Childhood asthma: Novel endotyping by cytokines, validated through sensitization profiles and clinical characteristics.

BACKGROUND: Specific allergy sensitization pattern, using "component-resolved diagnosis" (CRD), is a central component of allergy and asthma in childhood. Besides this, allergic asthma has been characterized by a Th2-shifted endotype with elevation of classical Th2 cytokines. Recently, other endotypes with distinct mechanisms focusing on cytokine regulation evolved, yet those pathways are still not well understood. OBJECTIVE: (a) To define reproducible immunological endotypes using cytokine expression in an asthma cohort and (b) to characterize their sensitization profile and clinical phenotype. METHODS: Supernatants from PBMCs of 234 children (median age 10 years) of an asthma cohort were analysed for cytokine expressions. The children were split into a training (n = 49) and validation (n = 185) group. The training group was used to identify immunological endotypes by clustering cytokine expressions, which were then assessed regarding clinical characteristics and specific IgE of recombinant allergen components. Next, our findings were validated in the validation group. RESULTS: We identified novel endotypes based on primarily unstimulated cytokine expression. One endotype showed an IFN-γ/Interleukin (IL)-17/IL-5 predominance, a different sensitization pattern (high in birch/apple; p < .01), and inferior lung function (p < .01). A second endotype grouped young children with food allergy and reduced lung function. Our findings were reproducible in the validation group. CONCLUSION AND CLINICAL RELEVANCE: We identified two novel clinical asthma endotypes via cytokine expression pattern with distinct sensitization patterns. These novel findings are critical for clinical guidance and open avenues for identifying underlying mechanisms and more patient-specific therapies.

Ca2+ and innate immune pathways are activated and differentially expressed in childhood asthma phenotypes.

BACKGROUND: Asthma is the most common chronic disease in children. Underlying immunologic mechanisms-in particular of different phenotypes-are still just partly understood. The objective of the study was the identification of distinct cellular pathways in allergic asthmatics (AA) and nonallergic asthmatics (NA) vs healthy controls (HC). METHODS: Peripheral blood mononuclear cells (PBMCs) of steroid-naïve children (n(AA/NA/HC) = 35/13/34)) from the CLARA study (n = 275) were stimulated (anti-CD3/CD28, LpA) or kept unstimulated. Gene expression was investigated by transcriptomics and quantitative RT-PCR. Differentially regulated pathways between phenotypes were assessed after adjustment for sex and age (KEGG pathways). Networks based on correlations of gene expression were built using force-directed graph drawing. RESULTS: Allergic asthmatics vs NA and asthmatics overall vs HC showed significantly different expression of Ca2+ and innate immunity-associated pathways. PCR analysis confirmed significantly increased Ca2+ -associated gene regulation (ORMDL3 and ATP2A3) in asthmatics vs HC, most prominent in AA. Innate immunity receptors (LY75, TLR7), relevant for virus infection, were also upregulated in AA and NA compared to HC. AA and NA could be differentiated by increased ATP2A3 and FPR2 in AA, decreased CLEC4E in AA, and increased IFIH1 expression in NA following anti-CD3/28 stimulation vs unstimulated (fold change). CONCLUSIONS: Ca2+ regulation and innate immunity response pattern to viruses were activated in PBMCs of asthmatics. Asthma phenotypes were differentially characterized by distinct regulation of ATP2A3 and expression of innate immune receptors (FPR2, CLEC4E, IFIH1). These genes may present promising targets for future in-depth investigation with the long-term goal of more phenotype-specific therapeutic interventions in asthmatics.

IRF-1 SNPs influence the risk for childhood allergic asthma: A critical role for pro-inflammatory immune regulation.

BACKGROUND: Allergic and non-allergic childhood asthma has been characterized by distinct immune mechanisms. While interferon regulating factor 1 (IRF-1) polymorphisms (SNPs) influence atopy risk, the effect of SNPs on asthma phenotype-specific immune mechanisms is unclear. We assessed whether IRF-1 SNPs modify distinct immune-regulatory pathways in allergic and non-allergic childhood asthma (AA/NA). METHODS: In the CLARA study, asthma was characterized by doctor's diagnosis and AA vs NA by positive or negative specific IgE. Children were genotyped for four tagging SNPs within IRF-1 (n = 172). mRNA expression was measured with qRT-PCR. Gene expression was analyzed depending on genetic variants within IRF-1 and phenotype including haplotype estimation and an allelic risk score. RESULTS: Carrying the risk alleles of IRF-1 in rs10035166, rs2706384, or rs2070721 was associated with increased risk for AA. Carrying the non-risk allele in rs17622656 was associated with lower risk for AA but not NA. In AA carrying the risk alleles, an increased pro-inflammatory expression of ICAM3, IRF-8, XBP-1, IFN-γ, RGS13, RORC, and TSC2 was observed. NOD2 expression was decreased in AA with risk alleles in rs2706384 and rs10035166 and with risk haplotype. Further, AA with risk haplotype showed increased IL-13 secretion. NA with risk allele in rs2070721 compared to non-risk allele in rs17622656 showed significantly upregulated calcium, innate, mTOR, neutrophil, and inflammatory-associated genes. CONCLUSION: IRF-1 polymorphisms influence the risk for childhood allergic asthma being associated with increased pro-inflammatory gene regulation. Thus, it is critical to implement IRF-1 genetics in immune assessment for childhood asthma phenotypes.

