Unraveling the unphosphorylated STAT3-unphosphorylated NF-κB pathway in loss of function STAT3 Hyper IgE syndrome.

Background: Patients with loss of function signal transducer and activator of transcription 3-related Hyper IgE Syndrome (LOF STAT3 HIES) present with recurrent staphylococcal skin and pulmonary infections along with the elevated serum IgE levels, eczematous rashes, and skeletal and facial abnormalities. Defective STAT3 signaling results in reduced Th17 cells and an impaired IL-17/IL-22 response primarily due to a compromised canonical Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway that involves STAT3 phosphorylation, dimerization, nuclear translocation, and gene transcription. The non-canonical pathway involving unphosphorylated STAT3 and its role in disease pathogenesis, however, is unexplored in HIES. Objective: This study aims to elucidate the role of unphosphorylated STAT3-unphosphorylated NF-κB (uSTAT3-uNF-κB) activation pathway in LOF STAT3 HIES patients. Methodology: The mRNA expression of downstream molecules of unphosphorylated STAT3-unphosphorylated NF-κB pathway was studied in five LOF STAT3 HIES patients and transfected STAT3 mutants post-IL-6 stimulation. Immunoprecipitation assays were performed to assess the binding of STAT3 and NF-κB to RANTES promoter. Results: A reduced expression of the downstream signaling molecules of the uSTAT3-uNF-κB complex pathway, viz., RANTES, STAT3, IL-6, IL-8, ICAM1, IL-8, ZFP36L2, CSF1, MRAS, and SOCS3, in LOF STAT3 HIES patients as well as the different STAT3 mutant plasmids was observed. Immunoprecipitation studies showed a reduced interaction of STAT3 and NF-κB to RANTES in HIES patients. Conclusion: The reduced expression of downstream signaling molecules, specially RANTES and STAT3, confirmed the impaired uSTAT3-uNF-κB pathway in STAT3 LOF HIES. Decreased levels of RANTES and STAT3 could be a significant component in the disease pathogenesis of Hyper IgE Syndrome.

Obstructive uropathy in STAT 3 hyper immunoglobulin E syndrome: A 5 year old Middle Eastern boy.

Autosomal dominant hyper immunoglobulin E (IgE) syndrome is a rare inborn error of immunity that affects approximately one in a million individuals worldwide. It presents with various symptoms owing to multisystem involvement (immunological and non-immunological). Recurrent infections (mainly in the skin and lungs) are common presentations. A 5-year-old Middle Eastern boy presented with symptoms suggestive of obstructive uropathy secondary to multiple large pelviabdominal abscesses and acute kidney injury with hyperkalemia that necessitated admission to the intensive care unit. Upon further investigation, the patient's genetic test (whole exome sequencing) demonstrated a heterozygous missense variant in the STAT3 gene. The patient completely recovered and did not require further admission after initiating prophylactic antibiotics. Although deep-seated infections are uncommon in STAT3 hyper IgE syndrome, skin and lung infections are most commonly observed. Multiple deep collections can occur and require prompt intervention and aggressive treatment.

Elevated Immunoglobulin E Serum Levels: Possible Underlying Factors That Can Cause an Inborn Error of Immunity in the Pediatric Population with Recurrent Infections.

Elevated immunoglobulin E (IgE) levels are commonly associated with allergies. However, high IgE levels are also found in several other infectious and non-infectious disorders. Elevated IgE levels typically suggest allergies, eczema, or recurrent skin infections. Hyperimmunoglobulin E (hyper-IgE) levels typically reflect a monogenic atopic condition or inborn immune defects with an atopic phenotype. The aim of our research is to investigate and observe the clinical characteristics of children with increased IgE levels who have previously manifested infectious diseases. Furthermore, the retrospective study considers other factors, such as demographic characteristics (sex, area/environment, and age), and their effect on IgE serum levels. To answer this question, we conducted a one-year hospital-based retrospective study that included 200 hospitalized children who had at least two viral or bacterial infections in the six months preceding hospitalization. Measurements of IgE and allergen panels (respiratory and digestive) using blood samples revealed that individuals who tested positive for the body's synthesis of hyper-IgE were not observably allergic to any potential allergens despite having higher total serum IgE. According to the results, there was a strong correlation between elevated IgE serum levels and a history of infectious diseases among the patients.

Staphylococcus aureus Serine protease-like protein A (SplA) induces IL-8 by keratinocytes and synergizes with IL-17A.

