Delayed Hypersensitivity Reaction Research Articles

Rapid Drug Desensitization Protocol in Delayed Hypersensitivity Reactions to CFTR Modulator Drugs: When Every Day Counts.

Rapid Drug Desensitization Protocol in Delayed Hypersensitivity Reactions to CFTR Modulator Drugs: When Every Day Counts.

Successful desensitization in a patient with metastatic colorectal cancer presenting with regorafenib-mediated fix drug eruption.

Regorafenib is an oral protein kinase inhinitor approved fot the treatment of metastatic colorecral cancer. We present a first successful case of desensitization in regorafenib-related fix-drug eruption in the literature. A 44-year-old female patient was diagnosed with metastatic colorectal adenocarcinoma. The patient received regorafenib treatment for malignancy recurrence. The patient was admitted to adult allergy clinic with developing recurrent fix drug eruption in the second cycle, on the 10th day of regorafenib treatment. The patient was given the third cycle of regorafenib treatment with a 6-day desensitization protocol, the first day of which consisted of 6 steps and and the third cycle was successfully completed. Regorafenib-mediated delayed hypersensitivity reactions occur less frequently and and regorafenib hypersensitivity reactions are difficult to manage and experience is limited. This is the first successful desensitization protocol developed by us for regorafenib-related fix drug eruption and more cases are needed to be reported to confirm the desensitization protocol. There is only one successful regorafenib desensitization protocol for severe delayed hypersensivity reaction in the literature, but there is no protocol developed for mild type delayed hypersensivity reaction. The management of fix-drug eruption primarily involves discontinuation and avoidance of the offending drug but our patient had a mild delayed-type reaction and there was no alternative to regarofenib treatment. We developed the rapid 6-step desensitization protocol (Day 1). According to this protocol, the patient was able to continue regorafenib treatment successfully.

Predictors of immediate and delayed cutaneous hypersensitivity reactions to paclitaxel.

Paclitaxel is one of the first-line treatments for breast, ovarian, and lung cancers. However, its use is limited by the high frequency of hypersensitivity reactions. In this retrospective chart review at Memorial Sloan Kettering Cancer Center, we assess clinical factors associated with immediate and delayed hypersensitivity reactions to paclitaxel and characterize delayed hypersensitivity reactions to paclitaxel in patients with breast cancer. 12,274 patients were treated with paclitaxel. 6,165 had breast cancer and 1,233 were seen by a dermatologist. 734 patients (11.9%) developed an immediate hypersensitivity reaction. Age (p < 0.001), race (p < 0.001), and prior history of allergy (p = 0.05) were associated with immediate hypersensitivity reactions. 147 patients (4.0%) had a rash of interest. The most common phenotypes were maculopapular (52%) and urticaria (36%). Race (p < 0.001) and history of allergy (p < 0.001) were associated with development of a cutaneous reaction. Patients with an immediate hypersensitivity reaction were more likely to have developed a delayed cutaneous reaction (OR = 1.80). Risk factors for development of immediate hypersensitivity reactions in this study were younger age, race, and history of allergy. Patients who developed an immediate hypersensitivity reaction were more likely to develop a delayed hypersensitivity reaction. Risk factors for development of the rash included Asian race and history of allergy. Identification of risk factors is critical to guide care coordination. Awareness of these clinical factors which are associated with development of a rash could guide providers in choosing treatment with paclitaxel or nab-paclitaxel. If the cutaneous reactions are bothersome to the patient, the transition of treatment from paclitaxel to nab-paclitaxel may be warranted, or a consideration of re-challenge or desensitization may be discussed.

Delayed allergic reaction from bupropion in a 27-year-old male with MDD: A case report and literature review

Introduction Bupropion is an antidepressant approved for the treatment of major depressive disorder (MDD), seasonal affective disorder, and smoking cessation. Nausea, headache, tremor, and insomnia are well-known adverse effects of this medication. Less well-recognized adverse effects include delayed allergic reactions, which, in some cases, can appear 2 or more weeks after bupropion initiation. Case Report A 27-year-old male with recurrent MDD was referred for medication treatment at an outpatient mental health clinic and prescribed bupropion XL. On day 28 of treatment, he reported significant improvement in depressive symptoms and the development of itchiness and urticaria on his extremities and back. Bupropion was tapered over the course of 7 days, and he was given cetirizine 10 mg daily. He was transitioned to venlafaxine treatment and experienced complete resolution of hives and pruritus. Discussion Despite published reports on bupropion causing delayed hypersensitivity reactions, there remains limited clinical recognition of this side effect, and the risk of underrecognition may be greater when the onset of the reaction is more than 2 weeks after bupropion initiation. Conclusion Bupropion can cause delayed hypersensitivity reactions, including delayed pruritis and urticaria. The risk may be highest in males aged 17 to 40 years and those with a history of allergic reactions.

