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Summary: In vitro diagnostics for drug hypersensitivity reactions distinguish between serological and cellular‐based tests. A serological test used for the diagnosis of immediate type reactions is the detection of specific IgE antibodies. The cellular tests include the basophil activation test for immediate type reactions and the lymphocyte transformation test, which is mainly used to detect delayed type hypersensitivity reactions. Further cellular‐based tests are the CAST‐ELISA and the mast cell activation test. None of the above‐mentioned tests can definitively exclude an allergy if the result is negative. In addition, it is important to note that even a positive test result is not necessarily associated with an allergy but has to be interpreted in the clinical context. [ABSTRACT FROM AUTHOR]

Drug causality assessment in severe cutaneous adverse reactions (SCARs) remains challenging. We investigated the usefulness of in‐vivo drug patch tests (PT), ex‐vivo interferon (IFN)‐γ enzyme‐linked immunospot (ELISpot) assay, and lymphocyte transformation test (LTT) in 30 SCARs patients within the past 36 months. Drug PT yielded a 20% positivity rate (n = 6), while IFN‐γ ELISpot and LTT showed positive rates of 56.67% (n = 17) and 41.38% (n = 12), respectively. Combining the three tests resulted in an overall positive rate of 66.67% (n = 20) of cases. IFN‐γ ELISpot offered additional positivity, especially with oxypurinol. Employing a combined diagnostic approach may enhance the chances of obtaining a positive result. [ABSTRACT FROM AUTHOR]

Objectives: To know the frequency and characteristics of neurological manifestations of probable immune origin occurring after exposure to COVID-19 vaccination. In addition, to pre-study the usefulness of the Spanish pharmacovigilance system and lymphocyte transformation test in establishing causality. Methods: Retrospective case study, including patients admitted to the Neurology department from January 2021 to May 2022 with a probable neuroimmune disorder. Demographic, clinical and COVID-19 vaccination antecedent data were collected from medical records. Results: Froma total of 108 patients, 30 were excluded due to a different etiological diagnosis after follow-up. Thirty-six patients (46.2%) had received the COVID-19 vaccine in the previous 3 months (21.8% during the previous month). BioNTech-Pfizer vaccine was the most frequent in this group (63.9%). 69/108 were female and mean age 51.2 years (SD 22.59), with no significant difference with not recentlyvaccinated (U-Mann Whitney, p = 0.256). The neurological syndromes found were (vaccinated/total): polyradiculoneuropathy (8/16), encephalitis (5/11), multiple sclerosis relapse (5/16), optic neuritis (1/4), myelitis (3/6), cranial neuropathy (6/10), aseptic meningitis (1/3) and others (7/11). Acute immunosuppressive treatment was administered in 61.1% of cases and 47.2% presented complete clinical improvement, without significant differences with non-vaccinated patients (chisquare, p = 0.570). Eleven vaccinated patients were studied in the pharmacovigilance office for possible adverse drug reaction. Causality according to the Spanish pharmacovigilance system (SPVS) algorithm was "Related" to COVID-19 vaccine (score = 4) in 11 cases with positive in vitro study (lymphocyte transformation test) to polyethylene glycol-2000 and polysorbate-80 in 4 cases. Conclusion: Neuroimmune disorders appearing after administration of COVID-19 vaccine do not seem to present important differentiating clinical and/or evolutive features. Delayed hypersensitivity to vaccine excipients could be one of the pathophysiological mechanisms, and lymphocyte transformation test is a useful tool to identify it. [ABSTRACT FROM AUTHOR]

Background: This longitudinal prospective study aimed to assess orthodontic patients' immune system response to metal ion release in saliva. Methods: Thirty adult patients (18–35 years) were equally divided into three groups: groups at the end (G1) and beginning (G2) of multibracket appliances (MBA) treatment and a non-treated control group (G3). Participants were evaluated at four timepoints within 21 days, with saliva samples being analyzed for metal ion concentrations and blood for the lymphocyte transformation test (LTT). Results: There were no significant differences between groups or timepoints for saliva. LTT analyses revealed hypersensitivity in one-third of all patients and 50% of G2 for nickel, with three developing sensitizations after MBA insertion. All nickel-sensitized patients exhibited varying elevated saliva nickel concentrations. The most nickel-sensitized patients had low ion saliva loads. In borderline nickel-sensitization cases, saliva ion concentrations were up to 20 times higher than the reference. Hypersensitivity to palladium, gold, and mercury was also observed. Conclusions: These findings indicate that increased MBA ion release was not inherently linked to the immune response (Type-IV sensitization), as reactions occurred even with ion levels below thresholds. This underlines the need for a comprehensive evaluation of the immune response to metal ion release in orthodontic patients. [ABSTRACT FROM AUTHOR]

Background: Metal allergy remains a controversial topic in the orthopaedic community. It is not known if or to what degree metal sensitivity contributes to inflammatory soft tissue failures, unexplained residual pain, or clinical complications after total joint replacement with metal prostheses. Methods: We investigated the efficacy of the lymphocyte transformation test (LTT) in predicting adverse outcomes in patients after receiving a metal joint replacement. Our study cohort consists of 135 metal-on-metal hip resurfacing arthroplasty cases performed between 2013 and 2015. All study patients had an LTT preoperatively. We retrospectively analyzed clinical outcomes and failures for our cohort. Results: There was no difference in LTT reactivity between men and women. Of the 135 patients tested, 46 (34.1% of cohort) tested positive to at least one of the materials comprising their implant, and 78 patients (57.8%) had at least one reactive score to any component of the LTT. After a minimum follow-up of two years, we did not observe an allergic response to the implant in any patients. There were no failures requiring revision. We observed a 2.2% rate of moderate residual pain; no patients with residual pain tested positive for metal sensitivity. When patients with moderate-high LTT reactivity (30.4% of cohort) were compared to the remainder of the study group, there was no difference in HHS or UCLA activity score. There was no correlation between blood metal ion levels and LTT reactivity. Conclusion: We were unable to prove any predictive value of the LTT. We failed to identify hypersensitivity to metals in patients with metal-on-metal hip resurfacing arthroplasty. [ABSTRACT FROM AUTHOR]

