HLA-DR+ regulatory T cells and IL-10 are associated with success or failure of desensitization outcomes.

BACKGROUND: Omalizumab (XOLAIR®)-assisted multi-food oral immunotherapy (mOIT) has been shown to safely, effectively, and rapidly desensitize patients with multiple food allergies. In our clinical trial (NCT02626611) on omalizumab-assisted mOIT, different desensitization outcomes (success or failure of desensitization) were observed following a period of either continued or discontinued mOIT. However, the association between the immunological changes induced by omalizumab-assisted mOIT and desensitization outcomes has not yet been fully elucidated. In this study, due to the key roles of regulatory T (Treg) cells and the type 2 helper T cell (Th2) pathway in immune tolerance to food allergens, we aimed to characterize their association with the desensitization outcomes of omalizumab-assisted mOIT. METHODS: Mass cytometry and multiplex cytokine assays were performed on blood samples obtained from participants with allergies to peanut, cashew, or milk in our phase 2 clinical study (NCT02626611). Comprehensive statistical and bioinformatic analyses were conducted on high-dimensional cytometry-based single-cell data and high-throughput multiplex cytokine data. RESULTS: Our results demonstrated that the frequency of HLA-DR+ Treg cells, and the production of Th2 cytokines (IL-4, IL-5, IL-13, and IL-9) as well as the immunoregulatory cytokine IL-10 by peripheral blood mononuclear cells (PBMCs) was significantly increased in cultures with allergen compared to cultures with media alone at baseline (Week 0). We also observed increased frequency of allergen responsive HLA-DR+ Treg cells and enhanced production of IL-10 by PBMCs in participants who achieved successful desensitization compared to those with failure of desensitization. However, the production of Th2 cytokines by PBMCs did not show significant differences between participants with different desensitization outcomes (success vs. failure of desensitization), despite omalizumab-assisted mOIT inducing a significant reduction in the production of Th2 cytokines. CONCLUSIONS: We demonstrated that the frequency of HLA-DR+ Treg cells and IL-10 cytokine production by PBMCs are associated with desensitization outcomes of omalizumab-assisted mOIT. These findings suggest potential immunological parameters that could be targeted to enhance desensitization success rates.

Omalizumab for the Treatment of Multiple Food Allergies.

BACKGROUND: Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS: In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS: Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS: In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696.).

Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) comprises a group of heterogenous disorders characterized by childhood-onset chronic joint inflammation. It is the most common rheumatologic disease in the pediatric population and an important cause of chronic illness in children. Early recognition and treatment are vital to prevent sequelae of uncontrolled inflammation on the developing skeleton. JIA can have significant complications that general pediatricians should be aware of, especially uveitis, which can be insidious and asymptomatic in very young children, and macrophage activation syndrome, which can be life-threatening if not recognized and appropriately treated. Although advances have been made in the past few decades, the etiology of JIA remains incompletely understood. Efforts are underway to refine the classification of JIA. The currently accepted classification scheme identifies subsets of JIA that are important clinically in terms of prognosis and tailoring treatment approaches. However, it is limited in identifying homogenous groups of children with early childhood onset and antinuclear antibody positivity, which may have different pathogenic mechanisms that could be important in developing more targeted and effective treatment approaches in the future. Treatment strategies for JIA have changed significantly in recent years with the availability of multiple newer targeted therapies, often modeled after medications used in adult-onset forms of arthritis. These treatments, and likely many others to come, have markedly improved symptom control and reduced complications in patients with JIA.

Treatment of food allergy: Oral immunotherapy, biologics, and beyond.

The prevalence of food allergy (FA) has been increasing globally and comes with a heavy burden not just economically, but also on quality of life. Although oral immunotherapy (OIT) is effective at inducing desensitization to food allergens, it has several limitations that weaken its success. Limitations include a long duration of build-up, especially when used for multiple allergens, and a high rate of reported adverse events. Furthermore, OIT may not be effective in all patients. Efforts are underway to identify additional treatment options, either as monotherapy or in combination, to treat FA or enhance the safety and efficacy of OIT. Biologics such as omalizumab and dupilumab, which already have US Food and Drug Administration approval for other atopic conditions have been the most studied, but additional biologics and novel strategies are emerging. In this review, we discuss therapeutic strategies including immunoglobulin E inhibitors, immunoglobulin E disruptors, interleukin-4 and interleukin-13 inhibitors, antialarmins, JAK1 and BTK inhibitors, and nanoparticles, and the data surrounding their application in FA and highlighting their potential.

