Drug-specific CD4+ T-cell immune responses are responsible for antituberculosis drug-induced maculopapular exanthema and drug reaction with eosinophilia and systemic symptoms syndrome.

BACKGROUND: A multidrug regimen including isoniazid, rifampicin, pyrazinamide and ethambutol is commonly used as first-line treatment for tuberculosis. However, this regimen can occasionally result in severe adverse drug reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and drug-induced liver injury. The culprit drug and mechanistic basis for the hypersensitive reaction are unknown. OBJECTIVES: To investigate drug-specific T-cell responses in patients with antituberculosis drug (ATD)-induced cutaneous hypersensitivity and its underlying mechanism. METHODS: We enrolled eight patients with ATD-induced maculopapular exanthema and DRESS and performed a lymphocyte transformation test. Subsequently, drug-specific T-cell clones were generated from four of the patients who showed proliferation in response to ATDs. We measured the drug-specific proliferative responses and counted the drug-specific interferon (IFN)-γ/granzyme B-producing cells after drug stimulation. Antihuman leukocyte antigen (HLA) class I and class II blocking antibodies were used to analyse human leukocyte antigen-restricted T-cell responses. RESULTS: Positive proliferative responses to ATDs were mostly found in patients with cutaneous hypersensitivity. Furthermore, we isolated isoniazid/rifampicin-specific T cells from patients, which consisted primarily of CD4+ T cells. Drug-specific CD4+ T cells proliferated and secreted IFN-γ/granzyme B when stimulated with isoniazid or rifampicin, respectively. Isoniazid-responsive T-cell clones did not proliferate in the presence of rifampicin and vice versa. Drug-specific T-cell responses were blocked in the presence of anti-HLA class II antibodies. CONCLUSIONS: This study identifies the presence of isoniazid/rifampicin-specific T cells in patients with ATD-induced maculopapular exanthema and DRESS. Furthermore, it highlights the important role of drug-specific T-cell immune responses in the pathogenesis of these reactions.

Neutrophil autophagy and extracellular DNA traps contribute to airway inflammation in severe asthma.

BACKGROUND: Autophagy and neutrophil extracellular DNA traps (NETs) are implicated in asthma; however, their roles in asthma pathogenesis have not been elucidated. OBJECTIVES: We compared autophagy and NET production levels from peripheral blood neutrophils (PBNs) of patients with severe asthma (SA) and non-severe asthma (NSA). Additionally, we investigated the inflammatory effects of NETs on human airway epithelial cells (AECs) and peripheral blood eosinophils (PBEs). METHODS: Peripheral blood neutrophils from patients with SA (n = 30) and NSA (n = 38) were treated with interleukin (IL)-8 (100 ng/mL). Autophagy (light chain 3-II expression) and NET production levels were evaluated by Western blot, immunofluorescence microscopy, and PicoGreen assay. The effects of NETs on AECs were assessed by investigating cell death, cell detachment, expression of occludin and claudin-1, and IL-8 production; the effects of NETs on PBEs were examined by investigating the activation and release of eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN). RESULTS: Untreated and IL-8-treated PBNs from the SA group produced higher autophagy and NET levels compared with those from the NSA group (P < 0.01). IL-8 increased autophagy and NET levels in PBNs from the SA group, but not from the NSA group. NET levels were correlated with autophagy levels in PBNs (P < 0.001). IL-8-induced NET production levels negatively were correlated with FEV1/FVC (r = -0.700, P = 0.016). NETs induced cell death, detachment, degradation of occludin and claudin-1, and IL-8 production from AECs. Higher levels of NET-induced ECP and EDN were released from PBEs in SA compared with NSA groups. CONCLUSIONS AND CLINICAL RELEVANCE: Neutrophil autophagy and NETs could enhance asthma severity by damaging airway epithelium and triggering inflammatory responses of AECs and PBEs. Modulating neutrophil autophagy and NET production may be a new target therapy for SA.

Metabolomic analysis identifies potential diagnostic biomarkers for aspirin-exacerbated respiratory disease.