BACKGROUND: Serine protease-like (Spl) proteins produced by Staphylococcus (S.) aureus have been associated with allergic inflammation. However, effects of Spls on the epidermal immune response have not been investigated. OBJECTIVES: To assess the epidermal immune response to SplA, SplD and SplE dependent on differentiation of keratinocytes and a Th2 or Th17 cytokine milieu. METHODS: Human keratinocytes of healthy controls and a STAT3-hyper-IgE syndrome (STAT3-HIES) patient were cultured in different calcium concentrations in the presence of Spls and Th2 or Th17 cytokines. Keratinocyte-specific IL-8 production and concomitant migration of neutrophils were assessed. RESULTS: SplE and more significantly SplA, induced IL-8 in keratinocytes. Suprabasal-like keratinocytes showed a higher Spl-mediated IL-8 production and neutrophil migration compared to basal-like keratinocytes. Th17 cytokines amplified Spl-mediated IL-8 production, which correlated with neutrophil recruitment. Neutrophil recruitment by keratinocytes of the STAT3-HIES patient was similar to healthy control cells. CONCLUSION: S. aureus-specific Spl proteases synergized with IL-17A on human keratinocytes with respect to IL-8 release and neutrophil migration, highlighting the importance of keratinocytes and Th17 immunity in barrier function.

A systematic review regarding the prevalence of malignancy in patients with the hyper-IgE syndrome.

The hyper-immunoglobulin E syndrome (HIES) is a primary immunodeficiency disease originally described as Job syndrome. The fundamental causative variant of the HIES is an autosomal dominant mutation in the signal transducer and activator of transcription 3 (STAT3) gene. It is characterized by recurrent staphylococcal cold skin abscess, sinopulmonary infection, eczema, head and face anomalies, frequent bone fractures, eosinophilia and extremely high serum IgE levels (IgE ≥ 2000 IU/mL). However, multiple other genetic defects are also known as HIES-like disorders. Apart from infectious manifestations, STAT3, DOCK8 and TYK2 gene mutations are associated with various malignancies. The most common malignancies reported in these patients are lymphomas, including Hodgkin's and non-Hodgkin's lymphomas (NHL) of B and T cells. This systematic review aimed to investigate the prevalence of malignancies in HIES and the factors associated with malignancy in these patients. In this survey, all articles published until April 1st, 2023, in Scopus, PubMed and Web of Science databases based on three groups of keywords related to HIES syndrome and malignancy were reviewed by three different researchers. Finally, 26 articles were evaluated from which 24 papers were meta-analyzed. In the current study, the demographic information of 1133 patients with HIES, which was mentioned in 24 articles enrolled in the project, was collected, and the information related to patients who had malignancy was analyzed and meta-analyzed. A total of 96 patients out of 1133 studied patients had at least one type of malignancy, the overall prevalence of malignancies reported in the articles was 6.5% (95% confidence interval 4.1-9%), and the total prevalence of malignancy in patients with NHL type and patients with squamous cell carcinoma (SCC) was 2.9% (95% confidence interval 1.7-4.4%) and 2.2% (95% confidence interval 0.3-4.1%), respectively. The results of this study indicated that in 6.5% of cases, HIES was complicated with malignancy, and considering the higher rate of these malignancies in women as well as in DOCK8 mutation sufferers, it is necessary for physicians to be aware of this association and includes malignancy screening in follow-up and periodic examinations of these patients. Indeed, more studies in this field will help to clarify the precise figures and predisposing factors of the relationship between HIES and malignancy.

Households food consumption pattern in Pakistan: Evidence from recent household integrated economic survey.

