Risk of venous thromboembolism in COVID-19 infection.

The incidence of venous thromboembolism (VTE) for non-hospitalised patients with coronavirus disease-2019 infection has not been very widely studied. 13 019 persons with a positive SARS-CoV-2 nucleic acid amplification test were identified. In total, 447 (0.2%) VTEs were identified in the study population, 293 (66%) of these were pulmonary embolisms. A positive SARS-CoV-2 test did not increase the risk for VTE in the univariate analysis (odds ratio (OR): 1.0, 95% confidence interval (CI): 0.69-1.4) or multivariable analysis (OR: 1.36, 95% CI: 0.93-1.97).

Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae.

Nuclear factor κ light-chain enhancer of activated B cells (NF-κB) family of evolutionarily conserved transcription factors are involved in key cellular signaling pathways. Previously, hypogammaglobulinemia and common variable immunodeficiency (CVID)-like phenotypes have been associated with NFKB1 variants and loss-of-function NFKB1 variants have been reported as the most common monogenic cause for CVID among Europeans. Here, we describe a Finnish cohort of NFKB1 carriers consisting of 31 living subjects in six different families carrying five distinct heterozygous variants. In contrast to previous reports, the clinical penetrance was not complete even with advancing age and the prevalence of CVID/hypogammaglobulinemia was significantly lower, whereas (auto)inflammatory manifestations were more common (42% of the total cohort). At current stage of knowledge, routine genetic screening of asymptomatic individuals is not recommended, but counseling of potential adult carriers seems necessary.

Population-Based Assessment of Contact Tracing Operations for Coronavirus Disease 2019 in Pirkanmaa Hospital District, Finland.

Background: The coronavirus disease 2019 (COVID-19) epidemic overwhelmed local contact tracing (CT) efforts in many countries. In Finland, severe acute respiratory syndrome coronavirus 2 incidence and mortality were among the lowest in Europe during 2020-2021. We evaluated CT efficiency, effectiveness, and transmission settings. Methods: Polymerase chain reaction (PCR) test-positive COVID-19 cases and high-risk contacts in the population-based CT database of Pirkanmaa Hospital District (population 540 000) during June 2020-May 2021 were interviewed. Results: Altogether 353 926 PCR tests yielded 4739 (1.3%) confirmed cases (average 14-day case notification rate, 34 per 100 000 population); about 99% of confirmed cases and high-risk contacts were reached by a CT team. Of 26 881 high-risk contacts who were placed in quarantine, 2275 subsequently tested positive (48% of new cases), 825 (17%) had been in quarantine ≥48 hours before symptoms, and 3469 (77%) of locally acquired cases were part of transmission chains with an identified setting. The highest secondary attack rates were seen in households (31%), healthcare patients (18%), and private functions (10%). Among the 311 hospitalized patients, COVID-19 diagnosis or exposure was known in 273 (88%) before emergency room admission (identified patients). Healthcare workers had the highest proportion of work-related infections (159 cases [35%]). The source of infection was classifiable in 65% and was most commonly a coworker (64 cases [62%]). Conclusions: Our data demonstrate the role of effective testing and CT implementation during the cluster phase of COVID-19 spread. Although half of newly diagnosed cases were already in quarantine, targeted public health measures were needed to control transmission. CT effectiveness during widespread community transmission should be assessed.

Nasal nitric oxide is decreased in acute mild COVID-19 and related to viral load.