BACKGROUND: To date, there has been no reliable in vitro test to diagnose aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: To investigate potential diagnostic biomarkers for AERD using metabolomic analysis. METHODS: An untargeted profile of serum from asthmatics in the first cohort (group 1) comprising 45 AERD, 44 patients with aspirin-tolerant asthma (ATA), and 28 normal controls was developed using the ultra-high-performance liquid chromatography (UHPLC)/Q-ToF MS system. Metabolites that discriminate AERD from ATA were quantified in both serum and urine, which were collected before (baseline) and after the lysine-aspirin bronchoprovocation test (Lys-ASA BPT). The serum metabolites were validated in the second cohort (group 2) comprising 50 patients with AERD and 50 patients with ATA. RESULTS: A clear discrimination of metabolomes was found between patients with AERD and ATA. In group 1, serum levels of LTE4 and LTE4 /PGF2 α ratio before and after the Lys-ASA BPT were significantly higher in patients with AERD than in patients with ATA (P < 0.05 for each), and urine baseline levels of these two metabolites were significantly higher in patients with AERD. Significant differences of serum metabolite levels between patients with AERD and ATA were replicated in group 2 (P < 0.05 for each). Moreover, serum baseline levels of LTE4 and LTE4 /PGF2 α ratio discriminated AERD from ATA with 70.5%/71.6% sensitivity and 41.5%/62.8% specificity, respectively (AUC = 0.649 and 0.732, respectively P < 0.001 for each). Urine baseline LTE4 levels were significantly correlated with the fall in FEV1 % after the Lys-ASA BPT in patients with AERD (P = 0.008, r = 0.463). CONCLUSIONS AND CLINICAL RELEVANCE: Serum metabolite level of LTE4 and LTE4 /PGF2 α ratio was identified as potential in vitro diagnostic biomarkers for AERD using the UHPLC/Q-ToF MS system, which were closely associated with major pathogenetic mechanisms underlying AERD.

Identification of phenotypic clusters of nonsteroidal anti-inflammatory drugs exacerbated respiratory disease.

BACKGROUND: Clinical presentation of nonsteroidal anti-inflammatory drugs exacerbated respiratory disease (NERD) is found to be heterogeneous. This study classified phenotypic clusters to determine NERD subtypes. METHODS: We performed two-step cluster analysis using urticaria, chronic rhinosinusitis (CRS), and atopy, in a NERD cohort comprising 302 patients. Asthma exacerbation was defined as receiving at least one burst of intravenous steroid treatment and/or at least two bursts of oral steroid use (≥ 45 mg/3 days) per year. The possession rate of anti-asthmatic medications was estimated during the follow-up period. RESULTS: There were four subtypes: subtype 1 (NERD with CRS/atopy and no urticaria), subtype 2 (NERD with CRS and no urticaria/atopy), subtype 3 (NERD without CRS/urticaria), and subtype 4 (NERD with urticaria). Significant differences were found between the four subtypes in the female proportion, baseline FEV1%, serum total IgE level, and sputum/peripheral eosinophil count. A higher frequency of asthma exacerbations was noted in subtype 1 compared to subtype 3. The possession rates of medium- to high-dose inhaled corticosteroids/long-acting beta2 -agonists showed significant differences among the four subtypes. Metabolomic analysis showed that the four subtypes of NERD had a higher serum leukotriene E4 (LTE4) level than those with aspirin-tolerant asthma. The patients with subtypes 1 and 3 had a higher urine LTE4 level than those with subtype 2. CONCLUSION: We found four distinct subtypes with different clinical/biochemical findings and asthma exacerbations in a NERD cohort. These findings suggest that stratified strategies by applying subtype classification may help achieve better outcomes in the management of NERD.

[Hospital costs and related influencing factors in patients with acute poisoning].

Objective: To investigate the hospital costs and related influencing factors in patients with acute poisoning. Methods: A retrospective analysis was performed for the general status and hospital costs of 373 patients with acute poisoning who were admitted to The Second Affiliated Hospital of Wenzhou Medical College from January 2009 to March 2015. The questionnaires were completed, the data were entered into Excel forms, and SPSS 18.0 was used to perform statistical analysis. Results: Among the 373 patients, 44.8% committed suicide and 31.1% were poisoned by accidental contact; 42.6% were poisoned by pesticides, and 32.7% were poisoned by drugs. After treatment, 64.1% achieved improvements, whereas 1.3% died. The highest hospital cost reached 62 710.26 RMB, and the lowest was 64.64 RMB (median 4 328 RMB) . The patients with an older age and a longer length of hospital stay tended to have higher hospital costs; the patients who underwent catharsis, mechanical ventilation, and blood purification and were admitted to the intensive care unit had relatively high hospital costs. Conclusion: The patients with acute poisoning have high hospital costs. Poisoning caused by pesticides and drugs should be prevented and treated with priority, so as to reduce the heavy economic burden caused by acute poisoning.