Objectives: To know the frequency and characteristics of neurological manifestations of probable immune origin occurring after exposure to COVID-19 vaccination. In addition, to pre-study the usefulness of the Spanish pharmacovigilance system and lymphocyte transformation test in establishing causality.Methods: Retrospective case study, including patients admitted to the Neurology department from January 2021 to May 2022 with a probable neuroimmune disorder. Demographic, clinical and COVID-19 vaccination antecedent data were collected from medical records.Results: From a total of 108 patients, 30 were excluded due to a different etiological diagnosis after follow-up. Thirty-six patients (46.2%) had received the COVID-19 vaccine in the previous 3 months (21.8% during the previous month). BioNTech-Pfizer vaccine was the most frequent in this group (63.9%). 69/108 were female and mean age 51.2 years (SD 22.59), with no significant difference with not recently-vaccinated (U-Mann Whitney, p = 0.256). The neurological syndromes found were (vaccinated/total): polyradiculoneuropathy (8/16), encephalitis (5/11), multiple sclerosis relapse (5/16), optic neuritis (1/4), myelitis (3/6), cranial neuropathy (6/10), aseptic meningitis (1/3) and others (7/11). Acute immunosuppressive treatment was administered in 61.1% of cases and 47.2% presented complete clinical improvement, without significant differences with non-vaccinated patients (chi-square, p = 0.570). Eleven vaccinated patients were studied in the pharmacovigilance office for possible adverse drug reaction. Causality according to the Spanish pharmacovigilance system (SPVS) algorithm was “Related” to COVID-19 vaccine (score ≥ 4) in 11 cases with positive in vitro study (lymphocyte transformation test) to polyethylene glycol-2000 and polysorbate-80 in 4 cases.Conclusion: Neuroimmune disorders appearing after administration of COVID-19 vaccine do not seem to present important differentiating clinical and/or evolutive features. Delayed hypersensitivity to vaccine excipients could be one of the pathophysiological mechanisms, and lymphocyte transformation test is a useful tool to identify it.

Drug-related acute pancreatitis (AP), acute interstitial nephritis (AIN) and druginduced liver injury (DILI) are rare but serious adverse drug reactions (ADRs) that can have life-threatening consequences. Although the diagnosis of these ADRs can be challenging, causality algorithms and the lymphocyte transformation test (LTT) can be employed to help with the diagnosis. In this report, we present 3 cases of drug-related AP, AIN and DILI. The first case involved a patient with AP to lacosamide and to the excipient polysorbate 80 in pantoprazole. The second case involved a patient with DILI secondary to polyethylene glycol (PEG) excipients and amoxicillin-clavulanate. In case 3, AIN was considered to be the result of sensitization to excipients. Diagnoses were made using causality algorithms and the LTT. The LTT is a useful tool for helping diagnose drug-related AP and DILI, and it can be used to identify the specific drug or excipient causing the ADR. These cases highlight the importance of considering PEG and polysorbate excipients in the causality diagnosis of ADRs. [ABSTRACT FROM AUTHOR]

Apalutamide is an antiandrogen used to treat prostate cancer. Although it sometimes induces mild cutaneous adverse events and occasionally severe ones, clinical differences between severe and mild cases remain unclear. To assess the risks in patients experiencing apalutamide‐related cutaneous adverse events (ARCAEs), we aimed to characterize severe and mild ARCAEs in terms of onset time and lymphocyte transformation test (LTT) for apalutamide. We reviewed 41 ARCAE cases: 24 from our institute and 17 from the literature, comprising (i) eight severe cases including six with toxic epidermal necrolysis, one with acute generalized exanthematous pustulosis, and one with drug reaction with eosinophilia and systemic symptoms, and (ii) 33 mild cases. Patients with evere cases developed ARCAEs significantly earlier than patients with mild cases (5.2 vs 9.6 weeks). No severe cases appeared ≥8 weeks after initiation of apalutamide. LTTs showed positive results in two of seven mild cases (28.6%) and four of four severe cases (100.0%). In conclusion, we found that severe ARCAEs are characterized by earlier onset and LTT positivity. Dermatologists and urologists should pay special attention to patients who develop ARCAEs <8 weeks after initiating apalutamide and/or show positive LTT results. [ABSTRACT FROM AUTHOR]

The word “Kampo medicine” means the traditional Japanese herbal medicine. Even “natural herb” can cause drug-induced liver injury (DILI). In this review, the characteristics of Kampo medicine-induced liver injury (KMILI) are reported. The main causative herb involved in Kampo medicine is Scutellariae Radix. KMILI is based on certain hypersensitivity reactions. A small amount of Kampo medicine can cause liver injury, and KMILI can develop after a short latency period. The incidence of liver injury related to Scutellariae Radix is about 1%. KMILI is usually mild and not fatal. The latency period usually lasts 4 weeks to 24 weeks. Fatigue and loss of appetite are sometimes observed. Eosinophilia is not frequently observed. All three types of liver injuries are observed in KMILI: cholestatic, hepatocellular, and mixed types. In Japan, lymphocyte transformation test (LTT) has been generally used for the diagnosis of DILI; however, LTT is likely to yield false-positive result for Kampo medicines, and thus often leads to misdiagnosis in many cases. Recently, researchers reported that a specific human leukocyte antigen (HLA) genotype is possibly associated with KMILI. This hypothesis needs to be examined further. Although Kampo medicine is based on rich knowledge and experience that occurred over a period of thousands of years, much is still unknown about KMILI.

Drug-related acute pancreatitis (AP), acute interstitial nephritis (AIN) and drug-induced liver injury (DILI) are rare but serious adverse drug reactions (ADRs) that can have life-threatening consequences. Although the diagnosis of these ADRs can be challenging, causality algorithms and the lymphocyte transformation test (LTT) can be employed to help with the diagnosis. In this report, we present 3 cases of drug-related AP, AIN and DILI. The first case involved a patient with AP to lacosamide and to the excipient polysorbate 80 in pantoprazole. The second case involved a patient with DILI secondary to polyethylene glycol (PEG) excipients and amoxicillin-clavulanate. In case 3, AIN was considered to be the result of sensitization to excipients. Diagnoses were made using causality algorithms and the LTT. The LTT is a useful tool for helping diagnose drug-related AP and DILI, and it can be used to identify the specific drug or excipient causing the ADR. These cases highlight the importance of considering PEG and polysorbate excipients in the causality diagnosis of ADRs.

