Association of interleukin-6 and tumor necrosis factor-α with mortality in hospitalized patients with cancer.

BACKGROUND: Severe cutaneous adverse reactions (SCARs) are associated with high morbidity and mortality in patients with cancer. Early identification and treatment of SCARs may improve outcomes. OBJECTIVE: To identify biomarkers to predict outcomes in hospitalized patients with cancer who developed SCARs. METHODS: Retrospective review of 144 hospitalized patients with cancer with a morbilliform rash, recorded testing for serum cytokines (interleukin [IL]-6, IL-10, and tumor necrosis factor [TNF]-α) or elafin, and a dermatology consultation. Rashes were categorized as simple morbilliform rash without systemic involvement or complex morbilliform rash with systemic involvement. RESULTS: Fifty-four of 144 (37.5%) patients died during follow-up. Elevated levels of IL-6, IL-10, and TNF-α were associated with decreased survival. Overall survivals in patients with elevated levels of IL-6, IL-10, and TNF-α were 53.7%, 56.6%, 53.6%, respectively, compared with 85.7%, 82.5% and 83.6%, respectively, in those with lower levels. Patients with increased levels of both IL-6 and TNF-α had a nearly 6-fold increase in mortality (hazard ratio, 5.82) compared with patients with lower levels. LIMITATIONS: Retrospective design, limited sample size, and high-risk population. CONCLUSIONS: Hospitalized patients with cancer with rash and elevated IL-6 and TNF-α were nearly 6 times more likely to die over the course of follow-up. These biomarkers may serve as prognostic biomarkers and therapeutic targets for this high-risk population.

Clinicopathologic overlap of psoriasis, eczema, and psoriasiform dermatoses: A retrospective study of T helper type 2 and 17 subsets, interleukin 36, and ß-defensin 2 in spongiotic psoriasiform dermatitis, sebopsoriasis, and tumor necrosis factor α inhibitor-associated dermatitis.

BACKGROUND: T helper (Th) type 17 and Th2 cells mediate psoriasis and eczema, respectively. Some dermatoses exhibit overlapping clinicopathologic features, and their immunopathology is relatively unexplored. OBJECTIVE: To determine whether Th17 and Th2 subsets and interleukin (IL) 36 and ß-defensin 2 (BD-2) markers of IL-17 signaling expression can discriminate between biopsy samples of psoriasis and eczematous/spongiotic dermatitis and to use those markers to immunophenotype cases with clinicopathologic overlap. METHODS: A retrospective study was performed on biopsy samples of psoriasis, eczema/spongiotic dermatitis, sebopsoriasis, tumor necrosis factor α inhibitor-associated psoriasiform dermatitis, and ambiguous cases diagnosed as spongiotic psoriasiform dermatitis. Dual CD4/GATA3 and CD4/RORC, IL-36, and BD-2 immunohistochemistry was performed. RESULTS: IL-36 and BD-2 were strongly expressed in biopsy samples of psoriasis compared with eczema/spongiotic dermatitis. No significant differences were observed in the percentages of Th2 and Th17 cells between disease types. Strong expression of IL-36 and BD-2 was observed in a subset of spongiotic psoriasiform dermatitis, sebopsoriasis, and tumor necrosis factor α inhibitor-associated psoriasiform dermatitis biopsy samples. LIMITATIONS: This was an exploratory study with a small sample size. No multiple testing adjustment was done. Clinical follow-up was limited. CONCLUSIONS: In cases with clinicopathologic overlap between psoriasis and spongiotic dermatitis, IL-36, and to a lesser extent BD-2, may be used to assess for a psoriasis-like/IL-17 phenotype, which could inform therapeutic clinical decisions.

HIV infection confers distinct mechanisms in severe drug eruption: Endogenous virus activation with aberrant Th2/Th1 and CD8+ T cells function.