Autophagy mechanisms in sputum and peripheral blood cells of patients with severe asthma: a new therapeutic target.

BACKGROUND: Autophagy and genetic predisposition have been suggested to potentially play roles in the development of asthma. However, little is known about the role of autophagy in the pathogenesis of severe asthma. OBJECTIVE: We compared autophagy in the sputum granulocytes, peripheral blood cells (PBCs) and peripheral blood eosinophils (PBEs) between patients with severe asthma and those with non-severe asthma and investigated the functional effects of autophagy. METHODS: We enrolled 36 patients with severe asthma, 14 with non-severe asthma and 23 normal healthy controls in this study. Sputum granulocytes, PBCs and PBEs were isolated from each subject. Autophagy was evaluated based on the expression of microtubule-associated protein light chain 3 (LC3) by Western blot, confocal microscopy, transmission electron microscopy and flow cytometry. IL-8 levels were measured by ELISA. To induce autophagy, HL-60 cells, human primary small airway epithelial cells (SAECs) and A549 cells were treated with IL-5, IL-1ß and TNF-α. To inhibit autophagy, PI3K inhibitors (LY29400 and 3-methyladenine [3-MA]) and hydroxychloroquine (HCQ) were used. Knockdown of ATG5 and Beclin-1 was performed in A549 cells, and the therapeutic effects of dexamethasone were evaluated. RESULTS: Higher autophagy levels were noted in sputum granulocytes, PBCs and PBEs from patients with severe asthma than from patients with non-severe asthma and healthy controls (P < 0.05 for all). IL-5 increased autophagy levels in both PBCs and PBEs (P < 0.05). 3-MA attenuated the increased expression of LC3-II and eosinophil cationic protein in HL-60 cells induced by IL-5 (P = 0.034 for both). Dexamethasone did not affect autophagy levels in PBEs. IL-1ß increased LC3-II expression and IL-8 production (P < 0.01) in SAECs, and this was attenuated by LY294002, 3-MA, HCQ and knockdown of ATG5 and Beclin-1 (in A549 cells) (P < 0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Autophagy could play a role in the pathogenesis of severe asthma. Autophagy modulation may be a novel therapeutic target for conventional therapy-resistant severe asthma.

Eosinophil activation and novel mediators in the aspirin-induced nasal response in AERD.

BACKGROUND: Eosinophil activation is the key feature of upper and lower airway inflammation in aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: To investigate the mechanism of eosinophil activation and identify novel inflammatory mediators using proteomics. METHODS: Thirty-two asthmatic subjects were enrolled: 18 AERD patients who showed positive responses to the lysine-aspirin nasal provocation test (L-ASA NPT) and 14 aspirin-tolerant asthma (ATA) patients who showed negative responses to the L-ASA NPT (control group). Nasal lavage fluid (NLF) was collected before (baseline), at 10, 30 and 60 min (early response), and at 3 h (late response) after the L-ASA NPT. Eosinophil cationic protein (ECP) and cysteinyl leucotriene (CysLT) levels were measured using an ImmunoCAP system and ELISA respectively. To identify proteins involved in AERD, comparative proteomics was applied using NLFs collected before and after L-ASA NPTs in AERD patients. The clinical relevance of identified novel proteins was evaluated by ELISA using NLFs from the AERD and ATA groups. RESULTS: Eosinophil cationic protein and CysLT levels both increased significantly during the early response in AERD. ECP levels increased until the late response in AERD, while CysLT levels were not significantly increased during the late response. Proteomic analysis showed up-regulation of apolipoprotein A1 (ApoA1), α2-macroglobulin (α2M) and ceruloplasmin (CP), with significant increases in NLF of AERD patients, which was significantly higher in AERD patients with chronic rhinosinusitis. Significant correlations were noted between ECP and CysLT, ApoA1, α2M and CP levels during the early response in AERD patients. CONCLUSION: Eosinophil activation occurred in early and late responses after L-ASA NPT in upper airway mucosa of AERD patients, where ApoA1, α2M and CP as well as CysLT may be involved in eosinophilic inflammation.

