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Data on immune responses following COVID-19 booster vaccinations and subsequent infections in the immunocompromised are limited. We studied antibody responses after the fourth dose and subsequent infections to define patient groups benefiting most from boosters. Fourth vaccine (booster) doses were, in Finland, first recommended for severely immunocompromised individuals, whom we invited to participate in our study in 2022. We assessed spike protein-specific IgG and neutralizing antibodies (NAb) against the ancestral and Omicron BA.1 strains one month after the fourth dose from 488 adult participants and compared them to the levels of 35 healthy controls after three doses. We used Bayesian generalized linear modeling to assess factors explaining antibody levels and assessed vaccine-induced and hybrid immunity six months after the last vaccine dose. Chronic kidney disease (CKD) and immunosuppressive therapy (IT) were identified as factors explaining sub-optimal antibody responses. The proportion of participants with a normal antibody response and NAbs was significantly lower regarding CKD patients compared to the controls. By the 6-month sampling point, one-third of the participants became infected (documented by serology and/or molecular tests), which notably enhanced antibody levels in most immunocompromised participants. Impaired antibody responses, especially NAbs against the Omicron lineage, suggest limited protection in individuals with CKD and highlight the need for alternative pharmaceutical preventive strategies. Vaccination strategies should take into account the development of robust hybrid immunity responses also among the immunocompromised. [ABSTRACT FROM AUTHOR]

Abstract Background The role of Epstein-Barr (EBV) virus in central nervous system (CNS) infections is not fully resolved. It is clearly associated with lymphoproliferative disease of immunosuppressed persons, and may cause encephalitis. Methods We reviewed the medical records, imaging and laboratory findings of all patients EBV DNA PCR positive in cerebrospinal fluid (CSF) during 2000 to 2009 in the Helsinki University Central Hospital. Results We identified 32 patients with EBV DNA in CSF. 11 had history of allogeneic hematopoietic stem cell transplantation, 7 solid organ transplantation and 5 HIV/AIDS. 5 patients had no preceding immunodeficiency. In 8 of the cases, another pathogen was identified in CSF. These were M. tuberculosis (2), T. gondii (2), Aspergillus (1), Herpes simplex virus 1 (1), C. neoformans (1) and Human herpesvirus 6 (1). Altogether in 15/32 (47%) of the cases the clinician had a strong suspicion of cause other than EBV for the patients' CNS symptoms/findings. Of note, 7 of 11 (64%) patients with stem cell transplantation had encephalitis (univariate odds ratio 5.6; confidence Interval 1.1-27.4). Of these 6 had no other pathogen identified. Conclusions EBV DNA was often found together with other microbial findings in CSF of immunocompromised patients. EBV seems to be associated with encephalitis in stem cell transplant recipients.

Background Health care–associated infective endocarditis (HAIE) and intravenous drug use–related IE (IDUIE) have emerged as major groups in infective endocarditis (IE). We studied their role and clinical picture in a population-based survey. Methods A population-based retrospective study including all adult patients diagnosed with definite or possible IE in Southern Finland in 2013–2017. IE episodes were classified according to the mode of acquisition into 3 groups: community-acquired IE (CAIE), HAIE, and IDUIE. Results Total of 313 episodes arising from 291 patients were included. Incidence of IE was 6.48/100 000 person-years. CAIE accounted for 38%, HAIE 31%, and IDUIE 31% of IE episodes. Patients in the IDUIE group were younger, and they more frequently had right-sided IE (56.7% vs 5.0%; P <.001) and S. aureus as etiology (74.2% vs 17.6%; P <.001) compared with the CAIE group. In-hospital (15.1% vs 9.3%; P =.200) and cumulative 1-year case fatality rates (18.5% vs 17.5%; P =.855) were similar in CAIE and IDUIE. Patients with HAIE had more comorbidities, prosthetic valve involvement (29.9% vs 10.9%; P =.001), enterococcal etiology (20.6% vs 5.9%; P =.002), and higher in-hospital (27.8% vs 15.1%; P =.024) and cumulative 1-year case fatality rates (43.3% vs 18.5%; P <.001) than patients with CAIE. Staphylococcus aureus caused one-fifth of IE episodes in both groups. Conclusions Our study indicates that in areas where injection drug use is common IDUIE should be regarded as a major risk group for IE, along with HAIE, and not seen as part of CAIE. Three different risk groups, CAIE, HAIE, and IDUIE, with variable characteristics and outcome should be recognized in IE. [ABSTRACT FROM AUTHOR]