Severe drug eruption (SDE), a common skin disease, becomes dangerous when it occurs in patients with human immunodeficiency virus (HIV). However, the molecular mechanisms are poorly understood. Forty patients including HIV+ SDE+ (n = 15), HIV- SDE+ (n = 15) and HIV+ SDE- (n = 10) subjects were enrolled in our study. All HIV+ patients were at acquired immune deficiency syndrome (AIDS) stage. Serum levels of TNF-α, IFN-γ, IL-4, IL-13, IL-6, CXCL9, and CCL17 were quantified by ELISA. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) loads were quantified by RT-qPCR. CD4, CD8, Th1, Th2, TNF-α-CD8, and IFN-γ-CD8 T cell populations were measured by flow cytometry. Levels of biochemical indexes in HIV+ SDE+ patients were significantly different from in HIV- SDE+ patients (P < .05). EBV and CMV viral loads were significantly higher in HIV+ SDE+ patients, but not in HIV- SDE+ patients (P < .05). Inflammatory cytokines TNF-α and IFN-γ were significantly elevated in HIV+ SDE+ patients (P < .05). Th2/Th1 populations and TNF-α secreting or IFN-γ secreting CD8+ T cells, were significantly up-regulated in HIV+ SDE+ patients compared to HIV- SDE+ patients (P < .05). Conversely, the CD4/CD8 ratio was significantly down-regulated in HIV+ SDE+ patients compared to HIV- SDE+ patients (P < .05). HIV infection confers distinct clinical phenotypes and immune inflammatory mechanisms in SDE. Sustained EBV and CMV activation, unbalanced Th2/Th1 and overactive CD8+ T cells mediating a pro-inflammatory response could act as distinct mechanisms in the aggravation of SDE in HIV+ SDE+ patients.

Association between serum ferritin and the severity of drug eruptions.

BACKGROUND: Early recognition and treatment for severe drug eruption are important in improving clinical outcomes. A few studies have reported laboratory parameters to evaluate the severity of drug eruptions. This study aimed to determine the association between serum ferritin and the severity of drug eruptions. METHODS: We retrospectively reviewed patients diagnosed with drug eruptions in our hospital from 2013 to 2018. RESULTS: We identified 85 patients (mean age 53.4 years), 20 in the severe cutaneous adverse drug reactions (SCADRs) group and 65 in the non-SCADRs group. Serum ferritin level was higher in the SCADRs group compared with that in the CADRs group (P<.001). Serum ferritin was positively associated with peripheral white blood cell count, aspartate aminotransferase level, alanine aminotransferase level, blood glucose level, blood creatinine level, and body temperature. Receiver operating characteristic (ROC) analysis revealed a good diagnostic value of ferritin (area under the curve [AUC]:0.87, 95% confidence interval [CI]:0.78-0.96) with a sensitivity of 80% and a specificity of 87.7% at a cutoff value of 416.15 ng/mL. CONCLUSIONS: Serum ferritin is significantly associated with the severity of CADRs and hence might be potentially used to evaluate the severity of CADRs.

Serum soluble Fas ligand levels and peripheral blood lymphocyte subsets in patients with drug-induced maculopapular rashes, dress, and viral exanthemas.

BACKGROUND: Fatty acid synthetase (Fas)/Fas ligand (FasL)-dependent apoptotic pathways have been reported as being involved in the pathogenesis of drug-induced maculopapular rashes. OBJECTIVE: We investigated serum soluble FasL (sFasL) levels and peripheral blood lymphocyte subtypes to discriminate maculopapular drug eruptions (MPDE) from viral exanthema (VE). PATIENTS/METHODS: Children with confirmed MPDE (group I), VE (group II), and drug rashes with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS) (group III) were included. Serum sFasL levels and peripheral blood lymphocyte subtypes were analyzed in groups I-III on admission, and repeated twice (only once for group IV - controls). RESULTS: There were no significant serum soluble FasL level differences among the groups for all the samples. In the initial samples, CD19+ cell numbers in group II were significantly higher than in group IV, and the CD4+/CD8+ ratio was higher than groups I and IV. In the second samples, CD4+ and CD19+ cell numbers were significantly higher in group II than group I. In the final samples, CD4+ cell numbers in group II were significantly higher than group I and group III. CD19+ cells numbers in group III were significantly lower than the other groups for all samples. CONCLUSION: Serum sFasL levels were not found to be useful in discriminating viral exanthemas from other drug rashes. The significant differences between MPDE, VE, and DRESS were high CD4+ and CD19+ cell-count numbers in VE but low B-cell numbers in DRESS. This might be important for discriminating VE from DRESS, and the low B-cell count in early symptoms might be a useful predictor of DRESS development.

