Hypersensitivity infusion-associated reactions induced by enzyme replacement therapy in a cohort of patients with late-onset Pompe disease: An experience from the French Pompe Registry.

BACKGROUND AND OBJECTIVES: Pompe disease is a rare hereditary glycogen storage disorder due to lysosomal acid alpha-glucosidase deficiency. Enzyme replacement therapy (ERT) is the only available treatment. Infusion-associated reactions (IAR) are challenging since there are no guidelines for ERT rechallenge after a drug hypersensitivity reaction (DHR) in Pompe disease. The objective of the present study was to describe IAR and their management in late-onset Pompe disease (LOPD) patients in France, and to discuss the various possibilities of ERT rechallenge. METHODS: An exhaustive screening of LOPD patients receiving ERT between 2006 and 2020 from the 31-participating hospital-based or reference centers was performed. The patients who had presented at least one hypersensitivity IAR (=DHR) episode were included. Demographic characteristics of the patients, IAR onset and timing, were retrospectively collected from the French Pompe Registry. RESULTS: Fifteen patients among 115 treated LOPD patients in France presented at least 1 IAR; 80.0% were women. Twenty-nine IAR were reported; 18 (62.1%) IAR were Grade I reactions, 10 (34.5%) IAR were Grade II, and 1 (3.4%) IAR was Grade III. IgE-mediated hypersensitivity was found in 2/15 patients (13.3%). The median [IQR] time from ERT introduction to the first IAR was 15.0 months [11.0-24.0]. ERT was safely and effectively re-introduced either with premedication alone, or in combination with either modified regimen or desensitization protocol, in all 9 rechallenged patients; including in patients with IgE-mediated hypersensitivity, in the patient with the Grade III reaction, as well as in patients with very high anti-GAA titer. DISCUSSION: Based on the results herein and previous reports, we discuss premedication and modified regimen for Grade I reactions, and desensitization in Grade II and III reactions. In conclusion, ERT-induced IAR can be safely and effectively managed with a modified regimen or desensitization protocol in LOPD patients.

[A RARE COMBINATION OF DELAYED TYPE HYPERSENSITIVITY REACTIONS TO BETA-LACTAMS IN A PATIENT WITH MSSA BACTEREMIA].

INTRODUCTION: A male patient aged 81, with a history of atrial fibrillation, pacemaker implantation and hip replacement was admitted due to pneumonia. Subsequent Methicillin Sensitive Staphylococcus Aureus (MSSA) bacteremia and septic arthritis of his prosthetic joint was diagnosed, and treated with Oxacillin. Two weeks later, an exanthematous rash appeared, involving most of his body surface, evolving to blisters that dried up and led to extensive exfoliation of the skin, consistent with a delayed type hypersensitivity drug reaction. Other possible etiologies for this rash were ruled out. Antibiotic treatment was changed to Cefalexin, assuming that there is no cross reactivity between penicillins and cephalosporins, regarding late drug reactions. Thereafter, the rash subsided, but his renal function deteriorated and interstitial nephritis due to a hypersensitivity reaction to cephalosporin was diagnosed. Hypersensitivity to penicillins and other beta-lactam antibiotics is reported by 10% of the population, only 1/10 of them are verified using standardized allergic testing (1-3). Delayed type hypersensitivity to beta-lactams is more common than immediate type allergy. It evolves days and weeks following exposure to the offending drug. Late responses are classified as type II- IV hypersensitivities, type IV being the most prevalent (4-7). We present a patient who developed two distinct delayed type phenomena to two different beta lactam antibiotics during the same hospitalization. The possibility of a hypersensitivity reaction should rise in the differential diagnosis of the deteriorating patient most notably as such might be life threatening on the one hand, and reversible, after drug withdrawal, on the other hand.

Dupilumab suppresses type 2 inflammatory biomarkers across multiple atopic, allergic diseases.