Retinal vasculopathy and choroiditis after pegcetacoplan injection: clinicopathologic support for a drug hypersensitivity reaction

PurposeTo report the detailed histopathology of two enucleated eyes from two patients who developed severe visual loss associated with retinal hemorrhages, vessel sheathing and vascular nonperfusion after administration of an initial dose of intravitreal pegcetacoplan, and to propose, with supportive histopathology, the pathogenesis of the clinical syndrome previously termed hemorrhagic occlusive retinal vasculitis (HORV). DesignCase series. SubjectsTwo enucleated eyes from two patients treated with intravitreal pegcetacoplan. MethodsRetrospective, multicenter consecutive clinical-pathologic analysis. Main Outcome MeasuresHistopathologic review and immunophenotypic characterization. ResultsBoth patients presented with inflammation and significant vision loss nine days following the initial injection of pegcetacoplan with no subsequent improvement and underwent enucleation for pain control. Histologic examination of the enucleated eyes (patient one at 4 months post-injection and patient two at 40 days) revealed extensive vascular thrombosis, retinal hemorrhages and necrosis, and a dense inflammatory infiltrate in the uvea and variably the optic nerve, episclera, and muscle tendons composed of predominantly of T-cells, macrophages, and eosinophils. Notably, the inflammatory infiltrate was absent from the retina. In addition, one eye demonstrated multiple foci of glomerular-like vascular proliferations in the uveal tract and thrombosis with focal recanalization of vessels in the optic nerve. ConclusionDrug-induced, immune-mediated, retinal vasculopathy and choroiditis (DIRVAC) is a rare complication following pegcetacoplan injection. Although some limitations arise in interpretation of histopathologic findings due to compensatory changes in the eyes over time (prior to enucleation), the authors propose that the combined clinical, histopathologic, and immunohistochemical findings suggest a mixed-type, delayed hypersensitivity reaction as mechanism of initial injury.

Tolerance of penicillin V in patients with confirmed delayed hypersensitivity reactions to aminopenicillins

Tolerance of penicillin V in patients with confirmed delayed hypersensitivity reactions to aminopenicillins

Delayed Hypersensitivity Reaction to Dermal Fillers Following mRNA COVID-19 Vaccination

Dear Editor, I wish to bring attention to a potential delayed immune reaction associated with dermal fillers in the context of mRNA COVID-19 vaccines. While severe vaccine reactions remain uncommon, the widespread administration of mRNA vaccines and the prevalent use of dermal fillers necessitate a closer examination of their possible interactions. We recently encountered a 59-year-old female patient who developed persistent facial swelling months after receiving the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine. Notably, the patient had a history of dermal filler injections, predominantly hyaluronic acid, administered three to four years prior. Despite various therapeutic interventions, including antihistamines, corticosteroids, and ACE inhibitors, she experienced recurrent episodes of swelling. Ultrasound assessment revealed the absence of residual filler material, leading us to consider an immune-mediated response potentially triggered by the mRNA vaccine. This case highlights the importance of further research into the interaction between mRNA COVID-19 vaccines and dermal fillers. It suggests that individuals with a history of dermal fillers may be susceptible to delayed inflammatory reactions post-vaccination. Clinicians should be aware of this potential adverse event, particularly when evaluating patients with unexplained facial swelling following vaccination.