Abstract Background The null hypotheses were tested that intraoral bone augmentation using two different allogeneic materials has no impact on the patient’s blood levels of material-specific lymphocytes and on the immunohistochemical detection of pro-inflammatory cytokines IL-1α, IL1ß and TNF-α and T-cell markers CD4, CD8 in biopsies of the test groups. Methods In this prospective RCT, 60 systemically healthy participants were randomly assigned to two allogeneic test groups (1: Maxgraft®, freeze-dried, multiple donors, and 2: Puros®, solvent-dehydrated, single donor) and an autologous control group (10 patients). Plasma samples were collected pre-(T1) and postoperatively (2 weeks (T2) and 4 months (T3)). The Lymphocyte Transformation Test (LTT) was used for analyzing levels of transformed lymphocytes for type IV immune reactions by 3H-thymidine activity. Bone biopsies were harvested at T3 and immunohistochemically analyzed for IL-1α, IL1ß, TNF-α, CD4, CD8 and correlated with the immunological and clinical findings. Results A statistically significant difference between the tested materials was observed for LTT measurements at T3 (p = 0.033). Furthermore, three groups were identified: Group A (LTT negative T1-T3, n = 48), group B (LTT positive T1-T3, n = 7), group C (developing positive LTT at T2, n = 5). A highly significant elevation of IL-1α, IL1ß, TNF-α in patients of group C (p = 0.0001) and a significant elevation of CD4+ cells in patients of group B (p = 0.005) was shown. Conclusion Our data show that following allogeneic bone grafting, local and systemic immunological reactions can be detected in some patients. These findings were statistically significant for the timepoint T3 between the tested materials as well as for the groups B and C correlated with group A for both tested materials. Therefore, the null hypotheses were rejected. A preoperative compatibility test for allogeneic materials in order to improve patient safety and the predictability of these materials would be desirable. Trial registration Ethical commission of the Ärztekammer Hamburg, Germany (PV5211) as well as by the German Registry of Clinical Studies (DRKS00013010) on 30/07/2018 ( http://apps.who.int/trialsearch/ ).

Background: Metal allergy testing may influence clinical decision-making for patients undergoing a total knee arthroplasty (TKA). Limited data were found to examine the consistency of available testing modalities. This study compares different metal allergy test results and clinical outcomes after primary and revision TKAs in patients with and without metal hypersensitivity. Methods: Primary (n = 28) and revision (n = 20) TKA patients receiving hypoallergenic implants for metal allergies diagnosed by skin patch testing (SPT), lymphocyte proliferation testing (LPT), or lymphocyte transformation testing (LTT) were retrospectively reviewed. The agreement between tests was assessed by percentage and kappa statistic within patients who used multiple testing modalities. Postoperative clinical outcomes of these patients were compared to those of patients without metal hypersensitivity matched by age (±5 years), body mass index (±5), gender, and follow-up duration (±2 years). Results: SPT and LPT showed weak agreement for nickel and minimal agreement for cobalt. SPT and LTT showed minimal agreement for nickel; weak agreement for titanium, bone cement, vanadium, and zirconium; but strong agreement for chromium and cobalt. LPT and LTT agreement was weak. Compared to matched controls, metal hypersensitivity patients undergoing primary TKAs with hypoallergenic implants experienced less improvement in Knee Society Scores, Veterans RAND 12 physical component scores, and range of motion. Patients undergoing revision TKAs for multiple indications including metal hypersensitivity had worse clinical outcomes with significantly worse improvements in Knee Society functional scores compared to matched controls. Conclusions: Metal allergy tests produce conflicting results. Hypersensitivity patients may experience inferior clinical outcomes even with hypoallergenic implants. Clinician awareness may influence the choice of testing and improve preoperative counseling of this patient population.

Severe acute respiratory syndrome coronavirus 2 caused the global COVID-19 pandemic and public health crisis, and it led to the rapid development of COVID-19 vaccines, which can cause rare and typically mild hypersensitivity reactions (HRs). Delayed HRs to COVID-19 vaccines have been reported, and the excipients polyethylene glycol (PEG)2000 and polysorbate 80 (P80) are the suspected culprits. Skin patch tests do not help in diagnosing delayed reactions. We aimed to perform lymphocyte transformation tests (LTT) with PEG2000 and P80 in 23 patients with suspected delayed HRs. Neurological reactions (n = 10) and myopericarditis reactions (n = 6) were the most frequent complications. Seventy-eight percent (18/23) of the study patients were admitted to a hospital ward, and the median time to discharge was 5.5 (IQR, 3–8) days. Some 73.9% of the patients returned to baseline condition after 25 (IQR, 3–80) days. LTT was positive in 8/23 patients (5/10 neurological reactions, 2/4 hepatitis reactions and 1/2 rheumatologic reactions). All myopericarditis cases had a negative LTT. These preliminary results indicate that LTT with PEGs and polysorbates is a useful tool for identifying excipients as causal agents in HRs to COVID-19 vaccines and can play an important role in risk stratification in patients with HRs. [ABSTRACT FROM AUTHOR]

Diagnosing Drug Hypersensitivity Reactions (DHRs) could be a complicated process especially in children, since allergic‐like manifestation at this age is more often the expression of concomitant infections rather than a actual DHRs. In vivo tests are usually suggested as a first step; however, prick and intradermal tests could be painful and have shown different sensitivity and specificity among published studies. In some cases, in vivo tests such as Drug Provocation test (DPT) could be even contraindicated. Therefore, the need for in vitro testing is compelling, to add useful information along the diagnostic pathway and to limit the need of DPT. In this review, we analyze the different types of in vitro tests, focusing on those used more widely such as specific IgE and on those that are still for research settings, such as basophil activation test and lymphocyte transformation test, but that have shown some useful diagnostic potential. [ABSTRACT FROM AUTHOR]

Nivolumab belongs to immune checkpoint inhibitors (ICIs). ICIs‐induced kidney injury is rare and acute interstitial nephritis (AIN) is the majority. A 58‐year‐old woman had gastric cancer treated with nivolumab. Her serum creatinine (Cr) increased to 5.94 mg/dL post 2 cycles of nivolumab and co‐administered with acemetacin. A kidney biopsy showed acute tubular injury (ATI). Nivolumab rechallenge was done and Cr worsened again. The lymphocyte transformation test (LTT) indicated a strong positive for nivolumab. Although rare, ATI due to ICIs could not be ruled out, and LTT is a tool to identify the culprit. [ABSTRACT FROM AUTHOR]

Abstract Nivolumab belongs to immune checkpoint inhibitors (ICIs). ICIs‐induced kidney injury is rare and acute interstitial nephritis (AIN) is the majority. A 58‐year‐old woman had gastric cancer treated with nivolumab. Her serum creatinine (Cr) increased to 5.94 mg/dL post 2 cycles of nivolumab and co‐administered with acemetacin. A kidney biopsy showed acute tubular injury (ATI). Nivolumab rechallenge was done and Cr worsened again. The lymphocyte transformation test (LTT) indicated a strong positive for nivolumab. Although rare, ATI due to ICIs could not be ruled out, and LTT is a tool to identify the culprit.