BACKGROUND: Type 2 inflammation is common in numerous atopic/allergic diseases and can be identified by elevated biomarker levels. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation. OBJECTIVE: Assessment of dupilumab effect on type 2 inflammatory biomarkers in atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilic esophagitis (EoE). METHODS: Data were extracted from three randomized placebo-controlled trials of dupilumab in AD (NCT02277743, N = 671; NCT02277769, N = 708; NCT02260986, N = 740); and one each in asthma (NCT02414854, N = 1902); CRSwNP (NCT02898454, N = 448); and EoE (NCT02379052, N = 47). Biomarkers assessed were serum thymus and activation-regulated chemokine (TARC), plasma eotaxin-3, serum total immunoglobulin E (IgE), serum periostin and blood eosinophil count. RESULTS: Dupilumab versus placebo significantly suppressed most type 2 inflammatory biomarker levels across all studies/indications where data were assessed. Reductions in serum TARC, plasma eotaxin-3 and serum periostin occurred rapidly, whereas reductions in serum total IgE were more gradual. Across diseases, at the end of treatment, median percentage change from baseline in TARC levels ranged from -24.8% to -88.6% (placebo +2.6% to -53.6%); -38.2% to -51.5% (placebo +8.3% to -0.16%) in eotaxin-3; -24.8% to -76.7% (placebo +8.3% to -4.4%) in total IgE; and -13.6% to -41.1% (placebo +10.1% to -6.94%) in periostin levels. Blood eosinophil responses to dupilumab varied by disease, with minimal changes in AD in the SOLO studies (median percentage change from baseline to end of treatment: 0% [95% CI: -15.8, 0]); transient increases followed by decreases to below-baseline levels in asthma (-14.6% [-20.0, -7.7]) and CRSwNP (-29.4% [-40.0, -16.3]); and significant decreases in EoE (-50.0% [-50.0, -33.3]). CONCLUSION AND CLINICAL RELEVANCE: Dupilumab reduced levels of type 2 biomarkers across clinical studies in patients with AD, asthma, CRSwNP and EoE.

Allergic disease, corticosteroid use, and risk of Hodgkin lymphoma: A United Kingdom nationwide case-control study.

BACKGROUND: Immunodeficiency syndromes (acquired/congenital/iatrogenic) are known to increase Hodgkin lymphoma (HL) risk, but the effects of allergic immune dysregulation and corticosteroids are poorly understood. OBJECTIVE: We sought to assess the risk of HL associated with allergic disease (asthma, eczema, and allergic rhinitis) and corticosteroid use. METHODS: We conducted a case-control study using the United Kingdom Clinical Practice Research Datalink (CPRD) linked to hospital data. Multivariable logistic regression investigated associations between allergic diseases and HL after adjusting for established risk factors. Potential confounding or effect modification by steroid treatment were examined. RESULTS: One thousand two hundred thirty-six patients with HL were matched to 7416 control subjects. Immunosuppression was associated with 6-fold greater odds of HL (adjusted odds ratio [aOR], 6.18; 95% CI, 3.04-12.57), with minimal change after adjusting for steroids. Any prior allergic disease or eczema alone was associated with 1.4-fold increased odds of HL (aOR, 1.41 [95% CI, 1.24-1.60] and 1.41 [95% CI, 1.20-1.65], respectively). These associations decreased but remained significant after adjustment for steroids (aOR, 1.25 [95% CI, 1.09-1.43] and 1.27 [95% CI, 1.08-1.49], respectively). There was no effect modification by steroid use. Previous steroid treatment was associated with 1.4-fold greater HL odds (aOR, 1.38; 95% CI, 1.20-1.59). CONCLUSIONS: In addition to established risk factors (immunosuppression and infectious mononucleosis), allergic disease and eczema are risk factors for HL. This association is only partially explained by steroids, which are associated with increased HL risk. These findings add to the growing evidence that immune system malfunction after allergic disease or immunosuppression is central to HL development.

Distinct associations of sputum and oral microbiota with atopic, immunologic, and clinical features in mild asthma.