Drug Allergies in Older Adults: A Major Problem in a Specific Population

Introduction: The use of medications in older adults is increasing due to the prevalence of chronic diseases. Data on the characteristics of drug allergies (DAs) in older adults are limited. This study investigated the prevalence and clinical characteristics of DAs in patients aged 65 years and older. Methods: Patient records were examined retrospectively between January 2018 and December 2022. The study included 200 patients aged ≥18 years who met the criteria for diagnosis of type B drug reactions. The patients were divided into two groups: the adult group (18–64 years) and the older adult group (≥65 years). Results: Advanced age was an independent risk factor for the development of anaphylaxis and immediate and delayed hypersensitivity reactions (odds ratio [OR] = 4.296; 95% confidence interval [CI] = 1.700–10.855; p = 0.002, OR = 3.800; 95% CI = 1.247–11.579; p = 0.019, OR = 3.028; 95% CI = 1.248–7.343; p = 0.014, respectively). Older adults had higher rates of comorbidities and polypharmacy (p < 0.001, p = 0.016, respectively), beta-lactam antibiotic allergy (p < 0.001), and hospitalization and intensive care unit (ICU) admission for DAs (p = 0.024, p = 0.045, respectively). Conclusion: Older age was an independent risk factor for anaphylaxis and both immediate and delayed reactions. Older adults had higher rates of comorbidities, polypharmacy, beta-lactam antibiotic triggers, and hospitalization and ICU admission.

Photopatch testing: Clinical characteristics, test results, and final diagnoses from the North American Contact Dermatitis Group, 2009-2020.

Photoallergic contact dermatitis (PACD) is a delayed hypersensitivity reaction to allergens only in the presence of ultraviolet radiation in sunlight. Photopatch testing (PhotoPT) is necessary to confirm the diagnosis of PACD. There are few published studies of PhotoPT in North America. To summarise the results of patients photopatch tested by members of the North American Contact Dermatitis Group (NACDG), 2009-2020. Retrospective analysis of patient characteristics and PhotoPT results to 32 allergens on the NACDG Photopatch Test Series. Most of the 454 tested patients were female (70.3%), 21-60 years old (66.7%) and White (66.7%). There were a total of 119 positive photopatch tests. Sunscreen agents comprised 88.2% of those, with benzophenones responsible for over half of them. Final diagnoses included PACD in 17.2%, allergic contact dermatitis (ACD) in 44.5%, polymorphous light eruption (PMLE) in 18.9% and chronic actinic dermatitis (CAD) in 9.0% of patients. In 454 patients with suspected photosensitivity referred for photopatch testing in North America, approximately one-fifth had PACD. Sunscreen agents, especially benzophenones, were the most common photoallergens. Other common diagnoses included ACD, PMLE and CAD. Photopatch testing is an important tool for differentiating these conditions.

Bullous Drug Eruption.

A 63-year-old woman presented at our emergency department with a disseminated dermatosis that developed after undergoing a cardiac catheterization procedure. Her past medical history included an end-stage renal disease undergoing hemodialysis. Clinical examination revealed erosions and hemorrhagic crusts located on her lips and along the arteriovenous fistula. Additionally, we observed five hyperpigmented macules on her left hand's dorsum and palm and multiple hypopigmented macules in the genital area. Upon medical record review, we discovered the occurrence of prior bullous eruptions following contrast administration. A fixed drug eruption (FDE) due to radiocontrast was diagnosed based on clinical history, clinical examination, eruption timeframe, and positive drug provocation test. Intravenous contrast media reactions can be immediate or delayed, with delayed hypersensitivity reactions (DHR) occurring one hour to seven days post-administration. DHRs often present as maculopapular rashes. FDEs are rare. Skin tests are used to identify culprit agents. Ideally, intradermal tests, with delayed readings, and patch tests are combined for optimal sensitivity. Despite lacking standardized protocols, premedication with corticosteroids may mitigate reaction severity.

Omalizumab for management of hypersensitivity reactions to anticancer drugs.

Hypersensitivity reactions to anticancer drugs include treatment-limiting toxicity. Standard drug desensitisation offers temporary tolerance and hence requires repetition. We used omalizumab, an anti-immunoglobulin E antibody, to overcome immediate and delayed hypersensitivity reactions to various anticancer drugs. Seven of the eight patients in the current studysuccessfully resumed the desired anticancerdrug regimen without standard desensitisation. No safety issues from omalizumab were observed.

Temporary Delayed Hypersensitivity Reaction to Botulinum Toxin-A After COVID-19 Vaccination: A Case Series.

