High Constitutive Interleukin 10 Level Interferes With the Immune Response to Varicella-Zoster Virus in Elderly Recipients of Live Attenuated Zoster Vaccine.

INTRODUCTION: Live attenuated zoster vaccine (Zostavax) was used to test the hypothesis that constitutive level of interleukin 10 (IL-10), which may be high in elderly subjects, impairs vaccine efficacy. If constitutive IL-10 impairs vaccine efficacy, the effectiveness of viral vaccines might be improved by transient inhibition of IL-10 before vaccination. METHODS: Zostavax was given to 26 patients (age, 60-80 years). IL-10 and immunity to varicella zoster virus (VZV) were measured at baseline and after vaccination. Fluorescent antibody to membrane antigen (FAMA) assays and glycoprotein enzyme-linked immunosorbent assays (gpELISAs) were used to assess humoral immunity; anti-varicella virus T-cell responses were studied in a subset of subjects. In a prospective animal model, T-cell responses to chimeric vaccines against lymphocytic choriomeningitis virus (LCMV) were assessed in mice that express or lack IL-10. RESULTS: FAMA assays revealed significant boosting (by 4-fold) of humoral immunity, which occurred only in subjects (10 of 26) with a low constitutive IL-10 level (ie, <20 pg/mL); moreover, the Zostavax-induced FAMA and gpELISA responses were inversely related to the constitutive IL-10 level. Significant VZV-specific T-cell responses followed vaccination only in subjects with a low constitutive IL-10 level. Vaccine-induced LCMV-specific T-cell responses in mice lacking IL-10 were greater than in wild-type animals. CONCLUSIONS: A high constitutive IL-10 level adversely affects vaccine efficacy.

A Tale of Two Knee Implants in the Same Person: Narcotics for the First and Anti-inflammatory Drugs for the Second.

Opioid addiction is a world-wide tragedy, with severe consequences for both the victims and the society that must care for them. The pathways to addiction are multiple but postoperative opioid prescriptions for pain management are a major contributor to this crisis. This case report describes the differences in pain management during 2 different arthroplasties of the knees in the same person. After the first arthroplasty of the right knee 10 years ago, postoperative opioids were used, but after the second arthroplasty of the left knee in 2007, anti-inflammatory drugs took the place of opioids. The first postoperative treatment with opioids was marked by addiction and a nasty withdrawal. The recovery of knee function, driving, and return to work were prolonged. After the second arthroplasty in 2007, a combination of meloxicam (COX-2 inhibitor), high-dose acetaminophen (COX-1 inhibitor at higher doses), and diclofenac topical gel (COX-1 inhibitor with local effects) produced excellent pain control and significant reduction in swelling of the operated knee. The clinical course was smooth and recovery was rapid. The patient was walking normally and driving a car at 2 weeks and took an airplane trip at 4 weeks. After arthroplasty, postoperative opioids may not be necessary for most people.

Current complications and treatment of aspirin-exacerbated respiratory disease.

INTRODUCTION: Aspirin-exacerbated respiratory disease is defined by the clinical tetrad of aspirin sensitivity, nasal polyps, asthma, and chronic rhinosinusitis. Patients experience acute upper and lower airway reactions with exposure to aspirin and other cyclooxygenase-1 inhibiting medications. However, airway inflammation and disease progression occur even in the absence of exposure to these medications, often leading to aggressive polyp formation and need for systemic corticosteroids to treat exacerbations in asthma and rhinosinusitis. Areas covered: This review focuses on the direct and indirect complications of aspirin-exacerbated respiratory disease. Current and potential management strategies are discussed with emphasis on aspirin desensitization. Expert commentary: Aspirin desensitization remains the gold standard of treatment. Demonstrated benefits of desensitization include improved symptom scores, reduction in use of systemic corticosteroids, slowing of polyp regrowth, and tolerance of aspirin and other NSAIDs for various therapeutic purposes. Continued investigation into the pathogenic mechanisms of AERD is likely to yield new diagnostic and therapeutic approaches.

Clinical Characteristics of Aspirin-Exacerbated Respiratory Disease.

Aspirin-exacerbated respiratory disease is a significant endotype of both asthma and chronic rhinosinusitis with nasal polyps. The disease demonstrates what seems to be a unified inflammatory mechanism culminating in highly eosinophilic nasal polyp disease and asthma. The rate of polyp recurrence and morbidity from asthma exacerbations are significant and warrant separating this group diagnostically from aspirin-tolerant peers. Given the unique anti-inflammatory effects of aspirin and the evolving landscape of new, targeted biologic treatments, it is even more incumbent to consider this diagnosis and offer patients treatment specific for the disease.

Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is manifested by adult-onset asthma, nasal polyposis, chronic rhinosinusitis, and aspirin sensitivity. Previously reported prevalence rates have been widely variable based on the population studied, method of diagnosis, and definition of aspirin sensitivity. OBJECTIVE: We sought to determine the prevalence of AERD among asthmatic adults. METHODS: A systematic review of databases was performed to identify all clinical trials published on or before June 16, 2013, that evaluated the prevalence of AERD. The studies were clustered into 7 different groups based on underlying disease (asthma, nasal polyps or chronic rhinosinusitis, or both), as well as on the methodology of prevalence determination. RESULTS: A total of 1770 articles were identified, with 27 considered appropriate for inclusion. Prevalence rates of AERD ranged from 5.5% to 12.4% based on study type. Among all studies in asthmatic patients, regardless of method, the prevalence of AERD was 7.15% (95% CI, 5.26% to 9.03%). The prevalence of AERD was highest among patients with severe asthma (14.89% [95% CI, 6.48% to 23.29%]). Among patients with nasal polyps and chronic rhinosinusitis, the prevalence was 9.69% (95% CI, 2.16% to 17.22%) and 8.7% (95% CI, -1.02% to 18.34%), respectively. CONCLUSION: AERD is a distinct and important subtype of asthma and polypoid sinus disease. The prevalence of AERD is 7% in typical adult asthmatic patients and twice that number in patients with severe asthma, which underscores the importance of recognizing this disorder. Early identification of this syndrome is critical in view of the increased morbidity and costs associated with asthma exacerbations and the option to treat patients with AERD with long-term aspirin treatment after desensitization.

Use of nasal inspiratory flow rates in the measurement of aspirin-induced respiratory reactions.

BACKGROUND: Nasal ketorolac challenge with modified oral aspirin challenge is a safe and effective alternative for desensitizing patients with aspirin-exacerbated respiratory disease. In addition to clinical judgment, objective tests assessing nasal flow may help in diagnosing nasal reactions. OBJECTIVE: To evaluate the feasibility of peak nasal inspiratory flow (PNIF) as an objective measurement in the assessment of a reaction to nasal ketorolac and to determine changes in PNIF that have adequate sensitivity and specificity. METHODS: One hundred fifty-one patients referred to the Scripps Clinic for aspirin challenge and desensitization and 14 healthy controls participated in the study. Percentages of decrease in PNIF during reactions were compared with the nonreactors' measurements. A receiver operating characteristic curve was constructed to assess the diagnostic performance of PNIF measurement during a clinically positive nasal challenge. RESULTS: A total of 165 subjects participated in the study. One hundred fourteen patients (69.1%) clinically reacted to the nasal ketorolac challenge. There was no statistical difference between nasal reactors and nonreactors regarding sex, baseline forced expiratory volume in 1 second, and use of systemic steroid before challenge. The mean percentage of decrease in PNIF was significantly higher in the reactor group (-0.30 ± 0.29 vs -0.07 ± 0.16, P < .001). A cutoff value of 25% decrease in PNIF had the maximum sensitivity and specificity (56.1% and 94.1%). CONCLUSION: The high specificity of a 25% decrease in PNIF found in receiver operating characteristic curve analysis indicated that PNIF measurements can be useful for assessing nasal reactions during nasal ketorolac challenges in the diagnosis of aspirin-exacerbated respiratory disease.

The clinical dilemma of "silent desensitization" in aspirin-exacerbated respiratory disease.

Aspirin desensitization is a treatment option for patients with aspirin-exacerbated respiratory disease (AERD). Some patients with an excellent history of aspirin or nonsteroidal anti-inflammatory drug (NSAID) reactions have negative aspirin challenges/desensitization. This study discusses the clinical entity of silent desensitization in AERD and the dilemma that this presents to the practicing allergist/immunologist. We discuss a series of patients with a strong history of NSAID reactions who initially underwent a negative challenge/silent desensitization. These patients were subsequently proven to have AERD after a second positive aspirin challenge. Silent desensitization is an uncommon but important outcome to recognize in AERD. Clinicians performing aspirin desensitization should understand that this can occur and consider a second confirmatory aspirin challenge in some patients.

Introduction: Szczeklik's contributions to our understanding of aspirin, NSAIDs, asthma, and allergy.

Andrew Szczeklik was born in 1938 and died on Feb 3rd, 2012. He was the most influential expert in the field of aspirin and NSAID sensitivity reactions and associated diseases in the world. This edition of NACAI is dedicated to Andrew. In the introductory chapter, we elected to highlight his accomplishments as reflected in his publications. Andrew published at least 503 articles including many invited review articles. We present 20 of his most important publications all of which contributed significantly to our understanding of these diseases.