To the Editor, The lymphocyte transformation test (LTT) is used for the in vitro detection of drug sensitization in assumed drug allergic reactions. Drug allergy, IL-5, IFN- , immediate type reaction, lymphocyte transformation test Keywords: drug allergy; IFN- ; IL-5; immediate type reaction; lymphocyte transformation test EN drug allergy IFN- IL-5 immediate type reaction lymphocyte transformation test 222 225 4 02/20/23 20230201 NES 230201 Key messages list IFN- secretion can be used as a read-out in the LTT in patients with Th2 phenotypes. [Extracted from the article]

Background: Stevens-Johnson syndrome is a severe drug reaction. Sulfonamides have been associated with drug reactions, complications, sequelae, even death. Case report: A 40-year-old female patient with a medical history of endometriosis and recently diagnosed chronic inflammatory ulcerative colitis. She was treated at the Allergology service of the San Juan de Dios Hospital of the Costa Rican Social Security Fund, and after 20 days of treatment with sulfasalazine she had a severe drug reaction on the skin, compatible with Stevens-Johnson syndrome. The lymphocyte transformation test was positive, confirming sulfasalazine as the causative agent. Conclusions: The lymphocyte transformation test is a useful method that can confirm the causative agent and prevent important complications in the future. [ABSTRACT FROM AUTHOR]

Background: The null hypotheses were tested that intraoral bone augmentation using two different allogeneic materials has no impact on the patient's blood levels of material-specific lymphocytes and on the immunohistochemical detection of pro-inflammatory cytokines IL-1α, IL1ß and TNF-α and T-cell markers CD4, CD8 in biopsies of the test groups. Methods: In this prospective RCT, 60 systemically healthy participants were randomly assigned to two allogeneic test groups (1: Maxgraft®, freeze-dried, multiple donors, and 2: Puros®, solvent-dehydrated, single donor) and an autologous control group (10 patients). Plasma samples were collected pre-(T1) and postoperatively (2 weeks (T2) and 4 months (T3)). The Lymphocyte Transformation Test (LTT) was used for analyzing levels of transformed lymphocytes for type IV immune reactions by 3H-thymidine activity. Bone biopsies were harvested at T3 and immunohistochemically analyzed for IL-1α, IL1ß, TNF-α, CD4, CD8 and correlated with the immunological and clinical findings. Results: A statistically significant difference between the tested materials was observed for LTT measurements at T3 (p = 0.033). Furthermore, three groups were identified: Group A (LTT negative T1-T3, n = 48), group B (LTT positive T1-T3, n = 7), group C (developing positive LTT at T2, n = 5). A highly significant elevation of IL-1α, IL1ß, TNF-α in patients of group C (p = 0.0001) and a significant elevation of CD4+ cells in patients of group B (p = 0.005) was shown. Conclusion: Our data show that following allogeneic bone grafting, local and systemic immunological reactions can be detected in some patients. These findings were statistically significant for the timepoint T3 between the tested materials as well as for the groups B and C correlated with group A for both tested materials. Therefore, the null hypotheses were rejected. A preoperative compatibility test for allogeneic materials in order to improve patient safety and the predictability of these materials would be desirable. Trial registration: Ethical commission of the Ärztekammer Hamburg, Germany (PV5211) as well as by the German Registry of Clinical Studies (DRKS00013010) on 30/07/2018 (http://apps.who.int/trialsearch/). [ABSTRACT FROM AUTHOR]

Purpose: The aims of this study were to determine the prevalence of metal hypersensitivity, and identify pre-operative factors which could predict susceptibility to hypersensitivity reactions among patients scheduled for primary total knee arthroplasty (TKA). The present study used a testing method consistent with the recognised biological response to metals. Methods: A prospective cross-sectional analysis of 220 patients was conducted. All patients received a testing protocol using lymphocyte transformation test to evaluate reactivity to possible contents of orthopaedic implants. Test response is interpreted as stimulation index (SI) values. A comprehensive questionnaire was used to evaluate prior exposure. Patients were categorised according to SI values and the odds ratios (OR) were calculated as comparative effect measure for each predetermined prior exposure factor. Results: The prevalence of metal sensitivity response was 28% (n = 61) among patients with susceptibility to at least one agent (SI = 2 to 4.9), and 3.2% (n = 7) among patients with true hypersensitivity (SI ≥ 5). The population-weighted prevalence, adjusted for sampling weights of symptomatic knee osteoarthritis, was SI ≥ 5 = 4.7% (95% CI 0.4–11.8%) and SI ≥ 2 = 35.2% (95% CI 24.8–48.6%). Stimulation index levels of response to materials were markedly varied with the highest being aluminium. Female sex, smoking history, cutaneous reaction to jewellery, occupational exposure, and dental procedures were among factors shown to increase the odds of having higher reactivity response to tested metals. Nevertheless, patients with well-functioning prior contralateral TKA did not appear at greater risk of having either sensitivity or susceptibility with odds ratio (OR) = 0.2 (95% CI 0.01–3.2), p: NS and OR = 0.6 (95% CI 0.3–1.2), p: NS, respectively. Prior positive patch test was neither predictor of susceptibility to hypersensitivity OR = 1.2 (95% CI 0.6–2.6) p: NS nor predictor of true hypersensitivity OR = 0.7 (95% CI 0.08–6.1), p: NS. Conclusion: Among patients scheduled for primary TKA with no prior clinical features of metal allergy the prevalence of true hypersensitivity to at least one metal is just over 3%. Patients are likely to encounter a material to which they have pre-existing susceptibility to hypersensitivity. With certain prior exposure factors, there was increased susceptibility to metal hypersensitivity reaction evoking an acquired condition. Level of evidence: Level II, prospective cross-sectional study. [ABSTRACT FROM AUTHOR]