The occurrence of a hypersensitivity reaction with the injection of botulinum toxin type A (BTX-A) in cosmetic use is a rare complication. We report the largest case series of temporary delayed hypersensitivity reaction (DHR) with BTX-A following COVID-19 vaccination and the first cases to incobotulinum toxin A (incoBTX-A). A retrospective multicentric case series of patients who developed a DHR to BTX-A after COVID-19 vaccination. Twelve patients were treated with BTX-A injections for the management of facial rhytids. The age range was between 29 and 45years. Ten (83.3%) were female. Ten (83.3%) patients received incoBTX-A, and two received onabotulinum toxin A (onaBTX-A). All patients had COVID-19 vaccination (mRNA vaccine) between 1 and 7months before. Within an average time of 24h after BTX-A injection, all patients developed progressive facial swelling and erythema that were more prominent at the injection points. Intradermal allergic tests to BTX-A were performed in six (50%) patients, and the results were all negative. Adequate clinical control was achieved with systemic corticosteroids and antihistamines. After 1year with no further vaccination, a new BTX-A treatment (provocation test) was performed in all patients with no secondary effects. Previous COVID-19 vaccination and the absence of new adverse events with further BTX-A injections suggest a temporary DHR. Clinicians should be aware of the importance of immunization history and its potential post-vaccine immunogenic effects with BTX-A. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Protocol for Successful Desensitization to Ivacaftor and Elexacaftor/Tezacaftor/Ivacaftor in a Delayed Hypersensitivity Reaction Confirmed by the Lymphocyte Transformation Test.

Protocol for Successful Desensitization to Ivacaftor and Elexacaftor/Tezacaftor/Ivacaftor in a Delayed Hypersensitivity Reaction Confirmed by the Lymphocyte Transformation Test.

Generalised pustular psoriasis triggered by monkeypox vaccination successfully treated with spesolimab

AbstractGeneralised pustular psoriasis (GPP) is characterised by a widespread rash with pustules and fever. Clinical and the histological overlap with the delayed hypersensitivity reaction acute generalised exanthematous pustulosis may delay the diagnostics and the initiation of correct treatment. In this case‐report, we describe an Human immunodeficiency virus positive patient with GPP possible triggered by monkeypox vaccination and eventually successfully treated with spesolimab, an interleukin‐36 inhibitor.

Cystic fibrosis: desensitization in delayed hypersensitivity reactions to elexacaftor/tezacaftor/ivacaftor.

Background: Cystic fibrosis transmembrane conductance regulator modulators are the only available treatment for cystic fibrosis. Although elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is well-tolerated, rash has been reported as very frequent. In severe rashes, ELX/TEZ/IVA withdrawal is necessary, leading to clinical deterioration. The objective of the study is to increment the experience of ELX/TEZ/IVA desensitization. Methods: Adult patients who developed a delayed hypersensitivity rash to ELX/TEZ/IVA between December 2021 and February 2023 and required withdrawal due to ineffective rescue medication were included. Skins test for ELX/TEZ/IVA and IVA were conducted to establish hypersensitivity mechanism. Balijepally ELX/TEZ/IVA desensitization protocol was selected. In cases where desensitization had to be discontinued due to rash, an extended desensitization was proposed. Clinical and health-related quality of life parameters were collected before ELX/TEZ/IVA and after desensitization. Results: 162 patients (81 women, 31.2 [23.8-42.5] years) started ELX/TEZ/IVA, developing rash 12 of them (7.4%, six women). Six patients (five women) required stopping ELX/TEZ/IVA and were selected for desensitization. Skin tests indicated delayed type-IV hypersensitivity in one patient. Two patients presented adequate tolerance to desensitization; while, four patients developed rash. Three of these patients, successfully concluded extended desensitization (one patient declined participation). No significant clinical deterioration or quality of life worsening was observed during desensitization; in fact, there was an improvement in practically all mesured parameters. All five patients who resumed ELX/TEZ/IVA are currently receiving therapy with good tolerance. Conclusion: Desensitization to ELX/TEZ/IVA could be a successful and safe strategy for reintroducing this essential treatment in cases of a delayed hypersensitivity rash.