Gaseous nitric oxide levels from the lungs (FeNO) and from the nose (nNO) have been demonstrated to react to acute infection or influenza vaccination. There are no published data on nNO levels during acute COVID-19, but normal levels of FeNO have been reported in one study. Our aim was to assess if acute mild COVID-19 alters nasal or bronchial NO output at the time of acute infection and at a two-month follow up, and if this is related to symptoms or viral load. This study included 82 subjects with mild acute airway infection who did not need hospitalization: 43 cases (reverse transcription polymerase chain reaction (RT-PCR)-positive for SARS-CoV-2 in routine testing from nasopharynx) and 39 age- (±5 years) and gender-matched controls (RT-PCR-negative for SARS-CoV-2). During acute infection, the cases had lower nNO compared to controls (158 [104-206] vs. 232 [203-279] nl min-1;p< 0.001), but after two months, there was no significant difference between the groups (230 [179-290] vs. 268 [222-320] nl min-1;p= 0.162). There was no difference in FeNO between the groups at either of the visits. Nasal NO correlated with the cycle threshold (Ct) value of the nasopharyngeal RT-PCR test for SARS-CoV-2 (Spearman'srs= 0.550;p< 0.001), that is, nNO was lower with a higher viral load. Nasal NO output was decreased in acute COVID-19 in relation to higher viral load, suggesting that the type and intensity of inflammatory response affects the release of NO from airway mucosa. In these subjects without significant lower airway involvement, there were no clinically relevant findings regarding FeNO.

Sampling site for SARS-CoV-2 RT-PCR-An intrapatient four-site comparison from Tampere, Finland.

BACKGROUND: SARS-CoV-2 diagnosis relies on the performance of nasopharyngeal swabs. Alternative sample sites have been assessed but the heterogeneity of the studies have made comparing different sites difficult. OBJECTIVES: Our aim was to compare the performance of four different sampling sites for SARS-CoV-2 samples with nasopharynx being the benchmark. STUDY DESIGN: COVID-19 positive patients were recruited prospectively, and samples were collected and analysed for SARS-CoV-2 with RT-PCR from all four anatomical sites in 43 patients, who provided written informed consent. RESULTS: All anterior nasal and saliva samples were positive, while two oropharyngeal samples were negative. There was no significant difference in the cycle threshold values of nasopharyngeal and anterior nasal samples while saliva and oropharynx had higher cycle threshold values. CONCLUSIONS: Anterior nasal swab performs as good as nasopharynx swab with saliva also finding all the positives but with higher cycle threshold values. Thus, we can conclude that anterior nasal swabs can be used for SARS-CoV-2 detection instead of nasopharyngeal swabs if the situation would require so.

Liver Fat, Adipose Tissue, and Body Composition Changes After Switching from a Protease Inhibitor or Efavirenz to Raltegravir.

Integrase inhibitors appear to increase body weight, but paradoxically some data indicate that raltegravir (RAL) may decrease liver fat. Our objective was to study the effects of switching from a protease inhibitor (PI) or efavirenz (EFV) to RAL on liver fat, body composition, and metabolic parameters among people living with HIV (PLWH) with high risk for nonalcoholic fatty liver disease (NAFLD). We randomized overweight PLWH with signs of metabolic syndrome to switch a PI or EFV to RAL (n = 19) or to continue unchanged antiretroviral therapy (control, n = 24) for 24 weeks. Liver fat was measured by magnetic resonance spectroscopy (MRS), body composition by magnetic resonance imaging, and bioimpedance analysis; subcutaneous fat biopsies were obtained. Median (interquartile range) liver fat content was normal in RAL 2.3% (1.1-6.0) and control 3.1% (1.6-7.3) group at baseline. Liver fat and visceral adipose tissue remained unchanged during the study. Body weight [from 85.9 kg (76.1-97.7) to 89.3 (78.7-98.7), p = 0.019], body fat mass [from 20.3 kg (14.6-29.7) to 22.7 (17.0-29.7), p = 0.015], and subcutaneous adipose tissue (SAT) volume [from 3979 mL (2068-6468) to 4043 (2206-6433), p = 0.048] increased, yet, adipocyte size [from 564 pL (437-733) to 478 (423-587), p = 0.019] decreased in RAL but remained unchanged in control group. Circulating lipids and inflammatory markers improved in RAL compared to control group. The median liver fat measured by MRS was unexpectedly within normal range in this relatively small study population with presumably high risk for NAFLD contradicting high prevalence of NAFLD reported with other methods. Despite weight gain, increase in SAT together with decreased adipocyte size and reduced inflammation may reflect improved adipose tissue function. Clinical Trial Registration number: NCT03374358.

