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Delayed drug hypersensitivity reactions are clinically diverse reactions that vary from isolated benign skin conditions that remit quickly with no or symptomatic treatment, drug discontinuation or even continued drug treatment, to the other extreme of severe cutaneous adverse reactions (SCARs) that are associated with presumed life-long memory T-cell responses, significant acute and long-term morbidity and mortality. Diagnostic “in clinic” approaches to delayed hypersensitivity reactions have included patch testing (PT), delayed intradermal testing (IDT) and drug challenges for milder reactions. Patch and IDT are, in general, performed no sooner than 4–6 weeks after resolution of the acute reaction at the maximum non-irritating concentrations. Functional in vitro and ex vivo assays have largely remained the province of research laboratories and include lymphocyte transformation test (LTT) and cytokine release enzyme linked ImmunoSpot (ELISpot) assay, an emerging diagnostic tool which uses cytokine release, typically IFN-γ, after the patient’s peripheral blood mononuclear cells are stimulated with the suspected drug(s). Genetic markers such as human leukocyte antigen have shown recent promise for both pre-prescription screening as well as pre-emptive and diagnostic testing strategies.

The objective of this study is to measure lymphocyte responses to metal antigens using MELISA (memory lymphocyte immunostimulation assay) test–modified lymphocyte transformation test (mLTT) and to evaluate metal sensitization in patients with and without the need of prosthetic surgery. This study is a case‐control retrospective survey. We retrospectively analyzed all patients from 2013 to 2018 who were referred to the Institute of Dental Medicine, General University Hospital in Prague, and First Faculty of Medicine, Charles University, Prague, either following joint prosthesis‐related complications or as a preoperative evaluation concerning metal hypersensitivity. For the control group, we selected healthy adults from our database. A group of 127 patients aged 25–81 years was chosen, 92 of which were female and 35 were male. The patients completed a special questionnaire aimed at information regarding their health status and history of metal exposure. After clinical examination, their peripheral blood samples were taken to perform mLTT. mLTT provided quantitative lymphocyte proliferation measurement, where a stimulation index of >2 indicated metal sensitivity. For statistical analysis, the Fisher’s exact test, χ 2 test, McNemar’s exact test Student’s paired t ‐test were used. By comparison of the study group and control group mLTT results, it can be stated that patients of the study group showed a higher level of lymphocyte reactivity to most of the tested metal antigens (Ag [silver], Cu [copper], Fe [iron], Mo [molybdenum], Pd [palladium], Pt [platinum], Ti [titanium], and Zn [zinc]) and an elevated incidence of metal hypersensitivity to Hg (mercury), Al (aluminum), Au (gold), Co (cobalt), Cr (chromium), Ni (nickel), and Sn (tin). The evaluation of the data obtained from patients in this study confirmed a significant clinical benefit of mLTT in diagnostics of metal hypersensitivity. Our study has revealed that the patients with the need of prosthetic surgery exhibited an elevated lymphocyte response to metal antigens. This result supports a metal‐specific adaptive immune response and suggests involvement of metal exposure as a trigger for their health problems. This knowledge could be helpful in effectively enhancing the treatment of patients with need of orthopedic joint prosthesis.

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.

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.

Background: The Roussel Uclaf Causality Assessment Method (RUCAM) is a validated tool for assessing causality in cases of suspected drug-induced liver injury (DILI). However, RUCAM cannot discriminate between concomitant hepatotoxic drugs with the same temporal sequence. Objective: To analyse the utility of the lymphocyte transformation test (LTT) for assisting updated RUCAM in 45 patients and 40 controls with a clinical diagnosis of DILI. Methods: Suspected DILI cases were detected through the Prospective Pharmacovigilance Program from Laboratory Signals in Hospital (PPLSH) or by consultations. The controls completed the drug therapy with no adverse reactions during the study period. A receiver operating characteristics (ROC) curve analysis was performed to calculate the optimal cut-off value for the stimulation index (SI), corresponding to the largest sum for the specificity and sensitivity values of LTT for true DILI cases. Results: Out of 45 patients diagnosed with DILI, 42 cases were detected by the PPLSH, two cases by consultation and one case by both methods. Most DILI cases (64.4%) arose during hospitalization. According to the biochemical parameters, 24 cases (53.3%) had the hepatocellular phenotype, 14 (31.1%) had the cholestatic phenotype, and 7 cases (15.6%) had the mixed phenotype. Considering the severity criteria, 7 (15.5%) cases were classified as moderate DILI, and 4 (8.9%) were severe DILI; there were no fatal cases. A total of 149 drugs (median/case, 3; IQR, 2–5) were suspected to be involved in the DILI cases (RUCAM score ≥3). In 8 cases, only one drug was suspected, and polypharmacy (≥5 drugs) was identified in 29% of the cases. Of all DILI cases, 46 (30.9%) of the 149 suspected drugs produced positive LTT results, and the LTT was positive in 34 (75.5%) of the 45 patients. No exposed controls produced positive LTT results. The optimal cut-off of 1.95 for the SI was obtained with a sensitivity of 77% and specificity of 100% (area under the curve, 0.91; 95% asymptotic confidence interval 0.84–0.97; p < 0.001). The sensitivity of the hepatocellular phenotype was 92%. Conclusion: Our results demonstrate that LTT is an add on strengthening causality in cases of suspected idiosyncratic DILI, especially for patients with several suspected drugs and a hepatocellular phenotype.