Predictors of immediate and delayed cutaneous hypersensitivity reactions to paclitaxel.

e24101 Background: Paclitaxel is one of the first-line treatments for breast, ovarian, and lung cancers. However, its use is limited by the high frequency of hypersensitivity reactions. The purpose of the current study was to assess clinical factors associated with immediate and delayed hypersensitivity reactions to paclitaxel and characterize delayed hypersensitivity reactions to paclitaxel in patients with breast cancer. Methods: We conducted a retrospective chart review of patients who received paclitaxel (Taxol) or nab-paclitaxel (Abraxane) between 1/1/2017 and 1/1/2022 at Memorial Sloan Kettering Cancer Center. Results: In total, 12,274 patients were identified who were treated with paclitaxel. Of these, 6,165 had breast cancer and 1,233 were seen by a dermatologist. 734 patients (11.9%) developed an immediate hypersensitivity reaction to paclitaxel. Age (p &lt; 0.001), race (p &lt; 0.001), and prior history of allergy based on prior ICD-10 code (p = 0.05) were significantly associated with immediate hypersensitivity reactions. Patients who developed an immediate HSR (mean 52.5 ± 12.5 years versus 54.8 ± 12.9 years) tended to be younger, on average, than those who did not experience a reaction. Compared to White patients, Black patients were 37% less likely (OR = 0.63; 95% 0.48 – 0.83) and Asian patients were 70% more likely (OR = 1.70; 95% 1.37 – 2.12) to experience a hypersensitivity reaction. 147 patients (4.0%) had a delayed hypersensitivity reaction (cutaneous rash). Delayed hypersensitivity reaction included toxic erythema of chemotherapy, urticaria, morbilliform, maculopapular, and pruritus phenotypes. The most common phenotypes were maculopapular (52%) and urticaria (36%). The majority had not been treated with nab-paclitaxel prior to rash (86%). Race (p &lt; 0.001) and history of allergy (p &lt; 0.001) were associated with development of a cutaneous reaction. Asian patients were almost twice as likely (OR = 1.99; 95% CI: 1.51 - 2.61, P &lt; 0.001) as White patients to present with a delayed HSR to paclitaxel. Patients with an immediate hypersensitivity reaction were more likely to develop a delayed cutaneous reaction (OR = 1.80; 95% confidence interval: 1.27-2.55) than those who did not get an immediate HSR, controlling for breast cancer stage and patient race. Conclusions: In conclusion, risk factors identified for development of immediate hypersensitivity reactions in this study were younger age, Asian race, and history of allergy. Patients who developed an immediate hypersensitivity reaction were more likely to develop a delayed hypersensitivity reaction. Risk factors for development of the rash included Asian race and history of allergy. Awareness of these clinical factors which are associated with development of a rash could guide providers in choosing treatment with paclitaxel or nab-paclitaxel.

An update on nonsteroidal anti-inflammatory drug-induced urticaria.

Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (HR-NSAIDs) are common adverse events related to the widespread use of over-the-counter NSAIDs for the treatment of a variety of inflammatory conditions. Urticaria is the most commonly reported immediate cutaneous clinical sign of HR-NSAIDs, but it can be a manifestation of pathophysiologically different clinical entities that require different therapeutic strategies. The aim of this study is to ease the identification of the correct phenotype of HR-NSAIDs in patients reporting urticaria associated with the intake of NSAIDs and provide updated information about their diagnosis and management. The study is a narrative review conducted by collecting the most relevant and up-to-date data related to the classification, pathophysiology, severity, and prognosis of NSAID hypersensitivity reactions. PubMed and Embase scientific databases were used as search engines to select relevant articles. Patients developing HR-NSAIDs can be divided into two categories: selective responders (SR), who develop reactions after the administration of a single specific NSAID due to an underlying IgE or T-cell mediated hypersensitivity mechanism, or cross-intolerant (CI), who develop reactions to more than one chemically unrelated NSAIDs due to abnormalities in the biochemical pathways related with prostaglandin metabolism, independently from an underlying immunological mechanism. Five major different categories of HR-NSAIDs have been identified: NSAIDs-exacerbated cutaneous disease (NECD), NSAIDs-induced urticaria/angioedema with/without respiratory and systemic symptoms of anaphylaxis (NIUAA), and NSAIDs-exacerbated respiratory disease (NERD), which are developed by CI patients, and single NSAIDs-induced urticaria, angioedema and/ or anaphylaxis (SNIUAA) and single NSAIDs-induced delayed hypersensitivity reactions (SNIDHR), which are developed by CI patients. In vivo and in vitro diagnostic tests have rarely been shown to be reliable in all these entities and therefore are not routinely used in clinical practice. The management in SR patients consists of strict avoidance of the culprit drug, while for cross-intolerance reactions oral tolerance tests with safe alternative drugs (e.g. weak COX-1 inhibitors or selective COX-2 inhibitors) can be performed. HR-NSAIDs are being observed with increasing frequency, however, the pathogenesis behind some NSAIDS-associated clinical entities is still unclear. Diagnosis is mostly based on a thorough clinical history and confirmed by a drug challenge test. Clinical management is based on strict avoidance and use of alternative tolerated medications. Overall, all therapeutic decisions depend on the correct identification of the type of reaction the patient experienced.

