Factors Affecting Adherence in Allergic Disorders and Strategies for Improvement.

Addressing patient adherence is a key element in ensuring positive health outcomes and improving health-related quality of life for patients with atopic and immunologic disorders. Understanding the complex etiologies of patient non-adherence and identifying real-world solutions is important for clinicians, patients, and systems to design and effect change. This review serves as a key resource for defining key issues related to patient non-adherence and outlines solutions, resources, knowledge gaps, and advocacy areas across five domains: healthcare access, financial considerations, socio-environmental factors, health literacy, and psychosocial factors. To allow for more easily digestible and usable content, we describe solutions based on three macro-levels of focus: patient, clinician, and system. This review and interactive toolkit serve as an educational resource and call to action to improve equitable distribution of resources, institutional policies, patient-centered care, and practice guidelines for improving health outcomes for all patients with atopic and immunologic disorders.

The gut microbiota posttranslationally modifies IgA1 in autoimmune glomerulonephritis.

Mechanisms underlying the disruption of self-tolerance in acquired autoimmunity remain unclear. Immunoglobulin A (IgA) nephropathy is an acquired autoimmune disease where deglycosylated IgA1 (IgA subclass 1) auto-antigens are recognized by IgG auto-antibodies, forming immune complexes that are deposited in the kidneys, leading to glomerulonephritis. In the intestinal microbiota of patients with IgA nephropathy, there was increased relative abundance of mucin-degrading bacteria, including Akkermansia muciniphila. IgA1 was deglycosylated by A. muciniphila both in vitro and in the intestinal lumen of mice. This generated neo-epitopes that were recognized by autoreactive IgG from the sera of patients with IgA nephropathy. Mice expressing human IgA1 and the human Fc α receptor I (α1KI-CD89tg) that underwent intestinal colonization by A. muciniphila developed an aggravated IgA nephropathy phenotype. After deglycosylation of IgA1 by A. muciniphila in the mouse gut lumen, IgA1 crossed the intestinal epithelium into the circulation by retrotranscytosis and became deposited in the glomeruli of mouse kidneys. Human α-defensins-a risk locus for IgA nephropathy-inhibited growth of A. muciniphila in vitro. A negative correlation observed between stool concentration of α-defensin 6 and quantity of A. muciniphila in the guts of control participants was lost in patients with IgA nephropathy. This study demonstrates that gut microbiota dysbiosis contributes to generation of auto-antigens in patients with IgA nephropathy and in a mouse model of this disease.

Benefits of Aeroallergen Testing on Oral Corticosteroid Bursts in Adults with Asthma.

BACKGROUND: Aeroallergen testing can improve precision care for persistent asthma and is recommended by the U.S. clinical guidelines. How testing benefits diverse populations of adults with asthma, and the importance of the testing modality used, are not fully understood. OBJECTIVE: We sought to evaluate whether receipt of aeroallergen testing was associated with a reduction in oral corticosteroid (OCS) bursts. METHODS: We used electronic health record data to conduct a retrospective, observational cohort study of adults with asthma who were prescribed an inhaled corticosteroid and had an Allergy/Immunology visit in a large health system between 1/1/2017-6/30/2022. Negative binomial regression models were used to evaluate whether OCS bursts in the 12-month period after an initial visit were reduced for patients who received aeroallergen testing. We also measured differences in benefit after excluding patients with chronic obstructive pulmonary disease (COPD) and smoking histories, and whether testing receipt was via skin prick or serum. RESULTS: 668/1,383 (48.3%) patients received testing. Receipt of testing was not associated with fewer bursts in all patients (incidence rate ratio (IRR)=0.83 versus no testing, p=0.059), but it was among never smokers without COPD (417/844 tested, IRR=0.68, p=0.004). The receipt of skin testing was associated with fewer bursts in all patients (418/1,383 tested, IRR=0.77, p=0.02) and among never smokers without COPD (283/844 tested, IRR=0.59 versus no testing, p=0.001). CONCLUSION: Guideline-concordant aeroallergen testing in the context of Allergy/Immunology care was associated with clinical benefit in a real-life, diverse cohort of adults with asthma. This benefit varied according to patient comorbidities and the testing modality.

