Risk Of Severe Adverse Reactions Research Articles

Elevated Baseline Mean Corpuscular Volume Predicts the Development of Severe Hematologic Toxicity After 177Lu-DOTATATE Therapy.

177Lu-DOTATATE is an effective second-line treatment for metastatic or nonresectable neuroendocrine tumors. This treatment can result in hematologic severe adverse reactions (SARs). Preemptive identification of patients at risk of SARs could mitigate this risk and improve treatment safety and outcomes. Methods: Demographic and oncologic history, pretreatment laboratory values, and SAR frequency were obtained for 126 sequential patients treated with 177Lu-DOTATATE. Univariable and multivariable logistic regression models identified factors correlating with SARs. Results: Relative pretreatment anemia, leukopenia, thrombocytopenia, and elevated mean corpuscular volume (MCV) were significantly correlated with SARs, with an odds ratio of 16 (95% CI, 5-65) in patients with an MCV greater than 95 fL. Conclusion: Pretreatment bone marrow dyscrasias, including an MCV greater than 95 fL, may predict patients at risk for SARs when treated with 177Lu-DOTATATE. Further study is needed to determine whether the risks of SARs outweigh the benefit in these patients.

#410 Novel renal pathology and treatment of TIN with monoclonal plasma cells invasion in a patient with Sjögren's syndrome and IgA monoclonal gammopathy

Abstract Background and Aims Patients with Sjögren's syndrome (SS) may occasionally present with monoclonal gammopathy of undetermined significance (MGUS), of the rare IgA type. Additionally, they may present with tubulointerstitial nephritis (TIN) infiltrated by polyclonal plasmacytes and lymphocytes. Previous reports indicate the development of IgA-type MGUS and TIN with monoclonal plasma cells in some SS patients, which are considered distinct from monoclonal gammopathy of renal significance (MGRS) because there is no evidence that monoclonal gammopathy affects nephropathy. Although treatment with prednisolone (PSL) has shown beneficial effects, the influence of monoclonal plasma cells on nephropathy remains unclear and a standardized treatment approach is lacking. Here we present a new renal pathological insight through a case of such a patient as described above, who underwent renal biopsy before and after PSL treatment. The aim is to propose a treatment strategy based on the findings of the second renal biopsy. Method and Results (Case Presentation) A 75-year-old Japanese man with primary complaint of dry mouth was diagnosed with SS by lip biopsy and anti-Ro/SSA and La/SSB antibody tests. Monoclonal proteins were found in both blood and urine. After immunoelectrophoresis, bone marrow puncture, and 18F-FDG PET/CT, we identified it as IgA kappa-type MGUS. At the same time, he developed renal dysfunction and was admitted to our hospital (week 1, Fig. 1) for a renal biopsy. The biopsy revealed severe and diffuse TIN infiltrated by lymphocytes with abundant interstitial plasma cell invasion (Fig. 2a). Minimal changes were observed in the glomeruli. Periodic acid–Schiff staining revealed Dutcher bodies in the nucleus of plasma cells. Immunohistochemical staining for immunoglobulins and light chains showed predominantly positive results for IgA and kappa (Fig. 2b). Monoclonality was confirmed by in situ hybridization. The infiltrates were positive for CD 45, CD 79a, and CD 138, partially positive for CD 19 and CD 20, and negative for CD 5, CD 10, and CD 23. Congo-red staining showed no evidence of amyloid. Immunofluorescence and electron microscopy revealed no detectable immunological deposits in the glomeruli and tubules. Mutations in the myeloid differentiation primary response gene 88 were not detected in the kidney. We diagnosed the condition as acute TIN by lymphocytes with IgA kappa-positive monoclonal plasma cells, distinct from MGRS. Considering the lack of evidence from previous reports on the impact of monoclonal plasma cells on nephropathy, we decided to treat the patient primarily for TIN with SS, initiating PSL at 30 mg/day (0.5 mg/kg/day). Renal function improved rapidly with the treatment, allowing for a gradual reduction in the dose of PSL; however, a low dose of PSL (10 mg/day) was required to prevent relapse. As a complication of PSL, the patient eventually developed a lumbar compression fracture, prompting us to evaluate the effect of PSL on renal function by a renal re-biopsy. The re-biopsy revealed significant recovery of TIN by lymphocytes (Fig. 2c). Other findings, including abundant interstitial plasma cells invasion were comparable to the initial biopsy. We diagnosed the condition as recovered TIN by lymphocytes with IgA kappa-positive monoclonal plasma cells. We concluded that TIN by lymphocytes, rather than monoclonal plasma cell invasion, primarily affected the nephropathy, and PSL mainly improved the former. The Nudix hydrolase 15 codon139 in blood was identified as Cys/Cys, indicating a high risk of severe adverse reactions to azathioprine in Asians. Therefore, we decided to concurrently administer mycophenolate mofetil, proven effective in the treatment of TIN with SS. Conclusion In the management patients with SS and IgA monoclonal gammopathy, the focus should be on TIN by lymphocytes rather than monoclonal plasma cell invasion. This case, considering similar cases, suggests that it should be defined as a new disease category. We demonstrate new renal pathology and treatment insights based on renal re-biopsy in a patient treated with PSL.

