Susceptibility To Respiratory Infections Research Articles

Basic Susceptibility of Patients with Psoriasis under Systemic Therapy for Respiratory Infections: Data from the German Psoriasis Registry PsoBest.

Background: Patients with psoriasis under systemic treatments are in focus regarding their susceptibility to respiratory infections. To analyse real-world data for respiratory infections in patients with psoriasis under systemic treatments. Methods: We analysed data of the prospective, non-interventional German Psoriasis Registry PsoBest and compared rates for respiratory infections of 13,823 patients on systemic treatments for psoriasis and/or psoriatic arthritis in different therapy cohorts before the COVID-19 pandemic. Results: In total, 1415 respiratory infections were observed in 970 patients. Significant differences were observed between biologics and non-biologics, but not within these groups. The highest event rates (events/100 patient years) were identified for TNF-α inhibitors, 8.1, (CI 7.4-8.9), followed by 7.0 for IL-17 inhibitors (6.2-7.9), 5.7 for IL-12/23 and IL-23 inhibitors (5.1-6.5), 4.8 for methotrexate (4.3-5.4), 3.7 for small molecules (3.3-4.2), and 2.7 for retinoids (1.2-5.1). Conclusions: Overall, the susceptibility for respiratory infections in patients under systemic therapy for psoriasis is low compared to published study data and is sufficient as comparative data for COVID-19 studies.

Genome-wide association study of susceptibility to hospitalised respiratory infections

Background: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. Methods: We conducted a genome-wide association study in 19,459 hospitalised respiratory infection cases and 101,438 controls from UK Biobank (Stage 1). We followed-up well-imputed top signals from our Stage 1 analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts (Stage 2). We aggregated effect estimates across studies using inverse variance-weighted meta-analyses. Additionally, we investigated the function of the top signals in order to gain understanding of the underlying biological mechanisms. Results: From our Stage 1 analysis, we report 56 signals at P<5 ×10 -6, one of which was genome-wide significant ( P<5 ×10 -8). The genome-wide significant signal was in an intron of PBX3, a gene that encodes pre-B-cell leukaemia transcription factor 3, a homeodomain-containing transcription factor. Further, the genome-wide significant signal was found to colocalise with gene-specific expression quantitative trait loci (eQTLs) affecting expression of PBX3 in lung tissue, where the respiratory infection risk alleles were associated with decreased PBX3 expression in lung tissue, highlighting a possible biological mechanism. Of the 56 signals, 40 were well-imputed in UK Biobank and were investigated in Stage 2. None of the 40 signals replicated, with effect estimates attenuated. Conclusions: Our Stage 1 analysis implicated PBX3 as a candidate causal gene and suggests a possible role of transcription factor binding activity in respiratory infection susceptibility. However, the PBX3 signal, and the other well-imputed signals, did not replicate in the meta-analysis of Stages 1 and 2. Significant phenotypic heterogeneity and differences in study ascertainment may have contributed to this lack of statistical replication. Overall, our study highlighted putative associations and possible biological mechanisms that may provide insight into respiratory infection susceptibility.

Oral and gut microbial biomarkers of susceptibility to respiratory tract infection in adults: A feasibility study

