Development Of Hypersensitivity Reactions Research Articles

Exploring antibiotic safety: A prospective observational study from a tertiary care public sector hospital

BackgroundAntibiotics are the most commonly used drugs to treat bacterial infections; however, these life-saving drugs can also cause adverse drug reactions. In several pharmacovigilance studies, adverse drug reactions are a cause of prolonged hospitalization. The development of hypersensitivity reactions even after a negative skin test and patch test makes antibiotic-associated adverse reactions unpredictable. Owing to the scarcity of data on antibiotic desensitization, these drugs are important for pharmacovigilance. Most of the previous studies conducted were retrospective and lacked data regarding the duration of adverse drug reactions. AimThis study aimed to examine adverse drug reactions associated with antibiotics and to provide knowledge on the duration of these reactions. MethodA prospective observational study was conducted on patients receiving antibiotics at a tertiary care hospital. The patients were followed until discharge, and causality and severity assessments were performed. Descriptive statistical analyses were performed to summarize the data. ResultsThe study results show the median duration of adverse drug reactions was two days, with an interquartile range of two to four days. Most (21,3%) of the reactions were caused by cephalosporins. The majority (44.7%) of the reactions were skin and subcutaneous tissue disorders. The majority (78.7%) of the reactions were moderately severe and were not responsible for prolonged hospital stay. ConclusionThe patients receiving antibiotics require close monitoring for early detection and management of adverse reactions to reduce the duration of hospital stay and the duration of adverse drug reactions.

Pharmacogenomics to Predict Asparaginase Premedication-Related Hypersensitivity in Pediatric and Adolescent Young Adults (AYAs) with Acute Lymphoblastic Leukemia or Lymphoma

Pediatric acute lymphoblastic leukemia (ALL) patients have had significantly improved outcomes over the last few decades with overall survival (OS) rates exceeding 90%. Several factors, including the incorporation of asparaginase therapy in chemotherapy regimens of pediatric and AYA patients with ALL have played a critical role in improving outcomes. Asparaginase is a bacteria-derived enzyme which depletes the non-essential amino acid asparagine and leads to subsequent apoptosis in lymphoblastic leukemia cells. One of the main limitations of the frontline pegaspargase (PEG) chemotherapy is the development of hypersensitivity reactions and subsequent development of anti-asparaginase neutralizing antibodies that lead to PEG inactivation. When hypersensitivity reactions to PEG occur, patients are often switched to alternative forms of asparaginase, such as that isolated from Erwinia chrysanthemi. A prospective multi-institutional study initiated by Children's Hospital of Orange County (CHOC) and conducted at 6 pediatric cancer centers: 1) evaluated the efficacy of premedicating pediatric and AYA patients with B or T-ALL or lymphoblastic lymphoma (LBL) receiving PEG with antihistamines (H1 and H2 blockers), and 2) performed therapeutic drug monitoring to better identify patients with true hypersensitivity reactions versus those with non-antibody mediated infusion reactions with the goal of reducing incidences of substitution to Erwinia asparaginase. This study also aimed to characterize the pharmacogenomics which may be driving differences in asparaginase hypersensitivity to better understand which single nucleotide polymorphisms (SNPs) are involved in the immunogenicity of PEG and whether certain populations are more at risk for hypersensitivity. Here, we report preliminary evidence showing an association between a combination of 3 SNPs in 3 genes and incidence of hypersensitivity to PEG. The analysis cohort consisted of 126 non-Down syndrome patients premedicated prior to PEG treatment. In this cohort, the median age was 7.7 years, 48 were female (38%) and 78 male (62%), 65 patients identified as Hispanic (52%), 56 as non-Hispanic (44%) and 5 declined to state (4%). Overall, 28 patients had a hypersensitive reaction to PEG within 15 minutes of infusion. Patient characteristics by hypersensitivity incidence are summarized in Fig 1A, with age and National Cancer Institute (NCI) risk groups being the factors that significantly differ by hypersensitivity. DNA from all 126 patients was used to genotype for 6 SNPs in 5 genes involved in pathways implicated in hypersensitivity to PEG. We tested each SNP genotype in 3 modes of inheritance (additive, dominant, and recessive) in all possible combinations of up to two SNPs per model using Cox-proportional hazard models for association with incidences of hypersensitivity post-infusion in 126 patients for whom clinical data was available. We then performed 1000 permutation tests for each model to determine the likelihood of obtaining them falsely. Models were ordered according to their Bayesian Information Criterion (BIC) and weight in favor of each model and those with least BIC and a 1000 permutation p<0.05 were selected for development of Asp_PGx3 score. This was defined by adding the genotype scores of 3 SNPs in 3 genes ( ARHGAP28, CNOT3, and NFATC2), accounting for the mode of inheritance and the direction of their association with outcome. This score ranged from -5 to 0, with patients with score <0 stratified as low score and those with scores of 0 as high score groups. A significantly higher proportion of patients in the low Asp_PGx3 score group (29%) had an incidence of PEG hypersensitivity compared to those in the high Asp_PGx3 score group (16%) (Fig 1B). In conclusion, we show a combination of 3 SNPs (in ARHGAP28, CNOT3, and NFATC2) associated with PEG hypersensitivity in a cohort of 126 pediatric and AYA ALL/LBL patients. Instead of a single SNP association approach, identifying combinations of variations in pathway specific genes provides a more robust means to predict drug response. Our preliminary results provide a rationale for identification of genome level variations in this cohort and association analysis to establish clinically relevant pharmacogenomics score to optimize PEG treatment. Funding for this study was provided by CHOC PSF Tithe Grant, CHOC Hyundai Cancer Institute Research Grant, and Servier Pharmaceuticals.