Clinical evaluation of the computerized chronic urticaria-specific quality of life questionnaire in Korean patients with chronic urticaria.

BACKGROUND: Chronic urticaria (CU) is a common skin disorder that affects the well-being and quality of life (QOL) of patients. Recently, we developed and validated a questionnaire for measuring QOL in Korean patients with CU, called the Chronic Urticaria-Specific Quality of Life (CU-QOL) questionnaire. AIM: To evaluate the clinical significance of a computerized version of the CU-QOL, in adult patients with CU. METHODS: This was a cross-sectional observational study that enrolled 249 Korean patients with CU from five university hospitals and measured computerized CU-QOL scores and Urticaria Activity Score (UAS) simultaneously. The internal consistency of the computerized CU-QOL was analysed using Cronbach α. To identify clinical correlations between the CU-QOL and patient characteristics, the atopic status and serum autoantibodies, including antinuclear, antithyroglobulin and antimicrosome antibodies, were measured. Multiple linear regression models were used to identify CU-QOL predictors. RESULTS: Cronbach α was 0.94 for the overall computerized CU-QOL score. The CU-QOL scores correlated significantly with the UAS (r= -0.49, P<0.001). Of the factors aggravating CU, delayed pressure, sunlight exposure and emotional stress significantly influenced the overall CU-QOL scores in the univariate analysis. Multivariate regression models indicated that UAS and emotional stress were significant predictors of the four domains and of the total CU-QOL scores. CONCLUSIONS: The computerized CU-QOL is a convenient and valid tool for measuring QOL in patients with CU. This study suggests that UAS, dermatographism and emotional stress are strong CU-QOL predictors in Korean patients with CU.

Combined pharmacogenetic effect of ADCY9 and ADRB2 gene polymorphisms on the bronchodilator response to inhaled combination therapy.

WHAT IS KNOWN AND OBJECTIVE: Inhaled combination therapy composing of long-acting ß2-agonist and corticosteroid has been widely applied in the management of asthma, but observed treatment responses vary. The aim of this study was to evaluate the pharmacogenetic effect of the adenylyl cyclase type 9 (ADCY9) gene polymorphism on combination therapy. MATERIALS AND METHODS: Eighty-six mild to moderate Korean asthmatics were enrolled in this clinical trial. After the 2-week 'run-in' period, patients received budesonide (an inhaled corticosteroid) and formoterol (long-acting ß2-agonist) during the following 12-week active treatment period. Forced expiratory volume in 1 s (FEV(1) ) and maximum mid-expiratory flow (MMEF) levels were measured at all visits as primary outcome. ADCY9 (Ile772Met, 150127 C/T, 150130 C/T, 150397 C/T, 150479 C/T, TTTA (5/4) ) and ß2-adrenergic receptor (ADRB2, Arg16Gly) gene polymorphisms were genotyped. RESULTS: Significant associations were observed between the ADCY9 single nucleotide polymorphisms and percent changes in FEV(1) (Ile772Met T/C, P = 0·030) and MMEF (150397 C/T, P = 0·016) after 8 weeks of combination therapy. Haplotype associations were also observed with respect to percent changes in FEV(1) after 8 weeks of therapy (Ht3[TTCC], P = 0·017). Additive therapeutic effect was observed in those with the ADCY9 Ile772Met and ADRB2 Arg16Gly gene polymorphisms in terms of percent change in FEV(1) after 8 and 12 weeks of therapy (P = 0·002 and P = 0·027 respectively). WHAT IS NEW AND CONCLUSION: Our results suggest that ADCY9 gene polymorphisms may alone, and in combination with ADRB2 gene polymorphisms, contribute to individual response to combination therapy in mild to moderate asthmatics.

Association of thromboxane A2 receptor (TBXA2R) gene polymorphism in patients with aspirin-intolerant acute urticaria.