Critically ill patients with acute kidney injury: clinical determinants and post-mortem histology.

Background: Acute kidney injury (AKI) requiring renal replacement therapy (RRT) in the intensive care unit (ICU) portends a poor prognosis. We aimed to better characterize predictors of survival and the mechanism of kidney failure in these patients. Methods: This was a retrospective observational study using clinical and radiological electronic health records, analysed by univariable and multivariable binary logistic regression. Histopathological examination of post-mortem renal tissue was performed. Results: Among 157 patients with AKI requiring RRT, higher serum creatinine at RRT initiation associated with increased ICU survival [odds ratio (OR) 0.33, 95% confidence interval (CI) 0.17-0.62, P = .001]; however, muscle mass (a marker of frailty) interacted with creatinine (P = .02) and superseded creatinine as a predictor of survival (OR 0.26, 95% CI 0.08-0.82; P = .02). Achieving lower cumulative fluid balance (mL/kg) predicted ICU survival (OR 1.01, 95% CI 1.00-1.01, P < .001), as supported by sensitivity analyses showing improved ICU survival with the use of furosemide (OR 0.40, 95% CI 0.18-0.87, P = .02) and increasing net ultrafiltration (OR 0.97, 95% CI 0.95-0.99, P = .02). A urine output of >500 mL/24 h strongly predicted successful liberation from RRT (OR 0.125, 95% CI 0.05-0.35, P < .001). Post-mortem reports were available for 32 patients; clinically unrecognized renal findings were described in 6 patients, 1 of whom had interstitial nephritis. Experimental staining of renal tissue from patients with sepsis-associated AKI (S-AKI) showed glomerular loss of synaptopodin (P = .02). Conclusions: Confounding of creatinine by muscle mass undermines its use as a marker of AKI severity in clinical studies. Volume management and urine output are key determinants of outcome. Loss of synaptopodin implicates glomerular injury in the pathogenesis of S-AKI.

Factors associated with aeroallergen testing among adults with asthma in a large health system.

Background: Aeroallergen testing informs precision care for adults with asthma, yet the epidemiology of testing in this population remains poorly understood. Objective: We sought to identify factors associated with receiving aeroallergen testing, the results of these tests, and subsequent reductions in exacerbation measures among adults with asthma. Methods: We used electronic health record data to conduct a retrospective, observational cohort study of 30,775 adults with asthma who had an office visit with a primary care provider or an asthma specialist from January 1, 2017, to August 26, 2022. We used regression models to identify (1) factors associated with receiving any aeroallergen test and tests to 9 allergen categories after the index visit, (2) factors associated with positive test results, and (3) reductions in asthma exacerbation measures in the year after testing compared with before testing. Results: Testing was received by 2201 patients (7.2%). According to multivariable models, receiving testing was associated with having any office visit with an allergy/immunology specialist during the study period (odds ratio [OR] = 91.3 vs primary care only [P < .001]) and having an asthma emergency department visit (OR = 1.62 [P = .004]) or hospitalization (OR = 1.62 [P = .03]) in the year before the index visit. Age 65 years or older conferred decreased odds of testing (OR = 0.74 vs age 18-34 years [P = .008]) and negative test results to 6 categories (P ≤ .04 for all comparisons). Black race conferred increased odds of testing (OR =1.22 vs White race [P = .01]) and positive test results to 8 categories (P < .04 for all comparisons). Exacerbation measures decreased after testing. Conclusion: Aeroallergen testing was performed infrequently among adults with asthma and was associated with reductions in asthma exacerbation measures.

IgA nephropathy in adults-treatment standard.

