Kai-Lung Chen

Human herpes virus reactivations and dynamic cytokine profiles in patients with cutaneous adverse drug reactions --a prospective comparative study.

Sequential human herpes virus (HHV) reactivation is well known in drug reaction with eosinophilia and systemic symptom (DRESS), but such a phenomenon has seldom studied in other types of cutaneous adverse drug reactions (cADRs). Moreover, the association between viral reactivations and cytokine or chemokine changes is largely unknown. We aimed to evaluate the viral reactivation rates of HHV‐6, HHV‐7, Epstein–Barr virus (EBV), and cytomegalovirus (CMV) in different cADRs and their impacts on clinical prognosis. Cytokine and chemokine changes with viral reactivations were also examined.

Long-term Sequelae of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions characterized by different extents of epidermal necrosis and mucosal breakdown. A limited number of studies have reported the long-term patterns of SJS and TEN complications in patient populations over long follow-up periods. The aim of this retrospective study was to collect data on long-term sequelae in patients admitted for SJS, SJS/TEN overlap, or TEN between 1998 and 2012. Among all 102 patients eligible for analysis, the 2 most common sequelae were cutaneous and ocular problems, both with incidences of 44.1%. Visceral organ involvement was observed in 2 patients with irreversible deterioration of chronic kidney disease and in one patient with interstitial lung disease. Autoimmune disease was present in 6 patients: Sjögrens syndrome or Sjögren-like syndrome in 5 patients and concomitant systemic lupus erythematosus and Hashimoto thyroiditis in one patient.

Comparison of Skin Toxic Effects Associated With Gefitinib, Erlotinib, or Afatinib Treatment for Non–Small Cell Lung Cancer

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used to treat non–small cell lung cancer. Four major skin toxic effects with different incidences have been reported from clinical studies, including acneiform eruption (60%-94%), pruritus (16%-60%), xerosis (4%-38%), and paronychia (6%-12%). 1,2 However, a direct comparison of the incidences and severities of the 4 types of skin toxic effects for 3 different EGFR-TKIs in the same patient cohort has been lacking to date. Methods | This retrospective study was approved by the research ethics committee of National Taiwan University Hospital. We recruited patients within a named patient program for compassionate use before registration who had ever received afatinib treatment for non–small cell lung cancer between November 1, 2007, and April 30, 2013. Most of the pa

Co-existence of histopathological features is characteristic in drug reaction with eosinophilia and systemic symptoms and correlates with high grades of cutaneous abnormalities

Only few studies had investigated the histopathological presentations of drug reaction with eosinophilia with systemic symptoms (DRESS). The results of these studies were diverse and not conclusive. A characteristic histopathological feature is still lacking.

Olmutinib‐induced palmoplantar keratoderma

olmutinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment of non-small cell lung cancer (NSCLC), especially for those harboring T790M mutations, the most common reason for other EGFR-TKI resistance. We describe three patients who developed acquired palmoplantar keratoderma (PPK) after taking olmutinib, an adverse event which has not been reported in previous generations of EGFR-TKIs. This article is protected by copyright. All rights reserved.

Purpuric Drug Eruptions Caused by Epidermal Growth Factor Receptor Inhibitors for Non–Small Cell Lung Cancer: A Clinicopathologic Study of 32 Cases

