained at least one variant with a P-value ≤0.05 in the IgAD metaanalysis. These data suggest that a complex network of genetic effects, including genes known to influence the biology of IgA production, contribute to IgAD.IgAD is the most common primary immunodeficiency and is defined by serum IgA level <0.07 g/L.1 The prevalence in Europeans is 1:600.1 Secretory IgA (sIgA) is important for mucosal immunity and gut commensalism2,3, and clinical features of IgAD include recurrent mucosal infections. In IgAD, B cells fail to terminally differentiate into IgA+ plasma cells, however IL-21 can restore B cell IgA production in vitro4,5. IgAD is strongly associated with HLA6 and aggregates in families with autoimmunity.7 The prevalence of Celiac disease is 35 times higher in IgAD patients whereas the prevalence of systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) is 10 times higher.8Ferreira et al.6 previously imputed HLA-B, HLA-DRB1 and HLA-DQB1 in IgAD cases and controls (>2,700 individuals).9 The primary signal mapped to HLA-DQB1*02 (OR = 2.8, P = 7.7x10 −57 ), due to combined independent effects of the HLA-B*08:01-DRB1*03:01-DQB1*02 and HLA-DRB1*07:01-DQB1*02 haplotypes.9 There was a secondary signal at HLA-DRB1*01:02 (OR = 4.28, P = 5.86x10 −17 ) and a protective effect for HLA-DRB1*15:01 (OR = 0.13, P = 2.24x10 −35 ).9 HLA-DQB1*02:01 is protective for IgA nephropathy (OR = 0.71, P = 2.61x10 −13 ). 10 None of the non-MHC IgAD loci overlapped with IgA nephropathy.10 A previous GWAS identified the common allele IFIH1 Thr946Ala (OR = 0.62, control allele frequency = 0.39) as the first and, to date, only non-HLA genome-wide significant IgAD To expand our understanding of IgAD risk, we studied four new IgAD cohorts, and performed a GWAS meta-analysis of ~9.5M SNPs in 1,635 cases and 4,852 controls (Table 1). Genotypes for untyped markers were imputed for each cohort separately (1000 Genomes Project) and genotypes for variants fully typed in the entire cohort. Up to four controls per new case were iteratively selected based on ancestry eigenvectors14 to minimize population substructure (Online Methods). Genomic inflation factor values were minimal ( Table 1), indicating that population substructure was adequately addressed. Association analyses were c...