BACKGROUND: The thromboxane A2 receptor (TBXA2R) is a potent broncho- and vaso-constrictor and is associated with leukotriene synthesis. Polymorphisms in the TBXA2R gene have been linked to atopy, asthma, and atopic dermatitis. This study evaluated the association between genetic TBXA2R variants and the development of acetyl salicylic acid (ASA)-intolerant acute urticaria (AIAU). METHODS: AIAU patients (n=167), ASA-intolerant chronic urticaria (AICU) patients (n=149), and healthy controls (NC) (n=265) were included. All patients were enrolled at Ajou University Hospital in Suwon, Korea. Two TBXA2R polymorphisms (-4684T>C and 795T>C) were genotyped by primer extension using a SNAPshot ddNTP primer extension kit. Luciferase activity was measured using a dual-luciferase reporter assay kit. An electrophoretic mobility shift assay (EMSA) was performed using a nuclear extract from a human mast cell line (HMC-1). RESULTS: Genetic association data demonstrated that compared with NC subjects, AIAU patients had a significantly higher frequency of the homozygous TT genotype of TBXA2R-4684T>C (P=0.005, P(corr) =0.03). No differences were identified between the AICU and the NC groups. Luciferase activity, reflecting promoter activity, was significantly lower with the TBXA2R-4684T-containing construct than with the -4684C-containing construct (P<0.001); the activity decreased further upon co-transfection with ETS-like gene transcription factor-1 (ELK-1) (P=0.012). EMSA revealed that the -4684T allele produced a specific shifted band, with a greater affinity than that produced by the -4684C allele. CONCLUSION AND CLINICAL RELEVANCE: These results suggest that the TBXA2R-4684T allele may be associated with lower TBXA2R expression, which may contribute to the development of the AIAU phenotype.

Functional variability of the adenosine A3 receptor (ADORA3) gene polymorphism in aspirin-induced urticaria.

BACKGROUND: To improve understanding of aspirin hypersensitivity, this study focused on adenosine as a noncyclooxygenase target molecule of aspirin. Adenosine may affect the release of histamine from cutaneous mast cells through a mechanism mediated by the adenosine A3 receptor. OBJECTIVES: To investigate the genetic contribution of adenosine A3 receptor gene (ADORA3) polymorphisms in the pathogenesis of aspirin-induced urticaria (AIU) in a case-control association study in a Korean population. METHODS: A case-control association study was performed in 385 patients with AIU and 213 normal controls from a Korean population. The functional variability of genetic polymorphisms in the ADORA3 gene was analysed in in vitro studies that included a luciferase reporter assay and an electrophoretic mobility shift assay (EMSA), and ex vivo studies that included real-time polymerase chain reaction for mRNA expression in peripheral blood mononuclear cells and a histamine release assay. RESULTS: A significant association of ADORA3 promoter polymorphism at -1050G/T was found with the phenotype of AIU. Patients with AIU showed higher frequency of the haplotype, ht1 (T(-1050) C(-564) ), compared with normal healthy controls. Moreover, ht1 (TC) was found to be a high-transcript haplotype by the luciferase activity assay, and a -564C allele-specific DNA binding protein was found by EMSA. Increased basophil histamine release was noted in subjects who had the high-transcript haplotype, ht1 (TC). CONCLUSION: These results suggest that the high-transcript haplotype, ht1 (TC), of the ADORA3 gene may contribute to the development of cutaneous hyper-reactivity to aspirin, leading to the clinical presentation of AIU.

Toluene diisocyanate (TDI) regulates haem oxygenase-1/ferritin expression: implications for toluene diisocyanate-induced asthma.

Diisocyanate is a leading cause of occupational asthma (OA). Diisocyanate-induced OA is an inflammatory disease of the airways that is associated with airway remodelling. Although the pathogenic mechanisms are unclear, oxidative stress may be related to the pathogenesis of diisocyanate-induced OA. In our previous report, we observed that the expression of ferritin light chain (FTL) was decreased in both of bronchoalveolar lavage fluid and serum of patients with diphenyl-methane diisocyanate (MDI)-induced OA compared to those of asymptomatic exposed controls and unexposed healthy controls. In this study of toluene diisocyanate (TDI)-OA, we found identical findings with increased transferrin and decreased ferritin levels in the serum of patients with TDI-OA. To elucidate whether diisocyanate suppresses FTL synthesis directly, we tested the effect of TDI on the FTL synthesis in A549 cells, a human airway epithelial cell line. We found that haem oxygenase-1 as well as FTL was suppressed by treatment with TDI in dose- and time-dependent manners. We also found that the synthesis of other anti-oxidant proteins such as thioredoxin-1, glutathione peroxidase, peroxiredoxin 1 and catalase were suppressed by TDI. Furthermore, TDI suppressed nuclear translocation of Nrf2 through suppressing the phosphorylation of mitogen-activated protein kinases (MAPKs); extracellular-regulated kinase 1/2 (ERK1/2); p38; and c-Jun N-terminal kinase (JNK). Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, 15-deoxy-Delta(12,14)-PGJ2 and rosiglitazone rescued the effect of TDI on HO-1/FTL expression. Collectively, our findings suggest that TDI suppressed HO-1/FTL expression through the MAPK-Nrf2 signalling pathway, which may be involved in the pathogenesis of TDI-induced OA. Therefore, elucidating these observations further should help to develop the therapeutic strategies of diisocyanate-induced OA.

