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Genetic Variants in Arachidonic Acid Pathway Genes Associated with Nsaids-Exacerbated Respiratory Disease
AB114 Abstracts
367
SUNDAY
Skin Testing with Betalactam Antibiotics for Diagnosis of Betalactam Hypersensitivity in Children Prapasiri Singvijarn, MD, Ramathibodi Hospital, Thailand. RATIONALE: Betalactam antibiotics are the most common causes of drug hypersensitivity reported in children. Penicilloyl polylysine (PPL) and minor determinant were used for skin test but PPL is not commonly available. This study was to determine negative predictive value (NPV) of skin testing with betalactam antibiotics for diagnosis of betalactam hypersensitivity. METHODS: Patients age 1-18 years old with history of betalactam hypersensitivity were evaluated by skin test (skin prick test, intradermal test) with culprit drugs (penicillin G, ampicillin, amoxicillin-clavulonic acid, cloxacillin and cephalosporin). Patients who have negative skin test were performed drug provocation test (DPT) in 3 dose graded challenge. The hypersensitivity reactions was classified into immediate and delay reactions. RESULTS: 86 patients were evaluated for drug allergy. Only 18 patients (20%) were confirmed allergic to culprit drugs. 11 (61 %) of them confirmed by skin test. Among 75 patients with negative skin test were performed DPT, 7 patients (9.3%) were reacted providing NPV 90.7%. The most common culprit drug was amoxicillin (66.7%), followed by amoxicillin-clavulonic acid (16.7%). The history of immediate reaction was associated with true drug allergy (p value5 0.01). There were no serious systemic reaction in our study. There was only minor reactions which were response to symptomatic treatments. CONCLUSIONS: Among children with history of betalactam hypersensitivity, skin testing with culprit drugs was safe and providing a good NPV when PPL was unavailable. However, skin test with betalactam antibiotics did not provide high sensitivity, thus DPT is necessary to confirm the diagnosis of drug hypersensitivity.
368
Viral Reactivation and Subsequent Cytotoxic Lymphocyte Activation Associates with Increased Morbidity in Children with Dress Syndrome Jinzhu Li, MD, PhD1, Amal H. Assa’ad, MD, FAAAAI1, Kara Shah, MD, PhD2, Carl Allen, MD, PhD3, Kimberly A. Risma, MD, PhD, FAAAAI1; 1Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 2Cincinnati Children’s Hospital Medical Center, 3Texas Children’s Hospital. RATIONALE: DRESS syndrome is a severe drug reaction with a reported mortality approaching 10%. It is classified as a Th2-mediated, type IV hypersensitivity reaction; however, viral reactivation of herpes viruses has been frequently identified in patients. Therefore, we hypothesized that cytotoxic lymphocyte against viral reactivation may also be implicated in the pathologic response. METHODS: Six pediatric patients who met the criteria for DRESS per RegiSCAR scoring system were evaluated during their illness. Reactivation of herpes viruses was evaluated in all patients and two markers of T cell activation were measured: expression of granzyme B in CD8 T cells and plasma soluble IL2 receptor levels (sIL2R). RESULTS: Positive PCR to Human Herpesvirus 6 (HHV6) was noted in three cases; two of these patients were evaluated for hemophagocytic lymphohistiocytosis (HLH) due to significant multi-organ pathology, including liver, kidney and lung involvement. The third patient had a milder clinical course but developed relapse on steroid taper. Granzyme B in CD8 T cell was assessed in 5/6 patients and was elevated in two patients with positive PCR to HHV6. Patients with negative viral PCR had normal expression of granzyme B, and less severe clinical courses. sIL2R was elevated in all cases but more remarkable (>10,000) in patients with severe presentations. CONCLUSIONS: In a case series of 6 children with DRESS syndrome, those patients presenting with both viral reactivation and significant CTL activation tend to suffer a more severe clinical course. We propose that these patients require early recognition and aggressive immunosuppression.
