Diverse Role of blaCTX-M and Porins in Mediating Ertapenem Resistance among Carbapenem-Resistant Enterobacterales.

Among carbapenem-resistant Enterobacterales (CRE) are diverse mechanisms, including those that are resistant to meropenem but susceptible to ertapenem, adding further complexity to the clinical landscape. This study investigates the emergence of ertapenem-resistant, meropenem-susceptible (ErMs) Escherichia coli and Klebsiella pneumoniae CRE across five hospitals in San Antonio, Texas, USA, from 2012 to 2018. The majority of the CRE isolates were non-carbapenemase producers (NCP; 54%; 41/76); 56% of all NCP isolates had an ErMs phenotype. Among ErMs strains, E. coli comprised the majority (72%). ErMs strains carrying blaCTX-M had, on average, 9-fold higher copies of blaCTX-M than CP-ErMs strains as well as approximately 4-fold more copies than blaCTX-M-positive but ertapenem- and meropenem-susceptible (EsMs) strains (3.7 vs. 0.9, p < 0.001). Notably, carbapenem hydrolysis was observed to be mediated by strains harboring blaCTX-M with and without a carbapenemase(s). ErMs also carried more mobile genetic elements, particularly IS26 composite transposons, than EsMs (37 vs. 0.2, p < 0.0001). MGE- ISVsa5 was uniquely more abundant in ErMs than either EsMs or ErMr strains, with over 30 more average ISVsa5 counts than both phenotype groups (p < 0.0001). Immunoblot analysis demonstrated the absence of OmpC expression in NCP-ErMs E. coli, with 92% of strains lacking full contig coverage of ompC. Overall, our findings characterize both collaborative and independent efforts between blaCTX-M and OmpC in ErMs strains, indicating the need to reappraise the term "non-carbapenemase (NCP)", particularly for strains highly expressing blaCTX-M. To improve outcomes for CRE-infected patients, future efforts should focus on mechanisms underlying the emerging ErMs subphenotype of CRE strains to develop technologies for its rapid detection and provide targeted therapeutic strategies.

A clinical informatics approach to bronchopulmonary dysplasia: current barriers and future possibilities.

Bronchopulmonary dysplasia (BPD) is a complex, multifactorial lung disease affecting preterm neonates that can result in long-term pulmonary and non-pulmonary complications. Current therapies mainly focus on symptom management after the development of BPD, indicating a need for innovative approaches to predict and identify neonates who would benefit most from targeted or earlier interventions. Clinical informatics, a subfield of biomedical informatics, is transforming healthcare by integrating computational methods with patient data to improve patient outcomes. The application of clinical informatics to develop and enhance clinical therapies for BPD presents opportunities by leveraging electronic health record data, applying machine learning algorithms, and implementing clinical decision support systems. This review highlights the current barriers and the future potential of clinical informatics in identifying clinically relevant BPD phenotypes and developing clinical decision support tools to improve the management of extremely preterm neonates developing or with established BPD. However, the full potential of clinical informatics in advancing our understanding of BPD with the goal of improving patient outcomes cannot be achieved unless we address current challenges such as data collection, storage, privacy, and inherent data bias.

Transforming neonatal care with artificial intelligence: challenges, ethical consideration, and opportunities.

Artificial intelligence (AI) offers tremendous potential to transform neonatology through improved diagnostics, personalized treatments, and earlier prevention of complications. However, there are many challenges to address before AI is ready for clinical practice. This review defines key AI concepts and discusses ethical considerations and implicit biases associated with AI. Next we will review literature examples of AI already being explored in neonatology research and we will suggest future potentials for AI work. Examples discussed in this article include predicting outcomes such as sepsis, optimizing oxygen therapy, and image analysis to detect brain injury and retinopathy of prematurity. Realizing AI's potential necessitates collaboration between diverse stakeholders across the entire process of incorporating AI tools in the NICU to address testability, usability, bias, and transparency. With multi-center and multi-disciplinary collaboration, AI holds tremendous potential to transform the future of neonatology.

Leveraging transcriptomics to develop bronchopulmonary dysplasia endotypes: a concept paper.

