Severe Hypersensitivity Reactions Research Articles

Iron deficiency therapy in pregnant women: advantages and new possibilities of iron carboxymaltose

Introduction. Impact of iron deficiency on pregnancy outcomes appears an urgent issue despite generally accepted standards of therapy. Iron needs increase during pregnancy and manifestations of its deficiency reduce QoL in pregnant women and worsen newborn health. Ferric carboxymaltose helps overcome iron deficiency in a quick and efficient manner from the 2nd trimester.Aim. To analyse the results of ferric carboxymaltose therapy of iron deficiency conditions in pregnant women.Materials and methods. In this article we presented our own experience in providing ferric carboxymaltose therapy to treat iron deficiency in 152 pregnant women from the 2nd trimester.Results and discussion. Correction of anaemic syndrome was observed in more than 73.3% (up to 93.3% depending on the severity of primary anaemia) as early as the first week after administration of ferric carboxymaltose. Haemoglobin and ferritin levels at 3 week post-infusion were significantly higher than pre-infusion levels (p < 0.001). Improvement of haemoglobin levels at 6 weeks after initiation of therapy was achieved in all women with mild anaemia and in 98.5% of women with severe anaemia. No definite severe hypersensitivity reactions were detected. The overall incidence of side effects was 10.5%, with headache being the most frequently reported type (7.9%). All pregnancies resulted in a live birth without malformations; the rate of preterm birth was 9.5%.Conclusion. Ferric carboxymaltose is an effective drug to quickly correct iron deficiency in pregnant women with a minimum number of adverse reactions and without negative impact on newborn health.

Is a low dose of dexamethasone sufficient to prevent paclitaxel-related hypersensitivity reactions? A retrospective study in patients with gynecologic malignancy

ABSTRACT Background Paclitaxel hypersensitivity reactions (HSRs) are prevalent, especially in females. The common paclitaxel pretreatment, dexamethasone, may inhibit chemotherapy efficacy and accelerate tumor progression. We aimed to balance paclitaxel HSRs and the lowest dexamethasone dose for gynecologic malignancies. Methods We retrospectively examined 1,074 cycles of 3-weekly paclitaxel-containing treatment for 231 gynecologic malignancies at Xiangya Hospital. HSR incidence with different dexamethasone regimens was the primary outcome. Risk factors were examined in all cycles using univariate and multivariate models with generalized estimating equations. A subgroup analysis of initial exposure to paclitaxel was also conducted. Results HSR occurred in 33 patients (14.29%) and 49 cycles (4.56%), including 69.39% in cycles 1–2. There were no severe HSRs (grade ≥3). Different premedication regimens, including dexamethasone dosage and route, ranitidine presence or absence, didn’t affect HSR incidence in univariate and multivariate analyzes (p > 0.05). Premenopausal women exerted fewer HSRs (ORadj 0.22, 95%CI 0.08–0.58; p = 0.002). At the first exposure to paclitaxel, more than 10 mg of dexamethasone didn’t diminish HSRs (OR 0.83, 95%CI 0.27–2.59; p = 0.753). Conclusions In gynecologic malignancies, 10 mg dexamethasone along with 20 mg diphenhydramine may be adequate to prevent paclitaxel HSRs without ranitidine. It is necessary to reevaluate paclitaxel premedication regimens.

Clinical-anamnestic analysis of patients diagnosed as "Anaphylaxis" hospitalized in Moscow medical hospitals