Adverse event signal mining and serious adverse event influencing factor analysis of fulvestrant based on FAERS database

Fulvestrant, as the first selective estrogen receptor degrader, is widely used in the endocrine treatment of breast cancer. However, in the real world, there is a lack of relevant reports on adverse reaction data mining for fulvestrant. To perform data mining on adverse events (AEs) associated with fulvestrant and explore the risk factors contributing to severe AEs, providing a reference for the rational use of fulvestrant in clinical practice. Retrieved adverse event report information associated with fulvestrant from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, covering the period from market introduction to September 30, 2023. Suspicious AEs were screened using the reporting odds ratio (ROR) and proportional reporting ratio methods based on disproportionality analysis. Univariate and multivariate logistic regression analyses were conducted on severe AEs to explore the risk factors associated with fulvestrant-induced severe AEs. A total of 6947 reports related to AEs associated with fulvestrant were obtained, including 5924 reports of severe AEs and 1023 reports of non-severe AEs. Using the disproportionality analysis method, a total of 210 valid AEs were identified for fulvestrant, with 45 AEs (21.43%) not listed in the product labeling, involving 11 systems and organs. The AEs associated with fulvestrant were sorted by frequency of occurrence, with neutropenia (325 cases) having the highest number of reports. By signal strength, injection site pruritus showed the strongest signal (ROR = 658.43). The results of the logistic regression analysis showed that concurrent use of medications with extremely high protein binding (≥ 98%) is an independent risk factor for severe AEs associated with fulvestrant. Age served as a protective factor for fulvestrant-related AEs. The co-administration of fulvestrant with CYP3A4 enzyme inhibitors did not show statistically significant correlation with the occurrence of severe AEs. Co-administration of drugs with extremely high protein binding (≥ 98%) may increase the risk of severe adverse reactions of fulvestrant. Meanwhile, age (60–74 years) may reduce the risk of severe AEs of fulvestrant. However, further clinical research is still needed to explore and verify whether there is interaction between fulvestrant and drugs with high protein binding through more clinical studies.

Plasma 6β-hydroxycortisol to cortisol ratio as a less invasive cytochrome P450 3A phenotyping method.