Oxaliplatin-induced hypersensitivity reactions: risk factors and management.

Chemotherapy-related adverse reactions have been steadily increasing in recent years. In patients who develop oxaliplatin-induced hypersensitivity reactions (HSRs), prognosis and quality of life are adversely affected. Proper management of cancer patients enables them to safely receive first-line treatments. This study aimed to assess the risk factors in oxaliplatin-induced HSRs and the effectiveness of the rapid desensitization protocol. In the study, 57 patients treated with oxaliplatin between October 2019 and August 2020 in the Medical Oncology Department of Elazig City Hospital were retrospectively evaluated. We analyzed patients' clinical histories to reveal any associations with the development of oxaliplatin-induced HSRs. Moreover, we re-evaluated 11 patients with oxaliplatin-induced HSRs through infusion time or desensitization procedures. Of 57 patients treated with oxaliplatin, 11 (19.3%) had HSRs. Patients with HSRs were younger and had higher peripheral blood eosinophil counts than those without HSRs (p=0.004, p=0.020, respectively). Prolongation of the infusion time was effective in the re-administration of oxaliplatin in six of the hypersensitive patients. Rapid desensitization protocol was performed for a total of 11 cycles in four patients with recurrent HSRs, and their chemotherapy regimens were successfully completed. This retrospective study has revealed that younger ages and higher peripheral eosinophil counts could be predictive for oxaliplatin-induced HSR. Furthermore, the study confirms that prolongation of the infusion time and rapid desensitization protocol are effective in patients with HSRs.

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Abstract. The article is devoted to an actual problem � the diagnosis of hypersensitivity to excipients that are the part of medicines. Hypersensitivity to drugs, the frequency of which is constantly increasing throughout the world, traditionally remains an important multidisciplinary problem in medicine. Any drug under certain conditions can cause the development of hypersensitivity reactions. More often, antibiotics, muscle relaxants, anesthetics, non-steroid anti-inflammatory drugs, acetaminophen, radiocontrast substances, vaccines, sera, biological preparations, etc. are considered as its etiological factors. But at the same time, attention is rarely paid to the possibility of developing hypersensitivity to excipients that are the part of almost all drugs. This publication considers the possibility of causing the development of drug allergies for such excipients as allergenic molecules of cow�s milk, chicken eggs, cereals, fish, soy lecithin, lactose, gelatin, lactic acid, vegetable oils, yeast proteins, probiotics, carboxymethylcellulose, polyethylene glycols, their derivatives and etc. Based on the analysis of numerous literature data, the authors conclude that the development of allergy to drug excipients is less common than their intolerance, which does not involve immunological mechanisms; clinical manifestations of hypersensitivity to excipients can range from mild skin, ocular and respiratory symptoms to life-threatening anaphylaxis; it is rather difficult to prove the role of excipients in the development of adverse reactions to drugs and food products, therefore, allergologic diagnosis in such cases is based on the use of data from an allergological history, skin, provocative and laboratory research methods, a significant part of which is not validated, insufficiently informative or not developed at all and is inaccessible to practical doctors of Ukraine; and the problem of hypersensitivity to drug excipients requires further investigation. Key words: excipientsdrugs, hypersensitivity, diagnostics

Oxaliplatin-Related Hypersensitivity Reactions: A Single Institution Series and Literature Review.