J ALLERGY CLIN IMMUNOL FEBRUARY 2015
369
Genetic Variants in Arachidonic Acid Pathway Genes Associated with Nsaids-Exacerbated Respiratory Disease Pedro Ayuso1,2, Maria del Carmen Plaza-Seron, Bsc1,2, Natalia BlancaLopez, MD PhD1, Inmaculada Do~na, MD, PhD3, Paloma Campo, MD PhD3, Jose Julio Laguna, MD, PhD4, Joan Bartra, MD, PhD5, Victor Soriano-Gomis6, Marıa Jose Torres, MD, PhD3, Miguel Blanca, MD, PhD3, Jose A Cornejo-Garcia, PhD2, James R. Perkins2; 1Allergy Service, Infanta Leonor Hospital, Madrid, Spain, 2Research Laboratory, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, Spain, 3Allergy Unit, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, Spain, 4De La Cruz Roja Hospital, Madrid, Spain, 5Allergy Unit, Service of Pneumology and Respiratory Allergy, Hospital Clinic (ICT), Barcelona, Spain, 6Allergy Service, Alicante General Hospital, Alicante, Spain. RATIONALE: Non steroidal anti-inflammatory drugs (NSAIDs) are the most frequent cause of hypersensitivity drug reactions (HDR). The mechanism of NSAIDs-exacerbated respiratory disease (NERD) has been attributed to the inhibition of prostaglandin-endoperoxide synthases (PTGS) by NSAIDs in susceptible individuals. This leads to a reduction in prostaglandin E2production and shunts arachidonic acid metabolism toward the lipooxygenase pathway, resulting in the release of cysteinyl leukotrienes. Here, we have examined the association between NERD and polymorphisms in genes encoding PTGS, lipoxygenases and their receptors. In addition, we have analyzed copy number variants (CNVs) for genes involved in arachidonic acid metabolism. METHODS: We included a total of 250 NERD patients, 260 NSAIDtolerant asthmatic subjects (NTA) and 315 unrelated healthy subjects. A total of thirty three single nucleotide polymorphisms (SNPs) in PTGS1, PTGS2, ALOX5, ALOX5AP, ALOX12, ALOX15, LTC4S, CYSLTR1, CYSLTR2, PTGER1, PTGER2, PTGER3, PTGER4, PTGDR and PTGFR genes were studied. Moreover, CNVs in PTGS1, PTGS2, LTC4S, ALOX5 and PTGER1-4 geneswere analyzed. RESULTS: Significant associations with NERD were identified for the following genes: ALOX15 (rs3892408) and PTGS-1 (rs10306135 and rs5789). Furthermore, the ALOX15 rs3892408-rs11568131 [T-G] haplotype was shown to be statistically significant associated with NERD. Significant differences in ALOX5CNVs among NERD, NTA and control subjects (NERD vs NTA; OR: 0.17; 95% CI: 0.0–0.8; P50.010; NERD vs Controls; OR: 0.03; CI: 0.0-0.5; P50.0001) were also found. CONCLUSIONS: These findings help contribute to a more precise knowledge of the underlying mechanisms of NERD and will be important for identifying predictive genetic markers for this pathology.
367
SUNDAY
Skin Testing with Betalactam Antibiotics for Diagnosis of Betalactam Hypersensitivity in Children Prapasiri Singvijarn, MD, Ramathibodi Hospital, Thailand. RATIONALE: Betalactam antibiotics are the most common causes of drug hypersensitivity reported in children. Penicilloyl polylysine (PPL) and minor determinant were used for skin test but PPL is not commonly available. This study was to determine negative predictive value (NPV) of skin testing with betalactam antibiotics for diagnosis of betalactam hypersensitivity. METHODS: Patients age 1-18 years old with history of betalactam hypersensitivity were evaluated by skin test (skin prick test, intradermal test) with culprit drugs (penicillin G, ampicillin, amoxicillin-clavulonic acid, cloxacillin and cephalosporin). Patients who have negative skin test were performed drug provocation test (DPT) in 3 dose graded challenge. The hypersensitivity reactions was classified into immediate and delay reactions. RESULTS: 86 patients were evaluated for drug allergy. Only 18 patients (20%) were confirmed allergic to culprit drugs. 11 (61 %) of them confirmed by skin test. Among 75 patients with negative skin test were performed DPT, 7 patients (9.3%) were reacted providing NPV 90.7%. The most common culprit drug was amoxicillin (66.7%), followed by amoxicillin-clavulonic acid (16.7%). The history of immediate reaction was associated with true drug allergy (p value5 0.01). There were no serious systemic reaction in our study. There was only minor reactions which were response to symptomatic treatments. CONCLUSIONS: Among children with history of betalactam hypersensitivity, skin testing with culprit drugs was safe and providing a good NPV when PPL was unavailable. However, skin test with betalactam antibiotics did not provide high sensitivity, thus DPT is necessary to confirm the diagnosis of drug hypersensitivity.