Background: Several studies have suggested that the known biomarkers and the diagnostic scales are unreliable for the diagnosis of Kampo‐induced liver injury (KMILI). Diagnostic Biomarkers: The lymphocyte transformation test (LTT) for Kampo medicines is likely to give false positive results, while the normal level of the basophil activation test (BAT) for diagnosing Kampo liver injury remains uncertain. Diagnostic Scale: Due to the lack of reliable biomarkers, diagnostic scales have been developed; however, the Digestive Disease Week [DDW])‐Japan criteria, which is widely used in Japan, has extremely low specificity for diagnosing KMILI. Conclusion: The diagnosis of KMILI remains challenging, and we eagerly await the development of reliable biomarkers for KMILI. [ABSTRACT FROM AUTHOR]

COVID-19, lymphocyte transformation test, SARS-CoV-2, BNT162b2, Erythema multiforme Keywords: BNT162b2; COVID-19; Erythema multiforme; lymphocyte transformation test; SARS-CoV-2 EN BNT162b2 COVID-19 Erythema multiforme lymphocyte transformation test SARS-CoV-2 e381 e385 5 11/14/22 20221101 NES 221101 Dear Editor, As more people are being vaccinated for SARS-CoV-2, its cutaneous adverse reactions are increasing. Erythema multiforme following vaccination for SARS-CoV-2: Report of a case and review of the literature - Secondary Publication. [Extracted from the article]

Background and Aims: Vitamins are bioactive compounds naturally found in many different types of food and required by the human body for many biological functions and enzymatic activities. Due to their antioxidant properties, certain vitamin derivatives have been synthesized for inclusion in many cosmetics, thus leading to an increasing incidence of allergic contact dermatitis (ACD) cases. Therefore, the present review may be helpful to provide an insight into the sensitizing role of at least certain vitamins and may also offer possible patch test alternatives for definitive diagnosis. Methods: This study was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA) guidelines. Literature search regarding ACD cases to vitamins was performed using the Medline, PubMed, Scopus, EMBASE, and Google Scholar databases from January 1940 up to June 2021. Results: A total of 4494 articles matched the keywords used for the researched. Records removed before screening included 15 duplicate articles and 3429 not eligible articles (e.g., not written in English, studies on animals, not relevant to the topic). A total of 1050 articles underwent the screening phase and 258 were therefore excluded as they were not primary studies. Subsequentially, 792 articles were considered eligible for the review and 688 of them were finally excluded as they did not report the outcome of interest. Therefore, 104 articles were definitely included in the present review. Conclusion: ACD to vitamins is still probably an underestimated issue in cosmetology, as many vitamins are considered "natural" and therefore "safe" ingredients. On the contrary, according to current literature, almost all vitamins contained in topical products are able to induce allergic reactions, with the exception of vitamin B2 and vitamin B9. Patch tests are not standardized, thus leading to difficulties in diagnosis. [ABSTRACT FROM AUTHOR]

Abstract Background and Aims Vitamins are bioactive compounds naturally found in many different types of food and required by the human body for many biological functions and enzymatic activities. Due to their antioxidant properties, certain vitamin derivatives have been synthesized for inclusion in many cosmetics, thus leading to an increasing incidence of allergic contact dermatitis (ACD) cases. Therefore, the present review may be helpful to provide an insight into the sensitizing role of at least certain vitamins and may also offer possible patch test alternatives for definitive diagnosis. Methods This study was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA) guidelines. Literature search regarding ACD cases to vitamins was performed using the Medline, PubMed, Scopus, EMBASE, and Google Scholar databases from January 1940 up to June 2021. Results A total of 4494 articles matched the keywords used for the researched. Records removed before screening included 15 duplicate articles and 3429 not eligible articles (e.g., not written in English, studies on animals, not relevant to the topic). A total of 1050 articles underwent the screening phase and 258 were therefore excluded as they were not primary studies. Subsequentially, 792 articles were considered eligible for the review and 688 of them were finally excluded as they did not report the outcome of interest. Therefore, 104 articles were definitely included in the present review. Conclusion ACD to vitamins is still probably an underestimated issue in cosmetology, as many vitamins are considered “natural” and therefore “safe” ingredients. On the contrary, according to current literature, almost all vitamins contained in topical products are able to induce allergic reactions, with the exception of vitamin B2 and vitamin B9. Patch tests are not standardized, thus leading to difficulties in diagnosis.

• The present study shows that the novel SARS-CoV-2 lymphocyte transformation test (LTT) may improve the identification of those with infection or vaccine-induced immunity to the coronavirus and our data suggests that this new approach can be rolled out to a range of clinical situations. • The SARS-CoV-2 LTT can not only differentiate between acquired immunity due to natural infection or vaccination, but it may also help us examine and understand the complexity of the cellular immune response at an individual level. Both infection with and vaccination against SARS-CoV-2 trigger a complex B-cell and T-cell response. Methods for the analysis of the B-cell response are now well established. However, reliable methods for measuring the T-cell response are less well established and their usefulness in clinical settings still needs to be proven. Here, we have developed and validated a T-cell proliferation assay based on 3H thymidine incorporation. The assay is using SARS-CoV-2 derived peptide pools that cover the spike (S), the nucleocapsid (N) and the membrane (M) protein for stimulation. We have compared this novel SARS-CoV-2 lymphocyte transformation test (SARS-CoV-2 LTT) to an established ELISA assay detecting Immunoglobulin G (IgG) antibodies to the S1 subunit of the SARS-CoV-2 spike protein. The study was carried out using blood samples from both vaccinated and infected health care workers as well as from a non-infected control group. Our novel SARS-CoV-2 LTT shows excellent discrimination of infected and/or vaccinated individuals versus unexposed controls, with the ROC analysis showing an area under the curve (AUC) of > 0.95. No false positives were recorded as all unexposed controls had a negative LTT result. When using peptide pools not only representing the S protein (found in all currently approved vaccines) but also the N and M proteins (not contained in the vast majority of vaccines), the novel SARS-CoV-2 LTT can also discriminate T-cell responses resulting from vaccination against those induced by infection. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a serious genetic condition affecting the respiratory and digestive systems impacting life expectancy.1 Patients with CF often require frequent high-dose antibiotics associated with cutaneous hypersensitivity in 30%-50% of patients.2 The discovery of cystic fibrosis transmembrane regulator (CFTR) modulators has transformed CF treatment. Keywords: cystic fibrosis (CF); Cystic fibrosis transmembrane regulator (CFTR); Drug related eosinophilia with systemic symptoms (DRESS); interferon-gamma ELIspot; lymphocyte transformation test EN cystic fibrosis (CF) Cystic fibrosis transmembrane regulator (CFTR) Drug related eosinophilia with systemic symptoms (DRESS) interferon-gamma ELIspot lymphocyte transformation test 1 4 4 06/29/22 20220601 NES 220601 PEER REVIEW The peer review history for this article is available at https://publons.com/publon/10.1111/pai.13815. Cystic fibrosis (CF), Cystic fibrosis transmembrane regulator (CFTR), Drug related eosinophilia with systemic symptoms (DRESS), interferon-gamma ELIspot, lymphocyte transformation test. [Extracted from the article]