Oxaliplatin-based chemotherapy is extensively used for the treatment of gastrointestinal tumors and other malignancies. Oxaliplatin-related hypersensitivity reactions (HSRs) are common during antitumor treatment. Several studies have been conducted to identify predictive risk factors for oxaliplatin-related HSRs, but findings remain controversial. No definitive approach has been identified to reduce the risk of developing HSRs. The aim of this article is to provide an overview of oxaliplatin-related HSRs, and to report our institution's experience. With our work, we reviewed available data from the literature and described our case series. A total of 153 patients were treated with oxaliplatin and 17 developed an HSR. On the whole, 70.6% of reactions were Grade 3, mostly with respiratory and cutaneous symptoms. Steroids and antihistamines were administered to reduce hypersensitivity symptoms and prevent further reactions. A stronger premedication and prolonged time of infusion resulted in milder reactions or absence of subsequent reactions. We did not find any clear predictive factor for the development of HSRs. Although it is not possible to cancel the risk of oxaliplatin-based HSRs, strategies to reduce the risk of occurrence could be stronger premedication and prolonged time of infusion.

Atopy, allergen sensitization and development of hypersensitivity reactions to paclitaxel.

Paclitaxel is a chemotherapeutic agent used in the treatment of multiple types of malignant tumors which was discovered from the Taxus brevofilia tree. In some patients, anaphylaxis develops during the first exposure to paclitaxel, suggesting that primary sensitization may have occurred through hidden or unidentified allergens that produce cross-reactivity. Skin testing may be useful in identifying sensitization to these allergens. Atopy has also been reported in patients with hypersensitivity reactions (HSR) to paclitaxel.The aim of this study is to evaluate the association between atopy and sensitization to allergens with the development of immediate HSR to paclitaxel. Skin prick tests (SPT) for environmental and food allergens were applied to 76 patients recently diagnosed with cancer. A SPT to paclitaxel was applied and if negative, an intradermal test was performed. After paclitaxel's infusion, the development of immediate HSR was observed. Of 76 skin tests, 43% of patients had allergen sensitization and 57% did not. HSR occurred in 12.1% and 11.6% of each group, respectively. Five percent of patients tested positive to paclitaxel and only one had an immediate HSR. Eighty-nine percent of patients who developed an HSR had a family or personal history of atopy. Sensitization to environmental or food allergens does not appear to be a risk factor for the development of immediate HSR to paclitaxel, suggesting that there are other non-IgE-mediated immunologic mechanisms responsible for their development, however, a personal and family history of atopy increases 8x the risk of developing anaphylaxis.

Immunogenetic features of HIV-infection and allergy comorbidity

Today, the comorbidity of infection caused by the human immunodeficiency virus (HIV) is an important problem due to the complexity of the selection of the optimal antiretroviral therapy and the diagnosing of associated pathological conditions. The study of the comorbidity of HIV-infection and allergy is an important area of research. This article presents a literature review on different types of comorbidity. Special attention is paid to the development of allergic reactions to antiretroviral drugs. The presence of an allergic reaction in a patient can cause low adherence to therapy and subsequent development of HIV resistance to the treatment. The review provides information on the possible causes of the development of hypersensitivity in HIV-infected patients. The data on the development of hypersensitivity reactions in response to treatment with the main classes of antiretroviral drugs (nucleoside and non-nucleoside reverse transcriptase inhibitors, synthesis inhibitors, protease inhibitors, integrase inhibitors, cysteine-cysteine chemokine receptor 5 inhibitors) are presented. The most common allergic reactions to these drug classes are itching and rash, as well as increasing hepatic transaminase levels and cough. The existing scientific data on allergic reactions to drugs prescribed for other concurrent conditions (tuberculosis, fungal diseases) is also considered. The examples of studies reflecting the relevance of using immunogenetic and molecular genetic approaches in the study of comorbidity of HIV-infection and allergy are given. The identification of immunogenetic markers of the development of the hypersensitivity to therapy will optimize the diagnostic and treatment algorithms, especially in complex comorbid conditions.