Clinical features and outcomes of adult idiopathic megarectum.

OBJECTIVE: Idiopathic megarectum is characterized by abnormal, pronounced rectal dilatation in the absence of identifiable organic pathology. Idiopathic megarectum is uncommon and under-recognized. This study aims to describe the clinical features and management of idiopathic megarectum. METHODS: A retrospective review was undertaken on patients diagnosed with idiopathic megarectum with or without idiopathic megacolon over a 14-year period until 2021. Patients were identified from the hospital's International Classification of Diseases codes, and pre-existing clinic patient databases. Patient demographics, disease characteristics, healthcare utilization and treatment history data were collected. RESULTS: Eight patients with idiopathic megarectum were identified; half of the patients were female, with the median age of symptom onset being 14 years (interquartile range [IQR] 9-24). The median rectal diameter measured was 11.5 cm (IQR 9.4-12.1). The most common presenting symptom was constipation, bloating and faecal incontinence. All patients required prior sustained periods of regular phosphate enemas and 88% were using ongoing oral aperients. Concomitant anxiety and or depression were found in 63% of patients and 25% were diagnosed with an intellectual disability. Healthcare utilization was high with a median of three emergency department presentations or ward admissions related to idiopathic megarectum per patient over the follow-up period; 38% of patients required surgical intervention during the period of follow-up. CONCLUSION: Idiopathic megarectum is uncommon and associated with significant physical and psychiatric morbidity and high healthcare utilization.

The role of biologics in pediatric food allergy and eosinophilic gastrointestinal disorders.

Continuing insight into the molecular mechanisms of atopic disorders has enabled the development of biologics to precisely target these diseases. Food allergy (FA) and eosinophilic gastrointestinal disorders (EGIDs) are driven by similar inflammatory molecular mechanisms and exist along the same atopic disease spectrum. Therefore, many of the same biologics are being investigated to target key drivers of mechanisms shared across the disease states. The enormous potential of biologics for the treatment of FA and EGIDs is highlighted by the significant increases in the number of ongoing clinical trials (more than 30) evaluating their use in these disease states, as well as by the recent US Food and Drug Administration approval of dupilumab for the treatment of eosinophilic esophagitis. Here we discuss past and current research into the use of biologics in FA and EGIDs and their potential role in improving treatment options in the future, with the need to have biologics widely clinically available.

Transitioning from epicutaneous to oral peanut immunotherapy.

Introduction: Epicutaneous immunotherapy (EPIT) has been tested in clinical trials for children with peanut allergy (PA) for its safety and efficacy in inducing desensitization. Aside from peanut avoidance and symptom management, oral immunotherapy (OIT) is another option for PA patients. However, OIT can be associated with adverse events and pose safety concerns to children and their caregivers. Methods: This study assessed 27 children who successfully completed a peanut EPIT trial. 18 of them transitioned to peanut OIT with starting doses ranging from 10-600 mg of peanut protein. Our aim was to learn more about the EPIT to OIT experience through descriptive survey responses and to gather information that may support the sequential use of the two immunotherapies for safe and positive outcomes that may not be achieved by either alone. Results: Overall, children and their caregivers had less anxiety about starting OIT after having had peanut exposure through EPIT. Most children who transitioned from EPIT to OIT had no or minor symptoms initially, with symptoms lessening later in OIT. Most were also able to maintain or increase their peanut dose over time, achieving maintenance doses of 60-2,000 mg. Discussion: In comparison with current literature on OIT for PA in children, the reported symptoms appeared less severe and less prevalent in the EPIT to OIT group. However, there were 3 participants who withdrew from OIT due to the development of intolerable symptoms. This study provides initial data in support of EPIT to OIT, and larger randomized controlled trials assessing effectiveness of the two therapies together are warranted.