Severe acute respiratory syndrome coronavirus 2 caused the global COVID-19 pandemic and public health crisis, and it led to the rapid development of COVID-19 vaccines, which can cause rare and typically mild hypersensitivity reactions (HRs). Delayed HRs to COVID-19 vaccines have been reported, and the excipients polyethylene glycol (PEG)2000 and polysorbate 80 (P80) are the suspected culprits. Skin patch tests do not help in diagnosing delayed reactions. We aimed to perform lymphocyte transformation tests (LTT) with PEG2000 and P80 in 23 patients with suspected delayed HRs. Neurological reactions (n = 10) and myopericarditis reactions (n = 6) were the most frequent complications. Seventy-eight percent (18/23) of the study patients were admitted to a hospital ward, and the median time to discharge was 5.5 (IQR, 3–8) days. Some 73.9% of the patients returned to baseline condition after 25 (IQR, 3–80) days. LTT was positive in 8/23 patients (5/10 neurological reactions, 2/4 hepatitis reactions and 1/2 rheumatologic reactions). All myopericarditis cases had a negative LTT. These preliminary results indicate that LTT with PEGs and polysorbates is a useful tool for identifying excipients as causal agents in HRs to COVID-19 vaccines and can play an important role in risk stratification in patients with HRs.

Background: Identification of culprit drugs when managing cutaneous drug eruptions is essential. Causality assessment methods (CAMs) have been proposed, including lab-based techniques. However, no consensus guidelines exist. Objectives: To identify and map the functionality and feasibility of lab-based CAMs. Methods: A scoping review was conducted to identify culprit drug identification methods. Publications on lab-based methods were analyzed. Medline, Embase, and Cochrane Central Register of Controlled Trials databases were searched. Results: Twenty-five publications met inclusion criteria. Nine lab-based CAMs were studied, including lymphocyte transformation test, cytokine measurement (ELISpot, ELISA, beads array assay), modified IFN-ɣ ELISpot, CellScan, histamine release, granzyme B-ELISpot, intracellular granulysin, lymphocyte toxicity assay, and HLA allele genotyping. Diagnostic accuracy was reported for 8/9 methods. Clinical assessment and operational algorithms were commonly used as validation benchmarks. Lab-based methods were assessed at different phases of a drug eruption including in the acute (18.1%), recovery (27.3%), acute and recovery (27.3%), or an unspecified phase (27.3%). Lymphocyte transformation test (specificity 30% to 100%, sensitivity 27% to 73%) and cytokine measurement (specificity 76% to 100%, sensitivity 20% to 84%) were the most common methods studied. Conclusions: Lab-based CAMs can be low-risk, effective, and complementary of clinical methods. High-quality studies are needed to adequately develop and validate these tools for clinical practice. [ABSTRACT FROM AUTHOR]

At present, iodinated contrast media (ICM) are mostly non-ionic, have low osmolality, and are safe. Even if adverse drug reactions (ADRs) occur, most are chemo-toxic symptoms and require only observation or H1 antihistamines. However, rare, unpredictable, and even life-threatening hypersensitivity can still occur. The aim of this review is to summarize the issues that all relevant staff need to know about and be able to respond to. The most significant risk factor for ICM hypersensitivity is a history of ICM hypersensitivity. For high-risk populations, we must cautiously weigh the advantages and disadvantages of premedication and be aware that breakthrough reactions may still occur. The best policy for patients with a history of severe ICM hypersensitivity is to avoid the same ICM. If ICM are inevitable, skin tests, in vitro tests, and drug provocation tests may help to find a feasible alternative that is safer. The severity of the hypersensitivity is correlated with the positivity rate of these tests, so there is no need for further investigations for patients with only mild reactions. We should also keep in mind that even excipients in ICM may induce hypersensitivity. Detailed, standardized documentation is essential for correct diagnosis and the prevention of future occurrence. [ABSTRACT FROM AUTHOR]

Tuberculin skin test, also known as the tuberculin or purified protein derivative (PPD) test, is an extensively applied diagnostic test for the detection of primary infection with Mycobacterium tuberculosis (Mtb). The production of PPD is accompanied by some difficulties that require a series of modifications in the production and purification processes. The present study aimed to determine the facilitation level of the manufacturing process by modifying evaluation methods for the production of PPD tuberculin. Mtb strains were cultured in Lowenstein-Jensen media, and the cultured strains were inoculated into the Dorset-Henley liquid medium by the biphasic medium of potato-Dorset-Henley. After incubation, flasks containing cultured strain were selected for bacterial inactivation, and the optimal gamma radiation dose(s) was determined. Tuberculoproteins were precipitated by ammonium sulfate (AS) and Trichloroacetic acid (TCA). Protein concentration was determined using the Bradford and Kjeldahl protein assay methods. Finally, the lymphocyte transformation test and potency test were performed. Based on the results, the Dorset-Henley liquid medium is suitable for the massive growth of the bacterium. The transferal of Mtb from solid to liquid medium was directly carried out without intermediate culture. It was found that during tuberculoprotein production, heating at 100°C for 3 h would be safe for killing mycobacterium. Furthermore, the simultaneous use of heating and gamma irradiation (8 kGgy) killed all of the mycobacteria, while doses of 1, 1.5, and 7 kGy decreased a significant number of bacterial cells. The results also indicated that the concentration of tuberculoprotein extracted by TCA precipitation method was higher than that obtained by AS precipitation. The tuberculoproteins which were produced by these two methods in the lymphocyte transformation test were not significantly different in terms of potency (P>0.05). Moreover, due to the high volume of produced protein, the protein measurement was more efficiently carried out by the Kjeldahl method, compared to the Bradford method. Finally, the results of the present study demonstrated that in addition to the novel approach of gamma irradiation, optimum methods are efficient and applicable in the production of PPD tuberculin.