Premedication and Longer Infusion Time Do Not Reduce the Incidence of Hypersensitivity Reactions to Pegaspargase

Introduction Pegaspargase (PEG) is a critical component of therapy for pediatric acute lymphoblastic leukemia (ALL); however, complete asparaginase treatment may be hampered by the development of hypersensitivity reactions. Inadequate exposure to asparaginase has been shown to result in inferior outcomes (Gupta 2020). Although Erwinia asparaginase can be utilized as a replacement in patients with PEG allergy, recent shortages of Erwinia leave some patients who develop allergy to PEG without an alternative. Premedication with antihistamines and corticosteroids, as well as decreasing the pegaspargase infusion rate have been proposed as approaches to reduce hypersensitivity reactions (Cooper 2019, Bade 2019, Stock 2019). We evaluated the episodes of hypersensitivity reactions to PEG during three time periods with differing premedication and infusion practices at a single institution. Methods We utilized pharmacy records to conduct a retrospective chart review on PEG administration at Children's Healthcare of Atlanta from June 2017 to May 2020. Abstraction captured data on clinical hypersensitivity reactions to PEG over 3 time periods. PEG 2500 units/m2 was delivered as an intravenous infusion according to the schedules used in Children's Oncology Group ALL protocols. In the first time period (P1, June 22, 2017 to June 21, 2018) PEG was infused over 1 hour without premedication. In the second period (P2, June 22, 2018 to May 19, 2019) PEG was infused over 1 hour following premedication with ranitidine and diphenhydramine. In the final period (P3, May 20, 2019 to May 19, 2020) PEG was infused over 2 hours with normal saline piggyback intravenous fluids following premedication with ranitidine (or famotidine), diphenhydramine and hydrocortisone. Asparaginase activity was measured 7-10 days after PEG doses in consolidation and subsequent phases in P1 and P2, and also after induction in P3. Silent inactivation was defined as asparaginase activity <0.1 IU/ml. A likelihood ratio test was used to compare the probability of a hypersensitivity reaction per dose of PEG between periods. Results The cohort included 277 recipients of at least one dose of PEG during the review period. Some patients received PEG across multiple periods. During P1, 121 patients received 298 PEG doses. Of these, fifteen patients (12.4%) had hypersensitivity reactions; 1 patient (0.8%) had silent inactivation. During P2, 94 patients received 235 PEG doses. Seventeen (18.1%) of these patients had hypersensitivity reactions, with no cases of silent inactivation cases. During P3, 125 patients received 332 PEG doses. Sixteen (12.8%) had hypersensitivity reactions and one (0.8%) had silent inactivation (Figure 1). The majority of reactions occurred with each patient's second (56%) or 3rd (38%) PEG dose. The probability of reaction per dose across all periods was 0.054 (95% CI: 0.039, 0.069). The reaction probability for the three phases are estimated to be 0.050, 0.068, and 0.048 for P1, P2, and P3 respectively (Figure 2). There was no statistically significant difference in the probability of PEG hypersensitivity reactions between the three different time periods (p = 0.56). Conclusions Premedication with antihistamines and corticosteroids or prolongation of infusion time did not affect the incidence of hypersensitivity reactions to PEG over a three-year period at our institution. The rate of silent inactivation was extremely low, and did not increase after premedication was instituted. These results contrast with prior single institution reports regarding reductions in hypersensitivity reactions and indicate that larger, multi-center trials are needed to determine the efficacy of premedication or prolongation of infusion time on reducing hypersensitivity reactions to PEG during pediatric ALL therapy. Disclosures No relevant conflicts of interest to declare.

Impact of carboplatin hypersensitivity and desensitization on patients with recurrent ovarian cancer.