BACKGROUND: Anaphylaxis is a severe hypersensitivity reaction. The incidence of anaphylaxis remains underestimated and there remains a low level of vigilance among all specialties, leading to underdiagnosis and consequent lack of appropriate treatment. This work is the first systematized clinical and epidemiological study performed on a cohort of patients with a history of anaphylactic reactions over 18 years of age.
 AIM: To study the epidemiological features of anaphylaxis within one region of the Russian Federation, identification of its most frequent phenotypes, as well as analysis of the main errors in the management of patients with anaphylactic reactions.
 MATERIALS AND METHODS: The study was conducted based on the retrospective stage analysis of data from medical records of patients with anaphylactic reactions of the Unified Medical Information and Analytical System (EMIAS) of Moscow for the period from 2019 to 2022. The final sample comprised a cohort of 241 patients.
 RESULTS: In the analyzed cohort, females (n=150; 62.2%) were predominant compared to males (n=91; 37.8%). Medications (n=171; 71%) dominated the list of causative agents. The leading clinical phenotype of anaphylactic reactions in the analyzed hospitalized cohort was characterized by cardiovascular symptoms (73; 30.3%). The risks of severe course increased with age (older than 44 years) (p=0.006). Information on prehospital therapy was obtained in 183 patients (75.9%), with only 128 (70%) patients receiving epinephrine therapy. A correlation was found between the absence of epinephrine administration in the prehospital phase and the development of a biphasic course of anaphylactic reactions subsequently (p 0.001). Only 15 (38.5%) patients with an aggravated history of anaphylaxis were previously informed about the need to carry epinephrine solution.
 CONCLUSIONS: Anaphylaxis is a life-threatening pathology requiring emergency medical care, regardless of the severity of the initial symptoms. Variations in the clinical symptoms that constitute the diagnostic criteria for anaphylaxis, differences in algorithms, and limitations of existing coding systems make it difficult to summarize epidemiological data and compare study results. Older age remains a risk factor for the development of severe anaphylactic reactions confirmed in our cohort.

Evaluate the in vitro effect of anthracycline and alkylating cytophosphane chemotherapeutics on dopaminergic neurons.

Iatrogenesis is an inevitable global threat to healthcare that drastically increases morbidity and mortality. Cancer is a fatal pathological condition that affects people of different ages, sexes, and races around the world. In addition to the detrimental cancer pathology, one of the most common contraindications and challenges observed in cancer patients is severe adverse drug effects and hypersensitivity reactions induced by chemotherapy. Chemotherapy-induced cognitive neurotoxicity is clinically referred to as Chemotherapy-induced cognitive impairment (CICI), chemobrain, or chemofog. In addition to CICI, chemotherapy also causes neuropsychiatric issues, mental disorders, hyperarousal states, and movement disorders. A synergistic chemotherapy regimen of Doxorubicin (Anthracycline-DOX) and Cyclophosphamide (Alkylating Cytophosphane-CPS) is indicated for the management of various cancers (breast cancer, lymphoma, and leukemia). Nevertheless, there are limited research studies on Doxorubicin and Cyclophosphamide's pharmacodynamic and toxicological effects on dopaminergic neuronal function. This study evaluated the dopaminergic neurotoxic effects of Doxorubicin and Cyclophosphamide. Doxorubicin and Cyclophosphamide were incubated with dopaminergic (N27) neurons. Neuronal viability was assessed using an MTT assay. The effect of Doxorubicin and Cyclophosphamide on various prooxidants, antioxidants, mitochondrial Complex-I & IV activities, and BAX expression were evaluated by Spectroscopic, Fluorometric, and RT-PCR methods, respectively. Prism-V software (La Jolla, CA, USA) was used for statistical analysis. Chemotherapeutics dose-dependently inhibited the proliferation of the dopaminergic neurons. The dopaminergic neurotoxic mechanism of Doxorubicin and Cyclophosphamide was attributed to a significant increase in prooxidants, a decrease in antioxidants, and augmented apoptosis without affecting mitochondrial function. This is one of the first reports that reveal Doxorubicin and Cyclophosphamide induce significant dopaminergic neurotoxicity. Thus, Chemotherapy-induced adverse drug reaction issues substantially persist during and after treatment and sometimes never be completely resolved clinically. Consequently, failure to adopt adequate patient care measures for cancer patients treated with certain chemotherapeutics might substantially raise the incidence of numerous movement disorders.

Audit of Hypersensitivity Reactions (HSRs) of Patients with Breast Cancer being Treated with Nab-paclitaxel after Severe HSR to Prior Taxane Chemotherapy; is it Safe?

Audit of Hypersensitivity Reactions (HSRs) of Patients with Breast Cancer being Treated with Nab-paclitaxel after Severe HSR to Prior Taxane Chemotherapy; is it Safe?