The analysis of food consumption pattern is a primary concern of any developing country because it is related with food security. Pakistan is one of the emerging nations of the developing world. Due to the similarities and differences in households' food consumption behavior, income distribution, the effects of alternative tax structures, cost-benefit analyses, and the choice of cost of living index, the study of households' food consumption pattern is crucial for a developing nation like Pakistan. Furthermore, for Pakistan's food security in the present and the future, an analysis of food consumption pattern is crucial. The main objective of this study is to analyze the households' food consumption pattern. Linear Approximation Almost Ideal Demand System (LA/AIDS) is applied using data from Household Integrated Economic Survey (HIES) for the year 2018-19. This study makes a significant contribution by estimating household age composition elasticities, which were absent from earlier studies. Results from the income elasticities reveal that milk, meat, and fruits are luxuries food items. Similarly, on the basis of inelastic income elasticities we declared cereals, pulses, vegetables, sugar, and ghee as necessity food items. Results from the compensated own price elasticities show that the eight food commodity groups have inelastic own-price elasticities. This implies that these food commodities are integral food items of household diet. Results from the compensated cross-price elasticities shows that cereals and pulses, cereals and vegetables, pulses and vegetables, milk and fruits, meat and fruits, and milk and ghee are gross substitutes. On the other hand, pulses and meat, pulses and fruits, and ghee and meat are gross complements. According to the findings of the household age composition elasticities, adding children to a household significantly increases its sugar consumption while significantly reducing its fruit consumption. Any increase in the size of the household by an adolescent, adult, or a person in their middle age results in a significant increase in the consumption of cereals and a significant drop in the consumption of fruits. Finally, any increase in the size of the households brought about by an elder resulted in a significant rise in the consumption of cereals and a significant drop in the consumption of vegetables.

Hyper IgE syndrome-related disease treated with dupilumab: A case report.

Phosphoglucomutase 3 (PGM3) catalyzes the glycosylation of immune system precursor proteins. Its impairment leads to severe infections and other developmental, musculoskeletal, and nervous system defects. We present a case of a 2-month-old female patient with recurrent infections and diffuse eczematous dermatitis recalcitrant to corticosteroids. A next-generation sequencing NGS gene panel for inherited immune dysfunction syndromes revealed multiple variants of unknown significance in key immune regulators, specifically heterozygous mutation c.337C⟩G (p.Pro113Ala) on exon 4 of PGM3 as a novel variant in the PGM3 associated diseases. Off-label use of dupilumab resulted in rapid improvement.

Long term longitudinal follow-up of an AD-HIES cohort: the impact of early diagnosis and enrollment to IPINet centers on the natural history of Job's syndrome.

Job's syndrome, or autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES, STAT3-Dominant Negative), is a rare inborn error of immunity (IEI) with multi-organ involvement and long-life post-infective damage. Longitudinal registries are of primary importance in improving our knowledge of the natural history and management of these rare disorders. This study aimed to describe the natural history of 30 Italian patients with AD-HIES recorded in the Italian network for primary immunodeficiency (IPINet) registry. This study shows the incidence of manifestations present at the time of diagnosis versus those that arose during follow up at a referral center for IEI. The mean time of diagnostic delay was 13.7 years, while the age of disease onset was < 12 months in 66.7% of patients. Respiratory complications, namely bronchiectasis and pneumatoceles, were present at diagnosis in 46.7% and 43.3% of patients, respectively. Antimicrobial prophylaxis resulted in a decrease in the incidence of pneumonia from 76.7% to 46.7%. At the time of diagnosis, skin involvement was present in 93.3% of the patients, including eczema (80.8%) and abscesses (66.7%). At the time of follow-up, under therapy, the prevalence of complications decreased: eczema and skin abscesses reduced to 63.3% and 56.7%, respectively. Antifungal prophylaxis decreased the incidence of mucocutaneous candidiasis from 70% to 56.7%. During the SARS-CoV-2 pandemic, seven patients developed COVID-19. Survival analyses showed that 27 out of 30 patients survived, while three patients died at ages of 28, 39, and 46 years as a consequence of lung bleeding, lymphoma, and sepsis, respectively. Analysis of a cumulative follow-up period of 278.7 patient-years showed that early diagnosis, adequate management at expertise centers for IEI, prophylactic antibiotics, and antifungal therapy improve outcomes and can positively influence the life expectancy of patients.

Multi-Omics Profiling in PGM3 and STAT3 Deficiencies: A Tale of Two Patients.