Hypersensitivity reactions (HSRs) to chemotherapy is an ongoing issue in cancer treatments. Strategies to induce tolerance and maximize chemotherapy efficacy include desensitization protocols. The precise impact of these protocols, however, in the long-term treatments remains unclear. We aim to compare overall survival (OS) in hypersensitive patients treated with carboplatin desensitization to patients without hypersensitivity reactions. We also sought to identify new risk factors for HSRs and reconfirm that the DNA repair enzyme, germline BRCA1/2 (gBRCA1/2), is a risk factor for hypersensitivity. Retrospective study in patients with ovarian cancer tested for gBRCA1/2 mutations who received more than six infusions of carboplatin from August 2005 to November 2016. Two-sided Fisher exact, Student's t test and Gehan-Breslow-Wilcoxon test were used for statistical analysis. Univariate and multivariate analyses were completed to identify independent predictors of survival. Statistical significance was set with a two-sided p value of 0.05. Ninety-one patients with gBRCA1/2 testing met inclusion. Forty patients (44%) were gBRCA1/2-deficient and 51 (56%) were gBRCA1/2-proficient. Patients with gBRCA1/2 deficiencies had a higher likelihood of developing carboplatin hypersensitivity, HR 6.433 (95% CI: 1.868-22.149). None of the patients with carboplatin hypersensitivity were given PARP inhibitors prior to the development of HSRs. The patients with recurrent advanced stage (III-IV) ovarian cancer had a higher likelihood of developing carboplatin hypersensitivity, HR 4.783 (1.008-22.689). Moreover, we found that hypersensitive patients who underwent carboplatin desensitization had a 48-month longer OS than patients without hypersensitivity to carboplatin not undergoing carboplatin desensitization (p = 0.0094). A subgroup analysis indicated that gBRCA1/2-proficient hypersensitive patients undergoing carboplatin desensitization had a 43-month longer OS than gBRCA1/2-proficient patients without HSRs (p = 0.034). We confirmed that gBRCA1/2 deficiency and advanced stage are independent risk factors for development of carboplatin hypersensitivity in ovarian cancer patients. Our study also shows improved OS in hypersensitive patients receiving CD compared to non-hypersensitive patients, independent of gBRCA1/2.

LIMITATIONS OF PEGYLATED NANOCARRIERS: UNFAVOURABLE PHYSICOCHEMICAL PROPERTIES, BIODISTRIBUTION PATTERNS AND CELLULAR AND SUBCELLULAR FATES

Assuming that polyethylene glycol (PEG)-conjugated or PEGylated nanocarriers always offer outstanding physicochemical properties and pharmacokinetics profiles when compared to non-PEGylated ones, is not always accurate. For example, drug-loaded PEGylated nanocarriers for the treatment of cancer will not magically escape the reticuloendothelial system (RES) sequestration and clearance, benefit from the enhanced permeability and retention (EPR) effect of the tumor leaky vasculature and preferentially accumulate in the target tissue or cells. This is too good to be true. In this review, several drawbacks of PEGylation will be discussed; for example, how PEGylation can give rise to unfavourable physicochemical characteristics (e. g. particle size and release patterns) and post in vivo administration limitations of the formulated nanocarriers (e. g. limited evasion of RES uptake, development of hypersensitivity reactions, reduced intracellular accumulation and interference with the subcellular processing of nanocarriers necessary to produce the intended pharmacological effect).This review aims at providing better understanding of the pros and cons of PEGylation, encouraging the use of PEGylation with caution, avoiding the assumption that PEGylation will provide all advantages needed to deliver nanocarriers to the target tissue and looking for alternatives to optimize nanocarriers’ utilization especially in the delivery of chemotherapeutic agents for the treatment of different types of cancer. This review comprises a summary of some of the reported literature between 2013 and 2018 using different search engines; PubMed, Science Direct and Google Scholar, and the keywords listed below.

Development of Hypersensitivity Reactions after Using Different Oral Iron Preparations

Development of Hypersensitivity Reactions after Using Different Oral Iron Preparations

Hypersensitivity to Carboplatin in Children with Malignancy.

Purpose: Carboplatin-based regimens have proven efficacy in children with cancer. However, the development of hypersensitivity reactions (HSRs) may have a negative impact on treatment intensity and patients’ outcome. The aim of this review is to summarize the incidence and the clinical features of HSRs occurring in children with cancer treated with carboplatin and their impact on treatment efficacy.Methods: Data were collected by searching for relevant studies on the incidence, clinical features and management of possible side effects about the use of carboplatin in children, published from March 1987 to October 2016 in the PubMed database.Results: Carboplatin HSRs present with mild/moderate to severe clinical patterns. The risk of HSR is related to the cumulative number of infusions. Moreover, a greater risk of developing an HSR has been observed in younger patients than in older age groups of children; risk is also greater in girls and in patients with a prior history of allergy to other drugs. Management options include cessation of carboplatin and switching to another agent, premedication with antihistamines and/or corticosteroids, and carboplatin desensitization. For sensitized patients who have obtained benefits from carboplatin, the continuation of the treatment is desirable and desensitization protocols have showed promising results.Conclusion: Clinicians must not underestimate the potential risk and occurrence of carboplatin HSRs in the pediatric population in order to outline adequate management strategies. Desensitization protocols should be considered for patients sensitive to carboplatin in order to avoid having to discontinue an effective chemotherapy.