IMPACT: Bronchopulmonary dysplasia has multiple definitions that are currently based on phenotypic characteristics. Using an unsupervised machine learning approach, we created BPD subclasses (e.g., endotypes) by clustering whole microarray data. T helper 17 cell differentiation was the most significant pathway differentiating the BPD endotypes. INTRODUCTION: Bronchopulmonary dysplasia (BPD) is the most common complication of extreme prematurity. Discovery of BPD endotypes in an unbiased format, derived from the peripheral blood transcriptome, may uncover patterns underpinning this complex lung disease. METHODS: An unsupervised agglomerative hierarchical clustering approach applied to genome-wide expression of profiling from 62 children at day of life five was used to identify BPD endotypes. To identify which genes were differentially expressed across the BPD endotypes, we formulated a linear model based on least-squares minimization with empirical Bayes statistics. RESULTS: Four BPD endotypes (A, B,C,D) were identified using 7,319 differentially expressed genes. Across BPD endotypes, 5,850 genes had a p value < 0.05 after multiple comparison testing. Endotype A consisted of neonates with a higher gestational age and birthweight. Endotypes B-D included neonates between 25 and 26 weeks and a birthweight range of 640 to 940 g. Endotype D appeared to have a protective role against BPD compared to Endotypes B and C (36% vs. 62% vs. 60%, respectively). The most significant pathway focused on T helper 17 cell differentiation. CONCLUSION: Bioinformatic analyses can help identify BPD endotypes that associate with clinical definitions of BPD.

Calcium and Phosphorus: All You Need to Know but Were Afraid to Ask.

Inadequate intake of calcium and phosphorus during the perinatal period can result in metabolic bone disease (MBD), characterized by decreased bone mass, altered bone mineralization, and increased risk for fractures. Preterm neonates have higher risk of developing MBD. Treating MBD involves ensuring adequate calcium and phosphorus intake, early fortification, and vitamin D supplementation. Health care providers should closely monitor nutrient intake, postnatal growth, and screening of preterm neonates at risk for MBD. This review summarizes the critical roles of calcium and phosphorus in regulating bone physiology, how they regulate bone formation and resorption, and their influence on overall bone health.

Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection.

Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.

Effects of human milk on body composition and growth in very low birthweight infants.

OBJECTIVE: To compare body composition and growth in very low birthweight infants according to their source of human milk: maternal expressed breast milk (MEBM) versus donor breast milk (DBM). We hypothesized that infants fed predominately MEBM would exhibit reduced body fat percentage compared to those fed predominately DBM. METHODS: Premature infants weighing ≤1500 g on an exclusive human milk diet were enrolled in a single-center study between 2017 and 2021. Demographic data and anthropometric measurements were collected. All infants underwent body composition analysis via dual energy x-ray absorptiometry at 36 weeks corrected post menstrual age. RESULTS: A total of 60 infants were enrolled and 48 were included in the primary analysis. No differences were detected in percent body fat (14 vs. 12%, p = 0.7) or fat-free mass (2050 vs. 2130 g, p = 0.7). Both groups displayed similar growth and anthropometric measurements. Caloric and macronutrient intake between groups was similar. CONCLUSION: In the cohort of patients studied, no differences were observed in percent body fat based on primary human milk type intake in the first 28 postnatal days. Further investigation is required in a larger population of exclusive human milk fed preterm infants to determine if body composition differences exist based on an infant's primary human milk source. IMPACT: Premature infants are at risk for altered body composition at term corrected age, specifically increased body fat percentage, which may have implications for the future. To our knowledge this is the first study exploring body composition outcomes based on an infant's primary human milk source. Infants fed exclusive human milk (e.g., donor vs. maternal) displayed similar percent body fat and growth outcomes.

Impact of Intrauterine Growth Restriction and Placental Insufficiency on Nutritional Outcomes of Extremely Low Birth Weight Infants.