IRF2BP2 Mutation Is Associated with Increased STAT1 and STAT5 Activation in Two Family Members with Inflammatory Conditions and Lymphopenia.

Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional coregulator that has an important role in the regulation of the immune response. IRF2BP2 has been associated with the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway, but its exact role remains elusive. Here, we identified a novel clinical variant, IRF2BP2 c.625_665del, from two members of a family with inflammatory conditions and investigated the function of IRF2BP2 and c.625_665del mutation in JAK-STAT pathway activation and inflammatory signaling. The levels of constitutive and cytokine-induced phosphorylation of STATs and total STAT1 in peripheral blood monocytes, T cells, and B cells from the patients and four healthy controls were measured by flow cytometry. Inflammation-related gene expression was studied in peripheral blood mononuclear cells using direct digital detection of mRNA (NanoString). Finally, we studied the relationship between IRF2BP2 and STAT1 activation using a luciferase reporter system in a cell model. Our results show that patients having the IRF2BP2 c.625_665del mutation presented overexpression of STAT1 protein and increased constitutive activation of STAT1. In addition, interferon-induced JAK-STAT signaling was upregulated, and several interferon-inducible genes were overexpressed. Constitutive phosphorylation of STAT5 was also found to be upregulated in CD4+ T cells from the patients. Using a cell model, we show that IRF2BP2 was needed to attenuate STAT1 transcriptional activity and that IRF2BP2 c.625_665del mutation failed in this. We conclude that IRF2BP2 has an important role in suppressing immune responses elicited by STAT1 and STAT5 and suggest that aberrations in IRF2BP2 can lead to abnormal function of intrinsic immunity.

SARS-CoV-2 late shedding may be infectious between immunocompromised hosts.

BACKGROUND: Immunocompromised patients shed SARS-CoV-2 for extended periods, but to our knowledge person-to-person transmission from late shedding has not been reported. THE CASE: We present a case in which a COVID-19 patient infected another over 28 days after the patient's initial symptoms, past current guideline recommendations of 20 days for length of isolation in immunocompromised patients. Whole genome sequencing of their viruses was performed to ascertain the transmission. DISCUSSION: Severely immunocompromised patients, whose clearance of the virus is impaired, may remain infectious for extended periods. Caution should be taken particularly in hospital settings where lapses in isolation procedures might pose increased risk, especially to other immunocompromised patients.

Nature-derived microbiota exposure as a novel immunomodulatory approach.

AIM: Current attempts to modulate the human microbiota and immune responses are based on probiotics or human-derived bacterial transplants. We investigated microbial modulation by soil and plant-based material. MATERIALS & METHODS: We performed a pilot study in which healthy adults were exposed to the varied microbial community of a soil- and plant-based material. RESULTS: The method was safe and feasible; exposure was associated with an increase in gut microbial diversity. CONCLUSION: If these findings are reproduced in larger studies nature-derived microbial exposure strategies could be further developed for testing their efficacy in the treatment and prevention of immune-mediated diseases.

Live attenuated enterovirus vaccine (OPV) is not associated with islet autoimmunity in children with genetic susceptibility to type 1 diabetes: prospective cohort study.