Death Due to Furosemide Anaphylaxis and The Importance of Serum Tryptase Level in Diagnosing Anaphylaxis: A Case Report

Anaphylaxis is a severe systemic hypersensitivity reaction with a sudden onset and may result in death. In this study, we report the case of a 71-year-old female patient who died within seconds after the administration of intravenous furosemide in emergency service; she had high serum tryptase levels at postmortem examination and nonspecific findings at autopsy, and death due to anaphylaxis was reported. With this study, we wanted to point to the rare and potentially fatal drug anaphylaxis, such as furosemide anaphylaxis. Also, our results indicate the importance of serum tryptase levels in the diagnosis of death due to anaphylaxis.

Successful switch to cisplatin-based chemotherapy in a patient with lung cancer who developed a carboplatin-induced hypersensitivity reaction.

Platinum-based chemotherapy is the mainstay of first-line therapy for advanced-stage non-small cell lung cancer (NSCLC). Although carboplatin-induced hypersensitivity reactions (HSRs) commonly occur following multiple cycles of therapy, they are rarely observed during the first cycle of the treatment. Here, we report the case of a 70-year-old man with advanced-stage NSCLC who developed HSR possibly caused by carboplatin during the first cycle of induction with platinum-doublet chemotherapy plus pembrolizumab. The patient presented with bronchial obstruction due to a centrally located tumor. No driver mutations were detected, and the programmed death-ligand 1 expression ranged from 1% to 24%. Consequently, the patient was treated with pembrolizumab combined with carboplatin and paclitaxel. However, immediately after the start of carboplatin, the blood pressure and oxygen levels of the patient dropped and he began exhibiting an altered level of consciousness. These findings indicated carboplatin-induced anaphylaxis. Hypotension and oxygen desaturation improved following carboplatin discontinuation and normal saline administration. The basophil activation test for both carboplatin and cisplatin was negative. Thus, the risk of anaphylaxis owing to both drugs was ruled out, and carboplatin was believed to have induced grade 3 HSR. Subsequently, carboplatin-based chemotherapy was switched to cisplatin-based chemotherapy. HSR was not observed during the four treatment cycles with pembrolizumab, cisplatin, and pemetrexed, and best response was partial response. Cisplatin-based chemotherapy could be used as an alternate treatment in patients with NSCLC who develop severe carboplatin-induced HSR.

Towards a better understanding of light-glucose induced modifications on the structure and biological activity of formulated Nivolumab

In the last years, monoclonal antibodies (mAbs) have rapidly escalated as biopharmaceuticals into cancer treatments, mainly for their target specificity accompanied by less side effects than the traditional chemotherapy, and stimulation of reliable long-term anti-tumoral responses. They are potentially unstable macromolecules under shaking, temperature fluctuations, humidity, and indoor and outdoor light exposure, all stressors occurring throughout their production, transport, storage, handling, and administration steps. The chemical and physical modifications of mAbs can lead not only to the loss of their bioactivity, but also to the enhancement of their immunogenicity with increasing risk of severe hypersensitivity reactions in treated patients because of aggregation. The photostability of Nivolumab, the active principle of Opdivo®, has been here studied. The chemical modifications detected by LC-MS/MS after the light stressor showed Trp and Met mono and double oxidations as primary damage induced by light on this mAb. The oxidations were stronger when the mAb was diluted in sterile glucose solution where 5-HMF, a major heat glucose degradation product, acted as singlet oxygen producer under irradiation. However, no significant changes in the mAb conformation were found. On the contrary, formation of a significant extent of aggregates has been detected after shining high simulated sunlight doses. This again took place particularly when Nivolumab was diluted in sterile glucose, thus raising a direct correlation between the aggregation and the oxidative processes. Finally, the biological activity under light stress assessed by a blockade assay test demonstrated the maintenance of the PD-1 target recognition even under high light doses and in glucose solution, in line with the preservation of the secondary and tertiary structures of the mAb. Based on our results, as sterile glucose is mostly used for children's therapies, special warnings, and precautions for healthcare professionals should be included for their use to the pediatric population.

Impact of Anti-PEG IgM Induced via the Topical Application of a Cosmetic Product Containing PEG Derivatives on the Antitumor Effects of PEGylated Liposomal Antitumor Drug Formulations in Mice.