A less invasive evaluation method of cytochrome P450 3A (CYP3A) activity provides an important tool for personalized medicine. We aimed to clarify the usefulness of the plasma 6β-hydroxycortisol to cortisol concentration (6β-OHF/F) ratio as a minimally invasive CYP3A phenotyping method. Plasma 6β-OHF and cortisol concentrations were measured via liquid chromatography/tandem mass spectrometry. The plasma 6β-OHF/F ratio was compared with 6β-hydroxylation clearance of endogenous cortisol (CLm(6β); which we previously developed as an index of CYP3A activity) before, during and after oral contraceptive administration in 3 healthy women. The plasma 6β-OHF/F ratio was observed during oral clarithromycin administration. The plasma 6β-OHF/F ratio was also measured in 39 healthy participants. The plasma 6β-OHF/F ratio in 3 healthy women on Day 21 of starting oral contraceptive administration decreased by 39, 49 and 61% compared with Day 0. These values were similar to CLm(6β) values (43, 54 and 59%, respectively). Plasma 6β-OHF/F ratio and CLm(6β) exhibited a good correlation (r = .9053). The 6β-OHF/F ratio decreased from 0.00921 to 0.00577 only 3h following clarithromycin administration. The plasma 6β-OHF/F ratio ranged 0.00565-0.01556 in 39 healthy participants. Based on its close relationship with CLm(6β) and its decrease upon inhibition by clarithromycin, the plasma 6β-OHF/F ratio serves as an index of CYP3A activity. Using this minimally invasive index, we can identify patients with extremely low CYP3A activity before treatment initiation and optimize the initial drug dose, thereby mitigating the risk of severe adverse reactions.

Macrophage infectivity potentiator protein, a peptidyl prolyl cis-trans isomerase, essential for Coxiella burnetii growth and pathogenesis.

Coxiella burnetii is a Gram-negative intracellular pathogen that causes the debilitating disease Q fever, which affects both animals and humans. The only available human vaccine, Q-Vax, is effective but has a high risk of severe adverse reactions, limiting its use as a countermeasure to contain outbreaks. Therefore, it is essential to identify new drug targets to treat this infection. Macrophage infectivity potentiator (Mip) proteins catalyse the folding of proline-containing proteins through their peptidyl prolyl cis-trans isomerase (PPIase) activity and have been shown to play an important role in the virulence of several pathogenic bacteria. To date the role of the Mip protein in C. burnetii pathogenesis has not been investigated. This study demonstrates that CbMip is likely to be an essential protein in C. burnetii. The pipecolic acid derived compounds, SF235 and AN296, which have shown utility in targeting other Mip proteins from pathogenic bacteria, demonstrate inhibitory activities against CbMip. These compounds were found to significantly inhibit intracellular replication of C. burnetii in both HeLa and THP-1 cells. Furthermore, SF235 and AN296 were also found to exhibit antibiotic properties against both the virulent (Phase I) and avirulent (Phase II) forms of C. burnetii Nine Mile Strain in axenic culture. Comparative proteomics, in the presence of AN296, revealed alterations in stress responses with H2O2 sensitivity assays validating that Mip inhibition increases the sensitivity of C. burnetii to oxidative stress. In addition, SF235 and AN296 were effective in vivo and significantly improved the survival of Galleria mellonella infected with C. burnetii. These results suggest that unlike in other bacteria, Mip in C. burnetii is required for replication and that the development of more potent inhibitors against CbMip is warranted and offer potential as novel therapeutics against this pathogen.

Analysis of Efficacy-To-Safety Ratio of Angiogenesis-Inhibitors Based Therapies in Ovarian Cancer: A Systematic Review and Meta-Analysis