Background: Common variable immunodeficiency (CVID) is the most common primary immunodeficiency. Prevalence varies greatly between countries and studies. Most diagnostic criteria include hypogammaglobulinemia and impaired vaccine response. Aim: To evaluate the minimum prevalence as well as the clinical and immunological phenotypes of CVID in Southern Finland. Methods: We performed a cross-sectional study to assess all adult CVID patients followed up in three hospital districts in Southern and South-Eastern Finland between April 2007 and August 2015. CVID diagnosis was based, with a minor modification, on the ESID/PAGID criteria for primary CVID. Antipolysaccharide responses to Pneumovax® were defined as impaired only if 50% or more of the serotypes did not reach a level of 0.35 µg/mL after vaccination. We further characterized the patients' B cell phenotypes and complications associated with CVID. Results: In total, 9 patients were excluded due to potential secondary causes before diagnosis. ESID/PAGID criteria were met by 132 patients (males 52%), of whom, 106 had "probable" and 26 "possible CVID." Based on the population statistics in the three hospital districts, the minimum adult prevalence per 100,000 inhabitants in Finland for all CVID ("probable CVID," respectively) patients was 6.9 (5.5). In the highest prevalence district (Helsinki and Uusimaa), the prevalence was 7.7 (6.1). CVID patients suffer from frequent complications. Ten patients died during follow-up. Of probable CVID patients, 73% had more than one clinical phenotype. Intriguingly, gradual B cell loss from peripheral blood during follow-up was seen in as many as 16% of "probable CVID" patients. Patients with possible CVID displayed somewhat milder clinical and laboratory phenotypes than probable CVID patients. We also confirm that large granular lymphocyte lymphoproliferation is a CVID-associated complication. Conclusion: The prevalence of CVID in Finland appears the highest recorded, likely reflecting the genetic isolation and potential founder effects in the Finnish population. Studies to discover potential gene variants responsible for the high prevalence in Finland thus seem warranted. Increased awareness of CVID among physicians would likely lead to earlier diagnosis and improved quality of care. [ABSTRACT FROM AUTHOR]

Background: Few systematically collected multi-centre surveillance data on nosocomial bloodstream infections (BSI) caused by extended-spectrum β-lactamase (ESBL) producing Escherichia coli or Klebsiellapneumoniae have been published. Aim: To evaluate trends, patient characteristics and mortality of such infections, nosocomial BSI data reported by the 4–17 hospitals participating in the prospective laboratory-based surveillance during 1999–2013 were analysed. Methods: Data were collected by local infection control nurses, patient-days were obtained from the hospital's administrative database, and dates of deaths from the population registry. Resistance to third-generation cephalosporins was further examined in the national reference laboratory. Findings: A total of 16 028 nosocomial BSIs were identified; 2217 (14%) were caused by E. coli and 661 (4%) by K. pneumoniae; 207 (7%) were non-susceptible to third-generation cephalosporins, with an increasing trend from 0% in 1999 to 17% in 2013. Patient characteristics did not differ significantly between BSIs caused by third-generation susceptible and resistant E. coli and K. pneumonia, but the case fatality tended to be higher. Most (88%) of the isolates reported as non-susceptible to third-generation cephalosporins had ESBL phenotype, CTX-M (79%) being the most common enzyme. Conclusion: A sharp increase in nosocomial BSIs caused by ESBL producing bacteria was observed. Identification of patients for screening pose a challenge, emphasising the role of infection control guidelines and antibiotic policy in prevention [ABSTRACT FROM AUTHOR]

Background: Complement protein C4d has been used as a marker of antibody mediated rejection in kidney allografts. C4d has been shown to be deposited also in chronic kidney allograft rejection. and frequently in acute liver allograft rejection. In chronic liver allograft rejection there is limited data of C4d positivity. Methods: 7 liver allografts explanted at retransplantation due to chronic rejection were examined for expression of C4d. Immunoperoxidase technique on frozen sections was used. The"`zero" biopsies of the same livers at the first transplantation served as controls. Results: Expression of C4d was significantly increased in portal and central veins as well as in the portal stroma of the grafts with chronic rejection when compared to the expression at implantation of the graft. Conclusion: The complement system and anti-donor antibodies may contribute to the process of chronic allograft rejection in the liver. [ABSTRACT FROM AUTHOR]

Background: The role of Epstein-Barr (EBV) virus in central nervous system (CNS) infections is not fully resolved. It is clearly associated with lymphoproliferative disease of immunosuppressed persons, and may cause encephalitis.Methods: We reviewed the medical records, imaging and laboratory findings of all patients EBV DNA PCR positive in cerebrospinal fluid (CSF) during 2000 to 2009 in the Helsinki University Central Hospital.Results: We identified 32 patients with EBV DNA in CSF. 11 had history of allogeneic hematopoietic stem cell transplantation, 7 solid organ transplantation and 5 HIV/AIDS. 5 patients had no preceding immunodeficiency.In 8 of the cases, another pathogen was identified in CSF. These were M. tuberculosis (2), T. gondii (2), Aspergillus (1), Herpes simplex virus 1 (1), C. neoformans (1) and Human herpesvirus 6 (1). Altogether in 15/32 (47%) of the cases the clinician had a strong suspicion of cause other than EBV for the patients' CNS symptoms/findings.Of note, 7 of 11 (64%) patients with stem cell transplantation had encephalitis (univariate odds ratio 5.6; confidence Interval 1.1-27.4). Of these 6 had no other pathogen identified.Conclusions: EBV DNA was often found together with other microbial findings in CSF of immunocompromised patients. EBV seems to be associated with encephalitis in stem cell transplant recipients. [ABSTRACT FROM AUTHOR]

Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity., Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants., Methods: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3., Results: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate., Conclusion: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Common variable immunodeficiency and other late-onset immunodeficiencies often co-manifest with autoimmunity and lymphoproliferation. The pathogenesis of most cases is elusive, as only a minor subset harbors known monogenic germline causes. The involvement of both B and T cells is however implicated. To study whether somatic mutations in CD4+ and CD8+ T cells associate with immunodeficiency, we recruited 17 patients and 21 healthy controls. Eight patients had late-onset common variable immunodeficiency and nine patients other immunodeficiency and/or severe autoimmunity. In total, autoimmunity occurred in 94% and lymphoproliferation in 65%. We performed deep sequencing of 2533 immune-associated genes from CD4+ and CD8+ cells. Deep T-cell receptor beta sequencing was used to characterize CD4+ and CD8+ T-cell receptor repertoires. The prevalence of somatic mutations was 65% in all immunodeficiency patients, 75% in common variable immunodeficiency and 48% in controls. Clonal hematopoiesis-associated variants in both CD4+ and CD8+ cells occurred in 24% of immunodeficiency patients. Results demonstrated mutations in known tumor suppressors, oncogenes, and genes that are critical for immune- and proliferative functions, such as STAT5B (two patients), C5AR1 (two patients), KRAS (one patient), and NOD2 (one patient). Additionally, as a marker of T-cell receptor repertoire perturbation, common variable immunodeficiency patients harbored increased frequencies of clones with identical complementarity determining region 3 sequences despite unique nucleotide sequences when compared to controls. In conclusion, somatic mutations in genes implicated for autoimmunity and lymphoproliferation are common in CD4+ and CD8+ cells of patients with immunodeficiency. They may contribute to immune dysregulation in a subset of immunodeficiency patients.

Objectives: Common variable immunodeficiency (CVID) is associated with a spectrum of autoimmune complications. We studied the prevalence of gastrointestinal (GI) manifestations and infections in patients with CVID., Methods: Complete clinical data of 132 Finnish patients with CVID (106 probable and 26 possible CVID) followed up between 2007 and 2016 were collected to a structured database. Data on endoscopies, histology, and laboratory studies were retrieved from patient files., Results: Most common referral indications were diarrhea and/or weight loss (47%-67%). Patients with probable CVID had higher fecal calprotectin and α1-antitrypsin and lower blood vitamin B12 than patients with possible CVID. Gastroscopy and colonoscopy were done to 71 (67%) and 63 (59%) patients with probable CVID, respectively. Endoscopies showed that 15% of them had chronic active gastritis and 17% atrophic gastritis and 3% had gastric adenocarcinoma. A celiac sprue-like condition was found in 7 patients (10%), of whom 3 responded to a gluten-free diet. Colonoscopies demonstrated unspecific colitis (14%), ulcerative colitis (8%), microscopic colitis (10%), and Crohn's disease (2%). Colonic polyps were noted in 30% of patients, and 3% had lower GI malignancies. Thirty-five patients with CVID had bacterial or parasitic gastroenteritis; chronic norovirus was detected in 4 patients with probable CVID. Patients with GI inflammation had higher levels of fecal calprotectin and blood CD8 T lymphocytes but lower counts of CD19CD27 memory B cells and/or CD19 B cells. Immunophenotype with low B-cell counts was associated with higher fecal calprotectin levels., Discussion: Patients with CVID had a high prevalence of GI manifestations and infections of the GI tract. GI inflammation was associated with a distinct immunophenotype and elevated fecal calprotectin.

Vascular adhesion protein-1 (VAP-1) has been shown to mediate lymphocyte adhesion to endothelia at sites of inflammation, but its functional role in vivo has not been tested in any rodent model. Here we report the effects of VAP-1 blockade on rat liver allograft rejection. BN recipients of PVG liver allografts (known to develop acute rejection by day 7) were treated with 2 mg/kg anti-VAP-1 (a new anti-rat VAP-1 mAb 174-5) or isotype-matched irrelevant antibody (NS1) every other day (n = 6/group) and one group with anti-VAP-1 2 mg/kg daily (n = 7). On day 7, samples were collected for transplant aspiration cytology, histology, and immunohistochemistry. Lymphocyte infiltration to the graft was clearly affected by VAP-blockade. The total inflammation, mainly the number of active lymphoid cells, in transplant aspiration cytology was significantly decreased in animals treated with anti-VAP-1 (4.7 +/- 1.0 and 2.4 +/- 1.0 corrected increment units, respectively) compared to control (6.6 +/- 1.0) (P < 0.05). In histology, the intensity of portal inflammation was significantly decreased (P < 0.05). The amount of T cells expressing activation markers diminished. This is the first demonstration in any prolonged in vivo model that VAP-1 plays an important role in lymphocyte infiltration to sites of inflammation, and, in particular, liver allograft rejection.