The ABO blood group antigens in patients with oral lichenoid reaction.

Evaluating the association of ABO blood group with different delayed hypersensitivity reactions, such as oral lichenoid reaction (OLR), can provide a new perspective for clinical practice. Therefore, this study designed to investigate ABO blood group antigens in OLR patients. In this case-control study, the ABO blood group of 112 OLR patients and 117 individuals without oral lesions were included. Gender, age, characteristics of the lesions, medications and restorative materials recorded. Chi-square test used to compare the frequency of ABO blood groups in OLR patients with controls. The O blood group was significantly higher in OLR patients and all its subtypes. Also, there were significant relation between O blood group, and severity of lesions. The frequency of dysplasia was non-statistically significant higher in OLR patients with O blood group than other blood group. Based on the results of the present study, O blood group was significantly more in patients with lichenoid reaction than control group, and AB blood group was the lowest. Also, O blood group showed a positive association with the more severe form of OLR lesions and frequency of dysplasia.

Machine Learning in Allergic Contact Dermatitis: Identifying (Dis)similarities between Polysensitized and Monosensitized Patients

Background: Allergic contact dermatitis (ACD) is a delayed hypersensitivity reaction occurring in sensitized individuals due to exposure to allergens. Polysensitization, defined as positive reactions to multiple unrelated haptens, increases the risk of ACD development and affects patients’ quality of life. The aim of this study is to apply machine learning in order to analyze the association between ACD, polysensitization, individual susceptibility, and patients’ characteristics. Methods: Patch test results and demographics from 400 ACD patients (Study protocol Nr. 3765/2022), categorized as polysensitized or monosensitized, were analyzed. Classic statistical analysis and multiple correspondence analysis (MCA) were utilized to explore relationships among variables. Results: The findings revealed significant associations between patient characteristics and ACD patterns, with hand dermatitis showing the strongest correlation. MCA provided insights into the complex interplay of demographic and clinical factors influencing ACD prevalence. Conclusion: Overall, this study highlights the potential of machine learning in unveiling hidden patterns within dermatological data, paving the way for future advancements in the field.

One-Year Safety Evaluation of New Hyaluronic Acid Fillers (YYS Series): A Prospective, Multicenter, Observational Study.

With the continuous increasing availability of new filler products, each hyaluronic acid filler brand has distinctive pharmacokinetics, which may be associated with different complications. Therefore, the long-term safety of new generations of fillers should be evaluated. This prospective, multicenter, observational, postmarketing study ( ClinicalTrials.gov identifier: NCT04738019) aimed to investigate the incidence of delayed-onset nodules and adverse reactions after the injection of new hyaluronic acid fillers (YYS series) into the facial skin. Subjects scheduled to receive an injection YYS series filler were followed up for 52 weeks. The authors aimed to determine the incidence of a self-reported delayed-onset nodule-a visible or palpable nodule or mass at the injection site that was detected beyond the 14th day following the injection-during the 1-year follow-up period. Among the 1,022 subjects who received an injection of the YYS series, the incidences of delayed-onset nodules were 0% for YYS 360, YYS 540, and YYS 720. A 0.21% incidence (1 delayed hypersensitivity reaction) of a delayed-onset adverse reaction was noted for YYS 720, although none were reported for YYS 360 and YYS 540. In this study, a notably low frequency of adverse reactions associated with the YYS series was observed.