Hyper-IgE Syndrome (HIES) is a heterogeneous group of primary immune-deficiency disorders characterized by elevated levels of IgE, eczema, and recurrent skin and lung infections. HIES that is autosomally dominant in the signal transducer and activator of transcription 3 (STAT3), and autosomal recessive mutations in phosphoglucomutase 3 (PGM3) have been reported in humans. An early diagnosis, based on clinical suspicion and immunological assessments, is challenging. Patients' metabolomics, proteomics, and cytokine profiles were compared to DOCK 8-deficient and atopic dermatitis patients. The PGM3 metabolomics profile identified significant dysregulation in hypotaurine, hypoxanthine, uridine, and ribothymidine. The eight proteins involved include bifunctional arginine demethylase and lysyl hydroxylase (JMJD1B), type 1 protein phosphatase inhibitor 4 (PPI 4), and platelet factor 4 which aligned with an increased level of the cytokine GCSF. Patients with STAT3 deficiency, on the other hand, showed significant dysregulation in eight metabolites, including an increase in protocatechuic acid, seven proteins including ceruloplasmin, and a plasma protease C1 inhibitor, in addition to cytokine VEGF being dysregulated. Using multi-omics profiling, we identified the dysregulation of endothelial growth factor (EGFR) and tumor necrosis factor (TNF) signaling pathways in PGM3 and STAT3 patients, respectively. Our findings may serve as a stepping stone for larger prospective HIES clinical cohorts to validate their future use as biomarkers.

STAT3 mutation-associated airway epithelial defects in Job syndrome.

BACKGROUND: Job syndrome is a disease of autosomal dominant hyper-IgE syndrome (AD-HIES). Patients harboring STAT3 mutation are particularly prone to airway remodeling and airway infections. OBJECTIVES: Airway epithelial cells play a central role as the first line of defense against pathogenic infection and express high levels of STAT3. This study thus interrogates how AD-HIES STAT3 mutations impact the physiological functions of airway epithelial cells. METHODS: This study created human airway basal cells expressing 4 common AD-HIES STAT3 mutants (R382W, V463del, V637M, and Y657S). In addition, primary airway epithelial cells were isolated from a patient with Job syndrome who was harboring a STAT3-S560del mutation and from mice harboring a STAT3-V463del mutation. Cell proliferation, differentiation, barrier function, bacterial elimination, and innate immune responses to pathogenic infection were quantitatively analyzed. RESULTS: STAT3 mutations reduce STAT3 protein phosphorylation, nuclear translocation, transcription activity, and protein stability in airway basal cells. As a consequence, STAT3-mutated airway basal cells give rise to airway epithelial cells with abnormal cellular composition and loss of coordinated mucociliary clearance. Notably, AD-HIES STAT3 airway epithelial cells are defective in bacterial killing and fail to initiate vigorous proinflammatory responses and neutrophil transepithelial migration in response to an experimental model of Pseudomonas aeruginosa infection. CONCLUSIONS: AD-HIES STAT3 mutations confer numerous abnormalities to airway epithelial cells in cell differentiation and host innate immunity, emphasizing their involvement in the pathogenesis of lung complications in Job syndrome. Therefore, therapies must address the epithelial defects as well as the previously noted immune cell defects to alleviate chronic infections in patients with Job syndrome.

An autopsy case of hyperimmunoglobulin E syndrome with coronary fibrinoid necrotizing arteritis and an aneurysm.

We report a case of hyperimmunoglobulin (Ig) E syndrome (HIES) with a coronary artery aneurysm (CAA) in a 25-year-old Japanese man. He died suddenly due to chronic heart failure associated with HIES. We noted a CAA at the trunk of the left coronary artery and granulomatous and fibrinoid necrotizing arteritis of the middle portion of the left anterior descending during the autopsy. We speculate herein on the relationship between the aneurysm and arteritis. These findings facilitate a better understanding of the pathogenesis underlying HIES.

Immunoglobulin Disorders and the Oral Cavity: A Narrative Review.

The oral mucosa is a mechanical barrier against the penetration and colonization of microorganisms. Oral homeostasis is maintained by congenital and adaptive systems in conjunction with normal oral flora and an intact oral mucosa. Components contributing to the defense of the oral cavity include the salivary glands, innate antimicrobial proteins of saliva, plasma proteins, circulating white blood cells, keratinocyte products of the oral mucosa, and gingival crevicular fluid. General disturbances in the level of immunoglobulins in the human body may be manifested as pathological lesions in the oral mucosa. Symptoms of immunoglobulin-related general diseases such as mucous membrane pemphigoid (MMP), pemphigus vulgaris (PV), linear IgA bullous dermatosis (LABD), Epidermolysis Bullosa Aquisita (EBA), and Hyper-IgE syndrome (HIES) may appear in the oral cavity. In this review, authors present selected diseases associated with immunoglobulins in which the lesions appear in the oral cavity. Early detection and treatment of autoimmune diseases, sometimes showing a severe evolution (e.g., PV), allow the control of their dissemination and involvement of skin or other body organs. Immunoglobulin disorders with oral manifestations are not common, but knowledge, differentiation and diagnosis are essential for proper treatment.