Introduction The aim of our study was to assess the impact of intrauterine growth restriction (IUGR) and placental insufficiency (PI) on the nutritional outcomes of extremely low birth weight (ELBW) infants. Methods We conducted a six-year retrospective case-control study that included 117 ELBW infants. Of these, 58 infants had IUGR and 59 were born appropriate-for-gestational age (AGA). Infants with IUGR were further divided based on the presence or absence of PI, as determined by umbilical arterial doppler velocimetry on serial ultrasounds. Results IUGR infants with PI had the lowest enteral calorie intake at 28 days of life (DOL) (median intake- IUGR+PI: 32 vs IUGR-PI: 93 vs AGA: 110 kcal/kg/day; p-value 0.011) and at 36 weeks corrected gestational age (CGA) (median intake- IUGR+PI: 102 vs IUGR-PI: 125 vs AGA: 119 kcal/kg/day; p-value 0.012). These infants also trended towards requiring a longer duration of total parenteral nutrition (TPN) (median duration - IUGR+PI: 35 vs IUGR-PI: 25 vs AGA: 21 days; p-value 0.054) and higher incidence of conjugated hyperbilirubinemia (IUGR+PI: 43% IUGR-PI: 29% vs AGA: 16%; p-value 0.058), but these results did not reach statistical significance. Despite challenges with enteral nutrition, IUGR infants with PI showed good catch-up growth and had higher growth velocities over the first month of life, compared to AGA controls. Conclusion IUGR in the presence of PI is associated with significantly poorer enteral nutritional outcomes in ELBW infants. However, with the support of optimal parenteral nutrition these infants showed good catch-up growth.

Assessment of clinical guidelines for medication-related osteonecrosis of the jaw: current status and future directions.

OBJECTIVE: To evaluate the current quality and utility of clinical practice guidelines (CPGs) issued for the diagnosis, prevention, and treatment of medication-related osteonecrosis of the jaw (MRONJ). STUDY DESIGN: We performed a systematic literature search of guidelines for MRONJ diagnosis, staging, prevention, or management. An appraisal of guidelines was completed using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. Scaled domain scores were calculated for each domain. Key recommendations were abstracted from guidelines distinguished as "high" quality. RESULTS: Six CPGs were identified from systematic review. Four of 6 (66.7%) guidelines were published within the last 2 years. Each guideline discussed management of antiresorptive and antiangiogenic therapy-associated osteonecrosis of the jaw. The highest-scoring domain was domain 1: "Scope and purpose," with an average score of 85.0% (range: 76.4%-100.0%). The lowest domain score was in domain 5: "Applicability," with an average score of 41.7% (range: 22.9%-92.7%). Only 2 guidelines (33.3%) met the quality threshold of > 60% in 5 or more AGREE II domains, distinguishing them as "high"-quality guidelines. The average kappa statistic calculated across domains was 0.77, suggesting substantial interrater correlation in the CPG appraisal process. CONCLUSIONS: Despite the increasing recognition of MRONJ as a debilitating consequence of antiresorptive and antiangiogenic therapy, clinical guideline recommendations may be lacking in overall quality and clinical utility.

Characterizing critical predictors of an academic career following head and neck fellowship in otolaryngology.

BACKGROUND: Historically, graduating head and neck (HN) fellows outpace available academic HN positions, resulting in a highly competitive job market. We identified factors that associate with full-time academic HN positions post-HN fellowship. METHODS: Graduates of American Head and Neck Society (AHNS)-accredited fellowships from 2005 to 2017 (n = 356) were extracted from the AHNS website. RESULTS: From 2015 to 2017, the supply-demand mismatch for academic HN jobs improved. Of the 57.3% (n = 204) of graduating HN fellows who entered academia, 64% (n = 130) trained at just 10 fellowship institutions, 47% (n = 94) attended OHNS residency at an NIH top 40 funded institution, and 54% (n = 111) attended OHNS residency at an AHNS-accredited institution offering HN fellowship. After multivariate regression, number of manuscripts (OR = 1.14; p = 0.01) was significantly associated with initial academic job post-fellowship. CONCLUSION: The recent improvement in supply-demand mismatch for academic jobs is promising for future HN fellows interested in academia.

Neonatal hyperoxia in mice triggers long-term cognitive deficits via impairments in cerebrovascular function and neurogenesis.