Poly(ethylene glycol) (PEG) is used in many common products, such as cosmetics. PEG, however, is also used to covalently conjugate drug molecules, proteins, or nanocarriers, which is termed PEGylation, to serve as a shield against the natural immune system of the human body. Repeated administration of some PEGylated products, however, is known to induce anti-PEG antibodies. In addition, preexisting anti-PEG antibodies are now being detected in healthy individuals who have never received PEGylated therapeutics. Both treatment-induced and preexisting anti-PEG antibodies alter the pharmacokinetic properties, which can result in a subsequent reduction in the therapeutic efficacy of administered PEGylated therapeutics through the so-called accelerated blood clearance (ABC) phenomenon. Moreover, these anti-PEG antibodies are widely reported to be related to severe hypersensitivity reactions following the administration of PEGylated therapeutics, including COVID-19 vaccines. We recently reported that the topical application of a cosmetic product containing PEG derivatives induced anti-PEG immunoglobulin M (IgM) in a mouse model. Our finding indicates that the PEG derivatives in cosmetic products could be a major cause of the preexistence of anti-PEG antibodies in healthy individuals. In this study, therefore, the pharmacokinetics and therapeutic effects of Doxil (doxorubicin hydrochloride-loaded PEGylated liposomes) and oxaliplatin-loaded PEGylated liposomes (Liposomal l-OHP) were studied in mice. The anti-PEG IgM antibodies induced by the topical application of cosmetic products obviously accelerated the blood clearance of both PEGylated liposomal formulations. Moreover, in C26 tumor-bearing mice, the tumor growth suppressive effects of both Doxil and Liposomal l-OHP were significantly attenuated in the presence of anti-PEG IgM antibodies induced by the topical application of cosmetic products. These results confirm that the topical application of a cosmetic product containing PEG derivatives could produce preexisting anti-PEG antibodies that then affect the therapeutic efficacy of subsequent doses of PEGylated therapeutics.

Toxic Skin Reactions Should Be Differentiated from Allergic Reactions to Chemotherapeutic Drugs in Children: A Case Series and Review of the Literature.

Background: Chemotherapeutic drugs can lead to a wide spectrum of cutaneous findings, ranging from nonimmune toxic reactions to severe immune-mediated hypersensitivity reactions. The aim of this study was to evaluate the clinical, histopathological features, and prognosis of toxic skin reactions to chemotherapeutic drugs and to compare them with characteristics of immune-mediated reactions in children with malignancies. Methods: The medical records of all children with cancer who experienced skin reactions after chemotherapy administration and diagnosed as a toxic skin reaction between 2010 and 2022 were retrospectively analyzed. The diagnosis was re-evaluated and differentiated from other similar disorders by using clinical manifestations, photodocumentation, and histopathological findings. Results: A total of 17 children aged 2-17 years were involved: toxic erythema of chemotherapy (TEC) in 14 children, methotrexate-induced epidermal necrosis in 2 children, and toxic epidermal necrolysis (TEN)-like TEC in 1 child. The most commonly implicated drug was methotrexate. Most patients recovered rapidly after drug cessation and supportive measures. In 10 of the 17 patients, reintroduction of the culprit chemotherapeutic drug at reduced doses or increased dosage intervals was possible without any recurrence. Six patients could not receive further doses since they deceased due to sepsis and other complications. Conclusions: Cutaneous toxic eruptions to chemotherapeutic drugs may present with a severe phenotype resembling Stevens-Johnson syndrome/TEN. An accurate diagnosis prevents potentially harmful therapeutic interventions, withholding of chemotherapy, and erroneous assignment of drug allergies.

Level of Awareness of Certified Non-critical Care Physicians in Diagnosing, Managing, and Disposing Anaphylactic Cases.

Anaphylaxis is known as an acute, severe hypersensitivity reaction that rapidly initiates after exposure to a triggering agent. It is a life-threatening condition, and early recognition and swift intervention are crucial to saving patients' lives. Objective: The objective of this study is to assess the ability of certified non-critical care physicians to recognize, manage, and dispose cases of anaphylaxis. A survey consisting of 19 questions was developed by expert emergency consultants to evaluate physicians' knowledge regarding the recognition, management, and disposition of anaphylactic episodes. Responses were collected through in-person surveys conducted with physicians from various specialties and varying clinical experience levels at a tertiary care center in the Eastern Province of Saudi Arabia. In this cross-sectional study, a total of 173 physicians completed the survey, with 81.5% being consultants and 18.5% specialists. Only 5.2% correctly identified all three proposed anaphylaxis clinical scenarios, 16.8% identified two scenarios correctly, and 51.4% identified only one scenario. While 42.8% recognized the first-line management of anaphylaxis, only 24.3% and 24.9% knew the correct epinephrine dose and route, respectively. Regarding the disposition of patients experiencing an anaphylactic episode, 61.9% of responders opted to dispose the case to the emergency department. Our study reveals a knowledge gap among non-critical care physicians practicing in a tertiary care center concerning the identification and management of anaphylaxis. Raising awareness of this life-threatening condition is imperative to address this serious issue.