Evaluating the Prostate Cancer Prevention Trial High Grade Prostate Cancer Risk Calculator in 10 international biopsy cohorts: results from the Prostate Biopsy Collaborative Group.

OBJECTIVES: To assess the applicability of the Prostate Cancer Prevention Trial High Grade (Gleason grade ≥ 7) Risk Calculator (PCPTHG) in ten international cohorts, representing a range of populations. METHODS: A total of 25,512 biopsies from 10 cohorts (6 European, 1 UK and 3 US) were included; 4 implemented 6-core biopsies, and the remaining had 10 or higher schemes; 8 were screening cohorts, and 2 were clinical. PCPTHG risks were calculated using prostate-specific antigen, digital rectal examination, age, African origin and history of prior biopsy and evaluated in terms of calibration plots, areas underneath the receiver operating characteristic curve (AUC) and net benefit curves. RESULTS: The median AUC of the PCPTHG for high-grade disease detection in the 10- and higher-core cohorts was 73.5% (range, 63.9-76.7%) compared with a median of 78.1% (range, 72.0-87.6%) among the four 6-core cohorts. Only the 10-core Cleveland Clinic cohort showed clear evidence of under-prediction by the PCPTHG, and this was restricted to risk ranges less than 15%. The PCPTHG demonstrated higher clinical net benefit in higher-core compared with 6-core biopsy cohorts, and among the former, there were no notable differences observed between clinical and screening cohorts, nor between European and US cohorts. CONCLUSIONS: The PCPTHG requires minimal patient information and can be applied across a range of populations. PCPTHG risk thresholds ranging from 5 to 20%, depending on patient risk averseness, are recommended for clinical prostate biopsy decision-making.

The impact of prostate volume, number of biopsy cores and American Urological Association symptom score on the sensitivity of cancer detection using the Prostate Cancer Prevention Trial risk calculator.

PURPOSE: We assessed the independent predictive value of prostate volume, number of biopsy cores and AUASS (American Urological Association symptom score) compared to risk factors included in the PCPTRC (Prostate Cancer Prevention Trial risk calculator for prostate cancer) and PCPTHG (Prostate Cancer Prevention Trial risk calculator for high grade cancer [Gleason grade 7 or greater]). MATERIALS AND METHODS: Of 5,519 PCPT (Prostate Cancer Prevention Trial) participants used to construct the PCPTRC 4,958 with AUASS and prostate specific antigen 10 ng/ml or less were included on logistic regression analysis. Risk algorithms were evaluated in 571 EDRN (Early Detection Research Network) participants using the ROC AUC. RESULTS: A total of 1,094 participants (22.1%) had prostate cancer, of whom 232 (21.2%) had high grade disease. For prostate cancer prediction higher prostate specific antigen, abnormal digital rectal examination, family history of prostate cancer and number of cores were associated with increased risk, while volume was associated with decreased risk. Excluding prostate volume and number of cores, a history of negative biopsy and increased AUASS were also associated with lower risk. For high grade cancer higher prostate specific antigen, abnormal digital rectal examination, black race and number of cores were associated with increased risk and volume, while AUASS was associated with decreased risk. The AUC of the PCPTRC adjusted for volume and number of cores was 72.7% (using EDRN data), 68.2% when adjusted for AUASS alone and 67.6% PCPTRC. For high grade disease the AUCs were 74.8%, 74.0% and 73.5% (PCPTHG), respectively. CONCLUSIONS: Adjusted PCPT risk calculators for volume, number of cores and AUASS improve cancer detection.

Evaluating the PCPT risk calculator in ten international biopsy cohorts: results from the Prostate Biopsy Collaborative Group.