Preterm birth is the leading cause of death in children under 5 years of age. Premature infants who receive life-saving oxygen therapy often develop bronchopulmonary dysplasia (BPD), a chronic lung disease. Infants with BPD are at a high risk of abnormal neurodevelopment, including motor and cognitive difficulties. While neural progenitor cells (NPCs) are crucial for proper brain development, it is unclear whether they play a role in BPD-associated neurodevelopmental deficits. Here, we show that hyperoxia-induced experimental BPD in newborn mice led to lifelong impairments in cerebrovascular structure and function as well as impairments in NPC self-renewal and neurogenesis. A neurosphere assay utilizing nonhuman primate preterm baboon NPCs confirmed impairment in NPC function. Moreover, gene expression profiling revealed that genes involved in cell proliferation, angiogenesis, vascular autoregulation, neuronal formation, and neurotransmission were dysregulated following neonatal hyperoxia. These impairments were associated with motor and cognitive decline in aging hyperoxia-exposed mice, reminiscent of deficits observed in patients with BPD. Together, our findings establish a relationship between BPD and abnormal neurodevelopmental outcomes and identify molecular and cellular players of neonatal brain injury that persist throughout adulthood that may be targeted for early intervention to aid this vulnerable patient population.

Metformin Attenuates Inflammatory Responses and Enhances Antibody Production in an Acute Pneumonia Model of Streptococcus pneumoniae.

Metformin may potentially reverse various age-related conditions; however, it is unclear whether metformin can also mitigate or delay the deterioration of immunological resilience that occurs in the context of infections that are commonly observed in older persons. We examined whether metformin promotes the preservation of immunological resilience in an acute S. pneumoniae (SPN) infection challenge in young adult mice. Mice were fed metformin (MET-alone) or standard chow (controls-alone) for 10 weeks prior to receiving intratracheal inoculation of SPN. A subset of each diet group received pneumococcal conjugate vaccine at week 6 (MET + PCV and control + PCV). Compared to controls-alone, MET-alone had significantly less infection-associated morbidity and attenuated inflammatory responses during acute SPN infection. Metformin lowered the expression of genes in the lungs related to inflammation as well as shorter lifespan in humans. This was accompanied by significantly lower levels of pro-inflammatory cytokines (e.g., IL6). MET + PCV vs. control + PCV manifested enhanced SPN anticapsular IgM and IgG levels. The levels of SPN IgM production negatively correlated with expression levels of genes linked to intestinal epithelial structure among MET + PCV vs. control + PCV groups. Correspondingly, the gut microbial composition of metformin-fed mice had a significantly higher abundance in the Verrucomicrobia, Akkermansia muciniphila, a species previously associated with beneficial effects on intestinal integrity and longevity. Together, these findings indicate metformin's immunoprotective potential to protect against infection-associated declines in immunologic resilience.

Clinical practice guidelines for pain management after tonsillectomy: Systematic quality appraisal using the AGREE II instrument.

PURPOSE: We identified and appraised clinical practice guidelines (CPGs) for the management of post-tonsillectomy pain using the Appraisal of Guidelines for Research and Evaluation (AGREE II) guideline research tool. MATERIALS AND METHODS: We conducted a literature search to identify CPGs addressing pain management after tonsillectomy. CPGs meeting inclusion criteria were then appraised by four independent reviewers in six areas of quality, as defined by AGREE II. Scaled domain scores were calculated for each quality domain. Intraclass correlation coefficients (ICC) were calculated in each domain to assess interrater reliability across guideline appraisals. RESULTS: Nine guidelines meeting inclusion criteria were identified from a systematic search of the literature. The American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guideline detailing tonsillectomy and postoperative management in pediatric patients received the highest average score, with a mean of 90.1% in the six areas of quality. Three guidelines scored higher than >60% in five domains or more, defining 'high' quality per AGREE II: AAO-HNS, Scottish Intercollegiate Guides Network (SIGN), and Ontario Ministry of Health CPGs. The highest-scoring domain was domain 4: Clarity of presentation (87.4%) across guidelines, while the lowest scoring domain was domain 5: Applicability (49.4%). Variability in scaled domain scores between all CPGs was relatively consistent across domains, with a mean standard deviation of 22.4%. The average ICC calculated across all six domains was 0.78, indicating 'strong agreement' between reviewers regarding guideline quality. CONCLUSION: Of the nine available guidelines detailing pain management following tonsillectomy we identified, only three (33%) were deemed 'high'-quality after appraisal using the AGREE II instrument, suggesting a need for development of novel, methodologically rigorous CPGs.

Quality appraisal of clinical practice guidelines for temporomandibular joint disorders using the AGREE II instrument.