A systematic review and meta-analysis of proteomic and metabolomic alterations in anaphylaxis reactions.

Anaphylaxis manifests as a severe immediate-type hypersensitivity reaction initiated through the immunological activation of target B-cells by allergens, leading to the release of mediators. However, the well-known underlying pathological mechanisms do not fully explain the whole variety of clinical and immunological presentations. We performed a systemic review of proteomic and metabolomic studies and analyzed the extracted data to improve our understanding and identify potential new biomarkers of anaphylaxis. Proteomic and metabolomic studies in both human subjects and experimental models were extracted and selected through a systematic search conducted on databases such as PubMed, Scopus, and Web of Science, up to May 2023. Of 137 retrieved publications, we considered 12 for further analysis, including seven on proteome analysis and five on metabolome analysis. A meta-analysis of the four human studies identified 118 proteins with varying expression levels in at least two studies. Beside established pathways of mast cells and basophil activation, functional analysis of proteomic data revealed a significant enrichment of biological processes related to neutrophil activation and platelet degranulation and metabolic pathways of arachidonic acid and icosatetraenoic acid. The pathway analysis highlighted also the involvement of neutrophil degranulation, and platelet activation. Metabolome analysis across different models showed 13 common metabolites, including arachidonic acid, tryptophan and lysoPC(18:0) lysophosphatidylcholines. Our review highlights the underestimated role of neutrophils and platelets in the pathological mechanisms of anaphylactic reactions. These findings, derived from a limited number of publications, necessitate confirmation through human studies with larger sample sizes and could contribute to the development of new biomarkers for anaphylaxis. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024506246.

Protective role of protease-activated receptor-2 in anaphylaxis model mice.

Anaphylaxis is a severe life-threatening hypersensitivity reaction induced by mast cell degranulation. Among the various mediators of mast cells, little is known about the role of tryptase. Therefore, we aimed to elucidate the role of protease-activating receptor-2 (PAR-2), a receptor activated by tryptase, in murine anaphylactic models using PAR-2-deficient mice and newly generated tryptase-deficient mice. Anaphylaxis was induced by IgE-dependent and IgE-independent mast cell degranulation in mice. PAR-2 deficiency exacerbated the decrease in body temperature and hypotension during anaphylaxis; however, the number of skin mast cells, degree of mast cell degranulation, and systemic and local vascular hyperpermeability were comparable in PAR-2 knockout and wild-type mice. Nitric oxide, which is produced by endothelial nitric oxide synthase (eNOS), is an indispensable vasodilator in anaphylaxis. In the lungs of anaphylactic mice, PAR-2 deficiency promoted eNOS expression and phosphorylation, suggesting a protective effect of PAR-2 against anaphylaxis by downregulating eNOS activation and expression. Based on the hypothesis that the ligand for PAR-2 in anaphylaxis is mast cell tryptase, tryptase-deficient mice were generated using CRISPR-Cas9. In wild-type mice, the PAR-2 antagonist exacerbated the body temperature drop due to anaphylaxis; however, the effect of the PAR-2 antagonist was abolished in tryptase-deficient mice. These results suggest that tryptase is a possible ligand of PAR-2 in anaphylaxis and that the tryptase/PAR-2 pathway attenuates the anaphylactic response in mice.