Importance Purpuric skin lesions have only rarely been reported in patients receiving epidermal growth factor receptor inhibitors. However, their clinical and histopathologic presentations have varied considerably. Objective To characterize purpuric skin eruptions caused by epidermal growth factor receptor inhibitors. Design, Setting, and Participants This prospective study enrolled 32 patients who presented to an integrated dermato-oncologic clinic in a tertiary referral medical center with purpuric skin lesions after using epidermal growth factor receptor inhibitors from January 1, 2013, through December 31, 2015. Exposures Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, erlotinib, and afatinib. Main Outcomes and Measures Clinical presentations, histopathologic features, laboratory examinations, and treatment outcomes of patients with purpuric drug eruptions. Results Thirty-two patients, 14 with purpuric drug eruptions without pustules (mean [SD] age, 60 [11] years; 12 female and 2 male) and 18 with purpuric drug eruptions with pustules (mean [SD] age, 64 [11] years; 12 female and 6 male), were identified. The median time to development of skin lesions was 3.5 months. The clinical presentations were characterized by purpuric macules, papules, and confluent plaques predominantly on the lower extremities. Pustules in various sizes could be found in 18 patients (56%). Eleven patients (34%) had skin lesions that covered places other than the lower extremities. Eczema craquelé–like features developed in 13 patients (41%). Bacterial pathogens were frequently identified in these skin lesions. Among them, Staphylococcus aureus was the most predominant and was found in 20 patients (63%), commonly in those with cutaneous pustules. Epidermal dysmaturation, neutrophil exocytosis, perivascular infiltration of lymphocytes and neutrophils, red blood cell extravasation, and plumping endothelium were the main histopathologic features. The expressions of filaggrin and human &bgr;-defensin 2 in lesional skin of these patients were markedly reduced. All patients improved after receiving at least 1 week of systemic antibiotic treatment; the doses of epidermal growth factor receptor inhibitors were also changed for 14 patients (44%). Conclusions and Relevance Purpuric drug eruptions caused by epidermal growth factor receptor inhibitors are uncommon and have characteristic clinical and histopathologic presentations. The role of bacterial pathogens in this reaction is important and requires further exploration.

Clinical pattern of liver injury in drug reaction with eosinophilia and systemic symptoms (DRESS): a retrospective study in Taiwan

Method To investigate the types of liver injury and factors involved, including the chronology, recovery time, relationship with culprit drugs and the pathology correlations, a retrospective study was conducted by reviewing all medical records of DRESS patients diagnosed between Dec. 2000 and Jan. 2013 in the National Taiwan University Hospital Database. DRESS was defined according to the International Registry of Severe Cutaneous Adverse Reactions (RegiSCAR). The pattern of liver damage is classified according to the International Consensus Meeting criteria.

Differential cytokine/chemokine profiles and reactivation of human herpes viruses in various forms of cutaneous adverse drug reactions. A comparative study in Taiwan

Background Sequential human herpes virus (HHV) reactivation is wellknown in drug reaction with eosinophilia and systemic symptoms (DRESS), but a comparison study to investigate the association of HHV reactivation with other types of cutaneous adverse drug reactions (cADRs) is still lacking. Besides, the pathomechanisms or mediators of viral reactivations are largely unknown. In this study, we aimed to investigate the cytokine/chemokine profiles before or concurrent with HHV reactivations. Method We conducted a prospective study to evaluate HHV-6, Epstein–Barr virus (EBV) and cytomegalovirus (CMV) reactivation rates in various cADRs. Dynamic changes of cytokines and chemokines were also determined by sequential blood tests during acute stages. Interleukin-1 £] (IL-1£]), IL-1 receptor antagonist (IL-1Ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, basic fibroblast growth factors, eotaxin, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-£^ (IFN-£^), interferon £^-induced protein-10 (IP-10), monocyte chemoattractant protein-1, macrophage inflammatory protein-1£\ (MIP-1£\), MIP-1£], platelet-derived growth factor, chemokine (C-C motif) ligand 5 (CCL5), tumor necrosis factor-£\ (TNF-£\) and vascular endothelial growth factor were measured using the Bio-Plex Human Cytokine 27-Plex panel. Results A total of 62 patients were enrolled in this prospective study including 23 DRESS, 17 SJS/TEN, 13 MPE, 5 GBFDE and 4 EMM. HHV-6 reactivation was observed in ten DRESS patients (43.5%) but in none of the other cADR patients. In contrast, EBV reactivation was detected in 35 patients distributed in every cADR groups. EBV reactivation rates were 73.9% for DRESS (17 in 23 patients), 29.4% for SJS/TEN (5 in 17 patients), 53.8% for MPE (7 in 13 patients), 80% for GBFDE (4 in 5 patients), and 50% for EMM (2 in 4 patients). CMV reactivation rates were 43.5% in DRESS (10 in 23 patients) and 11.8% in SJS/TEN (2 in 17 patients) respectively, but none of the other cADRs. HHV-6 reactivation in DRESS patients was associated with decreased proinflammatory cytokines and chemokines (IL-1£], IL-1Ra, IL-2, TNF-£\, IFN-£^, and MIP-1£\) before viral reactivations. Only one chemokine, IP-10, was expressed higher in the HHV-6 reactivation group (P = 0.018).