OBJECTIVE: We sought to systematically assess the quality of all clinical practice guidelines (CPGs) describing diagnosis and management of temporomandibular joint disorders (TMDs) using the Appraisal of Guidelines for Research and Evaluation instrument. STUDY DESIGN: CPGs detailing all aspects of diagnosis and management (both conservative and nonconservative) for TMDs were reviewed. RESULTS: Thirteen guidelines met inclusion criteria. The highest-scoring domain across guidelines was clarity of presentation (68.3%); the lowest-scoring domain was editorial independence (31.9%). The highest-scoring guideline described traditional Korean medicine approaches to the management of TMDs, earning a mean score of 79.2% across the six quality domains. Only three CPGs met a quality threshold of >60% in at least five domains, qualifying as 'high' per the Appraisal of Guidelines for Research and Evaluation criteria: these guidelines were the Korean medicine guidelines, Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) guidelines for diagnostic classification of TMDs, and the Japanese Society for the Temporomandibular Joint guidelines. An average intraclass correlation coefficient of 0.79 was calculated across all domains, denoting very strong agreement between independent reviewers. CONCLUSION: We identified a significant lack of quality in multiple areas of CPG development for the diagnosis and therapeutic management of TMDs, suggesting a need for new comprehensive and rigorously developed guidelines addressing TMDs.

Large-scale provocation studies identify maladaptive responses to ubiquitous aeroallergens as a correlate of severe allergic rhinoconjunctivitis and asthma.

BACKGROUND: Allergic asthma (AA) and allergic rhinoconjunctivitis (ARC) are common comorbid environmentally triggered diseases. We hypothesized that severe AA/ARC reflects a maladaptive or unrestrained response to ubiquitous aeroallergens. METHODS: We performed provocation studies wherein six separate cohorts of persons (total n = 217) with ARC, with or without AA, were challenged once or more with fixed concentrations of seasonal or perennial aeroallergens in an aeroallergen challenge chamber (ACC). RESULTS: Aeroallergen challenges elicited fully or partially restrained vs. unrestrained evoked symptom responsiveness, corresponding to the resilient and adaptive vs. maladaptive AA/ARC phenotypes, respectively. The maladaptive phenotype was evoked more commonly during challenge with a non-endemic versus endemic seasonal aeroallergen. In an AA cohort, symptom responses evoked after house dust mite (HDM) challenges vs. recorded in the natural environment were more accurate and precise predictors of asthma severity and control, lung function (FEV1), and mechanistic correlates of maladaptation. Correlates included elevated levels of peripheral blood CD4+ and CD8+ T-cells, eosinophils, and T-cell activation, as well as gene expression proxies for ineffectual epithelial injury/repair responses. Evoked symptom severity after HDM challenge appeared to be more closely related to levels of CD4+ and CD8+ T-cells than eosinophils, neutrophils, or HDM-specific IgE. CONCLUSIONS: Provocation studies support the concept that resilience, adaptation, and maladaptation to environmental disease triggers calibrate AA/ARC severity. Despite the ubiquity of aeroallergens, in response to these disease triggers in controlled settings (ie, ACC), most atopic persons manifest the resilient or adaptive phenotype. Thus, ARC/AA disease progression may reflect the failure to preserve the resilient or adaptive phenotype. The triangulation of CD8+ T-cell activation, airway epithelial injury/repair processes and maladaptation in mediating AA disease severity needs more investigation.

Clinical Practice Guidelines for the Management of Patients With Cleft Lip and Palate: A Systematic Quality Appraisal Using the Appraisal of Guidelines for Research and Evaluation II Instrument.

ABSTRACT: Patients with cleft lip and/or palate require complex and longitudinal care by a multidisciplinary cleft team. Unfortunately, delivery of cleft care is often fragmented, and care practices can vary significantly. Multiple clinical practice guidelines (CPGs) have been proposed to provide a standardized framework for cleft care delivery. As CPGs have gained popularity, there has been increasing demand to maintain the quality of existing guidelines. A comprehensive search of EMBASE, MEDLINE via PubMed, Scopus, Cochrane and grey literature sources published from January 1, 1990 to December 31, 2020 was conducted to identify CPGs for the care of cleft patients. The Appraisal of Guidelines for Research and Evaluation, 2nd edition II tool was used to assess the quality of selected CPGs. Intraclass coefficients were calculated to assess agreement among appraisers. Eleven guidelines were identified for study inclusion. One guideline was classified as "high" quality by Appraisal of Guidelines for Research and Evaluation II criteria, and the remaining guidelines were classified as "average" or "low" quality. The "Clarity of Presentation" domain achieved the highest mean score (76.9% ± 11.7%) across CPGs, whereas the "Rigor of Development" domain scored the lowest (35.6% ±â€Š21.2%). Intraclass coefficients analysis reflected very good inter-rater reliability across all domains (0.853-0.987). These findings highlight significant variability in the quality of existing CPGs for the global management of patients with cleft lip and/or palate. The "Rigor of Development" domain reflects the greatest opportunity for improvement. Given these findings, future guidelines may prioritize incorporating a systematic review of existing evidence into recommendations.