BACKGROUND: Whether microbiome characteristics of induced sputum or oral samples demonstrate unique relationships to features of atopy or mild asthma in adults is unknown. OBJECTIVE: We sought to determine sputum and oral microbiota relationships to clinical or immunologic features in mild atopic asthma and the impact on the microbiota of inhaled corticosteroid (ICS) treatment administered to ICS-naive subjects with asthma. METHODS: Bacterial microbiota profiles were analyzed in induced sputum and oral wash samples from 32 subjects with mild atopic asthma before and after inhaled fluticasone treatment, 18 atopic subjects without asthma, and 16 nonatopic healthy subjects in a multicenter study (NCT01537133). Associations with clinical and immunologic features were examined, including markers of atopy, type 2 inflammation, immune cell populations, and cytokines. RESULTS: Sputum bacterial burden inversely associated with bronchial expression of type 2 (T2)-related genes. Differences in specific sputum microbiota also associated with T2-low asthma phenotype, a subgroup of whom displayed elevations in lung inflammatory mediators and reduced sputum bacterial diversity. Differences in specific oral microbiota were more reflective of atopic status. After ICS treatment of patients with asthma, the compositional structure of sputum microbiota showed greater deviation from baseline in ICS nonresponders than in ICS responders. CONCLUSIONS: Novel associations of sputum and oral microbiota to immunologic features were observed in this cohort of subjects with or without ICS-naive mild asthma. These findings confirm and extend our previous report of reduced bronchial bacterial burden and compositional complexity in subjects with T2-high asthma, with additional identification of a T2-low subgroup with a distinct microbiota-immunologic relationship.

Ketoprofen hypersensibility and idiosyncratic response - a case report.

Context: Ketoprofen is widely used to remove pain. A steady increase on allergic reactions and photoallergic contact dermatitis related to ketoprofen has been reported when there is topical use. However, there are few documented cases of hypersensitivity when it is administered systemically.Objective: Present a case of hypersensitivity reaction after systemic administration of ketoprofen for pain control in nephritis crisis.Case description: A 43-years-old Caucasian man diagnosed with renal colic (kidney lithiasis), who was initially treated with 100 mg of tramadol (IV), followed by 4 mg of thiocolchicoside (IM) which caused no relief. Then 100 mg of ketoprofen was administered (IV). Right after the patient began to show hypersensitivity reaction type I characterized by intense coughing, rhinitis, angioedema, periorbital edema, rash, and scleral jaundice.Discussion and conclusion: Maybe it was a case of drug-induced liver disease, however therapeutic dosages of all administered drugs only once. The mechanisms involved were not investigated, but may be the result of allergic and immunologic aspects caused by ketoprofen and facilitated by a history of hypersensitivity to other NSAIDs as reported by the patient. As for jaundice can be attributed to drug toxicity since laboratory parameters did not reveal any evidence of liver disease.

Tricin Isolated from Enzyme-Treated Zizania latifolia Extract Inhibits IgE-Mediated Allergic Reactions in RBL-2H3 Cells by Targeting the Lyn/Syk Pathway.

Tricin, a flavone present in rice bran, is confirmed as the major efficacious compound present in the enzyme-treated Zizania latifolia extract (ETZL), which protects against UVB-induced skin-aging. However, the suppressive mechanism of tricin on allergic responses remains unknown. The present study, therefore, aimed to determine the mechanisms of tricin and ETZL on mast cell degranulation in IgE-activated rat basophilic leukemia cell line (RBL-2H3) cells. We investigated the regulatory effects of tricin and ETZL on degranulation, production of cytokines and lipid mediators, and signaling proteins involved in the IgE-bound high-affinity IgE receptor activation, mitogen-activated protein kinase, arachidonic acid and Syk. The production of ß-hexosaminidase, tumor necrosis factor-α, interleukin-4, leukotrienes (LT) B4, LTC4 and prostaglandin E2 in IgE-stimulated RBL-2H3 cells were significantly inhibited by exposure to tricin or ETZL. Moreover, tricin and ETZL inhibit the phosphorylation of cytosolic phospholipase A2, 5-lipoxygenase and cyclooxygenase-2. Furthermore, the phosphorylation of Akt, ERK, p38, JNK, protein kinase Cδ and phospholipase Cγ1 were effectively suppressed by both samples. Exposure to tricin or ETZL also significantly decreases the phosphorylation of Lyn and Syk, but has minimal effect on Fyn. Taken together, our data indicate that tricin and ETZL are potential anti-allergic materials that could be applied for the prevention of allergy-related diseases.

Amlexanox: A Novel Therapeutic for Atopic, Metabolic, and Inflammatory Disease.