We conducted a feasibility cohort study which aimed to recruit and retain adults from the community to collect saliva (oral) and stool (gut) samples at three time points, at the start of the study (baseline), during a respiratory tract infection (RTI) and post-RTI. Community RTIs place a huge burden on health care services, and a non-invasive microbial diagnostic tool to predict the most vulnerable to respiratory infection would be ideal. To this aim, we analysed oral-gut baseline samples comparing those who reported RTI symptoms to those who remained healthy throughout the study for microbial biomarkers of respiratory susceptibility. Amplicon sequence variants (ASV) were identified by 16S sequence profiling to reveal oral-gut microbes. Reverse transcriptase-polymerase chain reaction (RT-PCR) was applied to target common respiratory microbes. Two general practices were recruited, and the participant recruitment rate was 1.3%. A total of 40 adult participants were retained, of which 19 acquired an RTI whereas 21 remained healthy. In healthy baseline oral and gut samples, ASVs from participants with RTI symptoms compared to those who remained healthy were similar with a high relative abundance of Streptococcus sp., and Blautia sp., respectively. Linear discriminant analysis effect size (LEfSe) revealed baseline oral microbes differed, indicating participants who suffered RTI symptoms had enhanced Streptococcus sobrinus and Megamonas sp., and depletion of Lactobacillus salivarius, Synergistetes, Verrucomicrobia and Dethiosulfovibrio. Furthermore, a random forest model ranked Streptococcus (4.13) as the highest mean decrease in accuracy (MDA) and RT-PCR showed a higher level of carriage of coagulase-negative Staphylococcus. Baseline core gut microbes were similar in both participant groups whereas LEfSe analysis revealed enhanced Veillonella, Rikenellaceae, Enhydobacteria, Eggerthella and Xanthomonsdales and depleted Desulfobulbus and Coprobacillus. Sutterella (4.73) had a high MDA value. Overall, we demonstrated the feasibility of recruiting and retaining adult participants from the community to provide multiple biological samples for microbial profiling. Our analyses identified potential oral-gut microbial biomarkers of respiratory infection susceptibility in otherwise healthy participants.

Wearing masks to prevent one epidemic may mask another.

With attempts at lifting most COVID-19 pandemic-related restrictions, other common respiratory viruses have caused more health concern than in earlier seasons in pediatric populations. To explore the role of non-pharmaceutical interventions (NPIs) in a rebound in other respiratory viral pathogens, especially in light of general vaccination fatigue, COVID-19 boosters, and operational challenges in the healthcare system. A research-based commentary supported with recent literature review. Pandemic-related lockdowns in Europe, Australia, and New Zealand have created a significant population of susceptible young children without preexisting immunity due to lack of exposure during the colder months. Relying on NPIs for a prolonged period due to low vaccination rates may lead to increased respiratory infection susceptibility, especially among young children less than 5years old. The key public health question is whether NPIs should be implemented in the long run and what are the long-term implications on the dynamics of endemic infections and population immunity. Prevention cannot be the only cure for any infectious disease, and long-term impact of NPIs depends on the dynamics of population susceptibility. The SARS-CoV-2 pandemic has reinforced the importance of vaccination and the knowledge on vaccine use combined with NPIs will be of great value in controlling other known and unknown respiratory pathogens. Combining NPIs and vaccination is paramount in disease control, and the discussion on how to prevent collateral damage to sensitive populations while relaxing NPI-related measures should also merit attention.

A health-promoting role of exclusive breastfeeding on infants through restoring delivery mode-induced gut microbiota perturbations.

The establishment of human gut microbiota in early life is closely associated with both short- and long-term infant health. Delivery mode and feeding pattern are two important determinants of infant gut microbiota. In this longitudinal cohort study, we examined the interplay between the delivery mode and feeding pattern on the dynamics of infant gut microbiota from 6 weeks to 6 months post-delivery in 139 infants. We also assessed the relationship between infant respiratory infection susceptibility and gut microbial changes associated with delivery mode and feeding pattern. At 6 weeks postpartum, the composition and structure of gut microbiota of cesarean section-delivered (CSD) infants differed from those of vaginally delivered (VD) infants, with decreased Bacteroides and Escherichia-Shigella and increased Klebsiella, Veillonella, and Enterococcus. At 6 months postpartum, these delivery mode-induced microbial shifts were restored by exclusive breastfeeding, resulting in similar gut microbial profiles between VD and CSD infants who were exclusively breastfed (P = 0.57) and more variable gut microbial profiles between VD and CSD infants who were mixed fed (P < 0.001). We identified that the VD-associated genera were enriched in healthy infants, while the CSD-associated genera were enriched in infants who suffered from respiratory infections. Our findings indicate that exclusive breastfeeding may play a health-promoting role by reducing infant respiratory infection susceptibility through the restoration of gut microbiota perturbations caused by cesarean section.