OBJECTIVES: To evaluate the discrimination, calibration, and net benefit performance of the Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) across five European randomized study of screening for prostate cancer (ERSPC), 1 United Kingdom, 1 Austrian, and 3 US biopsy cohorts. METHODS: PCPTRC risks were calculated for 25,733 biopsies using prostate-specific antigen (PSA), digital rectal examination, family history, history of prior biopsy, and imputation for missing covariates. Predictions were evaluated using the areas underneath the receiver operating characteristic curves (AUC), discrimination slopes, chi-square tests of goodness of fit, and net benefit decision curves. RESULTS: AUCs of the PCPTRC ranged from a low of 56% in the ERSPC Goeteborg Rounds 2-6 cohort to a high of 72% in the ERSPC Goeteborg Round 1 cohort and were statistically significantly higher than that of PSA in 6 out of the 10 cohorts. The PCPTRC was well calibrated in the SABOR, Tyrol, and Durham cohorts. There was limited to no net benefit to using the PCPTRC for biopsy referral compared to biopsying all or no men in all five ERSPC cohorts and benefit within a limited range of risk thresholds in all other cohorts. CONCLUSIONS: External validation of the PCPTRC across ten cohorts revealed varying degree of success highly dependent on the cohort, most likely due to different criteria for and work-up before biopsy. Future validation studies of new calculators for prostate cancer should acknowledge the potential impact of the specific cohort studied when reporting successful versus failed validation.

Predicting risk of prostate cancer in men receiving finasteride: effect of prostate volume, number of biopsy cores, and American Urological Association symptom score.

OBJECTIVE: To examine the effect of prostate volume, number of biopsy cores, and American Urological Association symptom score (AUASS) for prostate cancer risk assessment among men receiving finasteride in the Prostate Cancer Prevention Trial. METHODS: Data from 4509 men on the finasteride arm of the Prostate Cancer Prevention Trial who were on treatment at the time of their AUASS and prostate-specific antigen (PSA) measurement before biopsy were included in multivariable logistic regression analyses. RESULTS: Six hundred eighty-two (15.1%) participants had prostate cancer; 257 (37.7%) of these had high-grade disease. For prostate cancer risk, the model included PSA (odds ratio corresponding to a 2-fold increase in PSA: 2.70; P <.0001), digital rectal examination (2.53; P <.0001), age (1.03; P = .001), and prostate volume (odds ratio 0.54 for a 2-fold increase in volume; P <.0001). For high-grade disease, PSA (3.39; P <.0001), digital rectal examination (2.75; P <.0001), age (1.05; P = .001), and volume (0.55; P <.0001) were statistically significant. AUASS was not statistically significant in any of the models that included prostate volume, but was in models in which volume was not included. The number of biopsy cores did not significantly improve risk assessment in any of the models considered. CONCLUSION: Although in the general population, obtaining a cancer diagnosis is improved by assessing prostate volume and increasing the number of biopsy cores, neither steps are required in men receiving finasteride. Obtaining fewer biopsy cores in men receiving finasteride preserves biopsy sensitivity and will likely reduce cost and morbidity.

Poor neurological sequelae of herpes simplex virus encephalitis in an infant despite adequate antiviral and adjunct corticosteroid therapy.

A 2-month-old infant presented to our emergency department with fever, altered consciousness, and focal seizures of acute onset. He had vesicular skin lesions over the right preauricular region. CT brain showed a large hypodense lesion involving the left temporo-parietal region, left basal ganglia and left thalamus. MRI brain revealed bilateral multifocal corticomedullary lesions suggestive of encephalitis. CSF-PCR was positive for herpes simplex virus (HSV) type I. He was treated with standard dose intravenous acyclovir for 15 days along with a trial of pulse methylprednisolone, but was readmitted within a week with features of an early relapse. The infant survived but developed significant neurological sequelae. Although treatment of HSV is available, the neurological outcome is guarded even with adequate antiviral therapy. Adjunct corticosteroid therapy did not appear to attenuate the neurological sequelae.

Trends and co-trends of prostate-specific antigen and body mass index in a screened population.

OBJECTIVES: This report investigated whether annual changes in body mass index (BMI) are associated with the opposite changes in prostate-specific antigen (PSA). Previous studies have confirmed lower PSA levels among men with higher BMI. METHODS: Normal linear mixed models were used to characterize annual PSA, BMI and the ratio of PSA to BMI profiles for 2641 men undergoing prostate cancer screening for up to 8 years as part of a San Antonio screening study. RESULTS: Among the 1898 participants (71.9%) who never received a prostate biopsy during the study and the 585 participants (22.1%) who had one or more biopsies, all negative for prostate cancer, BMI was higher for Hispanics than other racial groups, lower for older men at study entry, and increased every year during the study; and PSA and PSA/BMI ratios were higher for older men at study entry and increased each year on study (all P values<.05). Among the 158 men (6.0%) eventually diagnosed with prostate cancer, no trends in BMI were statistically significant, but PSA and PSA/BMI ratios were higher on average for older men at study entry and increased each year on study (both P values<.05). Correlations between BMI and PSA changes per year were negative but not statistically significantly different from zero. CONCLUSIONS: The individual man scrutinizing his PSA and weight year to year can expect a slight annual increase in both, but changes in PSA from one year to the next cannot be attributed to weight gain or loss.