Modeling Behavioral Economics Strategies in Social Marketing Messages to Promote Vegetable Consumption to Low-Resource Louisiana Residents: A Conjoint Analysis.

BACKGROUND: Behavioral economics strategies implemented within social marketing campaigns improve eating behavior. OBJECTIVE: To identify which behavioral economics strategies in social marketing messages particularly messengers, norms, and commitments will promote low-income Louisiana residents to add more vegetables to meals. DESIGN: Full profile traditional conjoint analysis survey with single concept ratings. PARTICIPANTS: Purposive sample of low-resource Louisiana residents (N = 213) SETTING: Online survey. INTERVENTION: Participants rated randomized concepts that featured a messenger and a message. MAIN OUTCOME MEASURE: Ratings (one to nine) of likelihood to add vegetables to meals. STATISTICAL ANALYSIS: A model of ratings was generated using mixed-effects multiple regression, which accounted for repeated measurement of participants. Interactions of variables and covariates were modeled. RESULTS: There was a significant main effect of the messenger variable (P = 0.02) and main effect of the message variable (P = 0.008). Pairwise comparisons demonstrated differences between friend (µ (predicted mean) = 6.80) and mother (µ = 7.06; P = 0.03) as well as friend and normal-weight doctor (µ = 7.03; P = 0.04). Pairwise comparisons demonstrated differences between descriptive norm (µ = 6.79) and grocery list precommitment (µ = 7.02; P = 0.05) along with descriptive norm and injunctive norm (µ = 6.98; P = 0.04). Covariate models demonstrated main effects of race (P = 0.006) and sex (P = 0.0001). There was significant variation in the message variable and frequency of vegetable intake interaction (P = 0.01). CONCLUSIONS: Both message and messenger variables predicted the likelihood to add vegetables to meals. Race and sex influenced ratings to add vegetables. As reported vegetable consumption increased, behavioral economics messages improved the likelihood to add vegetables to meals. Behavioral economic approaches are well suited to social marketing messages that aim to promote healthy eating behavior in low-income LA residents.

Immune dysregulation.

The understanding of immune dysregulation in many different diseases continues to grow. There is increasing evidence that altered microbiome and gut barrier dysfunction contribute to systemic inflammation in patients with primary immunodeficiency and in patients with rheumatic disease. Recent research provides insight into the process of induction and maturation of pathogenic age-associated B cells and highlights the role of age-associated B cells in creating tissue inflammation. T follicular regulatory cells are shown to help maintain B-cell tolerance, and therapeutic approaches to increase or promote T follicular regulatory cells may help prevent or decrease immune dysregulation. Meanwhile, novel studies of systemic-onset juvenile idiopathic arthritis reveal a strong HLA association with interstitial lung disease and identify key aspects of the pathogenesis of macrophage activation syndrome. Studies of hyperinflammatory syndromes, including the recently described multisystem inflammatory syndrome of children, characterize similarities and differences in cytokine profiles and T-cell activation. This review focuses on recent advances in the understanding of immune dysregulation and describes potential key factors that may function as biomarkers for disease or targets for therapeutic interventions. Future trials are necessary to address the many remaining questions with regards to pathogenesis, diagnosis, and treatment of autoimmune, inflammatory, and immunodeficiency syndromes.

Synovial Inflammatory Pathways Characterize Anti-TNF-Responsive Rheumatoid Arthritis Patients.