[Sebotropic drug eruption after ingestion of bee pollen]. / Éruption induite à tropisme sébacé après consommation de pollen d'abeille.

INTRODUCTION: The medical literature contains five cases of exanthema with sebaceous tropism induced by consumption of kava-kava extract filed under the name of sebotropic drug reaction. Herein we report a new case following consumption of bee pollen. PATIENTS AND METHODS: A 37-year-old man consulted for erythemato-papular and fixed plaques of the face, upper trunk and shoulders present for 3 days. Standard blood tests were normal except for neutrophil leukocytosis at 9.8 G/l and eosinophilia at 1.4 G/l. Cutaneous biopsy of a facial plaque revealed folliculocentric lesions with necrosis of sebocytes in the sebaceous gland, associated with an eosinophil-rich infiltrate. The patient had begun consuming bee-pollen granules 3 weeks before the onset of symptoms. The rash regressed within 3 weeks of cessation of pollen consumption. Patch tests (ICDRG battery, propolis 1% Vaseline dilution and bee pollen provided by the patient, both pure and in a 30% dilution in Vaseline) were negative at 48 and 72h. DISCUSSION: The clinical-pathological correlation was consistent with a diagnosis of sebotropic drug reaction induced by the consumption of bee pollen. The diagnosis was based on papular exanthema of the seborrheic zones occurring 2 to 3 weeks after initial intake of the offending substance, with histological evidence of inflammatory necrosis of the sebaceous glands. CONCLUSION: We report what is to our knowledge the first case of sebotropic drug reaction following ingestion of bee pollen.

The thymus and activation-regulated chemokine (TARC) level in serum at an early stage of a drug eruption is a prognostic biomarker of severity of systemic inflammation.

BACKGROUND: In severe drug eruptions, precise evaluation of disease severity at an early stage is needed to start appropriate treatment. It is not always easy to diagnose these conditions at their early stage. In addition, there are no reported prognostic biomarkers of disease severity in drug eruptions. The aim of this study was to test whether the thymus and activation-regulated chemokine (TARC) level in serum at an early stage of a drug eruption can serve as a prognostic biomarker of systemic inflammation. METHODS: Study participants included 76 patients who received a diagnosis of a drug eruption, one of the following: drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome, maculopapular exanthema, and erythema multiforme. Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) was eliminated in this study because scoring system for evaluating the severity was established. Correlation coefficients between serum TARC levels and indicators of systemic inflammation, including the neutrophil-to-lymphocyte ratio, Glasgow prognostic score, modified systemic inflammatory response syndrome (mSIRS) score, and C-reactive protein in serum were evaluated. RESULTS: Serum TARC levels positively correlated with the neutrophil-to-lymphocyte ratio, Glasgow prognostic score, mSIRS score, C-reactive protein, albumin, white blood cell count, body temperature, and pulse rate. TARC levels negatively correlated with systolic blood pressure. Among these parameters, the mSIRS score showed strong correlation (correlation coefficient: 0.68). CONCLUSIONS: Serum TARC levels correlate well with indicators of systemic inflammation and of disease severity among patients with a drug eruption except SJS/TEN. Serum TARC may be a prognostic biomarker of severity of inflammation in drug eruptions.

Pemphigus herpetiformis-type drug reaction caused by erdosteine containing mucolytic in a child.

Drug-related pemphigus is very rare in children. Erdosteine is a thiol compound having mucoactive, antioxidant, anti-inflammatory, and antitussive effects and is reported to be safe for treatment of acute respiratory tract diseases in children. Herein, we report a 9-year-old boy presented with pemphigus herpetiformis associated with anti-desmoglein 1 antibodies due to erdosteine consumption.