Amlexanox, a small molecule targeted therapy which has been used in the treatment of atopic conditions was previously but is not currently available in the United States. Amlexanox has also been legally utilized and administered in Japan as a treatment for asthma, a chronic pulmonary disease characterized by inflammation of the lower respiratory tract. Amlexanox's immune modulatory effects have been the subject of studies which have repurposed the drug for potential therapeutic applications in metabolic and inflammatory disease. Because amlexanox inhibits TANK-binding kinase1 (TBK1) and nuclear factor kB kinase epsilon (IKKε), several studies have demonstrated its usefulness through its evidence downregulation of the immune system and attenuation of downstream TBK1 signaling. Novel therapies, such as amlexanox, for inflammatory conditions such as asthma will continue to be of value in clinical management. This report summarizes key applications of the drug based on animal and human studies and explores its potential in treatment of metabolic and inflammatory diseases.

Impact of atopy on the severity and extrapulmonary manifestations of childhood Mycoplasma pneumoniae pneumonia.

OBJECTIVES: The impact of atopy on disease severity and extrapulmonary manifestations in children with Mycoplasma pneumoniae (MP) pneumonia is unknown. METHODS: Patients diagnosed with MP pneumonia between January 2016, and December 2017, were enrolled in this study. A total of 150 MP pneumonia patients were enrolled at diagnosis and divided into the atopic group (n = 48) and the nonatopic group (n = 102). Furthermore, these patients were also assessed after being divided into the pulmonary group (n = 120) and the extrapulmonary group (n = 30). Clinical characteristics, respiratory disease severity, any allergy history, and specific allergen sensitizations were collected from all patients. The serum interleukin-17 (IL-17) and total immunoglobulin E (lgE) levels were also measured. RESULTS: More children in the atopic group than those in the nonatopic group presented with severe MP pneumonia, tachypnea, oxygen therapy, steroid treatment, atopic conditions including asthma attack, a previous history of asthma, decreased IL-17 levels, and increased IgE levels (all P < 0.05). When compared with those in the pulmonary group, the patients in the extrapulmonary group showed higher percentages of atopy, higher total lgE levels, and lower IL-17 levels (all P < 0.05). CONCLUSIONS: Atopy may be a risk factor for disease severity and extrapulmonary manifestations in children with MP pneumonia.

Incidence of Childhood Eosinophilic Esophagitis in Central Brazil: How Many Are We Missing?

BACKGROUND: Few studies have assessed the incidence of eosinophilic esophagitis (EoE) in childhood. Our study aimed to determine the incidence of EoE in pediatric patients undergoing upper gastrointestinal endoscopy (UGE), with analysis of epidemiological data including sex, age, symptoms, frequency of atopy, and endoscopic and histological findings. METHODS: We performed a retrospective, observational, analytical study of the medical records of patients aged 0 to 14 years who underwent UGE in a tertiary hospital from January 2004 to January 2014. RESULTS: A total of 4071 upper digestive endoscopies were performed in 2651 patients. Esophageal eosinophilia was found in 405 biopsy reports, and 127 patients had ≥15/HPF. The clinical histories of 70 patients were analyzed. Sixty-three fulfilled the diagnostic criteria for EoE, 3 fulfilled the criteria for eosinophilic gastroenteritis, and 4 cases were secondary to caustic ingestion. The mean annual incidence was 2.48/100 000 individuals/year and the cumulative incidence over 10 years was 24.8/100 000. No statistical differences were found between responders to proton pump inhibitors and nonresponders for age, gender, atopic diseases, symptoms, and endoscopy findings. CONCLUSIONS: The incidence of EoE in the present study was similar to that reported in the literature. However, these data may be underestimated owing to difficulties accessing UGE. Increased knowledge of esophageal eosinophilic diseases in childhood requires associated improvements in health infrastructure.

Features of the bronchial bacterial microbiome associated with atopy, asthma, and responsiveness to inhaled corticosteroid treatment.