Fcγ receptor 3B polymorphism is associated with hypersensitivity reactions to adalimumab in Japanese patients with rheumatoid arthritis

Objectives: To examine the association between Fcγ receptor (FcγR) polymorphisms and the development of hypersensitivity reactions to adalimumab in patients with rheumatoid arthritis.Methods: Sixty-five patients receiving adalimumab were enrolled in the study. Genetic polymorphisms for FcγR3B were genotyped in FCGR3B NA1/2 alleles by real allelic discrimination assay. Clinical information and the occurrence of a hypersensitivity reaction to adalimumab were collected from the patients’ charts.Results: A hypersensitivity reaction was observed in 12% of the patients. Clinical information obtained from patients with a reaction and those without were the same. The FCGR3B NA1/NA1, NA1/NA2, and NA2/NA2 alleles were found in 75%, 13%, and 13% of the patients with hypersensitivity reaction, respectively, and in 28%, 42%, and 30% of those without a hypersensitivity reaction, respectively (p = 0.04). Multivariate logistic regression analysis identified only the NA1/NA1 as an independent relevant factor for a hypersensitivity reaction to adalimumab (OR 7.7, p = 0.01).Conclusions: The FCGR3B NA1/NA1 genotype is associated with hypersensitivity reactions to adalimumab.

A Modern View of the Pathogenesis of Allergy with Drug Etiology

Nowadays many diseases are associated with a high risk of drug allergy, and this risk can vary greatly depending on the type of disease. With the progression of disease in HIV-infected patients is increased IgE and decreased the number of CD4+ T-cells. In this case violated the ratio of interferon-gamma-producing (Th1 type) clones of CD4+ T-cells and IL-4 - producing (Th2 type) clones of CD4+ T-cells. In HIV-infected patients, there is the high risk of developing allergies in the form of skin rashes and temperature, and severe skin syndromes Stevens-Jones (SJS) and toxic epidermal necrolysis (TEN) in 6%-10% of cases. CD4+ T cells secrete cytokines, for instance Interleukin (IL-5), Gransim and Eotaxin involve eosinophils to be grown and differentiated. Studies on the antigenicity of antibiotics demonstrated the potential relevance of both categories of drug allergy: hapten and p-i models. In patients with allergic reaction to piperacillin, this medication acts as the hapten, with the formation of the immunogenic conjugate piperacillin - albumin, which stimulates the drug-responsive T-cells. Immunogenetic factors have been identified as risk indicators for the development of hypersensitivity reactions to the representatives of many classes of drugs, such as Abacavir and Nevirapine, Carbamazepine and Allopurinol, etc. Thus, considering the huge genetic polymorphism in systems of drug metabolism in the body and in the systems contributing immune response to the resulting products of conjugation of hapten-protein, evident is the need to further study the role of these systems in the occurrence of adverse reactions to drug therapy, in particular, in the development of allergic complications.

Intravenous tacrolimus and cyclosporine induced anaphylaxis: what is next?

Tacrolimus and cyclosporine have been used in various formulations, but their hypersensitivity reactions are rare in practice. Castor oil derivatives are nonionic surfactants used in aqueous preparations of hydrophobic active pharmaceutical ingredients. Castor oil derivatives that can be used as additives to tacrolimus and cyclosporine may play a role in the development of hypersensitivity reactions, especially anaphylaxis. Various immunologic and nonimmunologic mechanisms have been implicated in hypersensitivity reactions induced by castor oil derivatives. Physicians should be aware that not only the drug itself, but also its additives or metabolites could induce hypersensitivity reactions. We report a case of anaphylaxis caused by vitamin K (phytonadine), serotonin antagonist (granisetron), intravenous tacrolimus, and cyclosporine. Interestingly, the patient tolerated oral cyclosporine, which did not contain Cremophor EL or polysorbate 80.