Serum TARC levels are strongly correlated with blood eosinophil count in patients with drug eruptions.

BACKGROUND: This study aims to evaluate the relationship between serum thymus and activation-regulated chemokine (TARC) levels with various clinicopathological conditions in patients with drug eruptions. The value of TARC in diagnosing drug-induced hypersensitivity syndrome (DIHS) was also examined. METHODS: Study participants included 84 patients who presented with generalized eruptions suspected to be drug-related, including DIHS, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), maculopapular exanthema (MPE), erythema multiforme (EM), erythroderma, and toxicoderma. The correlation coefficients between serum TARC levels and clinical parameters in peripheral blood samples were calculated. RESULTS: Serum TARC levels in patients with DIHS were higher than those found in patients with SJS/TEN, MPE, EM, and toxicoderma. TARC levels had 100% sensitivity and 92.3% specificity in diagnosing DIHS, with a threshold value of 13,900 pg/mL. Serum TARC levels positively correlated with age, white blood cell (WBC) count, neutrophil count, eosinophil count, monocyte count, atypical lymphocyte (Aty-ly) count, serum blood urea nitrogen (BUN) levels, and creatinine (Cr) levels. It negatively correlated with serum total protein (TP), albumin (Alb), and estimated glomerular filtration rate (eGFR). Among these clinical parameters, blood eosinophil counts were most strongly correlated with serum TARC levels, with a correlation coefficient of 0.53. CONCLUSIONS: Serum TARC levels are well correlated with blood eosinophil counts in patients with generalized drug eruptions, indicating that Th2-type immune reactions underlie TARC production. Serum TARC measurements also have potent diagnostic value for DIHS, with high sensitivity and specificity.

Serum IFN-γ-inducible chemokines CXCL9 and CXCL10 are elevated in non-immediate drug hypersensitivity reactions.

BACKGROUND: The recruitment to the skin of drug-responsive T cells is responsible for the inflammatory profiles of non-immediate drug hypersensitivity reactions (niDHRs). Maculopapular exanthema (MPE) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) have quite distinct T cell infiltrating patterns. OBJECTIVE: To investigate serum levels of CXCL9, CXCL10 and IFN-γ in patients with niDHRs, including MPE and SJS/TEN, to evaluate correlations between the cytokines, and to determine whether the inflammatory factors correlate with clinical severity in patients with SJS/TEN. METHOD: Twenty-four patients with SJS/TEN, 24 patients with MPE, and 24 healthy donors with good tolerance to the drugs involved in the drug reactions were recruited into the study. The modified severity-of-illness score for TEN (SCORTEN) and detachment of body surface area (dBSA) were used to assess the clinical severity of SJS/TEN. Serum levels of CXCL9, CXCL10 and IFN-? were determined by ELISA. RESULTS: The niDHRs group, SJS/TEN and MPE subgroups all exhibited significantly higher levels of CXCL9, CXCL10 and IFN-γ compared with the control group (P < 0.001). Serum IFN-γ levels were positively correlated with CXCL9 levels and CXCL10 levels in patients with niDHRs (rs = 0.576, rs = 0.449, P < 0.05). None of the levels of CXCL9, CXCL10 and IFN-γ had any correlation with modified SCOTEN index or dBSA in SJS/TEN group. CONCLUSIONS: The results suggest Th1 cytokine IFN-γ and chemokines CXCL9 and CXCL10 may play roles in the pathogenesis of niDHRs.

Insights into the poor prognosis of allopurinol-induced severe cutaneous adverse reactions: the impact of renal insufficiency, high plasma levels of oxypurinol and granulysin.