Elevated third trimester corticosteroid levels are associated with fewer offspring infections

Respiratory infections are a leading cause of morbidity and mortality in early life, and recurrent infections increase the risk of developing chronic diseases. The maternal environment during pregnancy can impact offspring health, but the factors leading to increased infection proneness have not been well characterized during this period. Steroids have been implicated in respiratory health outcomes and may similarly influence infection susceptibility. Our objective was to describe relationships between maternal steroid levels and offspring infection proneness. Using adjusted Poisson regression models, we evaluated associations between sixteen androgenic and corticosteroid metabolites during pregnancy and offspring respiratory infection incidence across two pre-birth cohorts (N = 774 in VDAART and N = 729 in COPSAC). Steroid metabolites were measured in plasma samples from pregnant mothers across all trimesters of pregnancy by ultrahigh-performance-liquid-chromatography/mass-spectrometry. We conducted further inquiry into associations of steroids with related respiratory outcomes: asthma and lung function spirometry. Higher plasma corticosteroid levels in the third trimester of pregnancy were associated with lower incidence of offspring respiratory infections (P = 4.45 × 10–7 to 0.002) and improved lung function metrics (P = 0.020–0.036). Elevated maternal androgens were generally associated with increased offspring respiratory infections and worse lung function, with some associations demonstrating nominal significance at P < 0.05, but these trends were inconsistent across individual androgens. Increased maternal plasma corticosteroid levels in the late second and third trimesters were associated with lower infections and better lung function in offspring, which may represent a potential avenue for intervention through corticosteroid supplementation in late pregnancy to reduce offspring respiratory infection susceptibility in early life.Clinical Trial Registry information: VDAART and COPSAC were originally conducted as clinical trials; VDAART: ClinicalTrials.gov identifier NCT00920621; COPSAC: ClinicalTrials.gov identifier NCT00798226.

The microbiota in respiratory tract infections: from association to intervention.

The respiratory microbiota has a role in respiratory tract infection (RTI) pathogenesis. On the mucosa, the respiratory microbiota interacts with potential pathogenic viruses, bacteria and the host immune system, including secretory IgA (sIgA). This review discusses the role of the respiratory microbiota and its interaction with the (mucosal) immune system in RTI susceptibility, as well as the potential to exploit the microbiota to promote health and prevent RTIs. Recent studies confirm that specific microbiota profiles are associated with RTI susceptibility and during susceptibility and found accompanying RTIs, although clear associations have not yet been found for SARS-CoV-2 infection. sIgA plays a central role in RTI pathogenesis: it stands under control of the local microbiota, while at the same time influencing bacterial gene expression, metabolism and defense mechanisms. Respiratory microbiota interventions are still newly emerging but promising candidates for probiotics to prevent RTIs, such as Corynebacterium and Dolosigranulum species, have been identified. Improved understanding of the respiratory microbiota in RTIs and its interplay with the immune system is of importance for early identification and follow-up of individuals at risk of infection. It also opens doors for future microbiota interventions by altering the microbiota towards a healthier state to prevent and/or adjunctively treat RTIs.

NRF2 Protects against Altered Pulmonary T Cell Differentiation in Neonates Following In Utero Ultrafine Particulate Matter Exposure.

Early life exposure to particulate matter (PM) air pollution negatively impacts neonatal health. The underlying mechanisms following prenatal exposure, particularly to ultrafine particles (UFP, diameter ≤ 0.1 μm), are not fully understood; To evaluate the role of Nrf2 in response to in utero UFP exposure, we exposed time-mated Nrf2-deficient (Nrf2−/−) or wildtype (WT) mice to filtered air (FA) or 100 μg/m3 ultrafine PM daily throughout pregnancy. Offspring were evaluated for pulmonary immunophenotypes and pulmonary/systemic oxidative stress on postnatal day 5, a timepoint at which we previously demonstrated viral respiratory infection susceptibility; Nrf2−/− offspring exposed to FA had significantly lower average body weights compared to FA-exposed WT pups. Moreover, PM-exposed Nrf2−/− offspring weighed significantly less than PM-exposed WT pups. Notably, PM-exposed Nrf2−/− offspring showed a decreased pulmonary Th1/Th2 ratio, indicating a Th2 bias. Th17 cells were increased in FA-exposed Nrf2−/− neonates yet decreased in PM-exposed Nrf2−/− neonates. Analysis of oxidative stress-related genes in lung and oxidative stress biomarkers in liver tissues did not vary significantly across exposure groups or genotypes. Collectively, these findings indicate that the lack of Nrf2 causes growth inhibitory effects in general and in response to gestational UFP exposure. Prenatal UFP exposure skews CD4+ T lymphocyte differentiation toward Th2 in neonates lacking Nrf2, signifying its importance in maternal exposure and infant immune responses.