Molecular Assessment of Staphylococcus Aureus Strains in STAT3 Hyper-IgE Syndrome Patients.

Hyper-IgE syndromes (HIES) are a group of inborn errors of immunity (IEI) caused by monogenic defects such as in the gene STAT3 (STAT3-HIES). Patients suffering from HIES show an increased susceptibility to Staphylococcus aureus (S. aureus) including skin abscesses and pulmonary infections. To assess if the underlying immune defect of STAT3-HIES patients influences the resistance patterns, pathogenicity factors or strain types of S. aureus. We characterized eleven S. aureus strains isolated from STAT3-HIES patients (n = 4) by whole genome sequencing (WGS) to determine presence of resistance and virulence genes. Additionally, we used multi-locus sequence typing (MLST) and protein A (spa) typing to classify these isolates. Bacterial isolates collected from this cohort of STAT3-HIES patients were identified as common spa types in Germany. Only one of the isolates was classified as methicillin-resistant S. aureus (MRSA). For one STAT3 patient WGS illustrated that infection and colonization occurred with different S. aureus isolates rather than one particular clone. The identified S. aureus carriage profile on a molecular level suggests that S. aureus strain type in STAT3-HIES patients is determined by local epidemiology rather than the underlying immune defect highlighting the importance of microbiological assessment prior to antibiotic treatment.

Beyond Infections: New Warning Signs for Inborn Errors of Immunity in Children.

Patients with inborn errors of immunity (IEI) are susceptible to developing a severe infection-related clinical phenotype, but the clinical consequences of immune dysregulation, expressed with autoimmunity, atopy, and lymphoproliferation could represent the first sign in a significant percentage of patients. Therefore, during the diagnostic work-up patients with IEI are frequently addressed to different specialists, including endocrinologists, rheumatologists, and allergologists, often resulting in a delayed diagnosis. In this paper, the most relevant non-infectious manifestations of IEI are discussed. Particularly, we will focus on the potential presentation of IEI with autoimmune cytopenia, non-malignant lymphoproliferation, severe eczema or erythroderma, autoimmune endocrinopathy, enteropathy, and rheumatologic manifestations, including vasculitis and systemic lupus erythematosus. This paper aims to identify new warning signs to suspect IEI and help in the identification of patients presenting with atypical/non-infectious manifestations.

Antiviral Activity of Olanexidine-Containing Hand Rub against Human Noroviruses.

Human norovirus (HuNoV) is the leading cause of epidemic and sporadic acute gastroenteritis worldwide. HuNoV transmission occurs predominantly by direct person-to-person contact, and its health burden is associated with poor hand hygiene and a lack of effective antiseptics and disinfectants. Specific therapies and methods to prevent and control HuNoV spread previously were difficult to evaluate because of the lack of a cell culture system to propagate infectious virus. This barrier has been overcome with the successful cultivation of HuNoV in nontransformed human intestinal enteroids (HIEs). Here, we report using the HIE cultivation system to evaluate the virucidal efficacy of an olanexidine gluconate-based hand rub (OLG-HR) and 70% ethanol (EtOH70%) against HuNoVs. OLG-HR exhibited fast-acting virucidal activity against a spectrum of HuNoVs including GII.4 Sydney[P31], GII.4 Den Haag[P4], GII.4 New Orleans[P4], GII.3[P21], GII.17[P13], and GI.1[P1] strains. Exposure of HuNoV to OLG-HR for 30 to 60 s resulted in complete loss of the ability of virus to bind to the cells and reduced in vitro binding to glycans in porcine gastric mucin. By contrast, the virucidal efficiency of EtOH70% on virus infectivity was strain specific. Dynamic light scattering (DLS) and electron microscopy of virus-like particles (VLPs) show that OLG-HR treatment causes partial disassembly and possibly conformational changes in VP1, interfering with histo-blood group antigen (HBGA) binding and infectivity, whereas EtOH70% treatment causes particle disassembly and clumping of the disassembled products, leading to loss of infectivity while retaining HBGA binding. The highly effective inactivation of HuNoV infectivity by OLG-HR suggests that this compound could reduce HuNoV transmission. IMPORTANCE Human noroviruses (HuNoVs) are highly contagious and cause nonbacterial acute gastroenteritis in all age groups worldwide. Since the introduction of rotavirus vaccines, HuNoVs have become the leading cause of diarrheal illness in children. These viruses are very stable in the environment and resistant to common disinfectants. This study evaluated the virucidal efficacy of a new disinfectant, olanexidine-based hand rub (OLG-HR), against HuNoV strains in an ex vivo human intestinal stem cell-derived enteroid (HIE) cultivation system. Exposure of multiple HuNoV strains to OLG-HR for 30 to 60 s resulted in complete loss of infectivity and binding to HBGAs, possibly due to partial disassembly and conformational changes in the major virus capsid (VP1). By comparison, the virucidal efficiency of EtOH70% was strain specific, leading to loss of infectivity while retaining HBGA binding. These findings show the utility of the ex vivo HIE cultivation system to test the effectiveness of disinfectants and report a highly effective product.