Immunoglobulin A nephropathy (IgAN) is the most common primary form of glomerular disease worldwide and carries a high lifetime risk of kidney failure. The underlying pathogenesis of IgAN has been characterized to a sub-molecular level; immune complexes containing specific O-glycoforms of IgA1 are central. Kidney biopsy remains the gold-standard diagnostic test for IgAN and histological features (i.e. MEST-C score) have also been shown to independently predict outcome. Proteinuria and blood pressure are the main modifiable risk factors for disease progression. No IgAN-specific biomarker has yet been validated for diagnosis, prognosis or tracking response to therapy. There has been a recent resurgence of investigation into IgAN treatments. Optimized supportive care with lifestyle interventions and non-immunomodulatory drugs remains the backbone of IgAN management. The menu of available reno-protective medications is rapidly expanding beyond blockade of the renin-angiotensin-aldosterone system to include sodium-glucose cotransporter 2 and endothelin type A receptor antagonism. Systemic immunosuppression can further improve kidney outcomes, although recent randomized controlled trials have raised concerns regarding infectious and metabolic toxicity from systemic corticosteroids. Studies evaluating more refined approaches to immunomodulation in IgAN are ongoing: drugs targeting the mucosal immune compartment, B-cell promoting cytokines and the complement cascade are particularly promising. We review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and management of IgAN.

Factors Associated With Asthma Biologic Prescribing and Primary Adherence Among Adults in a Large Health System.

BACKGROUND: The availability of asthma biologics may not benefit all patients equally. OBJECTIVE: We sought to identify patient characteristics associated with asthma biologic prescribing, primary adherence, and effectiveness. METHODS: A retrospective, observational cohort study of 9,147 adults with asthma who established care with a Penn Medicine asthma subspecialist was conducted using Electronic Health Record data from January 1, 2016, to October 18, 2021. Multivariable regression models were used to identify factors associated with (1) receipt of a new biologic prescription; (2) primary adherence, defined as receiving a dose in the year after receiving the prescription, and (3) oral corticosteroid (OCS) bursts in the year after the prescription. RESULTS: Factors associated with a new prescription, which was received by 335 patients, included being a woman (odds ratio [OR] 0.66; P = .002), smoking currently (OR 0.50; P = .04), having an asthma hospitalization in the prior year (OR 2.91; P < .001), and having 4+ OCS bursts in the prior year (OR 3.01; P < .001). Reduced primary adherence was associated with Black race (incidence rate ratio 0.85; P < .001) and Medicaid insurance (incidence rate ratio 0.86; P < .001), although most in these groups, 77.6% and 74.3%, respectively, still received a dose. Nonadherence was associated with patient-level barriers in 72.2% of cases and health insurance denial in 22.2%. Having more OCS bursts after receiving a biologic prescription was associated with Medicaid insurance (OR 2.69; P = .047) and biologic days covered (OR 0.32 for 300-364 d vs 14-56 d; P = .03). CONCLUSIONS: In a large health system, primary adherence to asthma biologics varied by race and insurance type, whereas nonadherence was primarily explained by patient-level barriers.

New considerations of health disparities within allergy and immunology.

The pandemic, political upheavals, and social justice efforts in our society have resulted in attention to persistent health disparities and the urgent need to address them. Using a scoping review, we describe published updates to address disparities and targets for interventions to improve gaps in care within allergy and immunology. These disparities-related studies provide a broad view of our current understanding of how social determinants of health threaten patient outcomes and our ability to advance health equity efforts in our field. We outline next steps to improve access to care and advance health equity for patients with allergic/immunologic diseases through actions taken at the individual, community, and policy levels, which could be applied outside of our field. Key among these are efforts to increase the diversity among our trainees, providers, and scientific teams and enhancing efforts to participate in advocacy work and public health interventions. Addressing health disparities requires advancing our understanding of the interplay between social and structural barriers to care and enacting the needed interventions in various key areas to effect change.

Is There a Role for Gut Microbiome Dysbiosis in IgA Nephropathy?