Genome-wide association study of susceptibility to hospitalised respiratory infections

Background: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. Methods: We conducted a genome-wide association study in 19,459 hospitalised respiratory infection cases and 101,438 controls from UK Biobank. We followed-up well-imputed top signals from the UK Biobank discovery analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts. We aggregated effect estimates across studies using inverse variance-weighted meta-analyses. Additionally, we investigated the function of the top signals in order to gain understanding of the underlying biological mechanisms. Results: In the discovery analysis, we report 56 signals at P&lt;5×10-6, one of which was genome-wide significant (P&lt;5×10-8). The genome-wide significant signal was in an intron of PBX3, a gene that encodes pre-B-cell leukaemia transcription factor 3, a homeodomain-containing transcription factor. Further, the genome-wide significant signal was found to colocalise with gene-specific expression quantitative trait loci (eQTLs) affecting expression of PBX3 in lung tissue, where the respiratory infection risk alleles were associated with decreased PBX3 expression in lung tissue, highlighting a possible biological mechanism. Of the 56 signals, 40 were well-imputed in UK Biobank and were investigated in the 11 follow-up cohorts. None of the 40 signals replicated, with effect estimates attenuated. Conclusions: Our discovery analysis implicated PBX3 as a candidate causal gene and suggests a possible role of transcription factor binding activity in respiratory infection susceptibility. However, the PBX3 signal, and the other well-imputed signals, did not replicate when aggregating effect estimates across 11 independent cohorts. Significant phenotypic heterogeneity and differences in study ascertainment may have contributed to this lack of statistical replication. Overall, our study highlighted putative associations and possible biological mechanisms that may provide insight into respiratory infection susceptibility.

Cortisol and perceived stress are associated with cytokines levels in patients infected with influenza B virus

Influenza B virus (IBV) causes respiratory infectious disease. Cytokines are important immune mediators during infectious diseases. Cortisol and stress have been related to respiratory infection susceptibility and cytokine regulation. Little is known about systemic cytokines, cortisol, and perceived stress in the early stages of IBV infection. We researched the systemic cytokines and cortisol, as well as the perceived stress and blood cell count in patients infected with IBV. The diagnosis was established using the Luminex xTAG RVP kit and confirmed with qRT-PCR for IBV viral load. The perceived stress was evaluated using the perceived stress scale (PSS-10). Twenty-five plasma cytokines were determined using multiplex immunoassay and cortisol by ELISA. The leukocyte differential count was measured with a standard laboratory protocol. Th1, Th17, and IL-10 cytokines were higher in IBV infected patients (P < 0.05). Leukocytes and neutrophil count negatively correlated with viral load (P < 0.05). Perceived stress had a negative effect on monocyte and systemic cytokines in IBV infected patients (P < 0.05). Cortisol was higher in patients infected with IBV and correlated positively with CCL20 (P < 0.05). Cortisol showed a positive effect on most of the systemic cytokines (P < 0.05). In conclusion, a cytokine pattern was found in IBV infected patients, as well as the possible role of leukocyte counts in the control of IBV. Our results suggest the importance of cortisol and perceived stress on systemic cytokines in patients infected with IBV, but more studies are needed to understand their role in cytokine production in respiratory infectious disease.

HLA Loci and Respiratory Infectious Diseases

The HLA system harbour a wide set of genes that plays an important role in the regulation and action of the immune system against invading pathogens, making them natural candidates for research on the genetic susceptibility for respiratory infections. Thus, along past decades, this topic has been subject to intense research and, consequently, several alleles of those loci have been implicated in the ability, more or less effective, to tackle and control invading pathogens in the respiratory system. Current editorial introduce, revise, summarize and comment the major advances in the role of HLA genes for the development of, and protection against, respiratory infectious disease. A general picture is drawn and new challenges on the field are relocated, especially those that might enlighten respiratory diseases aetiology and, thus, contribute in advances for diagnosis and treatment.