(1) Background: Among new anti-angiogenesis agents being developed and ever-changing guidelines indications, the question of the benefits/safety ratio remains unclear. (2) Methods: We performed a systematic review combined with a meta-analysis of 23 randomized controlled trials (12,081 patients), evaluating overall survival (OS), progression free survival (PFS) and toxicity (grade ≥ 3 toxic effects, type, and number of all adverse effects. (3) Results: The analysis showed improvement of pooled-PFS (HR, 0.71; 95% CI, 0.64-0.78; I2 = 77%; p < 0.00001) in first-line (HR, 0.85; 95% CI, 0.78-0.93; p = 0.0003) or recurrent cancer (HR, 0.62; 95% CI, 0.56-0.70; p < 0.00001) and regardless of the type of anti-angiogenesis drug used (Vascular endothelial growth factor (VEGF) inhibitors, VEGF-receptors (VEGF-R) inhibitors or angiopoietin inhibitors). Improved OS was also observed (HR, 0.95; 95% CI, 0.90-0.99; p = 0.03). OS benefits were only observed in recurrent neoplasms, both platinum-sensitive and platinum-resistant neoplasms. Grade ≥ 3 adverse effects were increased across all trials. Anti-angiogenetic therapy increased the risk of hypertension, infection, thromboembolic/hemorrhagic events, and gastro-intestinal perforations but not the risk of wound-related issues, anemia or posterior leukoencephalopathy syndrome. (4) Conclusions: Although angiogenesis inhibitors improve PFS, there are little-to-no OS benefits. Given the high risk of severe adverse reactions, a careful selection of patients is required for obtaining the best results possible.

Molecular prediction of clinical response to anti-PD-1/anti-PD-L1 immune checkpoint inhibitors: New perspectives for precision medicine and mass spectrometry-based investigations.

Monoclonal antibodies (mAbs) acting as immune checkpoint inhibitors (ICIs) are among the most frequently used immunotherapies in oncology. However, precision medicine approaches to adapt the treatment to the patient are still poorly exploited. Given the risk of severe adverse reactions, predicting patient eligibility for ICI therapy represents a great asset for precision medicine. Today, the extended panel of mass spectrometric approaches, accompanied by newly developed sample preparation methods is a strategy of choice for responder and non-responder stratification on a molecular basis, and early detection of resistance. In this perspective article, we review the biodisposition of mAbs, the interest in molecular stratification of patients treated with these mAbs, and the possible analytical strategies to achieve this goal, with a major emphasis on mass spectrometric approaches.

The role of alcohol intake in the pharmacogenetics of treatment with clozapine.

Clozapine (CLZ) is an atypical antipsychotic reserved for patients with refractory psychosis, butit is associated with a significant risk of severe adverse reactions (ADRs) that are potentiated with the concomitant use of alcohol. Additionally, pharmacogenetic studies have explored the influence of several genetic variants in CYP450, receptors and transporters involved in the interindividual response to CLZ. Herein, we systematically review the current multiomics knowledge behind the interaction between CLZ and alcohol intake, and how its concomitant use might modulate the pharmacogenetics. CYP1A2*1F, *1Cand other alleles not yet discoveredcould support a precision medicine approach for better therapeutic effects and fewer CLZ ADRs. CLZ monitoring systems should be amended and include alcohol intake to protect patients from severe CLZ ADRs.

Serious Adverse Events of Oral and Topical Carbonic Anhydrase Inhibitors

Some ophthalmologists may be reluctant to prescribe oral carbonic anhydrase inhibitors, given the potential for life-threatening systemic adverse reactions. To conduct a population-based analysis of the safety of oral or topical carbonic anhydrase inhibitors in clinical care. This matched longitudinal cohort study took place in Ontario, Canada. Consecutive patients older than 65 years who were prescribed an oral or topical carbonic anhydrase inhibitor in Ontario, Canada, between January 1, 1995, and January 1, 2020, were identified. Patients were matched 1-to-1 based on age, sex, and diabetes status. Time zero was defined as the date of the first identified prescription for the medication, and the primary analysis focused on the first 120 days of follow-up. The primary end point was a severe complicated adverse event of either Stevens-Johnson syndrome, toxic epidermal necrolysis, or aplastic anemia. Overall, 128 942 matched patients initiated an oral or topical carbonic anhydrase inhibitor during the 25-year study period. The mean (SD) age was 75 (6.6) years, 71 958 (55.8%) were women, and 25 058 (19.4%) had a diagnosis of diabetes. The oral and topical carbonic anhydrase inhibitor groups had similar baseline demographics. Patients prescribed an oral carbonic anhydrase inhibitor had an absolute risk of a severe complicated adverse event of 2.90 per 1000 patients, whereas patients prescribed a topical carbonic anhydrase inhibitor had an absolute risk of 2.08 per 1000 patients. This difference was equivalent to a risk ratio of 1.40, with a number needed to harm of 1 in 1220 patients (95% CI, 1.12-1.74; P = .003). This generally low risk was replicated in multivariable regression controlling for confounding factors. Additional risk factors for a severe complicated adverse event included patients with more comorbidities and those with more frequent clinic contacts. The risk of a serious adverse reaction following prescription of an oral or topical carbonic anhydrase inhibitor was low and similar between agents. Given the low risk of severe adverse reactions, this population-level analysis supports reconsidering the reluctance toward prescribing an oral carbonic anhydrase inhibitor.