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis and one of the leading causes of renal failure worldwide. The pathophysiology of IgAN involves nephrotoxic IgA1-immune complexes. These complexes are formed by galactose-deficient (Gd) IgA1 with autoantibodies against the hinge region of Gd-IgA1 as well as soluble CD89, an immune complex amplifier with an affinity for mesangial cells. These multiple molecular interactions result in the induction of the mesangial IgA receptor, CD71, injuring the kidney and causing disease. This review features recent immunological and microbiome studies that bring new microbiota-dependent mechanisms developing the disease based on data from IgAN patients and a humanized mouse model of IgAN. Dysbiosis of the microbiota in IgAN patients is also discussed in detail. Highlights of this review underscore that nephrotoxic IgA1 in the humanized mice originates from mucosal surfaces. Fecal microbiota transplantation (FMT) experiments in mice using stools from patients reveal a possible microbiota dysbiosis in IgAN with the capacity to induce progression of the disease whereas FMT from healthy hosts has beneficial effects in mice. The continual growth of knowledge in IgAN patients and models can lead to the development of new therapeutic strategies targeting the microbiota to treat this disease.

Safety and outcomes of penicillin allergy evaluation in pregnant women.

BACKGROUND: Penicillin allergy in pregnancy is associated with increased morbidity and the use of less effective antibiotics. Penicillin allergy evaluation in pregnancy is now recommended as per obstetrical guidelines but remains infrequent. OBJECTIVE: We studied pregnant women who underwent penicillin allergy evaluation in an allergy clinic to assess the effectiveness and safety of penicillin skin testing (PST) and incremental drug challenge (IDC) in pregnancy. METHODS: Index drug reactions, PST, and IDC results were reviewed. Antibiotic use, pregnancy outcomes, and pregnancy complications were compared with a control cohort of pregnant women with penicillin allergy who did not undergo allergy evaluation before delivery. RESULTS: Penicillin allergy was evaluated in 136 women. Culprit drugs included penicillin (37%), amoxicillin (30%), and unknown (20%). Index reactions occurred greater than 5 years ago in 91%, and these reactions were cutaneous or unknown in 92%. Of the 133 patients who underwent skin testing, 131 (99%) had negative or equivocal results and proceeded to incremental challenge. All 131 women passed penicillin IDC. Of the 69 women who ultimately used intrapartum beta-lactam antibiotics, all but 1 patient tolerated them. Women who underwent penicillin allergy evaluation did not have an increased risk of cesarean delivery or other pregnancy complications when compared with women without penicillin allergy evaluation. CONCLUSION: PST and IDC can be safely conducted in pregnant women. When evaluated as low risk, most women tolerate IDC and can receive penicillin intrapartum without adverse reactions or negative pregnancy outcomes.

Specific immune biomarker monitoring in two children with severe IgA nephropathy and successful therapy with immunoadsorption in a rapidly progressive case.

BACKGROUND: Childhood IgA nephropathy (cIgAN) is one of the most common primary glomerulonephritides with the potential to evolve to kidney failure. IgAN is an autoimmune disease involving 3 key factors: galactose-deficient IgA1 (Gd-IgA1), anti-IgA1 autoantibodies, and soluble (s)CD89 IgA Fc receptor. These molecules and immune complexes have been described recently as potential biomarkers of disease progression in childhood IgAN but their evolution in time under immunosuppressive treatment remains unknown. METHODS: We performed a prospective study of two proliferative cIgAN patients by sequentially biomonitoring immune IgA complexes (sCD89-IgA, IgG-IgA), sCD89, and Gd-IgA1 and correlating them with clinical and histological outcome after treatment. RESULTS: After patient 1's treatment, a decrease in sCD89-IgA, IgG-IgA, and free sCD89 was linked to a decrease in proteinuria whereas eGFR (estimated glomerular filtration rate) and Gd-IgA1 levels remained stable. Patient 1 received tacrolimus and monthly intramuscular steroid injections of Kenacort for 10 months. At the end, a relapse induced an increase in proteinuria consistent with an increase of the 3 biomarkers. Patient 2 displayed rapidly progressive IgAN with crescents in more than 90% of glomeruli and received intense immunosuppression treatment associated with the immunoadsorption (IA) approach. During IA, proteinuria decreased rapidly, as well as levels of CD89-IgA, IgG-IgA, sCD89, and Gd-IgA1 biomarkers. After discontinuation of IA, proteinuria increased as well as IgG-IgA complexes whereas sCD89-IgA and sCD89 remained low. Further re-intensification of IA and addition of cyclophosphamide improved proteinuria again with reduced IgG-IgA. A second biopsy was performed showing a reduction of extracapillary proliferation to 6% of glomeruli and only 9% glomerulsoclerosis. CONCLUSIONS: In conclusion, sequential biomonitoring of Gd-IgA1, IgA-immune complexes, and sCD89 in cIgAN was found to be valuable, by correlating with clinical features and glomerular proliferative lesions in cIgAN. These biomarkers could represent useful tools to evaluate kidney injury without repeat kidney biopsies.