Genetic variability in CRTH2 polymorphism increases eotaxin-2 levels in patients with aspirin exacerbated respiratory disease.

INTRODUCTION: CRTH2 is expressed on the surface of eosinophils and has been shown to mediate PGD2-induced eosinophil migration in vitro. Eosinophilic infiltration in the upper and lower airways is the key feature of asthma. Considering the fact that eosinophil infiltration is prominent in the upper and lower airways of aspirin exacerbated respiratory disease (AERD) compared to aspirin-tolerant asthma (ATA) patients, we hypothesized that activation of eosinophils via dysregulation of the CRTH2 gene may play an important role and be an important marker for AERD. METHODS: The three study groups - 107 with AERD, 115 with ATA and 133 normal healthy controls (NC) - were recruited from Ajou University Hospital, South Korea. Two polymorphisms of the CRTH2 gene at -466T>C and -129C>A were genotyped using primer extension methods. RESULTS: AERD patients had significantly higher serum eotaxin-2 levels than did those with ATA (P = 0.034). A significant difference in the genotype frequencies of CRTH2 -466T>C was detected between AERD and ATA patients (P < 0.05). The serum eotaxin-2 level was significantly higher in AERD patients carrying the TT genotype of CRTH2 -466T>C than those with the CT and CC (P < 0.05). In vitro functional study demonstrated that the -466T allele had lower luciferase activity (P < 0.001) and lower mRNA expression with higher production of eotaxin-2 (P = 0.003) in human lung epithelial cells. EMSA showed that CRTH2 -466T produced a specific band with a higher affinity than CRTH2 -466C had. CONCLUSION: The CRTH2 -466T>C polymorphism increases serum and cellular eotaxin-2 production through lowered CRTH2 expression, leading to eosinophilic infiltration in AERD patients.

Serum lactoferrin level as a serologic biomarker for allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is a very common disease and a risk factor for allergic asthma. The discovery of new biomarkers for the early detection of AR would improve the clinical outcomes and reduce socio-economic burden. We sought to identify a novel serologic marker for detection of AR using a proteomic approach. METHODS: To identify the proteins involved in AR, comparative proteomics was applied using nasal lavage fluids (NLFs) taken before and after a nasal provocation test (NPT) with Dermatophagoides pteronyssinus (Dpt) in a subject with AR sensitized to Dpt. The clinical relevance of the identified proteins was evaluated by ELISA using NLFs and sera from the three study groups: Dpt-sensitive AR; asymptomatic Dpt-sensitive controls; and non-atopic healthy controls. The sensitivities and specificities of the candidate proteins for predicting AR were determined using receiver operating characteristic (ROC) curves. RESULTS: In proteomic analysis, lactoferrin expression was up-regulated after NPT. The validation study using ELISA showed a significantly lower serum lactoferrin level in the AR group than those of the other two groups (P<0.05, respectively). To discriminate between subjects with or without AR, the optimal serum cut-off level of lactoferrin was set at <307 ng/mL using the ROC curve. The sensitivity and specificity for predicting AR were 81.4% and 58%. When combined with serum Dpt-specific IgE level, the sensitivity and specificity for predicting AR were 76.7% and 79.2%. CONCLUSION: These results suggest that the serum lactoferrin level is associated with the phenotype of Dpt-sensitive AR, and in combination with the serum Dpt-specific IgE level, may be a potential serologic marker for early detection of AR.