The Evolving Landscape of Gout in the Female: A Narrative Review

Gout is at least three times more prevalent in males than in females. However, concurrent with rising total gout prevalence, complex factors, including comorbidities, diet, lifestyle, and aging, have promoted higher gout prevalence in females. This narrative review focuses on summarizing recent developments in the landscape of gout in females and the mechanisms involved. New knowledge on sex hormone effects on both urate-excreting and urate-reabsorbing transporters and higher hypertension and chronic kidney disease prevalence in females compared to males may help explain why gout incidence rises robustly after menopause in females, to approach that in males. Racial and ethnic factors, risk profiles based on heritable genetic polymorphisms of urate transporters, diet, body mass index, and lifestyle factors differ according to sex. In addition, sex differences in clinical phenotypes, outcomes of gout, and non-gout illnesses include more frequent comorbidities, more pain and disability during gout flares, different perceptions of disease burden, and more frequent severe cutaneous hypersensitivity reaction to allopurinol in females. Collectively, such findings support the potential clinical benefits of tailoring gout and hyperuricemia treatment according to sex.

DRESS syndrome complicated by a severe acute hemolytic anemia

A 25-year-old female patient, who had been receiving treatment for psychosis with carbamazepine, olanzapine, and haloperidol for the past 2 years, was admitted to the hospital after developing a widespread febrile rash. This occurred 15 days after taking fluoxetine and clomipramine. Upon examination, the patient presented with fever, tachycardia, and hypotension. Dermatological examination revealed a generalized erythema with fine scales, accompanied by eyelid swelling and bilateral cervical lymphadenopathy. Laboratory tests showed a normochromic normocytic anemia with a hemoglobin level of 3.5g/dL and lymphopenia with an elevation in LDH. The direct Coombs test was positive. A skin biopsy suggested a drug eruption. The diagnosis of DRESS syndrome was considered probable based on the diagnostic criteria of the RegiSCAR group. DRESS syndrome is a severe hypersensitivity reaction with various clinical manifestations that can be life-threatening. To date, no cases of DRESS syndrome associated with acute hemolytic anemia have been reported in the literature. However, it has been implicated in the development of autoimmune diseases in the medium and long term.

Real-World Evidence of Hetrombopag for Cancer Therapy-Induced Thrombocytopenia Among Patients with Gynecologic Malignancies

Background: Despite the widespread use of platinum-based combination chemotherapy, particularly when complemented with taxanes, for the treatment of gynecologic malignancies, its administration often results in myelosuppression. This effect can be potentiated across cumulative chemotherapy cycles, thereby inducing a more persistent condition known as cancer therapy-induced thrombocytopenia (CTIT). Traditionally, preferred treatments for CTIT entail platelet transfusion or the use of recombinant human thrombopoietin (rhTPO), or recombinant human interleukin-11 (rhIL-11). However, the efficacy of platelet transfusion tends to decrease with repetitive administration, and it carries inherent risks of infectious diseases. Additionally, rhIL-11 may induce severe hypersensitivity reactions, necessitating permanent discontinuation of the drug. Emerging as an appealing alternative, thrombopoietin-receptor agonists (TPO-RAs) present a promising approach for CTIT treatment. Among these, hetrombopag, an orally administered small-molecule TPO-RA, has demonstrated notable platelet-boosting effects and a favorable safety profile not only in patients with immune thrombocytopenia and severe aplastic anemia but also in those suffering from persistent CTIT. This study aims to appraise the real-world effectiveness and safety of hetrombopag, administered either alone or in conjunction with other platelet-boosting agents, for the management of CTIT in patients diagnosed with gynecologic malignancies. Methods: In this retrospective study conducted from January 2022 to June 2023, we examined the role of hetrombopag in treating CTIT among patients with gynecologic malignancies. The patients, aged 18 years and above, had experienced thrombocytopenia (platelet counts<100×10 9/L) following platinum-based chemotherapy or other antitumor treatments and subsequently received hetrombopag either as monotherapy or in combination with other platelet-boosting agents, such as rhTPO or rhIL-11. The primary outcome was platelet response within 14 days, denoted by a recovery in platelet counts to ≥100×10 9/L or an increase of ≥50×10 9/L or at least double from the baseline. Results: This study comprised 38 patients, with 55.3% diagnosed with ovarian cancer, 36.8% with cervical cancer, 5.3% with endometrial cancer, and 2.6% with other types. The median age was 58 years, with the majority (73.7%) at clinical stages III/IV. As for the antitumor regimens, 89.5% incorporated platinum, 68.4% included taxanes, 26.3% used antiangiogenic agents, and 15.8% employed PD-1 inhibitors. Among the patients, 15.8% received hetrombopag 2.5 mg/day monotherapy, while the remainder received hetrombopag in combination with rhTPO or rhIL-11. Baseline platelet counts prior to hetrombopag therapy averaged 46.5±24.9×10 9/L. Encouragingly, the 14-day platelet response rate was 71.1%, with a median time to response of 10 days (95% confidence interval, 5-14). Following treatment with hetrombopag, patients exhibited a gradual increase in platelet levels, recording mean platelet counts of 48.7, 67.1, 95.5, 108.5, 146.5, and 131.9×10 9/L on days 3, 5, 7, 9, 11, and 14 respectively. Importantly, hetrombopag was well-tolerated, with no treatment-related adverse events observed during the treatment course. Conclusion: In conclusion, our findings suggest hetrombopag, either alone or in combination with other therapies, displays preliminary effectiveness and safety in treating CTIT. Given its convenient oral administration and promising platelet-boosting effects observed in this study, prospective investigations of hetrombopag monotherapy for CTIT in gynecologic malignancies are warranted.