ROLE OF RESPIRATORY TRACT INFECTION IN FORMATION OF INFANTILE ATOPIC PHENOTYPE

Aim. To study the formation of atopic phenotype in children who had respiratory infection in the newborn period. Materials and methods. Retrospective study of 36 children who had respiratory infection in the neonatal period with subsequent examination at the age of 5-6 years was carried out on the basis of Perm Children’s City Clinical Hospital № 13. Results. Children with congenital pneumonia in 94,4 % of cases were found to suffer from atopic dermatitis, that is reliably more often than children with acute respiratory infection (50,0 %) in the neonatal period ( p < 0,01). All children with newborn respiratory infection form later the group of children who frequently fall ill. However, in the group of children with congenital pneumonia, complications of acute respiratory diseases occur more often, in particular, bronchoobstructive syndrome (44,4 % vs. 5,6 %, p < 0,05). No reliable differences between the groups were detected while studying respiratory resistance (hyperreactivity of bronchi was observed in 33,3 and 45,5 % of cases, respectively). In children who suffered from congenital pneumonia, IgE level is raised significantly more often ( p < 0,05). Conclusions. Children with congenital pneumonia, later on have high susceptibility to respiratory infections with development of complications that is an unfavorable factor for development of allergic diseases. Presence of atopic dermatitis, bronchial hyperreactivity and elevated sensitizing level contributes to formation of atopic phenotype as a risk factor for development of bronchial asthma.

Defective B-cell memory in patients with Down syndrome

Patients with Down syndrome carry immunologic defects, as evidenced by the increased risks for autoimmune diseases, hematologic malignancies, and respiratory tract infections. Moreover, the low numbers of circulating B cells suggest impaired humoral immunity. We sought to study how immunodeficiency in patients with Down syndrome results from immunologic defects in the B-cell compartment. We studied blood B-cell subset composition, replication history, somatic hypermutation status, and class-switch recombination in 17 children with Down syndrome. Germinal centers and plasma cells were studied in tonsils from 4additional children with Down syndrome. Blood transitional B-cell numbers were normal, but naive mature and memory B-cell numbers were reduced despite slightly increased serum B cell-activating factor levels. Germinal centers and plasma cells in tonsils appeared normal, as were serum immunoglobulin levels. CD27(+)IgD(+)IgM(+) "natural effector" B cells showed reduced proliferation and somatic hypermutation levels, whereas these were normal in CD27(+)IgD(-) memory B cells. Furthermore, IgM(+) and IgA(+), but not IgG(+), memory B cells showed impaired molecular signs for antigen selection. The B-cell pattern was highly similar to that of patients with common variable immunodeficiency and a defect in B-cell activation and proliferation. Children with Down syndrome seem capable of normal germinal center and plasma cell formation. Still, blood memory B-cell numbers were reduced and showed impaired molecular maturation of IgA and IgM, which are important for mucosal immunity. The observed molecular defects in circulating IgA and IgM B-cell memory could reflect impaired local responses, which underlie the increased susceptibility torespiratory tract infections of patients with Down syndrome.

Effect Of Prenatal Exposure To Indoor PM2.5 and Environmental Tobacco Smoke Affecting Lower Respiratory Tract Infection Was Modified By ROS Genes: Cocoa Study

Prenatal air pollution exposure associates with impaired fetal growth, decreased lung function, respiratory morbidity and mortality. We aimed to investigate the influence of prenatal indoor fine particulate matter (PM2.5) and environmental tobacco smoke (ETS) exposure and genetic polymorphisms on the susceptibility to respiratory tract infection (RTI) in infancy.

Effect Of Prenatal Antioxidant Intake On Infants' Respiratory Infection

Prenatal maternal diet may influence disease susceptibility of offspring with genetic backgrounds. The effect of prenatal antioxidant intake on the development of respiratory tract infection (RTI) during infancy has not been studied. The interactions between prenatal antioxidant intake and genetic factors on RTI susceptibility at 12- months of age was evaluated.