Hyper IgE Syndrome in an Isolated Population in Israel.

Introduction: Hyper IgE syndromes (HIES) are a group of rare primary immunodeficiency characterized by high levels of serum IgE, cold abscesses, pulmonary infections, and eczema. ZNF341 deficiency was described in 2018 in 11 patients clinically diagnosed previously with HIES. Eight of those patients, all offspring of consanguineous couples, are from three families who live in a Muslim village in Israel which has approximately 15,000 residents. Objective: Our study aimed to evaluate the prevalence of ZNF341 mutation in the population of the village. Methods: Three hundred DNA samples of females were included in the study. The samples belong to females that were referred to the Meir Medical Center for prenatal genetic testing before pregnancy, during 2017-2019: 200 samples were from the village, and 100 samples of Muslim females were from other villages.All samples were tested by Sanger sequencing for the ZNF341 mutation (c.904C>T, NM_001282933.1). Results: Heterozygous nonsense mutation in ZNF341 was found in ten samples (5%) of the study group compared to zero in the control group (p<0.01). Conclusion: The carrier frequency of the mutation in ZNF341 in the studied village population is 1:20. This high frequency is probably due to founder mutation and consanguineous marriages.

Profound differences in IgE and IgG recognition of micro-arrayed allergens in hyper-IgE syndromes.

BACKGROUND: The specificities of IgE and IgG for allergen molecules in patients with inborn errors of immunity (IEI) have not been investigated in detail. OBJECTIVE: To study IgE and IgG antibody specificities in patients with defined hyper-IgE syndromes (HIES) using a comprehensive panel of allergen molecules. METHODS: We used chips containing micro-arrayed allergen molecules to analyze allergen-specific IgE and IgG levels in sera from two groups of HIES patients: Autosomal recessive mutations in phosphoglucomutase-3 (PGM3); Autosomal dominant negative mutations of STAT3 (STAT3); and age-matched subjects with allergic sensitizations. Assays with rat basophil leukemia cells transfected with human FcεRI were performed to study the biological relevance of IgE sensitizations. RESULTS: Median total IgE levels were significantly lower in the sensitized control group (212.9 kU/L) as compared to PGM3 (5042 kU/L) and STAT3 patients (2561 kU/L). However, PGM3 patients had significantly higher allergen-specific IgE levels and were sensitized to a larger number of allergen molecules as compared to STAT3 patients. Biological relevance of IgE sensitization was confirmed for PGM3 patients by basophil activation testing. PGM3 patients showed significantly lower cumulative allergen-specific IgG responses in particular to milk and egg allergens as compared to STAT3 patients and sensitized controls whereas total IgG levels were comparable to STAT3 patients and significantly higher than in controls. CONCLUSION: The analysis with multiple micro-arrayed allergen molecules reveals profound differences of allergen-specific IgE and IgG recognition in PGM3 and STAT3 patients which may be useful for classification of IEI and clinical characterization of patients.

A NATIONAL SURVEY ASSESSING HEALTH INFORMATION EXCHANGE: READINESS FOR CHANGES TO VETERANS AFFAIRS ACCESS STANDARDS.

We conducted a national survey of Health Information Exchanges (HIEs), targeting both not-for profit geographic and enterprise or federated exchanges. The aim of this study is to identify current best practices when exchanging information between Veterans Affairs (VA) systems and non-VA health systems. We identified and classified current interactions between HIEs and VA systems given recent passage of the MISSION Act. The MISSION Act allows veterans to seek care outside the VA health system, necessitating the need to reconcile care planning between VA systems and private care settings. We identified several differing best practices concerning information exchange between VA health systems and HIEs and assessed capabilities for HIEs to appropriately identify eligible VA participants within extant databases.