AIMS/HYPOTHESIS: Animal and human studies have implied that enterovirus infections may modulate the risk of islet autoimmunity and type 1 diabetes. We set out to assess whether serial administration of live oral poliovirus vaccine (OPV) in early life can influence the initiation of islet autoimmunity in a cohort of genetically predisposed children. METHODS: OPV was administered to 64 children and a further 251 children received inactivated poliovirus vaccine (IPV). The emergence of type 1 diabetes-associated autoantibodies in serum (autoantibodies to GAD, insulinoma-associated protein 2, insulin and islet cells) was monitored during prospective follow-up. Stool and serum samples were collected for enterovirus detection by RT-PCR. RESULTS: Administration of OPV increased enterovirus detected in stool samples from 11.3% to 38.9% (p < 0.001) during the first year of life. During the follow-up (median 11.0 years), at least one autoantibody was detected in 17.2% of children vaccinated with OPV and 19.1% with IPV (p = 0.723). At least two autoantibodies were observed in 3.1% and 6.8% of children, respectively (p = 0.384). CONCLUSIONS/INTERPRETATION: Replication of attenuated poliovirus strains in gut mucosa is not associated with an increased risk of islet autoimmunity. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02961595.

Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity.

AIMS/HYPOTHESIS: This case-control study was nested in a prospective birth cohort to evaluate whether the presence of enteroviruses in stools was associated with the appearance of islet autoimmunity in the Type 1 Diabetes Prediction and Prevention study in Finland. METHODS: Altogether, 1673 longitudinal stool samples from 129 case children who turned positive for multiple islet autoantibodies and 3108 stool samples from 282 matched control children were screened for the presence of enterovirus RNA using RT-PCR. Viral genotype was detected by sequencing. RESULTS: Case children had more enterovirus infections than control children (0.8 vs 0.6 infections per child). Time-dependent analysis indicated that this excess of infections occurred more than 1 year before the first detection of islet autoantibodies (6.3 vs 2.1 infections per 10 follow-up years). No such difference was seen in infections occurring less than 1 year before islet autoantibody seroconversion or after seroconversion. The most frequent enterovirus types included coxsackievirus A4 (28% of genotyped viruses), coxsackievirus A2 (14%) and coxsackievirus A16 (11%). CONCLUSIONS/INTERPRETATION: The results suggest that enterovirus infections diagnosed by detecting viral RNA in stools are associated with the development of islet autoimmunity with a time lag of several months.

Enrichment of rare variants in population isolates: single AICDA mutation responsible for hyper-IgM syndrome type 2 in Finland.

Antibody class-switch recombination and somatic hypermutation critically depend on the function of activation-induced cytidine deaminase (AID). Rare variants in its gene AICDA have been reported to cause autosomal recessive AID deficiency (autosomal recessive hyper-IgM syndrome type 2 (HIGM2)). Exome sequencing of a multicase Finnish family with an HIGM2 phenotype identified a rare, homozygous, variant (c.416T>C, p.(Met139Thr)) in the AICDA gene, found to be significantly enriched in the Finnish population compared with other populations of European origin (38.56-fold, P<0.001). The population history of Finland, characterized by a restricted number of founders, isolation and several population bottlenecks, has caused enrichment of certain rare disease-causing variants and losses of others, as part of a phenomenon called the Finnish Disease Heritage. Accordingly, rare founder mutations cause the majority of observed Finnish cases in these mostly autosomal recessive disorders that consequently are more frequent in Finland than elsewhere. Screening of all currently known Finnish patients with an HIGM2 phenotype showed them to be homozygous for p.(Met139Thr). All the Finnish p.(Met139Thr) carriers with available data on their geographic descent originated from the eastern and northeastern parts of Finland. They were observed to share more of their genome identity by descent (IBD) than Finns in general (P<0.001), and they all carried a 207.5-kb ancestral haplotype containing the variant. In conclusion, the identified p.(Met139Thr) variant is significantly enriched in Finns and explains all thus far found AID deficiencies in Finland.

Maternal enterovirus infection as a risk factor for type 1 diabetes in the exposed offspring.