Genome-wide analysis of the mouse lung transcriptome reveals novel molecular gene interaction networks and cell-specific expression signatures

BackgroundThe lung is critical in surveillance and initial defense against pathogens. In humans, as in mice, individual genetic differences strongly modulate pulmonary responses to infectious agents, severity of lung disease, and potential allergic reactions. In a first step towards understanding genetic predisposition and pulmonary molecular networks that underlie individual differences in disease vulnerability, we performed a global analysis of normative lung gene expression levels in inbred mouse strains and a large family of BXD strains that are widely used for systems genetics. Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics.MethodsSteady-state polyA+ mRNA levels were assayed across a diverse and fully genotyped panel of 57 isogenic strains using the Affymetrix M430 2.0 array. Correlations of expression levels between genes were determined. Global expression QTL (eQTL) analysis and network covariance analysis was performed using tools and resources in GeneNetwork http://www.genenetwork.org.ResultsExpression values were highly variable across strains and in many cases exhibited a high heri-tability factor. Several genes which showed a restricted expression to lung tissue were identified. Using correlations between gene expression values across all strains, we defined and extended memberships of several important molecular networks in the lung. Furthermore, we were able to extract signatures of immune cell subpopulations and characterize co-variation and shared genetic modulation. Known QTL regions for respiratory infection susceptibility were investigated and several cis-eQTL genes were identified. Numerous cis- and trans-regulated transcripts and chromosomal intervals with strong regulatory activity were mapped. The Cyp1a1 P450 transcript had a strong trans-acting eQTL (LOD 11.8) on Chr 12 at 36 ± 1 Mb. This interval contains the transcription factor Ahr that has a critical mis-sense allele in the DBA/2J haplotype and evidently modulates transcriptional activation by AhR.ConclusionsLarge-scale gene expression analyses in genetic reference populations revealed lung-specific and immune-cell gene expression profiles and suggested specific gene regulatory interactions.

The influence of acute respiratory acidosis on the pulmonary defense mechanisms in rats.

Respiratory acidosis and infection often occur together. Because metabolic abnormalities can enhance susceptibility to respiratory infection, the effect of acute respiratory acidosis on murine resistance to bacterial infection was investigated. After infection with Staphylococcus aureus labeled with phosphorus-32, rats were anesthetized for 4 hours with gas mixtures containing 5, 8, or 10 per cent carbon dioxide with 30 per cent oxygen and 1 per cent halothane in nitrogen. Pulmonary bactericidal activity rates were determined in excised lungs. Bactericidal activity decreased progressively with increasing degrees of respiratory acidosis; arterial blood threshold values were pH 75 mm Hg. Hypoxia was not a factor (arterial oxygen tension > 88 mm Hg), and there was no significant base deficit. Pulmonary edema, as judged histologically and by wet and dry lung weight measurements, was not present. It was concluded that respiratory acidosis impairs pulmonary defense mechanisms...

EFFECT OF ATMOSPHERIC POLLUTANTS ON SUSCEPTIBILITY TO RESPIRATORY INFECTION. II. EFFECT OF NITROGEN DIOXIDE.

Effect of 2 hr of 0 to 25 ppM NO/sub 2/ before or after exposure to Klebsiella pneumoniae was determined on survival of mice. Five, 10, 15, or 25 ppM NO/sub 2/ given 1 or 6 hr before challenge resulted in increasing mortality. When given 27 hr before challenge, only > 15 ppM increased mortality. 2.5 ppM did not increase mortality significantly. 25 ppM NO/sub 2/ given 1, 6, 27, 48, or 72 hr post-challenge increased mortality but 2.5 ppM did not. Concentrations of 3.5 or 5.0 ppM NO/sub 2/ given for 2 hr increased mortality of mice challenged 1 hr later but 1.5 or 2.5 ppM did not. Temporary (< 72 hr) edema and congestion and dilatation of veins and capillaries were noted in mice exposed to 5 ppM NO/sub 2/ or more for 2 hr.