OBJECTIVE: This study was undertaken to understand the mechanistic basis of response to anti-tumor necrosis factor (anti-TNF) therapies and to determine whether transcriptomic changes in the synovium are reflected in peripheral protein markers. METHODS: Synovial tissue from 46 rheumatoid arthritis (RA) patients was profiled with RNA sequencing before and 12 weeks after treatment with anti-TNF therapies. Pathway and gene signature analyses were performed on RNA expression profiles of synovial biopsies to identify mechanisms that could discriminate among patients with a good response, a moderate response, or no response, according to the American College of Rheumatology (ACR)/EULAR response criteria. Serum proteins encoded by synovial genes that were differentially expressed between ACR/EULAR response groups were measured in the same patients. RESULTS: Gene signatures predicted which patients would have good responses, and pathway analysis identified elevated immune pathways, including chemokine signaling, Th1/Th2 cell differentiation, and Toll-like receptor signaling, uniquely in good responders. These inflammatory pathways were correspondingly down-modulated by anti-TNF therapy only in good responders. Based on cell signature analysis, lymphocyte, myeloid, and fibroblast cell populations were elevated in good responders relative to nonresponders, consistent with the increased inflammatory pathways. Cell signatures that decreased following anti-TNF treatment were predominately associated with lymphocytes, and fewer were associated with myeloid and fibroblast populations. Following anti-TNF treatment, and only in good responders, several peripheral inflammatory proteins decreased in a manner that was consistent with corresponding synovial gene changes. CONCLUSION: Collectively, these data suggest that RA patients with robust responses to anti-TNF therapies are characterized at baseline by immune pathway activation, which decreases following anti-TNF treatment. Understanding mechanisms that define patient responsiveness to anti-TNF treatment may assist in development of predictive markers of patient response and earlier treatment options.

Current insights: a systemic review of therapeutic options for peanut allergy.

PURPOSE OF REVIEW: With increasing prevalence of peanut allergy (PA) globally and the greater risk of potential reactions occurring due to the leading role of nuts in food products, PA has become a significant public health concern over the past decade, affecting up to 5 million of the US adult population. This review details updates and advances in prevalence, diagnosis, and immunotherapies that have occurred over the past year. RECENT FINDINGS: Therapeutic and diagnostic advances remain at the forefront of research and have continued to push the food allergy (FA) field forward to provide a promising role in the detection and treatment of PA. The FA field has researched significant advances in peanut immunotherapy, biomarker diagnosis, and quality of life (QoL) improvement. SUMMARY: Given the burden and consequences for individuals with PA, these advances delivered in clinical practice can significantly improve the QoL of individuals with PA and their caregivers. Ongoing studies will continue to investigate long-term outcome measures of desensitisation and effective management plans tailored to the families' needs.

Food allergy, mechanisms, diagnosis and treatment: Innovation through a multi-targeted approach.

The incidence of food allergy (FA) has continued to rise over the last several decades, posing significant burdens on health and quality of life. Significant strides into the advancement of FA diagnosis, prevention, and treatment have been made in recent years. In an effort to lower reliance on resource-intensive food challenges, the field has continued work toward the development of highly sensitive and specific assays capable of high-throughput analysis to assist in the diagnosis FA. In looking toward early infancy as a critical period in the development of allergy or acquisition of tolerance, evidence has increasingly suggested that early intervention via the early introduction of food allergens and maintenance of skin barrier function may decrease the risk of FA. As such, large-scale investigations are underway evaluating infant feeding and the impact of emollient and steroid use in infants with dry skin for the prevention of allergy. On the other end of the spectrum, the past few years have been witness to an explosive increase in clinical trials of novel and innovative therapeutic strategies aimed at the treatment of FA in those whom the disease has already manifested. A milestone in the field, 2020 marked the approval of the first drug, oral peanut allergen, for the indication of peanut allergy. With a foundation of promising data supporting the safety and efficacy of single- and multi-allergen oral immunotherapy, current efforts have turned toward the use of probiotics, biologic agents, and modified allergens to optimize and improve upon existing paradigms. Through these advancements, the field hopes to gain footing in the ongoing battle against FA.

Pharmacological Inhibition of MALT1 Ameliorates Autoimmune Pathogenesis and Can Be Uncoupled From Effects on Regulatory T-Cells.