OBJECTIVE: Maternal enterovirus infections during pregnancy have been linked to an increased risk of type 1 diabetes in the offspring. The aim of this study was to evaluate this association in a unique series of pregnant mothers whose child progressed to clinical type 1 diabetes. RESEARCH DESIGN AND METHODS: Maternal and in utero enterovirus infections were studied in 171 offspring who presented with type 1 diabetes before the age of 11 years and in 316 control subjects matched for date and place of birth, sex, and HLA-DQ risk alleles for diabetes. Acute enterovirus infections were diagnosed by increases in enterovirus IgG and IgM in samples taken from the mother at the end of the first trimester of pregnancy and cord blood samples taken at delivery. RESULTS: Signs of maternal enterovirus infection were observed in altogether 19.3% of the mothers of affected children and in 12.0% of the mothers of control children (P = 0.038). This difference was seen in different HLA risk groups and in both sexes of the offspring, and it was unrelated to the age of the child at the diagnosis of diabetes or the age of the mother at delivery. CONCLUSIONS: These results suggest that an enterovirus infection during pregnancy is not a major risk factor for type 1 diabetes in childhood but may play a role in some susceptible subjects.

Role of enterovirus infections in IgE sensitization.

Among other infectious agents, enteroviruses have been associated with protection against allergic diseases. The aim of the present study was to confirm these findings using a highly sensitive and specific neutralization antibody assay and to investigate whether the protective effect is related to certain enterovirus serotypes. Antibodies against 12 enterovirus serotypes were measured in 60 children who were positive for allergen-specific IgE and in 190 control children. Echoviruses seemed to be more protective than coxsackie-B-viruses and echovirus 11 had the strongest independent protective effect (P = 0.001; OR = 0.35, 95% CI: 0.18-0.67). The results support previous observations suggesting that infections by certain enterovirus types are associated with protection against IgE sensitization.

Viral interference induced by live attenuated virus vaccine (OPV) can prevent otitis media.

BACKGROUND: The goal of this study was to evaluate whether a live attenuated poliovirus vaccine (OPV) has clinically relevant interfering effect with non-polio infections causing otitis media in young children. METHODS: Open trial in which the intervention group (64 children) received OPV at the age of 2, 3, 6 and 12 months. The control group (250 children) received IPV (inactivated polio vaccine) at the age of 6 and 12 months. Clinical symptoms were recorded by a questionnaire at the age of 3, 6, 12, 18 and 24 months. RESULTS: Otitis media episodes were less frequent in the OPV than in the control group. A significant difference was seen at the age of 6-18 months (IRR=0.76 [95% CI 0.59-0.94], P=0.011) and was particularly clear among children, who attended daycare (IRR 0.37 [95% CI 0.19-0.71], P=0.003). CONCLUSIONS: OPV provides some protection against otitis media. This effect may be mediated by viral interference with non-polio viruses.

Co-occurrence of allergic sensitization and type 1 diabetes.

BACKGROUND: The mechanisms leading to abnormal immune regulation in type 1 diabetes and allergic diseases may be partly overlapping. If so, these diseases should co-occur more often than expected. We investigated this phenomenon in two contrasting socio-economic environments, Finland and Russian Karelia. METHODS: We screened 413 Finnish children (of whom 147 had type 1 diabetes) and 244 Russian Karelian children (132 had type 1 diabetes) for total immunoglobulin E (IgE) levels and specific IgE against birch, cat, and egg albumen. In addition we analysed diabetes-related human leukocyte antigen (HLA) haplotypes and antibodies against hepatitis A virus (HAV) and recorded allergic diseases by a questionnaire in Russian Karelia. RESULTS: In Russian Karelia 15% of the patients with type 1 diabetes, but only 4% of the control subjects had allergen-specific IgE (P = 0.012). A similar difference was observed in the frequency of allergic symptoms. Co-occurrence of allergic sensitization and type 1 diabetes was associated with lack of HAV antibodies and was not seen in Finland where infections are less frequent than in Karelia. CONCLUSION: Our findings support the idea of common mechanisms in the pathogenesis of allergic diseases and type 1 diabetes, which may be particularly important in an environment with low penetrance of these diseases.

Time trends in allergic sensitisation and Helicobacter pylori prevalence in Finnish pregnant women.