Basophil activation: theoretical aspects and use in the diagnosis of allergic diseases

Diagnostics of allergic diseases is a difficult issue, which requires distinct solutions, since this disorder is very common among the population. The overview focuses on complex diagnostics, including various methods that are most in demand at the present stage. The allergy diagnostics primarily include taking anamnesis, physical examination, instrumental and functional tests. Less often, the provocative tests are used, due to risk of severe adverse reactions. At the present stage, the role of laboratory diagnostics of allergies is growing, since, firstly, there is an increase in difficult-to-diagnose cases that require involvement of the entire medical armamentarium, and, secondly, the sensitivity and specificity of laboratory tests are improving. Among laboratory methods, the most significant are the assessment of the level of specific IgE, and the relatively new basophile activation test. The latter test is the main focus of the present review. It is functional and combines the advantages of provocative tests, during which conditions are created for the interaction of a potential allergen and effector cells of allergic inflammation, keeping safety for the patient. The data on the life cycle of basophils, their expression of membrane receptors, the content of granules, and ability to produce additional inflammatory mediators by the cells are presented. Participation of these cells in pathogenesis of allergic inflammation is being considered. Various mechanisms of basophil activation are discussed, both IgE-mediated and IgE-independent, which are similar in vivo and in vitro. Theoretical aspects of using the in vitro basophil activation test to estimate the hypersensitivity to a wide range of allergens are discussed. High sensitivity and specificity of the test for diagnosing allergies to food, household, pollen, insect and drug allergens are presented. Specific features of the basophil activation test related to the preanalytical, analytical and postanalytical stages of the study are highlighted. The factors influencing evaluation of this method are known. For example, difficulties in interpreting the test may arise while taking glucocorticosteroid hormones, in acute period of inflammation, with severe edema. The possibility of using this test to assess effectiveness of allergen-specific and anti-IgE therapy is being considered. A comparison of the basophil activation test, measurement of specific IgE and skin tests by various parameters related to performance and interpretation of results is carried out. Comprehensive diagnostics of allergic diseases, including usage of pathogenetically determined laboratory methods, will contribute to adequate treatment and, as a result, improve the health of the population.

Short dosing intervals during oral challenge increase the risk of severe adverse reactions in children with milk allergy

Short dosing intervals during oral challenge increase the risk of severe adverse reactions in children with milk allergy

Molecular Dynamics and MM-PBSA Studies for Deciphering Molecular Interactions of Valproic Acid with CYP2C9 Mutants F114L and I207T

Valproic Acid (VPA) is a widely used drug, particularly in neuropsychiatric disorders, while showing promise in other types of diseases such as cancer. VPA metabolism via cytochrome P450 (CYP) pathway is responsible from only ~10% of the total drug dose. However, due to high risk of severe adverse reactions in liver and pancreas, interaction of VPA with CYP2C9 remains to be delineated chiefly in CYP2C9 mutants. Hence, here we implemented a molecular dynamics study, followed by MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method based relative binding energy estimation to understand how F114L and I207T CYP2C9 mutants changed their binding mode towards VPA in comparison to wild type (WT) CYP2C9. Results indicated that while F114L and I207T mutants have showed significant decrease in total relative binding energy, compared with WT, there were a clear shift of occupied amino acids responsible for VPA interaction in mutants vs WT. Overall, here for the first time in literature, this novel shift of VPA interacting amino acids in F114L and I207T mutants were reported. Limitations and future perspective of the data were also discussed.