Classification of reactions to nonsteroidal antiinflammatory drugs.

Hypersensitivity reactions to NSAIDs may occur in susceptible individuals and vary in symptom (skin, respiratory tract, and solid organs), severity (from mild skin or respiratory reactions to severe generalized) and timing (from acute to delayed). The current classification of NSAID-induced reactions emerged with the understanding of the pathologic mechanism of reactions to NSAIDs which may be either non-allergic (related to cyclooxygenase inhibition) or immunologically mediated. In this chapter we discuss the implications of accurate NSAIDs hypersensitivity classification for proper diagnosis and patient management.

Aspirin desensitization in aspirin-exacerbated respiratory disease.

Although aspirin desensitization was discovered in 1922, it was not until 1979 that a therapeutic use for aspirin treatment, under the protection of desensitization, was discovered. In the last 33 years, details of aspirin treatment have been refined to the point where it is now recognized and accepted as a major therapeutic intervention in the treatment of aspirin-exacerbated respiratory disease, with therapeutic efficacy in approximately two-thirds of patients. It is only effective in patients who have aspirin-exacerbated respiratory disease and none of the other nonsteroidal anti-inflammatory drugs, despite their cross-reactive inhibition of cyclooxygenase-1, can effectively take the place of aspirin.

Approach to patients with aspirin hypersensitivity and acute cardiovascular emergencies.

The occurrence of an emergent need for aspirin therapy in an aspirin or nonsteroidal anti-inflammatory drug (NSAID)-"allergic" individual presents one of the more challenging situations the allergist may face. A common request is for the allergist to evaluate an acutely ill patient in a monitored hospitalized setting with a vague and remote history of a "reaction to aspirin." Because of significant diagnostic limitations, introducing aspirin can be very difficult. The concern about the potential for causing anaphylaxis in an acutely ill patient can lead to fear about performing any challenge or desensitization in these patients. The objective of this article was to review the literature regarding aspirin challenges and desensitization in the emergency setting and present a rational approach to administering aspirin to patients that require this drug.

Characterization of aspirin allergies in patients with coronary artery disease.

BACKGROUND: Aspirin prevents coronary thrombosis and is used extensively in cardiovascular prophylaxis. However, patients with a prior history of an aspirin "reaction" are routinely denied this medication. OBJECTIVE: To characterize the clinical presentation of a cohort of patients with coronary artery disease (CAD) and aspirin reactions. METHODS: Between 2009 and 2012, using a retrospective computer analysis, information was collected on all patients within a county-wide health care system presenting with CAD and a prior history of aspirin reactions. RESULTS: Of 9,565 patients with CAD, a prior history of aspirin reactions was recorded in 142 patients. Of these 142 patients, 30 (21%) had histories compatible with cutaneous and/or respiratory reactions. The other patients described adverse effects to aspirin, mostly gastrointestinal intolerance and bleeding. Aspirin-induced anaphylaxis was recorded in patients but may have been misdiagnosed, describing instead respiratory hypersensitivity reactions. Of the 142 patients, only 34 (24%) were receiving daily cardiovascular prophylaxis with aspirin. Of 108 patients not receiving aspirin, 25 (17.6%) were prescribed clopidogrel. CONCLUSION: Histories of aspirin reactions in patients with CAD are uncommon, occurring in only 1.5% of our study population. The 21% of patients with histories compatible with aspirin hypersensitivities can be challenged and, if the results are positive, successfully desensitized. Moreover, almost all patients with gastric intolerance to aspirin can be treated with aspirin and a proton pump inhibitor. However, both approaches, which result in restoration of cardiovascular prophylaxis, were seriously underused in our study population.

Aspirin-exacerbated respiratory disease: update on pathogenesis and desensitization.

Aspirin-exacerbated respiratory disease (AERD) is a unique syndrome of airway inflammation that frequently occurs in patients with nasal polyposis, chronic sinusitis, and asthma. These patients tend to have progressive and recalcitrant sinus disease requiring frequent surgical intervention and in many cases systemic corticosteroids. Much about the pathogenesis of AERD remains unclear, but environmental factors likely play a prominent role in its development. Avoidance of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs) is imperative in the initial counseling of these patients. Because most of the exposure to these medications is available over the counter, most patients will experience a significant respiratory reaction to full therapeutic doses of seemingly innocent NSAIDs. Although the history of a reaction to aspirin or another NSAID is a very important part of making the diagnosis, the gold standard remains an observed aspirin challenge. Given the prevalence and usefulness of aspirin and NSAID therapy in primary care clinics, an accurate diagnosis should be made in all patients. Desensitization is an effective treatment option for many patients. Recent advances have made this procedure considerably safer and outpatient aspirin desensitization is now the standard of care.