OBJECTIVE: Allopurinol, an antihyperuricaemic agent, is one of the common causes of life-threatening severe cutaneous adverse reactions (SCAR), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The prognostic factors for allopurinol-related SCAR remain unclear. This study aimed to investigate the relationship of dosing, renal function, plasma levels of oxypurinol and granulysin (a cytotoxic protein of SJS/TEN), the disease severity and mortality in allopurinol-SCAR. METHODS: We prospectively enrolled 48 patients with allopurinol-SCAR (26 SJS/TEN and 22 DRESS) and 138 allopurinol-tolerant controls from 2007 to 2012. The human leucocyte antigen (HLA)-B*58:01 status, plasma concentrations of oxypurinol and granulysin were determined. RESULTS: In this cohort, HLA-B*58:01 was strongly associated with allopurinol-SCAR (p<0.001, OR (95% CI) 109 (25 to 481)); however, the initial/maintenance dosages showed no relationship with the disease. Poor renal function was significantly associated with the delayed clearance of plasma oxypurinol, and increased the risk of allopurinol-SCAR (p<0.001, OR (95% CI) 8.0 (3.9 to 17)). Sustained high levels of oxypurinol after allopurinol withdrawal correlated with the poor prognosis of allopurinol-SCAR. In particular, the increased plasma levels of oxypurinol and granulysin linked to the high mortality of allopurinol-SJS/TEN (p<0.01), and strongly associated with prolonged cutaneous reactions in allopurinol-DRESS (p<0.05). CONCLUSIONS: Impaired renal function and increased plasma levels of oxypurinol and granulysin correlated with the poor prognosis of allopurinol-SCAR. Allopurinol prescription is suggested to be avoided in subjects with renal insufficiency and HLA-B*58:01 carriers. An early intervention to increase the clearance of plasma oxypurinol may improve the prognosis of allopurinol-SCAR.

Chemokine expression in diverse nonimmediate drug hypersensitivity reactions: focus on thymus activation-regulated chemokine, cutaneous T-cell-attracting chemokine, and interleukin-10.

BACKGROUND: Skin infiltration of different types of T lymphocytes is responsible for inflammatory profiles of nonimmediate drug hypersensitivity reactions (niDHRs). Important chemokines attracting skin-specific homing T cells include thymus activation-regulated chemokine (TARC) and cutaneous T-cell-attracting chemokine (CTACK). Interleukin-10 (IL-10) is a potent chemokine attracting CD8(+) T cells. OBJECTIVE: To investigate serum levels of TARC, CTACK, and IL-10 in patients with niDHRs and evaluate the correlation among these 3 chemokines. METHODS: Forty patients, including 19 patients with Stevens-Johnson syndrome and toxic epidermal necrolysis and 21 patients with maculopapular exanthema, and 21 healthy donors were recruited into the study. Clinical data of patients were obtained. Serum TARC, CTACK, and IL-10 levels were determined by enzyme-linked immunosorbent assay. RESULTS: Serum levels of TARC, CTACK, and IL-10 were significantly elevated in patients with niDHRs compared with those in normal controls (P < .05, P < .001, P < .001, respectively). The CTACK and IL-10 levels were significantly higher (P < .05, P < .001) in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis than in normal controls. Patients with maculopapular exanthema exhibited higher levels of TARC, CTACK, and IL-10 compared with normal controls (P < .001, P < .001, P < .05). Serum CTACK levels were positively correlated with TARC levels in all 40 patients (rs = 0.3422, P < .05). Serum CTACK levels positively correlated with detachment of body surface area in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis (rs = 0.510, P < .05). CONCLUSION: These results support a role for TARC, CTACK, and IL-10 in the pathogenesis of niDHRs for their chemotactic ability to attract different T-cell subtypes and different functional severities in niDHRs.

Identification of serum biomarkers for occupational medicamentosa-like dermatitis induced by trichloroethylene using mass spectrometry.