368
Viral Reactivation and Subsequent Cytotoxic Lymphocyte Activation Associates with Increased Morbidity in Children with Dress Syndrome Jinzhu Li, MD, PhD1, Amal H. Assa’ad, MD, FAAAAI1, Kara Shah, MD, PhD2, Carl Allen, MD, PhD3, Kimberly A. Risma, MD, PhD, FAAAAI1; 1Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 2Cincinnati Children’s Hospital Medical Center, 3Texas Children’s Hospital. RATIONALE: DRESS syndrome is a severe drug reaction with a reported mortality approaching 10%. It is classified as a Th2-mediated, type IV hypersensitivity reaction; however, viral reactivation of herpes viruses has been frequently identified in patients. Therefore, we hypothesized that cytotoxic lymphocyte against viral reactivation may also be implicated in the pathologic response. METHODS: Six pediatric patients who met the criteria for DRESS per RegiSCAR scoring system were evaluated during their illness. Reactivation of herpes viruses was evaluated in all patients and two markers of T cell activation were measured: expression of granzyme B in CD8 T cells and plasma soluble IL2 receptor levels (sIL2R). RESULTS: Positive PCR to Human Herpesvirus 6 (HHV6) was noted in three cases; two of these patients were evaluated for hemophagocytic lymphohistiocytosis (HLH) due to significant multi-organ pathology, including liver, kidney and lung involvement. The third patient had a milder clinical course but developed relapse on steroid taper. Granzyme B in CD8 T cell was assessed in 5/6 patients and was elevated in two patients with positive PCR to HHV6. Patients with negative viral PCR had normal expression of granzyme B, and less severe clinical courses. sIL2R was elevated in all cases but more remarkable (>10,000) in patients with severe presentations. CONCLUSIONS: In a case series of 6 children with DRESS syndrome, those patients presenting with both viral reactivation and significant CTL activation tend to suffer a more severe clinical course. We propose that these patients require early recognition and aggressive immunosuppression.
J ALLERGY CLIN IMMUNOL FEBRUARY 2015
369
Genetic Variants in Arachidonic Acid Pathway Genes Associated with Nsaids-Exacerbated Respiratory Disease Pedro Ayuso1,2, Maria del Carmen Plaza-Seron, Bsc1,2, Natalia BlancaLopez, MD PhD1, Inmaculada Do~na, MD, PhD3, Paloma Campo, MD PhD3, Jose Julio Laguna, MD, PhD4, Joan Bartra, MD, PhD5, Victor Soriano-Gomis6, Marıa Jose Torres, MD, PhD3, Miguel Blanca, MD, PhD3, Jose A Cornejo-Garcia, PhD2, James R. Perkins2; 1Allergy Service, Infanta Leonor Hospital, Madrid, Spain, 2Research Laboratory, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, Spain, 3Allergy Unit, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, Spain, 4De La Cruz Roja Hospital, Madrid, Spain, 5Allergy Unit, Service of Pneumology and Respiratory Allergy, Hospital Clinic (ICT), Barcelona, Spain, 6Allergy Service, Alicante General Hospital, Alicante, Spain. RATIONALE: Non steroidal anti-inflammatory drugs (NSAIDs) are the most frequent cause of hypersensitivity drug reactions (HDR). The mechanism of NSAIDs-exacerbated respiratory disease (NERD) has been attributed to the inhibition of prostaglandin-endoperoxide synthases (PTGS) by NSAIDs in susceptible individuals. This leads to a reduction in prostaglandin E2production and shunts arachidonic acid metabolism toward the lipooxygenase pathway, resulting in the release of cysteinyl leukotrienes. Here, we have examined the association between NERD and polymorphisms in genes encoding PTGS, lipoxygenases and their receptors. In addition, we have analyzed copy number variants (CNVs) for genes involved in arachidonic acid metabolism. METHODS: We included a total of 250 NERD patients, 260 NSAIDtolerant asthmatic subjects (NTA) and 315 unrelated healthy subjects. A total of thirty three single nucleotide polymorphisms (SNPs) in PTGS1, PTGS2, ALOX5, ALOX5AP, ALOX12, ALOX15, LTC4S, CYSLTR1, CYSLTR2, PTGER1, PTGER2, PTGER3, PTGER4, PTGDR and PTGFR genes were studied. Moreover, CNVs in PTGS1, PTGS2, LTC4S, ALOX5 and PTGER1-4 geneswere analyzed. RESULTS: Significant associations with NERD were identified for the following genes: ALOX15 (rs3892408) and PTGS-1 (rs10306135 and rs5789). Furthermore, the ALOX15 rs3892408-rs11568131 [T-G] haplotype was shown to be statistically significant associated with NERD. Significant differences in ALOX5CNVs among NERD, NTA and control subjects (NERD vs NTA; OR: 0.17; 95% CI: 0.0–0.8; P50.010; NERD vs Controls; OR: 0.03; CI: 0.0-0.5; P50.0001) were also found. CONCLUSIONS: These findings help contribute to a more precise knowledge of the underlying mechanisms of NERD and will be important for identifying predictive genetic markers for this pathology.