Drug-induced cytopenias are serious adverse drug reactions (ADRs), often challenging to diagnose. While causality algorithms offer high sensitivity and positive predictive values, they exhibit low specificity and negative predictive values for identifying the causative drug(s). Therefore, complementary diagnostic tools are required. This study aimed to evaluate the utility of the lymphocyte transformation test (LTT) in supporting the causality assessment of the Spanish Pharmacovigilance System (SPS) causality algorithm in the diagnosis of the implicated drug(s) in drug-induced cytopenias, using a sample of 40 cases and 85 controls. Suspected cytopenia cases were identified through the Proactive Pharmacovigilance Program for Laboratory Signals in Hospital or via pharmacovigilance consultation. Control patients completed their treatment without experiencing any ADR. A receiver-operating characteristic (ROC) curve analysis was performed to determine the optimal stimulation index (SI) cut-off for the LTT, maximizing the sum of specificity and sensitivity values to accurate identify cytopenias cases. The case group included 29 cases (72.5%) of agranulocytosis, 6 (15.0%) of neutropenia, 2 (5.0%) of haemolytic anaemia, 2 (5.0%) of bicytopenia and 1 (2.5%) of bone marrow aplasia in 39 patients. Most had ≥3 comorbidities (66.7%) and no previous allergies (71.8%). Eighty-four drugs were suspected as causative agents (SPS-score ≥+4), with metamizole being the most frequent (17.2%), followed by acetaminophen (9.1%) and amoxicillin-clavulanate (8.1%). Eight cases (20.0%) involved a single suspected drug, while two cases (5.0%) involved polypharmacy (≥5 drugs). LTT was positive in 75% of cases and in 1.2% of controls. Forty one (41.4%) of the 99 suspected drugs yielded positive LTT result. With an optimal SI cut-off of 1.95, the LTT achieved a sensitivity of 72% and a specificity of 99% (area under the curve, 0.86; 95% CI 0.77-0.96; < 0.001). With monitoring, drug re-exposure was fully tolerated in patients with negative LTT results (100%), but poorly tolerated in one-third of those with positive LTT results. A causality score below 6 and a negative LTT yielded a 100% negative predictive value for drug tolerance (95% CI: 94.4%-100%). This study demonstrates that the LTT can be a valuable tool for strengthening causality assessment in suspected drug-induced cytopenias.

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.

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/ ).

We report on a patient who developed acute liver failure while being treated with metamizole. After liver transplantation, the patient recovered rapidly. Liver biopsy showed massive necrosis and lobular infiltration of lymphocytes. A lymphocyte transformation test performed 20 months after transplantation was positive for metamizole. In vitro investigations with N -methyl-4-aminoantipyrine (MAA) and 4-aminoantipyrine (AA), the two active metabolites of metamizole, did not reveal relevant toxicity in HepG2 and HepaRG cells. The demonstration of activated lymphocytes by the lymphocyte transformation test and the absence of relevant cytotoxicity by MAA and AA in hepatocyte cell lines suggest an immunological mechanism of metamizole-associated hepatotoxicity.

Background Metal sensitivity as a cause for painful joint replacement has become increasingly prevalent; however, there is a lack of reported clinical outcome data from total knee arthroplasty patients with metal allergies. The purpose of this study was to determine whether patients presenting with a painful total knee arthroplasty with a positive metal sensitivity have improved outcomes following revision to a hypoallergenic implant. Methods A retrospective review was conducted for patients that underwent a revision total knee arthroplasty after metal sensitivity testing over a 3-year period from January 1, 2015, to December 31, 2017. Based on the results of sensitivity testing, patients underwent revision total knee arthroplasty to a hypoallergenic component or a standard component. Following revision, patients returned to the clinic at an interval of 6 weeks, 5 months, and 12 months for functional, pain, and satisfaction assessment. Outcomes were compared within and between sensitivity groups. Results Of the included patients, 78.3% (39/46) were positive for metal sensitivity. The most common metal sensitivity was to nickel (79.5%, 32/39). Both non-reactive and reactive patients significantly improved in range of motion after revision arthroplasty. The reactive group saw a 37.8% decrease in pain at 6 weeks post-revision ( p  < 0.001) Whereas, the non-reactive group only saw a moderate, non-significant improvement in pain reduction at 6 weeks post-revision (27.0%; p  = 0.29). Frequency of pain experienced did not vary significantly between groups. Maximum metal lymphocyte transformation test (LTT) sensitivity score did not correlate with pain level at the time of revision ( R 2  = 0.02, p  = 0.38) or percent improvement after revision ( R 2  = 0.001, p  = 0.81). Overall, all patients reported being very satisfied after revision total knee arthroplasty; there was no difference between positive and negative sensitivity groups ( W  = 62, p  = 0.89). Conclusions Patients presenting with a painful knee arthroplasty and positive metal LTT have improved pain scores, walking function, and range of motion following revision to a hypoallergenic component. This study also provides a treatment algorithm for patients presenting with a painful knee replacement, in order to provide effective and timely diagnosis and management.