BACKGROUND: Compositional differences in the bronchial bacterial microbiota have been associated with asthma, but it remains unclear whether the findings are attributable to asthma, to aeroallergen sensitization, or to inhaled corticosteroid treatment. OBJECTIVES: We sought to compare the bronchial bacterial microbiota in adults with steroid-naive atopic asthma, subjects with atopy but no asthma, and nonatopic healthy control subjects and to determine relationships of the bronchial microbiota to phenotypic features of asthma. METHODS: Bacterial communities in protected bronchial brushings from 42 atopic asthmatic subjects, 21 subjects with atopy but no asthma, and 21 healthy control subjects were profiled by using 16S rRNA gene sequencing. Bacterial composition and community-level functions inferred from sequence profiles were analyzed for between-group differences. Associations with clinical and inflammatory variables were examined, including markers of type 2-related inflammation and change in airway hyperresponsiveness after 6 weeks of fluticasone treatment. RESULTS: The bronchial microbiome differed significantly among the 3 groups. Asthmatic subjects were uniquely enriched in members of the Haemophilus, Neisseria, Fusobacterium, and Porphyromonas species and the Sphingomonodaceae family and depleted in members of the Mogibacteriaceae family and Lactobacillales order. Asthma-associated differences in predicted bacterial functions included involvement of amino acid and short-chain fatty acid metabolism pathways. Subjects with type 2-high asthma harbored significantly lower bronchial bacterial burden. Distinct changes in specific microbiota members were seen after fluticasone treatment. Steroid responsiveness was linked to differences in baseline compositional and functional features of the bacterial microbiome. CONCLUSION: Even in subjects with mild steroid-naive asthma, differences in the bronchial microbiome are associated with immunologic and clinical features of the disease. The specific differences identified suggest possible microbiome targets for future approaches to asthma treatment or prevention.

The anti-inflammatory effect of topical tofacitinib on immediate and late-phase cutaneous allergic reactions in dogs: a placebo-controlled pilot study.

BACKGROUND: Topical Janus kinase (JAK) inhibition is a promising therapeutic target for several inflammatory skin diseases of humans. OBJECTIVES: To evaluate the anti-inflammatory effect of tofacitinib, a JAK 1/3 inhibitor, on immediate and late-phase skin reactions in dogs. ANIMALS: Five healthy laboratory beagle dogs. METHODS: Topical tofacitinib (total daily dosage: 0.5 mg/cm2 ) or its gel vehicle were applied on either the left or right lateral thorax of each dog for eight days. Three days before application and after eight days of topical treatment, intradermal injections of histamine and anticanine-IgE antibodies were performed on both sides; they were evaluated by an investigator blinded to the interventions. RESULTS: The tofacitinib gel was well-tolerated; one dog developed mild erythema at Day 5 that resolved by the next application. Treatment with tofacitinib reduced histamine and anticanine-IgE global wheal scores (one-way ANOVA, P ≤ 0.005 for both) compared to baseline; there was no significant difference for the vehicle placebo (histamine; P = 0.163; IgE, P = 0.223). Late-phase reactions (LPRs) were markedly, but not significantly reduced after tofacitinib treatment (P = 0.071). A blinded histological evaluation of 6 h-anti-IgE-associated LPRs revealed a significant reduction in the total leucocyte superficial dermal cellularity (P = 0.022), as well as eosinophil (P = 0.022) and mast cell (P = 0.022) counts at tofacitinib-treated sides compared with pretreatment values. Post-treatment complete blood counts and serum chemistry profiles did not show relevant tofacitinib-induced changes. CONCLUSIONS: Our observations suggest that topical tofacitinib exerts an inhibitory effect on activated canine skin-emigrating immune cells; this drug should be investigated further as a topical immunosuppressive drug in dogs.

Atopic status and latex sensitization in a cohort of 1,628 students of health care faculties.