Soluble CD89 is a critical factor for mesangial proliferation in childhood IgA nephropathy.

Childhood IgA nephropathy (IgAN) includes a wide spectrum of clinical presentations, from isolated hematuria to acute nephritis with rapid loss of kidney function. In adults, IgAN is an autoimmune disease and its pathogenesis involves galactose deficient (Gd) IgA1, IgG anti-Gd-IgA1 autoantibodies and the soluble IgA Fc receptor (CD89). However, implication of such factors, notably soluble CD89, in childhood IgAN pathogenesis remains unclear. Here, we studied these biomarkers in a cohort of 67 patients with childhood IgAN and 42 pediatric controls. While Gd-IgA1 was only moderately increased in patient plasma, levels of circulating IgA complexes (soluble CD89-IgA and IgG-IgA) and free soluble CD89 were markedly increased in childhood IgAN. Soluble CD89-IgA1 complexes and free soluble CD89 correlated with proteinuria, as well as histological markers of disease activity: mesangial, endocapillary hypercellularity and cellular crescents. Soluble CD89 was found in patient's urine but not in urine from pediatric controls. Mesangial deposits of soluble CD89 were detected in biopsies from patients with childhood IgAN. Serum chromatographic fractions containing covalently linked soluble CD89-IgA1 complexes or free soluble CD89 from patients induced mesangial cell proliferation in vitro in a soluble CD89-dependent manner. Recombinant soluble CD89 induced mesangial cell proliferation in vitro which was inhibited by free soluble recombinant CD71 (also a mesangial IgA receptor) or mTOR blockers. Interestingly, injection of recombinant soluble CD89 induced marked glomerular proliferation and proteinuria in mice expressing human IgA1. Thus, free and IgA1-complexed soluble CD89 are key players in mesangial proliferation. Hence, our findings suggest that soluble CD89 plays an essential role in childhood IgAN pathogenesis making it a potential biomarker and therapeutic target.

Is complement the main accomplice in IgA nephropathy? From initial observations to potential complement-targeted therapies.

IgA Nephropathy (IgAN) is the main cause of primary glomerulonephritis, globally. This disease is associated with a wide range of clinical presentations, variable prognosis and a spectrum of histological findings. More than fifty years after its first description, this heterogeneity continues to complicate efforts to understand the pathogenesis. Nevertheless, involvement of the complement system in IgAN was identified early on. Dysfunction of the immunoglobulin A (IgA) system, the principal offender in this disease, including modification of isoforms and glycoforms of IgA1, the nature of immune complexes and autoantibodies to galactose deficient IgA1 might all be responsible for complement activation in IgAN. However, the specific mechanisms engaging complement are still under examination. Research in this domain should allow for identification of patients that may benefit from complement-targeted therapy, in the foreseeable future.

Rifaximin as a Potential Treatment for IgA Nephropathy in a Humanized Mice Model.