MALT1 forms part of a central signaling node downstream of immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors, across a broad range of immune cell subsets, and regulates NF-κB driven transcriptional responses via dual scaffolding-protease activity. Allosteric inhibition of MALT1 activity has demonstrated benefit in animal models of inflammation. However, development of MALT1 inhibitors to treat autoimmune and inflammatory diseases (A&ID) has been hindered by reports linking MALT1 inhibition and genetic loss-of-function to reductions in regulatory T-cell (Treg) numbers and development of auto-inflammatory syndromes. Using an allosteric MALT1 inhibitor, we investigated the consequence of pharmacological inhibition of MALT1 on proinflammatory cells compared to regulatory T-cells. Consistent with its known role in ITAM-driven responses, MALT1 inhibition suppressed proinflammatory cytokine production from activated human T-cells and monocyte-derived macrophages, and attenuated B-cell proliferation. Oral administration of a MALT1 inhibitor reduced disease severity and synovial cytokine production in a rat collagen-induced arthritis model. Interestingly, reduction in splenic Treg numbers was less pronounced in the context of inflammation compared with naïve animals. Additionally, in the context of the disease model, we observed an uncoupling of anti-inflammatory effects of MALT1 inhibition from Treg reduction, with lower systemic concentrations of inhibitor needed to reduce disease severity compared to that required to reduce Treg numbers. MALT1 inhibition did not affect suppressive function of human Tregs in vitro. These data indicate that anti-inflammatory efficacy can be achieved with MALT1 inhibition without impacting the number or function of Tregs, further supporting the potential of MALT1 inhibition in the treatment of autoimmune disease.

Upper Limit on the QCD Axion Mass from Isolated Neutron Star Cooling.

The quantum chromodynamics (QCD) axion may modify the cooling rates of neutron stars (NSs). The axions are produced within the NS cores from nucleon bremsstrahlung and, when the nucleons are in superfluid states, Cooper pair breaking and formation processes. We show that four of the nearby isolated magnificent seven NSs along with PSR J0659 are prime candidates for axion cooling studies because they are coeval, with ages of a few hundred thousand years known from kinematic considerations, and they have well-measured surface luminosities. We compare these data to dedicated NS cooling simulations incorporating axions, profiling over uncertainties related to the equation of state, NS masses, surface compositions, and superfluidity. Our calculations of the axion and neutrino emissivities include high-density suppression factors that also affect SN 1987A and previous NS cooling limits on axions. We find no evidence for axions in the isolated NS data, and within the context of the Kim-Shifman-Vainshtein-Zakharov QCD axion model, we constrain m_{a}≲16 meV at 95% confidence level. An improved understanding of NS cooling and nucleon superfluidity could further improve these limits or lead to the discovery of the axion at weaker couplings.

No Evidence for Axions from Chandra Observation of the Magnetic White Dwarf RE J0317-853.

Axions with couplings g_{aγγ}∼few×10^{-11} GeV^{-1} to electromagnetism may resolve a number of astrophysical anomalies, such as unexpected ∼TeV transparency, anomalous stellar cooling, and x-ray excesses from nearby neutron stars. We show, however, that such axions are severely constrained by the nonobservation of x rays from the magnetic white dwarf (MWD) RE J0317-853 using ∼40 ks of data acquired from a dedicated observation with the Chandra X-ray Observatory. Axions may be produced in the core of the MWD through electron bremsstrahlung and then convert to x rays in the magnetosphere. The nonobservation of x rays constrains the axion-photon coupling to g_{aγγ}≲5.5×10^{-13}sqrt[C_{aγγ}/C_{aee}] GeV^{-1} at 95% confidence for axion masses m_{a}≲5×10^{-6} eV, with C_{aee} and C_{aγγ} the dimensionless coupling constants to electrons and photons. Considering that C_{aee} is generated from the renormalization group, our results robustly disfavor g_{aγγ}≳4.4×10^{-11} GeV^{-1} even for models with no ultraviolet contribution to C_{aee}.

Phase 2, randomized multi oral immunotherapy with omalizumab 'real life' study.