Occupational medicamentosa-like dermatitis induced by trichloroethylene (OMLDT) is an autoimmune disease and it has become a serious occupational health hazard. In the present study, we collected fasting blood samples from patients with OMLDT (n=18) and healthy volunteers (n=33) to explore serum peptidome patterns. Peptides in sera were purified using weak cation exchange magnetic beads (MB-WCX), and analyzed by matrix-assisted laser desorption ionization time-of-flight-mass spectrometry (MALDI-TOF-MS) and ClinProTools bioinformatics software. The intensities of thirty protein/peptide peaks were significantly different between the healthy control and OMLDT patients. A pattern of three peaks (m/z 2106.3, 2134.5, and 3263.67) was selected for supervised neural network (SNN) model building to separate the OMLDT patients from the healthy controls with a sensitivity of 95.5% and a specificity of 73.8%. Furthermore, two peptide peaks of m/z 4091.61 and 4281.69 were identified as fragments of ATP-binding cassette transporter family A member 12 (ABCA12), and cationic trypsinogen (PRRS1), respectively. Our findings not only show that specific proteomic fingerprints in the sera of OMLDT patients can be served as a differentiated tool of OMLDT patients with high sensitivity and high specificity, but also reveal the novel correlation between OMLDT with ABC transports and PRRS1, which will be of potential value for clinical and mechanistic studies of OMLDT.

[Analysis of subgroups of lymphocyte in peripheral blood among dermatitis medicamentosa-like of trichloroethylene patients and healthy exposed workers].

OBJECTIVE: To study the effects of trichloroethylene (TCE) to lymphocyte subsets among exposed workers, and explore the early immunological effect biomarkers for prevention of hypersensitivity dermatitis induced by TCE. METHODS: Twenty-eight patients with TCE-induced hypersensitivity dermatitis, 56 healthy TCE-exposed workers from the same workshops with patients, and 28 comparable unexposed controls were recruited in this study. The total lymphocyte count and the major lymphocyte subsets including T cell, CD4(+) T cell, CD8(+) T cell, B cell, NK cell in peripheral blood were measured by Flow Cytometer analysis and Standard blood count analysis. RESULTS: The total lymphocyte count and T cell, CD4(+) T cell, CD8(+) T cell among patients (median at 2810.00, 1846.17, 831.87, 904.05 cell counts/µl blood) were significantly increased compared with TCE-exposed workers (median at 2101.00, 1218.59, 643.87, 482.81 cell counts/µl blood, Z = -3.19, -4.96, -3.22, -4.99, P < 0.001) and unexposed controls (median at 1900.00, 1223.60, 558.60, 325.80 cell counts/µl blood, Z = -3.30, -4.46, -3.45, -5.03, P < 0.001), the NK cell and CD3(+)CD4(+)/CD3(+)CD8(+) ratio among patients (median at 255.50 cell counts/µl blood and 1.11) were significantly decreased compared with the unexposed controls (median at 642.60 cell counts/µl blood and 1.96, Z = -3.56 and -3.11, P < 0.01). Meanwhile, for the exposed workers, the CD8(+) T cell (median at 482.81 cell counts/µl blood) was significantly increased and the NK cell and CD3(+)CD4(+)/CD3(+)CD8(+) ratio (median at 318.76 cell counts/µl blood and 1.27) were significantly decreased compared with unexposed controls (median at 325.80 and 642.60 cell counts/µl blood and 1.96, Z = -2.63, -3.52, -2.29, P < 0.05). CONCLUSION: Occupational exposure to TCE could affect the lymphocyte subsets, especially T cell and NK cell. The total lymphocyte count, T cell and CD4(+) T cell might be effect biomarkers for subjects with hypersensitivity dermatitis among TCE-exposed workers.

In vitro detection of cytotoxic T and NK cells in peripheral blood of patients with various drug-induced skin diseases.