BACKGROUND: An increase in the prevalence of allergic conditions has been documented in Finland, correlating with the diminishing prevalence of Helicobacter pylori infections. We investigated whether the increase of allergic sensitisation still continues and correlates with the prevalence of H. pylori infections. METHODS: The sera from 958 pregnant women in 1983, 1989, 1995 and 2001 were analysed for the presence of antibodies against H. pylori. In addition, allergen-specific IgE antibodies and total levels of IgE antibodies were measured. RESULTS: A clear birth cohort effect was found in the prevalence of allergic sensitization: allergen-specific IgE was more frequent among recent birth cohorts than earlier ones (p = 0.001). The frequency of H. pylori antibodies followed the opposite trend (p < 0.001) and the increase in allergic sensitisation was only seen among H. pylori-negative women. A modest increase was also seen in allergic sensitisation between the 4 time series among the H. pylori-negative subjects (p = 0.04). Total IgE levels did not differ between birth cohorts or time series. CONCLUSION: The results suggest that hygiene-related environmental factors have played a role in the increase of allergic sensitisation during the last decades.

PCR inhibition in stool samples in relation to age of infants.

BACKGROUND: PCR is rapidly replacing traditional methods in diagnostic virus laboratories. PCR inhibitors, which are often present in clinical samples, may lead to false negative test results. OBJECTIVES: The aim was to study the presence of PCR inhibitors in stool samples collected from 3- to 24-month old children. STUDY DESIGN: Total RNA fraction extracted from stool samples was spiked with a standardized amount of Semliki Forest Virus RNA and amplified using specific PCR primers. The presence of PCR inhibitors was detected by a decrease in amplification rate compared to spiked water samples. Inhibition in different age groups and dietary origin of PCR inhibitors were analyzed by comparing the samples taken during exclusive and non-exclusive breastfeeding periods. The inactivation of PCR inhibitors was also assessed. RESULTS: Complete inhibition was seen in 12% (13/108) and partial inhibition in 19% (21/108) of the samples. Inhibition was seen in none of the stool samples (0/31) taken from infants younger than 6 months compared to 17% of samples (13/77) taken from 6 to 24 months old infants (p<0.036). Breastfeeding was more common in younger age group. Addition of bovine serum albumin (BSA) into the reaction mixtures eliminated the effect of inhibitors leading to all samples being positive. CONCLUSIONS: PCR inhibitors are frequent in stool samples. They may originate from dietary components and can lead to false negative PCR results. The addition of BSA to the cDNA and PCR reactions proved to be an easy and effective method for eliminating the inhibitory effect of these compounds.

Lower economic status and inferior hygienic environment may protect against celiac disease.

BACKGROUND: The populations in adjacent Russian Karelia and Finland are equally exposed to grain products and share partly the same ancestry, but live in completely different socioeconomic environments. AIM: This creates an ideal epidemiological setting to study gene-environmental interactions in pathogenesis of celiac disease. METHODS: The prevalence of celiac disease and predisposing human leukocyte antigen (HLA) alleles was compared between Russian Karelia and Finland. Tissue transglutaminase antibodies and HLA-DQ alleles were screened from 1988 schoolchildren from Karelia and 3654 children from Finland. Children with transglutaminase antibodies were invited to small-bowel biopsy. Results. Transglutaminase antibodies were less frequent in Russian Karelia than in Finland (0.6% versus 1.4%, P = 0.005). Immunoglobulin class G (IgG) antigliadin antibodies were also less frequent in Russian Karelia (10.2% versus 28.3%, P<0.0001). Celiac disease was confirmed by duodenal biopsy in four of the eight transglutaminase antibody-positive Karelian children, giving a prevalence of 1 in 496 compared to 1 in 107 children in Finland. The same HLA-DQ alleles were associated with celiac disease and transglutaminase antibody positivity in both populations. CONCLUSIONS: The prevalence of transglutaminase antibodies and celiac disease is lower in Russian Karelia than in Finland. This may be associated with a protective environment characterized by inferior prosperity and standard of hygiene in Karelia.