BACKGROUND: Oral immunotherapy (OIT) is frequently discontinued due to adverse events (AEs) and current data suggests that lowering OIT doses can minimize severity and frequency of AEs. However, the minimum daily dose that can enable desensitization and induce immune responses in multi-food OIT (mOIT) is unknown. METHODS: Participants aged 2-25 years with multi-food allergies were pretreated with fixed-dose omalizumab (150 mg, 3 doses, every 4 weeks), and randomized 1:1 to receive mOIT to a total maintenance dose of either 300 or 1200 mg total protein, (total dose includes at least two and up to a max of five allergens) and then transitioned to real-food protein equivalents after 18 weeks of treatment. The primary endpoint was the proportion of subjects with increases in IgG4/IgE ratio of at least 2 allergens by ≥25% from baseline after 18 weeks of therapy. The primary efficacy and safety analyses were done in the intention-to-treat population. RESULTS: Sixty participants were enrolled across two sites. Seventy percent of participants in both arms showed changes in sIgG4/sIgE ratio in at least 2 allergens with no difference between the treatment groups (OR [95% CI] = 1.00 [0.29, 3.49]). Overall, there were no differences in AEs between the 300 and 1200 mg groups (19% vs. 17%, p = .69), respectively. CONCLUSIONS: Our data suggest that plasma marker changes are induced early, even at a total protein dose of 300 mg inclusive of multiple allergens when mOIT is combined with fixed-dose omalizumab. Identification of optimal mOIT dosing with adjunct omalizumab is needed for the long-term success of OIT. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03181009).

Protocol design and synopsis: Omalizumab as Monotherapy and as Adjunct Therapy to Multiallergen OIT in Children and Adults with Food Allergy (OUtMATCH).

Background: Food allergy is common and causes substantial morbidity and even mortality. Safe and effective treatments for food allergy would therefore be highly desirable, especially for individuals with multiple food allergies. Objectives: Our aim was to describe a phase 3 study on treatment of patients with multiple food allergies with omalizumab. Methods: The study was developed as a collaboration between the Consortium for Food Allergy Research, the National Institute of Allergy and Infectious Diseases, and 2 industry sponsors (Genentech and Novartis). Results: The study is currently under way, enrolling participants from age 1 year to age 55 years who are allergic to peanut and at least 2 other foods (including milk, egg, wheat, cashew, hazelnut, and walnut). The study is designed to address 3 major questions. First, stage 1 will study the potential value of omalizumab for the treatment of patients with peanut allergy and at least 2 other common food allergens. Second, stage 2 will directly compare treatment of patients with multifood allergies using omalizumab as monotherapy versus treatment with omalizumab-facilitated multiallergen oral immunotherapy in which omalizumab is used as an adjunctive treatment. Third, stage 3 will address the longer-term outcomes following these treatment approaches, including the introduction of dietary forms of the study foods to induce or maintain desensitization. Conclusions: This phase 3 study will provide important information on the potential of omalizumab to treat patients with multiple food allergies.

Turning up the volume to address biases in predicted healthcare-associated infections and enhance U.S. hospital rankings: A data-driven approach.

OBJECTIVES: To examine potential biases in standardized infection ratio (SIR) metrics due to static U.S. Centers for Disease Control and Prevention (CDC) parameters and non-linearity of infection outcomes with volume. Correspondingly, to enhance the CDC predictions by incorporating additional information from volume metrics and explore an alternative approach to more fairly rank hospitals to address the SIR=0 problem. METHODS: This population-based study uses publicly available 2019 healthcare-associated infections (HAI) data from 3096 acute care U.S. hospitals. HAI-specific Poisson generalized additive models illustrate the recalibration of CDC predictions, using volume-based spline functions to adjust for biases. Implied cumulative distribution functions (CDF) were derived, and HAI-facility-specific probabilities were calculated. Hospital rankings implied from these HAI-stratified probabilities were calculated. RESULTS: Calibration plots demonstrate existing biases associated with CDC infection over-predictions. Volume-based spline functions were significant for all HAIs (P<.0004). CDF-based rankings resulted in larger discrimination across hospitals based on strength of evidence, especially among SIR=0 facilities. National maps depict ranking differences by HAI and state. CONCLUSION: Adjustment of SIR biases, which differ by facility volume, is needed to produce more accurate and fairer hospital rankings.