Lack of benefit from premedication for pegylated asparaginase during pediatric acute lymphoblastic leukemia/lymphoma therapy: A side-by-side comparison.

Pegylated l-asparaginase (PEG) is integral to treatment regimens for acute lymphoblastic leukemia (ALL) and lymphoma. Hypersensitivity reactions (HSRs) to PEG are common and can preclude continued administration. Data supporting recommendations for universal premedication (UPM) prior to PEG infusion to reduce incidence of HSRs are limited; UPM has become common practice. Two free-standing children's hospitals independently implemented UPM prior to PEG infusions in 2016 and 2019, respectively. In a side-by-side retrospective analysis, incidence and severity of HSRs were analyzed pre- and postimplementation of UPM in youth ≥1 years old treated with frontline PEG-containing ALL regimens (2015-2018, 2016-2020). All HSRs were centrally reviewed within each institution to confirm and grade the HSR (Common Terminology Criteria for Adverse Events, v5). Planned analyses of subsets at potentially greater risk for HSRs included intensive PEG regimens (≥5 doses), adolescent and young adults (AYA), Hispanic/Latinx ethnicity, and obesity. In 410 patients (by institution, n=282 and n=128), the overall incidence of Grade≥3 HSRs was 20% (56 out of 282) and 18% (23 out of 128), respectively. No difference in incidence of Grade≥3 HSRs in patients with versus without UPM was found at either institution (23vs. 19%, p=.487 and 19vs. 17%, p=.845). UPM also did not reduce the severity of HSRs, nor influence HSR risk within any patient subset. UPM prior to PEG infusion did not alter incidence or severity of HSRs at either institution. HSR remains a common complication of PEG therapy, impacting the patient experience. Alternative strategies to reduce HSRs are urgently required.

Repurposing HLA genotype data of renal transplant patients to prevent severe drug hypersensitivity reactions.

Introduction: Specific alleles in human leukocyte antigens (HLAs) are associated with an increased risk of developing drug hypersensitivity reactions induced by abacavir, allopurinol, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, or flucloxacillin. Transplant patients are genotyped for HLA as a routine practice to match a potential donor to a recipient. This study aims to investigate the feasibility and potential impact of repurposing these HLA genotype data from kidney transplant patients to prevent drug hypersensitivity reactions. Methods: A cohort of 1347 kidney transplant recipients has been genotyped in the Leiden University Medical Center (LUMC) using next-generation sequencing (NGS). The risk alleles HLA-A*31:01, HLA-B*15:02, HLA-B*15:11, HLA-B*57:01, and HLA-B*58:01 were retrieved from the NGS data. Medical history, medication use, and allergic reactions were obtained from the patient's medical records. Carrier frequencies found were compared to a LUMC blood donor population. Results: A total of 13.1% of transplant cohort patients carried at least one of the five HLA risk alleles and therefore had an increased risk of drug-induced hypersensitivity for specific drugs. HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01 were found in carrier frequencies of 4.61%, 1.19%, 4.46%, and 3.35% respectively. No HLA-B*15:11 carrier was found. In total nine HLA-B*57:01 carriers received flucloxacillin and seven HLA-B*58:01 carriers within our cohort received allopurinol. Discussion: Our study shows that repurposing HLA genotype data from transplantation patients for the assignment of HLA risk alleles associated with drug hypersensitivity is feasible. The use of these data by physicians while prescribing drugs or by the pharmacist when dispensing drugs holds the potential to prevent drug hypersensitivity reactions. The utility of this method was highlighted by 13.1% of the transplant cohort patients carrying an actionable HLA allele.