A systematic quality appraisal of clinical practice guidelines for Ménière's disease using the AGREE II instrument.

PURPOSE: To systematically appraise clinical practice guidelines for the diagnosis and treatment of Ménière's disease using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. MATERIALS AND METHODS: A systematic literature search was performed to identify guidelines pertaining to the diagnosis and treatment of Ménière's disease. Data were abstracted from guidelines that met inclusion criteria and appraised by four independent reviewers in the six domains of quality defined by the AGREE II. Domain scores reflecting quality in each domain were calculated. Intraclass correlation coefficients (ICC) were calculated across domains to qualify interrater reliability. RESULTS: Six guidelines were found to meet inclusion criteria after a systematic literature search. Of the six clinical practice guidelines appraised using the AGREE II, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guideline received the highest average score, with a mean of 90.7% spanning six quality domains. The guideline with the lowest average score across all domains was the European Position Statement on diagnosis and treatment of Ménière's disease, receiving an average score across domains of 34.6%. Overall quality scores of clinical practice guidelines for Ménière's disease had a standard deviation of 21.3%. Two guidelines met the quality threshold of > 60% in at least five domains, qualifying as 'high': AAO-HNS and National Institute for Health and Care Excellence. Average ICC across all six domains was 0.87, suggesting near total agreement between reviewers. CONCLUSION: Ménière's disease remains a challenging entity to diagnose and treat; few existing clinical guidelines meet the standards of quality established by the AGREE II appraisal instrument.

Immunologic resilience and COVID-19 survival advantage.

BACKGROUND: The risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). OBJECTIVE: We sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality. METHODS: IR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n = 13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes. RESULTS: IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females. CONCLUSIONS: Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19.

Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases.

BACKGROUND: Signifying the 2-compartments/1-disease paradigm, allergic rhinoconjunctivitis (ARC) and asthma (AA) are prevalent, comorbid conditions triggered by environmental factors (eg, house dust mites [HDMs]). However, despite the ubiquity of triggers, progression to severe ARC/AA is infrequent, suggesting either resilience or adaptation. OBJECTIVE: We sought to determine whether ARC/AA severity relates to maladaptive responses to disease triggers. METHODS: Adults with HDM-associated ARC were challenged repetitively with HDMs in an aeroallergen challenge chamber. Mechanistic traits associated with disease severity were identified. RESULTS: HDM challenges evoked maladaptive (persistently higher ARC symptoms), adaptive (progressive symptom reduction), and resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Nasal airway traits, defined by low inflammation-effectual epithelial integrity, moderate inflammation-effectual epithelial integrity, and higher inflammation-ineffectual epithelial integrity, were hallmarks of the resilient, adaptive, and maladaptive evoked phenotypes, respectively. Highlighting a crosstalk mechanism, peripheral blood inflammatory tone calibrated these traits: ineffectual epithelial integrity associated with CD8+ T cells, whereas airway inflammation associated with both CD8+ T cells and eosinophils. Hallmark peripheral blood maladaptive traits were increased natural killer and CD8+ T cells, lower CD4+ mucosal-associated invariant T cells, and deficiencies along the TLR-IRF-IFN antiviral pathway. Maladaptive traits tracking HDM-associated ARC also contributed to AA risk and severity models. CONCLUSIONS: Repetitive challenges with HDMs revealed that maladaptation to disease triggers may underpin ARC/AA disease severity. A combinatorial therapeutic approach may involve reversal of loss-of-beneficial-function traits (ineffectual epithelial integrity, TLR-IRF-IFN deficiencies), mitigation of gain-of-adverse-function traits (inflammation), and blocking of a detrimental crosstalk between the peripheral blood and airway compartments.