Implementation of immunotherapy into the treatment of neuroblastoma - single center experience with the administration of dinutuximab and management of its adverse effects.

Neuroblastoma is the most common extracranial solid tumour of childhood with extremely heterogeneous bio-logical and clinical behaviour. Despite advances in its treatment, the long-term prognosis of patients with a high-risk and relapsed neuroblastoma remains poor. The implementation of immunotherapy into the treatment protocols has the potential to improve it. Dinutuximab, a chimeric monoclonal antibody, leads to the apoptosis of tumour cells through binding to the GD2 receptor. The article aim is to present the first experience of our centre with dinutuximab treatment. In 2018-2019, we administered 31 cycles of dinutuximab to seven patients. Five patients with high-risk neuroblastoma received dinutuximab in the first line, in two patients with relapse, dinutuximab was administered in the second line of treatment. To evaluate the toxicity of the treatment, the nursing records of patients during immunotherapy were retrospectively analysed. Two patients treated with dinutuximab in the first line are in complete remission, three patients achieved a partial response. Both patients with relapsed neuroblastoma were dia-gnosed with a second relapse after immunotherapy and died of disease progression. The treatment tolerance was acceptable in most patients - in six patients adverse events were managed with adequate supportive care. These were mainly symptoms of capillary leak syndrome, pain and hypersensitivity reactions. In one patient, the treatment was discontinued due to severe neurotoxicity. Dinutuximab has a proven benefit in the eradication of the minimal residual disease in the treatment of neuroblastoma. Immunotherapy is currently the standard for first-line treatment of high-risk neuroblastoma. Its role in the treatment of relapsed neuroblastoma is a subject of several ongoing studies as well as the optimization of therapeutic regimens. Dinutuximab administration is associated with a considerable risk of severe adverse reactions, so the treatment belongs to the hands of an experienced paediatric oncology centre.

Food Allergy: Unproven diagnostics and therapeutics.

Food allergy or intolerance is often attributed by patients as the cause of many symptoms unknown to be directly related to food ingestion. For immunoglobulin E (IgE) mediated food allergy, diagnostic modalities are currently limited to the combination of clinical history, evidence of sensitization with food-specific IgE testing and skin-prick testing, and oral food challenge. Many patients find an appeal in the promise of identification of the etiology of their symptoms through alternative food allergy or intolerance diagnostic modalities. These patients may seek guidance from allergists or their general providers as to the legitimacy of these tests or interpretation of results. These tests include food-specific serum IgG or IgG4 testing, flow cytometry to measure the change in leukocyte volume after exposure to food, intradermal or sublingual provocation-neutralization, electrodermal testing, applied kinesiology, hair analysis, and iridology. In addition, there are some unconventional therapeutic modalities for adverse reactions to foods, including rotary diets. None of these have been supported by scientific evidence, and some even carry the risk of severe adverse reactions. It is important that we offer our patients evidence-based, accurate counseling of these unproven modalities by understanding their methods, their paucity of credible scientific support, and their associated risks.

Prospective comparison of the value of CRASH and CARG toxicity scores in predicting chemotherapy toxicity in geriatric oncology.