Although hepatitis C virus (HCV) infection is often associated with extrahepatic cutaneous manifestations such as lichen planus, it is unclear whether HCV per se or HCV-specific immune responses play a pathophysiological role in the development of HCV-related cutaneous diseases. We recently treated a patient who developed parapsoriasis en plaque-like lesions after ingestion of various drugs. She showed hypersensitivity to multiple drugs after interferon therapy. Her clinical course was complicated by flares of parapsoriasis-like lesions which returned at precisely the same sites. The flares had begun within hours of ingesting nicardipine hydrochloride, amlodipine besilate, candesartan cilexetil and atenolol for the first time despite showing a low level of HCV RNA. Interestingly, the flares gradually subsided during continued treatment with these drugs while her HCV RNA level paradoxically increased: thus, there was an inverse correlation between flares and HCV RNA level. The eruptions were eventually diagnosed as fixed drug eruption, although the clinical manifestations mimicked parapsoriasis en plaque. Our results suggest that multiple drug hypersensitivity could be induced by antiviral immune responses that are cross-reactive to multiple drugs, but not by HCV per se.

Purpose: The purpose of this study is to determine if there is a relationship between clinical outcomes and nickel allergy by evaluating asymptomatic total knee arthroplasty (TKA) patients with well-functioning implants through quantitative metal allergy (MA) testing., Methods: A prospective case series was performed on 50 patients with well-functioning TKA of various implant types. Inclusion criteria included primary TKA with a minimum 12-month follow-up and Oxford knee score (OKS) ≥ 40. A commercially available Lymphocyte Transformation Test measured the amount of a hypersensitivity lymphocyte immune response after exposure to a particular antigen. MA results were stratified based on the stimulation index (SI). The Cochran-Mantel-Haenzel test was used to test the homogeneity of metal reactivities. The Wilcoxon-Mann-Whitney test was used to compare individual metal SI by gender and the association of OKS and metal SI was ascertained with the Spearman correlation., Results: Nickel, cobalt, and chromium do not have the same reactivity scores (p < 0.001), and only nickel showed reactive/highly reactive scores. Females were found to have 3.41 times the odds of males for higher Ni reactivity (p = 0.0295, odds ratio [OR], 95% confidence interval [CI] = 3.41 [1.13-10.3]) only. Clinically, there was no correlation between metal SI and OKS score by metal (Ni rho = -0.1779; Co rho = -0.0036; Cr rho = -0.1748)., Conclusion: This is the first study looking at MA in well-functioning TKA. There is no correlation between clinical results and nickel reactivity. Surgeons should exercise caution when revising a painful or poorly functioning TKA based solely on a 'positive' Nickel Allergy test and look for other possible reasons for failure., Level of Evidence: Level II., (© 2024 European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Deep-seated dermatomycosis is a rare disease that is often caused by trauma and/or systemic immunodeficiency. We describe a case of chromoblastomycosis complicated by hyalohyphomycosis that occurred simultaneously at different sites. A 92-year-old Japanese man who had been taking oral prednisolone for an IgG4-related respiratory disease visited our clinic. He developed brownish plaques with grayish-white scales with pseudo-carcinomatous hyperplasia and numerous brownish muriform cells developing in the dermis of his right hand, and multiple painful abscesses with pustules and papules and numerous hyphae within and around the histiocytes in the dermis of his right lower leg. Upon skin tissue culture and DNA sequencing, Exophiala xenobiotica and Scedosporium apiospermum were detected separately. He had severe cellular immunodeficiency indicated by low levels in the phytohemagglutinin (PHA)-stimulated lymphocyte transformation test (LTT) and serum interferon-gamma (IFN-γ), although his humoral immunity was normal. The patient died of bacterial pneumonia, despite antifungal drug treatment for 2 months. IFN-γ producing type 1 T helper (Th1) cells play an important role in the defense against fungal infections, however, corticosteroids specifically suppress Th1 cell responses and promote the induction of fungal infection. Measurement of PHA-stimulated LTT and serum IFN-γ may be useful in determining the severity and prognosis of deep-seated dermatomycosis in patients undergoing corticosteroid treatment., (© 2024 Japanese Dermatological Association.)

The immune checkpoint inhibitor pembrolizumab is now considered a first-line treatment for recurrent or metastatic head and neck squamous cell cancer. Pembrolizumab is less toxic than conventional chemotherapy but may result in immune-related adverse events. We report a case in which liver injury occurred just two days after the administration of pembrolizumab plus chemotherapy. A 48-year-old woman achieved a complete response after chemoradiotherapy for cT2N3bM0 squamous cell carcinoma of the oropharynx with multiple lymph node metastases. However, the tumor recurred one year later, and she was started on pembrolizumab plus chemotherapy. On day 3, her alanine aminotransferase and aspartate transaminase concentrations markedly increased. She was initially diagnosed with drug-induced liver injury and all medications were withdrawn. Her liver function recovered within two weeks without intervention. The lymphocyte transformation test was only positive for pembrolizumab. Clinicians should consider pembrolizumab-induced allergic hepatitis as a possible cause of liver injury after excluding liver metastasis and immune-related adverse events., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Ethics Review Committee of Kansai Rosai Hospital issued approval IRB# 230501. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Saho Nakatani, Munehisa Fukushima, Shiro Akahani declare(s) a grant from The Japan Society for the Promotion of Science (JSPS) KAKENHI. This work was partially supported by JSPS KAKENHI Grant Number JP24K12657. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nakatani et al.)

Abstract Previously positive lymphocyte transformation test (LTT) results changed to negative during influenza infection. As observed in the current article, results of LTT may be influenced by infection; therefore, it is crucial to consider the timing of LTT.

Introduction: Mild non‐immediate reactions (NIRs) to beta‐lactams (BLs) are the most frequent manifestation of drug allergy in children. The diagnostic approach is complex as the utility of skin tests (STs) and lymphocyte transformation tests (LTTs) is controversial. Drug provocation test (DPT) is the gold standard, although no standardized protocols exist. We aimed to investigate the utility of DPT in a unique dose without previous STs, and LTTs in the diagnosis of NIRs to BLs in children. Methods: We prospectively evaluated children 0–14 years old referred to the Regional University Hospital of Málaga during 2017–2020 reporting NIRs to BLs. We performed a DPT with a unique dose followed by regular treatment at home. If positive, STs and LTTs were done after the reaction had disappeared. Results: We included 194 children, having 24 (12.4%) a positive DPT. The main culprit was AX (70.1%) followed by AX‐clavulanic acid (CLV) (26.8%) and the main symptoms maculopapular exanthema (MPE) (49.5%) and delayed‐urticaria (48.5%). A decrease (p = 0.013) in the interval of days between drug administration and onset of symptoms was observed in positive DPT compared with the original reaction (3.5 vs 6 days), with no differences in the overall percentage of MPE and delayed‐appearing urticaria (p = 0.551). No severe reactions occurred during DPT. Moreover, STs were positive in 13.33% and LTTs in 52.9%. Conclusions: Single‐dose DPT without previous STs is a safe and useful way to assess NIRs to BLs in children. LTT has shown to be useful, confirming a T‐cell mechanism involved in these reactions. [ABSTRACT FROM AUTHOR]