BACKGROUND: Atopic diseases have increased since the second half of the previous century. Atopic workers are at higher risk to be sensitized to latex, and the first years of exposure are supposed to be especially risky. OBJECTIVE: To assess atopic status and rate of latex sensitization in health care students starting their exposure to latex gloves. METHODS: We analyzed medical surveillance data from 1,628 health care students from 2010 to 2016. Students completed a questionnaire focused on their previous and current latex exposure and personal and family histories of allergic diseases; underwent skin prick testing with common allergens and latex extract (and/or total and latex-specific immunoglobulin E in serum); and underwent a medical examination. RESULTS: Skin prick test results for common inhalant allergens showed that 807 of 1,628 students (49.6%) had atopy. Atopy by skin prick testing was associated with male sex (odds ratio 1.49, 95% confidence interval 1.18-1.86), a personal history of oculorhinitis or asthma (odds ratio 10.22, 95% confidence interval 7.4-14.13), and atopic eczema (odds ratio 1.87, 95% confidence interval 1.05-3.36) at multivariate regression analysis. Eleven students (0.7% of total population) were found to be sensitized to latex and all had atopy. CONCLUSION: Despite the high prevalence of atopy in health care students of Trieste, the latex sensitization rate is very low and comparable to general population. This is reasonably due to the low exposure to latex gloves at the time of the evaluation and to low latex release from the gloves currently used in our hospital.

Association Between Migraine and Atopic Diseases in Childhood: A Potential Protective Role of Anti-Allergic Drugs.

BACKGROUND: Migraine is a common cause of headache in childhood. Several studies have investigated the association between migraine and atopic diseases, mostly in the adult population. OBJECTIVE: This study aimed to investigate this association in children. METHODS: A case-control study was conducted across 3 European tertiary care hospitals between June 2014 and August 2014. Cases (n = 229) were children aged 6-18 years consulting for a migraine episode. Controls in the same age range (n = 406) were consulting for a minor injury and did not have a history of recurrent headache. Logistic regression analyses tested the effect of atopic diseases and anti-allergic therapies on occurrence of migraine. RESULTS: Children with migraine were more likely to have persistent asthma compared to absence of asthma (odds ratio [OR]: 4.57, 95% confidence interval [CI]: 2.04-10.24) and less likely to have been treated by inhaled or nasal corticosteroid (OR: 0.34, 95% CI: 0.15-0.76) or antihistamine therapy (OR: 0.33, 95% CI: 0.18-0.60). The median number of monthly migraine episodes was higher in children with persistent asthma (3; interquartile [IQR]: 1-4; range: 0.5-10) compared to children with intermittent asthma (2; IQR: 1-3; range: 0.1-4) or non-asthmatic children (2; IQR: 1-3; range: 0.1-12) (P < .01). CONCLUSION: Persistent childhood asthma was associated with increased risk of migraine and higher frequency of migraine attacks. History of anti-asthmatic or anti-allergic therapies was associated with decreased risk of migraine in children and adolescents. The role of these therapies on the pathogenesis and occurrence of migraine needs to be further elucidated because of the huge potential impact in terms of public health.

American Academy of Asthma, Allergy & Immunology membership experience with venom immunotherapy in chronic medical conditions and pregnancy, and in young children.

BACKGROUND: Few data exist regarding the use of venom immunotherapy (VIT) in specific high-risk chronic medical conditions and pregnancy, and in young children. METHODS: A Web-based survey was sent to American Academy of Asthma Allergy & Immunology members to explore their VIT experience in potential high-risk medical conditions and pregnancy, and in young children. Major problems were defined as "activation of underlying disease and/or VIT not well tolerated (systemic adverse events) and/or VIT discontinued for medical reasons." Results were expressed descriptively. RESULTS: A total of 697 of 5123 surveys (14%) were completed: 87% of the respondents were based in the United States, and 28% worked in an academic setting. Most respondents (71%) believed that pregnancy was a contraindication for starting VIT. Most were comfortable continuing VIT (51%) if the woman became pregnant after starting therapy. Of the allergists who treated children, many would give VIT down to age 5 years (42%) or younger, ages 1-4 years (35%). The following list is of the specific medical condition, the number of allergists who used VIT in patients with this condition, and the percentage who reported major problems: severe asthma, 212 (4.2%); hypertension, 287 (1.1%); coronary artery disease, 222 (3.6%); arrhythmias, 136 (3.4%); cerebrovascular disease, 104 (5.1%); cancer in remission, 166 (0%); cancer stable but still under treatment, 44 (7.2%); a history of bone marrow transplantation, 15 (4.9%); a history of solid organ transplantation, 29 (3.6%); human immunodeficiency virus, 53 (1.4%); acquired immunodeficiency syndrome, 24 (6.2%); stable autoimmune disease, 164 (2.8%); mastocytosis, 66 (18.4%); elevated serum tryptase, 101 (10.8%); immunodeficiency 59 (2.5%). CONCLUSION: Many allergists were comfortable using VIT in young children and continuing but not starting pregnant women on VIT. VIT was commonly used in patients with hypertension, coronary artery disease, arrhythmias, cancer in remission, and stable autoimmune disease. Major problems were most frequently reported in use with mastocytosis, elevated tryptase, and cancer still under treatment.