Hypersensitivity Reactions to Oxaliplatin: Identifying the Risk Factors and Judging the Efficacy of a Desensitization Protocol

PurposeWe examined the clinical data of patients treated with oxaliplatin to determine the risk factors of oxaliplatin-related hypersensitivity reaction (HSR). In addition, we evaluated the efficacy of rechallenging patients with HSRs with oxaliplatin using prophylactic agents or desensitization procedures. MethodsThis study consisted of 162 patients with colorectal cancer (88 men and 74 women) who were treated consecutively at the outpatient chemotherapy department at University Hospital, Kyoto Prefectural University of Medicine. Patients underwent chemotherapy, including oxaliplatin, between March 2006 and June 2012. We analyzed the patients’ clinical backgrounds (eg, age, sex, performance status, disease stage, and allergic history) to uncover any connections to the development of HSR to oxaliplatin. In addition, we rechallenged 10 patients who had oxaliplatin-related HSR using prophylactic agents or desensitization procedures. FindingsOf 162 patients, 28 (17.2%) developed oxaliplatin-related HSRs (16, 2, 9 and 1 patient had grade 1, 2, 3, and 4 HSRs, respectively). The total cumulative dose of oxaliplatin at the onset of the HSR was 301 to 1126 mg/m2 (median, 582 mg/m2), and the first reactions developed in these patients after 5 to 17 infusions of oxaliplatin (median, 8 infusions). Logistic regression analysis indicated that sex (male: odds ratio = 3.624; 95% CI, 1.181–11.122; P = 0.024) and eosinophil count in peripheral blood (odds ratio = 35.118; 95% CI, 1.058–1166.007; P = 0.046) were independent variables for oxaliplatin-related HSRs. Rechallenging patients with prophylactic agents was successful in 2 (28.6%) of 7 patients who successfully completed their treatment. On the other hand, all 3 patients rechallenged with oxaliplatin using a desensitization protocol successfully completed their treatment without new HSRs. ImplicationsIn this retrospective study, we observed that being male and having higher counts of peripheral eosinophil could be predictors for HSR to oxaliplatin. In addition, this study confirms that oxaliplatin desensitization protocol allows patients who developed HSRs to continue with their treatment. However, the optimum desensitization protocol for oxaliplatin administration in terms of tolerability and efficacy needs to be defined.

Skin tests in patients with hypersensitivity reaction to iodinated contrast media: a meta-analysis.

Patients with a previous history of hypersensitivity reaction (HSR) to iodinated contrast media (ICM) are at high risk of the development of HSR to ICM. Many studies have tried to evaluate the diagnostic potential of skin tests in this population but have not yet reached a common conclusion. We investigated the role of skin tests in patients with HSR to ICM in terms of positive rate, cross-reactivity rate, and tolerability to skin test-negative ICM according to the type of HSR. We performed literature searches of the MEDLINE and EMBASE databases and included studies where skin tests were performed in patients with HSR to ICM, with extractable outcomes. Outcomes were pooled using a random-effects model. Twenty-one studies were included. Pooled per-patient positive rates of skin tests were 17% (95% CI, 10-26%) in patients with immediate HSR, and up to 52% (95% CI, 31-72%) when confined to severe immediate HSR. Among patients with nonimmediate HSR, the positive rate was 26% (95% CI, 15-41%). The pooled per-patient cross-reactivity rate was higher in nonimmediate HSR (68%; 95% CI, 48-83%) than that in immediate HSR (39%; 95% CI, 29-50%). Median per-test cross-reactivity rates between pairs of ICM were 7% (IQR, 6-9%) in immediate HSR and 38% (IQR, 22-51%) in nonimmediate HSR. Pooled per-patient recurrence rates of HSR to skin test-negative ICM were 7% (95% CI, 4-14%) in immediate HSR and 35% (95% CI, 19-55%) in nonimmediate HSR. Skin tests may be helpful in diagnosing and managing patients with HSR to ICM, especially in patients with severe immediate HSR.

P3-1-4 - Safety Profile of the Desensitizing Carboplatin Infusion for Patients Documented Carboplatin Hypersensitivity