Predicting the risk of severe adverse reactions to chemotherapy is of great clinical significance for proper selection of effective and safe treatment for elderly cancer patients. The present study aimed to verify and compare the value of two evaluation models of chemotherapy risk prediction for elderly cancer patients through prospective analysis. The two evaluation models assessed were the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) and Cancer Aging Research Group (CARG) toxicity scores. Elderly patients aged ≥70 with cancer were recruited at two participating hospitals in China and completed an assessment prior to starting chemotherapy. CRASH and CARG toxicity scores of each participant were calculated. Chemotherapy-related toxicity was recorded through each cycle of chemotherapy. A total of 106 participants were recruited between September 2015 and August 2018. The CRASH and CARG toxicity scores were positively correlated (r=0.689; P<0.01). Of the participants, 54 (50.9%) participants underwent a grade 3–5 chemotherapy-related toxicity and 21 (19.8%) experienced grade 3–5 nonhematological toxicity in the process of treatment. CRASH and CARG toxicity scores predicted severe chemotherapy-related toxicity and had a high discriminatory value based on receiver operating characteristic curve analysis (area under the curve of 0.772 and 0.760, respectively; P<0.001). The results of the present study indicate that the CRASH and CARG toxicity scores are helpful tools for the prediction of severe chemotherapy-related toxicity, and are recommended for routine oncology practice.

The use of biologics in children with allergic rhinitis and chronic rhinosinusitis: Current updates.

The therapeutic goals of the treatment of allergic rhinitis (AR) and chronic rhinosinusitis (CRS) are symptom relief, avoiding complications, and improving quality of life. In the treatment of AR and CRS, several limitations of currently prescribed medicines have been identified. Antihistamine administration (both oral and topical) together with intranasal corticosteroids bring relief to the majority of patients, but their dependency on the medications and a necessity to maintain strict compliance with regular medication regimes pose a challenge. Immunotherapeutic agents are an option in some patients, but polysensitized patients, the risk of anaphylaxis, and the need for daily administration for years are limiting it from becoming the main therapy modality. Immunotherapy in any form requires commitment by the patient, which renders adherence and compliance issues particularly relevant. The procedure involved are generally time‐consuming and entail an associated risk of severe adverse reactions. The use of biologics could overcome the limitations of other therapeutic modalities. They could be used as a monotherapy or combined with pre‐existing medications. The benefits of targeted therapy include less adverse effects and optimal efficacy. The aim of the present review was to investigate the collective literature to date pertaining to the role of biologics in managing children with AR and CRS.

PSS2 - Risk of Severe Adverse Reactions Related to Allopurinol and Febuxostat in Asians

Allopurinol, an anti-hyperuricaemic agent, is one of the common causes of life-threatening cutaneous adverse reactions. Febuxostat is a newer urate-lowering drug. The safety of these two drugs remain unclear. This study aimed to compare the incidence and mortality associated with allopurinol or febuxostat related hypersensitivity in Asians. We conducted a cohort study and collected data of patients receiving allopurinol or febuxostat from the electronic medical records from January, 2012, through June, 2015, of the Chang Gung Memorial Hospital Health System in Taiwan. Among 51,505 and 10,034 patients receiving allopurinol and febuxostat prescriptions, 12,007 and 5,680 patients were identified as new users who had not previously exposed to these two drugs The incidence of hypersensitivity reactions, including maculopapular exanthema (MPE), drug reaction with eosinophilia and systemic symptom (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) related to allopurinol or febuxostat were analyzed. Proportion t-test performed, and P < .05 was considered statistically significant. There were 33 patients with allopurinol-induced hypersensitivity reactions (10 SJS/TEN, 8 DRESS, and 15 MPE) and only 1 case of febuxostat-induced MPE were indentified in this study. The overall incidence of hypersensitivity reactions induced by febuxostat was significantly lower than that induced by allopurinol (0.2 v.s. 2.7 per 1000 new users, P< 0.001). There were 4 deceased patients identified in patients with allopurinol-induced SJS/TEN but none in febuxostat users. Fourteen patients with allopurinol-induced hypersensitivity reactionsshifted to further febuxostat therapy were all well tolerant without any adverse reactions, even in patients with chronic kidney diseases or carried the risk HLA-B*58:01 allele. The incidence and severity of hypersensitivity reactions related to febuxostat are less than that of allopurinol in Asians. There was no risk of cross hypersensitivity between allopurinol and febuxostat of patients with allopurinol hypersensitivity.