Delayed-type hypersensitivity to oral and parenteral drugs.

Adverse drug reactions of the delayed type rank among the most common dermatoses and are predominantly characterized by exanthematous macular or maculopapular eruptions. However, approximately 2 % of affected individuals develop severe or even life-threatening systemic immune reactions associated with organ involvement, requiring immediate diagnosis and treatment. Numerous drugs are capable of eliciting delayed-type hypersensitivity reactions, with antibiotics, anticonvulsant drugs, and the xanthine oxidase inhibitor allopurinol being the most common. Apart from genetic susceptibility, predisposing factors for the development of drug hypersensitivity reactions include high drug doses, polypharmacy, long treatment duration, female gender, as well as acute or chronic infections.

Diagnostic utility of fractional exhaled nitric oxide in prolonged and chronic cough according to atopic status.

BACKGROUND: Cough-variant asthma (CVA) and cough-predominant asthma (CPA) are the major causes of persistent cough in Japan. The utility of fractional exhaled nitric oxide (FeNO) measurement in the differential diagnosis of persistent cough has been reported, but the influence of atopic status, which is associated with higher FeNO levels, on the diagnostic utility of FeNO has been unknown. METHODS: We retrospectively analyzed 105 non-smoking patients with prolonged and chronic cough that were not treated with corticosteroids and anti-leukotrienes. RESULTS: CPA was diagnosed in 37 patients, CVA in 40, and non-asthmatic cough (NAC) in 28. FeNO levels were significantly higher in the CPA [35.8 (7.0-317.9) ppb] and CVA [24.9 (3.1-156.0) ppb] groups than in the NAC group [18.2 (6.9-49.0) ppb] (p < 0.01 by Kruskal-Wallis test). The optimal cut-off for distinguishing asthmatic cough (AC; CPA and CVA) from NAC was 29.2 ppb [area under the curve (AUC) 0.74, p < 0.01]. Ninety-one percent of subjects with FeNO levels ≥29.2 ppb had AC. Meanwhile, 40% of AC patients had FeNO levels <29.2 ppb. Stratified cut-off levels were 31.1 ppb (AUC 0.83) in atopic subjects vs. 19.9 ppb (AUC 0.65) in non-atopic subjects (p = 0.03 for AUC). CONCLUSIONS: Although high FeNO levels suggested the existence of AC, lower FeNO levels had limited diagnostic significance. Atopic status affects the utility of FeNO levels in the differential diagnosis of prolonged and chronic cough.

New opportunities and challenges in the assessment of drugs for atopic diseases.

Atopic conditions (atopic dermatitis, rhinitis, and asthma) belong to the most common noncommunicable diseases and are driven by chronic inflammatory reactions. They have a strong impact on the quality of life and represent a substantial and growing socio-economic burden. Interestingly, there is an increasing interest in the development of new therapeutic options with a number of biologics and small molecules targeting potential key mechanisms in atopic conditions. However, besides the safety issue, most of the new active substances are still evaluated according to the traditional efficacy paradigm focusing on the success in treating exacerbations and flares. Instead, the future approaches in drug development and assessment should rather concentrate on the long-term control of these diseases and consider their potential as disease-modifying strategies in the era of precision medicine. To reach this goal, a number of unsolved issues have to be addressed and consensually accepted by the stakeholders in this field. Thus, a successful and rapid development of new treatments requests a paradigm shift and a new way of thinking in the mind of physicians, pharmaceutical industry, regulators, and HTAs. This seems mandatory in order to optimize drug development and to facilitate the accessibility of new therapies to the growing population of patients suffering from atopic conditions on a global level.