Background: The combination of carboplatin and other cytotoxic drug is the current standard chemotherapy regimen for platinum sensitive recurrent epithelial ovarian, and peritoneal cancer. Hypersensitivity reaction (HSR) is one of adverse events of platinum agents. Because repeated exposure to platinum agents, particularly carboplatin, is associated with development of HSR, it is often difficult to use continuous platinum combination therapy.On the other hands, Peter G Rose et al. had reported successful administration of carboplatin with desensitizing method for clinically documented carboplatin HSR. This report aims to assess the safety of the carboplatin desensitizing therapy through the analysis in single institution.Method: We reviewed medical record, and evaluated the safety profile of the carboplatin desensitizing therapy for the patients with platinum sensitive recurrent epithelial ovarian, and peritoneal cancer, who had history of HSR of carboplatin. The carboplatin dose was administrated with 1/1000th of the total carboplatin dose infused 60min in turn was followed by 1/100th and 1/10th infused 60min. The remaining dose was infused 2h. Patients were pretreated with 20mg intravenous dexamethasone prior to the initiation of carboplatin.Results: Between Feb 2012 and Jan 2014, 14 patients whose First HSR had occurred median 17 courses (range 8-43); Grade 1 8%, Grade 2 25%, Grade 3 33%, Grade 4 33%, received total 72 courses of carboplatin contained regimen. 9 patient, 59 courses were successfully rechallenged while 5 patients, 13 coarses had a recurrent carboplatin hypersensitivity; Grade 1 8%, Grade 2 8%, Grade 3 2%. All cases in which HSR recurred were handled with termination of the carboplatin infusion, followed by intravenous steroids and antihistamines with successful resolution, and were able to completely administrate carboplatin with slow infusion.Conclusion: A CBDCA desensitizing carboplatin infusion regimen is safe and well tolerated.

Population Pharmacokinetic and Pharmacogenetic Analysis of Nevirapine in Hypersensitive and Tolerant HIV-Infected Patients from Malawi

We modeled nevirapine (NVP) pharmacokinetics in HIV-infected Malawian patients to assess the relationship between drug exposure and patient characteristics, genetic polymorphisms, and development of hypersensitivity reaction (HSR). One thousand one hundred seventeen patients were prospectively recruited and followed for 26 weeks with multiple or single serum samples obtained in a subset of patients for NVP quantification. Single nucleotide polymorphisms (SNPs) within CYP2B6 and CYP3A4 genes were typed. Nonlinear mixed effects modeling was utilized to assess the influence of patient characteristics and host genetics on NVP apparent oral clearance (CL/F) and to explore the relationship between NVP CL/F and HSR. Published haplotype distributions were used to simulate NVP concentrations in Caucasians versus Africans. One hundred eighty patients (101 female) were included in the model; 25 experienced HSR. No associations between patient demographics or HSR and NVP CL/F were evident. A significant relationship between CYP2B6 c.983T>C and CYP2B6 c.516G>T and NVP CL/F was observed (P < 0.01). NVP CL/F was reduced by 23% and 36% in patients with CYP2B6 983TT/516TT and 983TC/516GG or GT, respectively, compared to the reference genotype. Simulated exposures suggested similar proportions (13 to 17%) of patients with subtherapeutic NVP among Caucasians and an African population. Influence of CYP2B6 polymorphisms on NVP CL/F in this population is in agreement with other reports. Our data indicate a lack of association between NVP exposure and HSR. Based on these data, dose optimization based solely on ethnicity (without individual gene testing) is unlikely to impact on risk of treatment failure or toxicity even in an African population with high carriage of poor metabolizer mutations.

Comparison of safety and efficacy of papaya dressing with hydrogen peroxide solution on wound bed preparation in patients with wound gape

Objective:Indian papaya or Carica papaya is known to have de-sloughing and wound-healing properties due to the presence of protease enzymes. The present study was done to compare the efficacy and safety of papaya dressing with hydrogen peroxide solution for preparation of wound bed in patients of postoperative wound gape.Materials and Methods:A randomized, open-labeled interventional study was carried out over a period of 8 months at a tertiary care hospital on post-caesarean section patients with wound gape. The efficacy parameters studied were duration of time required to induce development of healthy granulation tissue and total duration of hospitalization. Safety parameters studied were adverse effects reported by patients and development of hypersensitivity reaction.Results:A total of 64 patients were enrolled, of which 32 patients received hydrogen peroxide dressing and 31 patients received papaya dressing (one patient withdrew after randomization). Time required to induce the development of healthy granulation tissue and total duration of hospitalization were 6.2 ± 1.6 days vs 2.5 ± 0.5 days and 19.2 ± 5.8 days vs 12.92 ± 4.6 days in papaya and hydrogen peroxide dressing groups, respectively. Both primary efficacy parameters were significantly shorter in papaya dressing group. The incidence of adverse effects like local irritation and itching were comparable in both groups and the difference was not statistically significant.Conclusion:Papaya dressing is more efficacious and equally safe as compared to hydrogen peroxide dressing when used for wound bed preparation in patients with postoperative wound gape.