IgA Nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by the mesangial deposition of abnormally glycosylated IgA1 (Gd-IgA). The production of Gd-IgA occurs in mucose-associated lymphoid tissue (MALT). The microbiota plays a role in MALT modulation. Rifaximin (NORMIX®), a non-absorbable oral antibiotic, induces positive modulation of the gut microbiota, favoring the growth of bacteria beneficial to the host. Here, we evaluate the effect of rifaximin on a humanized mice model of IgAN (α1KI-CD89Tg). Methods: The α1KI-CD89Tg mice were treated by the vehicle (olive oil) or rifaximin (NORMIX®). Serum levels of hIgA, hIgA1-sCD89, and mIgG-hIgA1 immune complexes were determined. Glomerular hIgA1 deposit and CD11b+ cells recruitment were revealed using confocal microscopy. Furthermore, the mRNA of the B-Cell Activating Factor (BAFF), polymeric immunoglobulin receptor (pIgR), and Tumor Necrosing Factor-α (TNF-α) in gut samples were detected by qPCR. Results: Rifaximin treatment decreased the urinary protein-to-creatinine ratio, serum levels of hIgA1-sCD89 and mIgG-hIgA1 complexes, hIgA1 glomerular deposition, and CD11b+ cell infiltration. Moreover, rifaximin treatment decreased significantly BAFF, pIgR, and TNF-α mRNA expression. Conclusions: Rifaximin decreased the IgAN symptoms observed in α1KI-CD89Tg mice, suggesting a possible role for it in the treatment of the disease.

Denatonium benzoate bitter taste perception in chronic rhinosinusitis subgroups.

BACKGROUND: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP), and aspirin-exacerbated respiratory disease (AERD) have varying levels of inflammation and disease severity. Solitary chemosensory cells (SCCs) are enriched in nasal polyps, are the primary source of interleukin 25 (IL-25) in upper airways, leading to type 2 inflammation, and are activated by bitter-tasting denatonium benzoate (DB). Thus, we sought to evaluate DB taste perception at a range of concentrations in order to identify 1 that most differentiates CRS subgroups from controls. METHODS: CRSsNP (n = 25), CRSwNP (n = 26), and AERD (n = 27) patients as well as controls (n = 25) tasted 6 DB concentrations in a fixed, random order, rating on a category scale of 0 (no intensity) to 12 (extremely intense). Sinonasal epithelial cultures were treated with and without denatonium and analyzed for IL-25 via flow cytometry. RESULTS: CRSsNP patients rated DB as significantly less intense than did controls at all concentrations: 5.62 × 10-9 M, 1.00 × 10-8 M, 1.78 × 10-8 M, 3.16 × 10-8 M, 5.62 × 10-8 M, and 1.00 × 10-7 M (all p < 0.0083). CRSwNP patients did not show significant differences from controls. AERD patients rated DB as significantly more intense than did controls at concentrations of 1.00 × 10-8 M and 3.16 × 10-8 M (p < 0.0083). In vitro data demonstrated significant increase in IL-25-positive cells after denatonium stimulation (n = 5), compared to control (n = 5) (p = 0.012). CONCLUSION: Our findings link in vitro DB stimulation of sinonasal tissue with increased IL-25 and show differential DB taste perception in CRS subgroups relative to the control group, with CRSsNP being hyposensitive and AERD being hypersensitive. We propose a concentration of 3.16 × 10-8 M for future study of clinical utility.

New therapeutic perspectives for IgA nephropathy in children.

Childhood IgA nephropathy (cIgAN) differs from the adult by having an abrupt clinical onset, often presenting as an acute attack that can progress to a chronic phase. No treatment guidelines have been established for the treatment of cIgAN. Given the severity of acute attack in children, and the number of life-years at stake, pediatricians prescribe immunosuppression in addition to renin-angiotensin system blockade. Non-specific immunosuppressors, such as corticosteroids, have systemic toxic effects, and given recent therapeutic advances in adult glomerulonephritis, new tailored strategies should be expected for children. The mucosal immune system has been highlighted as a key player in IgAN pathogenesis, and several biomarkers have been identified with a direct role in pathogenesis. In this review, we discuss current studies of conventional and novel therapeutic approaches for cIgAN.