Background: An allergic reaction may rarely cause a painful or stiff total knee arthroplasty (TKA). However, no consensus diagnostic criteria for TKA immune failure exist. Lymphocyte transformation testing (LTT) measures immune sensitivity to various materials, but its role in diagnosing an allergic reaction to a TKA has not been established. This study compares TKA periprosthetic tissues in a) LTT-positive versus -negative patients and b) patients with conventional CoCrNi versus hypoallergenic implants.Methods: Periprosthetic tissues from 26 revision cases of well-fixed, aseptic, but painful or stiff TKAs were analyzed. Twelve patients LTT positive for nickel (Ni) were matched as a cohort to 6 LTT-negative patients. In 4 patients LTT positive for Ni, tissue from first revision of CoCrNi implants was compared with tissue from subsequent revision of hypoallergenic implants. Histology was evaluated using the aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL) score.Results: No correlation was found between LTT and any ALVAL score component. The mean total ALVAL score was 3.8 ± 1.5 for LTT-negative patients and 3.3 ± 1.2 for LTT-positive patients (P = .44). The mean total ALVAL score at revision of CoCrNi implants was 3.0 ± 1.8 compared with 5.8 ± 0.5 at rerevision of hypoallergenic implants (P = .053).Conclusion: Periprosthetic TKA tissue reactions were indistinguishable between LTT-positive and -negative patients. LTT does not predict the periprosthetic tissue response. ALVAL scores of hypoallergenic revision implant tissue trended higher than primary CoCrNi implant tissue. A positive LTT may not indicate that a periprosthetic immune reaction is the cause of pain and stiffness after TKA.Level Of Evidence: 3, retrospective cohort study. [ABSTRACT FROM AUTHOR]

Amoxicillin (AX) and clavulanic acid (CLV) are the betalactam antibiotics (BLs) most used to treat bacterial infections, although they can trigger immediate hypersensitivity reactions (IDHRs). The maturation analysis of monocyte-derived dendritic cells (moDCs) and their capacity to induce proliferative response of lymphocytes are useful to test the sensitisation to a drug, although without optimal sensitivity. Nevertheless, this can be improved using directly isolated DCs such as myeloid DCs (mDCs). mDCs and moDCs were obtained from 28 allergic patients (AP), 14 to AX, 14 to CLV and from 10 healthy controls (HC). The expression of CCR7, CD40, CD80, CD83, and CD86 was analysed after stimulation with both BLs. We measured the capacity of these pre-primed DCs to induce drug-specific activation of different lymphocyte subpopulations, CD3+, CD4+, CD8+, CD4+Th1, and CD4+Th2, by flow cytometry. Higher expression of CCR7, CD40, CD80, CD83, and CD86 was observed on mDCs compared to moDCs from AP after stimulating with the culprit BL. Similarly, mDCs induced higher proliferative response, mainly of CD4+Th2 cells, compared to moDCs, reaching up to 67% of positive results with AX, whereas of only 25% with CLV. mDCs from selective AP efficiently recognise the culprit drug which trigger the IDHR. mDCs also trigger proliferation of lymphocytes, mainly those with a Th2 cytokine pattern, although these responses depend on the nature of the drug, mimicking the patient's reaction. • Activation, maturation, and migration markers on mDCs can be used to assess sensitisation in a more efficiently way than using moDCs. • Drug pre-primed mDCs have a greater capacity to activate autologous lymphocytes compared to moDCs. • The inclusion of pre-primed mDCs in LTT induced proliferative response of CD4+Th2 cells mimicking the acute reaction. [ABSTRACT FROM AUTHOR]

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse drug reactions, and SJS/TEN in infancy is rare. Here, we present a case of a 4-month-old infant with generalized exanthema, flaccid blisters, and mucosal erosions. He was diagnosed with TEN within 2 days using a granulysin quick screen test and subsequently verified with histopathologic findings. Transmission of cephalexin through breastfeeding was suspected to be a possible cause based on drug history, breastfeeding history, and lymphocyte transformation test. The patient survived with only skin hyperpigmentation remaining.

Thus, even if it does not seem to be mandatory sending to an allergy workup all these patients, it can still be useful to make an allergy evaluation as even a low % detection rate can help patients' management (since test specificity if often close to 100%) in order to give indication about avoiding drugs in the future. Keywords: children; erythema multiforme; hypersensitivity drug reaction; lymphocyte transformation test; Mycoplasmapneumoniae; Mycoplasma-induced rash and mucositis; paediatrics; Stevens-Johnson syndrome EN children erythema multiforme hypersensitivity drug reaction lymphocyte transformation test Mycoplasmapneumoniae Mycoplasma-induced rash and mucositis paediatrics Stevens-Johnson syndrome 740 744 5 05/08/21 20210501 NES 210501 To the Editor, I Mycoplasma pneumoniae i (MP) infection is a common cause of community-acquired pneumonia in children sometimes associated with intriguing mucocutaneous manifestations variable in severity such as erythema multiforme (EM) or Stevens-Johnson syndrome (SJS).1 Various papers attempted to distinguish the clinical features of MP-associated diseases, but the topic is still confusing, ending in conflicting classifications.2-6 A systematic review suggested that they should be considered as distinct entities from the genuine drug-induced SJS, introducing the term ' I Mycoplasma i -induced rash and mucositis' (MIRM).7 Other authors used the expression ' I Mycoplasma pneumoniae i -associated mucositis' (MPAM) to distinguish a variant with isolated mucosal involvement without rash.8 Recently, MIRM have been included in a larger group called RIME (reactive infectious mucocutaneous eruption).9 Erythema multiforme is a cutaneous rash characterized by typical target lesions. Children, erythema multiforme, hypersensitivity drug reaction, lymphocyte transformation test, Mycoplasmapneumoniae, Mycoplasma-induced rash and mucositis, paediatrics, Stevens-Johnson syndrome. [Extracted from the article]