Antibiotic Allergies – Is De-labeling Based on Clinical History Feasible?

BackgroundUp to 25% of patients admitted to hospital have an antibiotic allergy label (AAL), most of which are towards penicillin. However, up to 90% of patients who claim to be allergic to penicillin are actually able to tolerate them1. Whilst skin testing is safe and efficacious in de-labeling patients with a penicillin allergy label, it is usually not widely available. Therefore, we investigated the feasibility of de-labeling based solely upon clinical grounds. Quality of allergy documentation and subsequent antibiotic use was also assessed.MethodsThis was a cross-sectional study assessing all patients admitted to a tertiary referral teaching hospital over a 5-month period in 2016. All newly admitted patients were prospectively screened for the presence of an antibiotic allergy documented in their electronic medical record. Unless unable to participate, patients were interviewed regarding the detailed nature of their antibiotic allergy. Information regarding allergy documentation, medical condition and antibiotic use was obtained from medical records.Results3855 patients were screened, 553 (14.35%) had an AAL, and 352 were interviewed. There were 426 allergies, 276 (64.8%) towards a penicillin. Only 52% of patients had a convincing history consistent with antibiotic allergy, and 48% of these were mild cutaneous reactions. It was felt that de-labeling and direct re-challenge would be relatively safe in 70% (298/42) of AALs (if the mild cutaneous allergic group were included). In patients who were prescribed antibiotics during study admission, 25.6% (41/160) of antibiotic prescriptions in our cohort were found to be inappropriate in patients with AALs.ConclusionDirect re-challenge based upon clinical grounds appears to be a feasible clinical option in many patients with AALs and would allow de-labeling of these patients. The major barriers continue to be patient acceptance and risk of severe adverse reactions. Our study also found that major improvements could be made in the specific documentation of allergy and also in selection of guideline-recommended alternate antibiotics.1. Joint Task Force on Practice Parameters. Drug Allergy: An Updated Practice Parameter. Ann Allergy Asthma Immunol. 2010; 105(4): p. 259–273.Disclosures All authors: No reported disclosures.

Biomarkers in autism spectrum disorder: the old and the new

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder with onset during early childhood and typically a life-long course. The majority of ASD cases stems from complex, 'multiple-hit', oligogenic/polygenic underpinnings involving several loci and possibly gene-environment interactions. These multiple layers of complexity spur interest into the identification of biomarkers able to define biologically homogeneous subgroups, predict autism risk prior to the onset of behavioural abnormalities, aid early diagnoses, predict the developmental trajectory of ASD children, predict response to treatment and identify children at risk for severe adverse reactions to psychoactive drugs. The present paper reviews (a) similarities and differences between the concepts of 'biomarker' and 'endophenotype', (b) established biomarkers and endophenotypes in autism research (biochemical, morphological, hormonal, immunological, neurophysiological and neuroanatomical, neuropsychological, behavioural), (c) -omics approaches towards the discovery of novel biomarker panels for ASD, (d) bioresource infrastructures and (e) data management for biomarker research in autism. Known biomarkers, such as abnormal blood levels of serotonin, oxytocin, melatonin, immune cytokines and lymphocyte subtypes, multiple neuropsychological, electrophysiological and brain imaging parameters, will eventually merge with novel biomarkers identified using unbiased genomic, epigenomic, transcriptomic, proteomic and metabolomic methods, to generate multimarker panels. Bioresource infrastructures, data management and data analysis using artificial intelligence networks will be instrumental in supporting efforts to identify these biomarker panels. Biomarker research has great heuristic potential in targeting autism diagnosis and treatment.

Component-resolved diagnosis of peach allergy and its relationship with prevalent allergenic pollens in China

Component-resolved diagnosis of peach allergy and its relationship with prevalent allergenic pollens in China