BACKGROUND: Cytotoxic cells are involved in most forms of drug-induced skin diseases. Till now, no in vitro test addressed this aspect of drug-allergic responses. Our report evaluates whether drug-induced cytotoxic cells can be detected in peripheral blood of nonacute patients with different forms of drug hypersensitivity, and also whether in vitro detection of these cells could be helpful in drug-allergy diagnosis. METHODS: GranzymeB enzyme-linked immunosorbent spot-forming (ELISPOT) and cell surface expression of the degranulation marker CD107a were evaluated on peripheral blood mononuclear cells from 12 drug-allergic patients in remission state and 16 drug-exposed healthy controls. RESULTS: In 10/12 allergic patients culprit but not irrelevant drug elicited granzymeB release after 48-72 h stimulation. It was clearly positive in patients with high proliferative response to the drug, measured in lymphocyte transformation tests. In patients, who showed moderate or low proliferation and low drug-response in granzymeB ELISPOT, overnight preincubation with interleukin (IL)-7/IL-15 enhanced drug-specific granzymeB release and allowed to clearly identify the offending agent. CD107a staining was positive on CD4+/CD3+, CD8+/CD3+ T cells as well as CD56+/CD3- natural killer cells. None of the drug-exposed healthy donors reacted to the tested drugs and allergic patients reacted only to the offending, but not to tolerated drugs. CONCLUSION: GranzymeB ELISPOT is a highly specific in vitro method to detect drug-reacting cytotoxic cells in peripheral blood of drug-allergic patients even several years after disease manifestation. Together with IL-7/IL-15 preincubation, it may be helpful in indentifying the offending drug even in some patients with weak proliferative drug-response.

Enzyme replacement therapy in a patient with Fabry disease and the development of IgE antibodies against agalsidase beta but not agalsidase alpha.

Fabry disease is an X-linked inherited lysosomal storage disorder caused by an inborn deficiency of the enzyme α-galactosidase A. Enzyme replacement therapy (ERT) with agalsidase alpha or beta isozymes is an effective treatment. Cross-reactivity of immunoglobulin G (IgG) antibodies with agalsidase alpha and beta has been reported, but no such reaction has been recorded for IgE antibodies. We present the case of a patient with Fabry disease who developed antiagalsidase beta IgE antibodies without cross-reactivity to agalsidase alpha. A 17-year-old boy with Fabry disease had suffered from severe atopic dermatitis since infancy, and he complained for several years of peripheral pain during the summer months and when exercising. Fabry disease was confirmed by family history and a positive enzyme test, and ERT was commenced. Following infusion of agalsidase beta (1.0 mg/kg), the patient complained of a high temperature in his hands and feet, and purulent eczema developed. The infusion dose was reduced to 0.2 mg/kg, but the hyperthermia did not change, although its duration decreased. After three infusions, eosinophilia developed (9.4%; 573 cells/µl blood) and remained unresolved after four infusions with agalsidase beta. Treatment with this enzyme was discontinued, and agalsidase alpha (0.2 mg/kg) started. This produced immediate resolution of the eosinophilia, which has been maintained during follow-up. In conclusion, this patient developed IgE antibodies against agalsidase beta, which demonstrated no cross-reactivity to agalsidase alpha. These findings emphasize the importance of analyzing IgE antibodies against both enzymes when patients exhibit severe infusion-related events.

Differences in immunological alterations and underlying viral infections in two well-defined severe drug eruptions.

BACKGROUND: Similar drugs (e.g. anticonvulsants) have been implicated in the development of two distinct forms of severe cutaneous drug reactions, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS). AIM: To investigate immunological alterations and underlying viral infections that could contribute to the variability in the clinical presentations of these diseases. METHODS: We retrospectively analysed clinical variables, serum immunoglobulin levels, numbers of circulating white blood cells, lymphocytes and their subsets, serum levels of several cytokines, and underlying viral infections in both drug reactions, using samples obtained at onset from 9 patients with SJS/TEN and 19 patients with DIHS/DRESS. RESULTS: There were significant differences between the two drug eruptions in the duration of drug intake before onset, the levels of IgG, IgA and IgM, the numbers of circulating white blood cell, lymphocyte, CD3+ T cell and CD8+ T cells, the serum levels of interferon-γ, and the titres of anti-herpes simplex virus IgG at onset. CONCLUSIONS: The difference in the pattern of immune responses shaped in part by previous and underlying viral infections at the time of drug exposure could cause a marked deviation in the pathological phenotype of severe drug eruptions. Elucidating these host factors may provide a basis for therapeutic approaches in patients with severe drug reactions.