Evaluation of pediatricians' awareness about anaphylaxis.

Anaphylaxis is a severe hypersensitivity reaction with a rapid onset and is potentially life-threatening if not treated promptly. This study aimed to determine the level of knowledge of pediatricians in Turkey in recognizing and treating the clinical symptoms of anaphylaxis, compare the previous studies conducted in Turkey chronologically, and show the current trends on awareness of anaphylaxis in developed and developing countries in the world. Pediatric residents and specialists from all over Turkey were included in the study. A questionnaire was prepared by compiling the current literature. Questions were sent to pediatricians via online applications. Statistical tests were used to analyze the data. A total of 524 pediatricians participated in the study. All participants accepted that anaphylaxis was a life-threatening condition. Almost all suggested epinephrine as the primary drug used in anaphylaxis. The proportion of pediatricians who knew the appropriate dose, route of administration, and place of administration of epinephrine was 82.8%, 88.9%, and 89.7%, respectively. The rate of pediatricians who recognized the clinical features of anaphylaxis was over 90%. The proportion of pediatricians who knew the epinephrine auto-injector and dose was 74.4% and 53.1%, respectively. Pediatricians with less than 10 years of experience and those working in public hospitals had better knowledge about atypical symptoms of anaphylaxis. Although there are still inadequacies in identifying atypical symptoms and treating anaphylaxis, our study revealed that the level of awareness of anaphylaxis had shown an increasing trend in Turkey over time. On the other hand, the knowledge on diagnosing and treating anaphylaxis still needs to be improved, especially for physicians working in rural areas of developing countries.

A case of possible anaphylaxis to ASA and structurally unrelated NSAIDs

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used classes of medications, and are among the leading causes of drug hypersensitivity. NSAIDs hypersensitivity reactions are classified by symptom involvement and NSAIDs subclass cross-reactivity. Reactions varying from cutaneous involvement to respiratory symptoms can be triggered by multiple NSAIDs subclasses. Anaphylaxis, while rare, can be induced by a single NSAID, with tolerability of other structurally unrelated subclasses. Reactions that fall outside of these traditional categories are deemed “blended reactions”. We report a unique case of possible anaphylaxis to acetylsalicylic acid (ASA) and ibuprofen, two structurally dissimilar NSAIDs, indicating a severe blended reaction outside of the typical NSAIDs hypersensitivity reaction categories.Case presentationAn otherwise healthy 45 year old woman was referred to the Allergy and Immunology clinic after developing acute onset dyspnea, lip swelling, and generalized urticaria with ibuprofen use requiring treatment with intramuscular epinephrine in the emergency department. She previously tolerated ibuprofen, naproxen, and acetaminophen and had no history of urticaria, angioedema, asthma, or nasal polyps. She underwent an oral challenge to ASA whereby she developed urticaria and throat irritation with rebound symptoms requiring 2 doses of intramuscular epinephrine. On subsequent visits she passed treatment dose acetaminophen and celecoxib challenges. She was counseled to avoid all other NSAIDs and ASA desensitization was offered should this medication be clinically indicated in the future.ConclusionsNSAIDs hypersensitivity reactions can be triggered by individual NSAIDs with tolerance of other subclasses or by multiple structurally unrelated NSAIDs due to COX-1 inhibition. Determining the type of reaction (NERD, NECD, NIUA, SNIUAA, or SNIDHR) allows for appropriate oral challenges and safe alternative therapy recommendations. However, not all clinical reactions fit perfectly into these categories. Patients may also develop blended reactions. Our case highlights a severe blended reaction to multiple unrelated NSAIDs, including likely anaphylaxis to ASA. We note the utility of drug provocation tests (DPTs) to identify safe alternative medication options, as well as the importance of performing DPTs in settings properly equipped to assess and manage severe hypersensitivity reactions including anaphylaxis.