Bobby Q. Lanier

The effects of triamcinolone acetonide aqueous nasal spray on adrenocortical function in children with allergic rhinitis

BACKGROUND Suppression of adrenocortical function, a risk associated with oral corticosteroids, is minimized with intranasal corticosteroids. Triamcinolone acetonide (TAA) aqueous nasal spray, at therapeutic doses, has no measurable effect on adrenocortical function in adults with allergic rhinitis. OBJECTIVE This double-blind, placebo-controlled study compared the effect of once-daily TAA aqueous nasal spray (220 or 440 microg) with placebo on adrenocortical function after 6 weeks of treatment in pediatric (children 6 to 12 years of age) patients with allergic rhinitis. The pharmacokinetic profile of TAA was examined after once-daily intranasal administration of TAA aqueous nasal spray 440 microg for 6 weeks. METHODS Eighty children received TAA aqueous nasal spray 220 microg or 440 microg or placebo for 6 weeks. Adrenocortical function was assessed by analyzing plasma cortisol levels before stimulation (0 hour) and at 30 and 60 minutes after a rapid 1-hour intravenous cosyntropin stimulation test performed before treatment and after 6 weeks of treatment. Samples for pharmacokinetic evaluation were collected from 19 patients at baseline (0 hour) and at 0.5, 1, 1.5, and 6 hours after the final dose of study medication. RESULTS After 6 weeks, no significant effects on adrenocortical function were observed at 30 or 60 minutes after cosyntropin stimulation with either dose of TAA aqueous nasal spray. TAA concentrations in plasma showed rapid elimination of the drug, with little or no accumulation. CONCLUSIONS TAA aqueous nasal spray (220 or 440 microg/day) has no measurable effect on adrenocortical function in pediatric patients with allergic rhinitis. Pharmacokinetic parameters after 440 microg/day of TAA aqueous nasal spray indicate a rapid decline of plasma drug levels, with little or no systemic accumulation of study drug.

Pathophysiology and progression of nasal septal perforation

OBJECTIVE To review the prevalence, causes, and treatments of nasal septal perforation (NSP). DATA SOURCES A literature search was conducted in MEDLINE to identify peer-reviewed articles related to NSP using the keywords nasal septal perforation and septal perforation for articles published between January 1, 1969, and December 31, 2006, and references cited therein. STUDY SELECTION Articles were selected based on their direct applicability to the subject matter. RESULTS Causes of NSPs include piercings, exposure to industrial chemicals, illicit drug use, intranasal steroid use, surgical trauma, bilateral cautery, and possibly improper use of nasal applicators. Prevalence is poorly reported. Mechanisms of substance-induced NSP formation are not understood. Progression from epistaxis to ulceration to NSP could not be substantiated by the literature. CONCLUSION Depending on the patient, NSP may be viewed as desirable (nose rings), problematic (whistling, congestion), or inconsequential. Understanding the pathogenesis of NSP is important for the practicing physician required to make decisions about whether to recommend surgical correction or medical treatment. Although the etiology of NSP is overwhelmingly iatrogenic, there is an association with a number of medical diseases in addition to use of illicit drugs and/or prescription nasal sprays.

Clinical efficacy of olopatadine vs epinastine ophthalmic solution in the conjunctival allergen challenge model

SUMMARY Background: Olopatadine hydrochloride 0.1% ophthalmic solution (Patanol*) and epinastine hydrochloride 0.05% ophthalmic solution (Elestat†) are two topical antiallergic agents. Olopatadine is indicated for the treatment of the signs and symptoms of allergic conjunctivitis that include itching, redness, tearing, lid swelling, and chemosis. Epinastine is indicated for the prevention of itching associated with allergic conjunctivitis. Objective: This study compared the clinical efficacy of olopatadine and epinastine in the prevention of itching and conjunctival redness in the conjunctival allergen challenge (CAC) model. Research design and methods: This was a prospective, randomized, double-masked, contralaterally-controlled, single center allergen challenge study. Ninety-six subjects with a history of allergic conjunctivitis were screened, and the 66 who responded to conjunctival allergen challenge at visits 1 and 2 were randomized into 1 of 3 treatment groups at visit 3 to receive one drop of study medication in each eye: (1) olopatadine in one eye and epinastine in the fellow eye, (2) olopatadine in one eye and placebo in the fellow eye, and (3) epinastine in one eye and placebo in the fellow eye. Five minutes after study drop instillation, subjects were bilaterally challenged with the allergen concentration that had elicited a positive conjunctival allergic response at Visits 1 and 2. Subjective itching assessments were given at 3 min, 5 min, and 7 min post challenge. Objective redness and chemosis assessments were made at 10 min, 15 min, and 20 min post challenge. Paired sample two-tailed t-tests were performed on the mean scores at each time point to assess statistical significance in the differences between treatments. Main outcome measures; results: Fifty-three subjects were randomized into the olopatadine/epinastine treatment group, the primary analysis group. Olopatadine treated eyes exhibited significantly lower mean itching and conjunctival redness scores than the contralateral epinastine treated eyes, –0.19 ( p = 0.003) and –0.52 ( p < 0.001), respectively. Olopatadine treated eyes also exhibited significantly less chemosis –0.24 ( p < 0.001), ciliary redness –0.55 ( p < 0.001), and episcleral redness –0.58 ( p < 0.001) than epinastine treated eyes. Conclusion: Olopatadine is significantly more effective than epinastine in controlling itching, redness and chemosis associated with allergic conjunctivitis in the CAC model. * Patanol is a registered tradename of Alcon Laboratories Inc, Forth Worth, TX, USA

Safety and tolerability of a short ragweed sublingual immunotherapy tablet

BACKGROUND MK-3641 is a short ragweed sublingual tablet under investigation for immunotherapy of ragweed pollen-induced allergic rhinitis. OBJECTIVE To characterize the safety and tolerability of a ragweed sublingual tablet (Merck/ALK-Abelló) in ragweed-allergic adults with or without conjunctivitis. METHODS Data from 4 randomized, double-blinded, placebo-controlled trials of MK-3641 (2 28-day and 2 52-week trials) were evaluated. Pooled analyses examined short-term safety over 28 days from all 4 trials and long-term safety from the 52-week trials. RESULTS Across all studies, 757, 198, 454, and 1,058 subjects were randomized to placebo or 1.5, 6, or 12 Amb a 1-U of MK-3641, respectively. Treatment-related adverse events were more frequent in the 6- and 12-Amb a 1-U MK-3641 groups than in the placebo group and were primarily local application-site reactions occurring in the first few days of treatment. There was no treatment-associated loss of asthma control or worsening of asthma associated with treatment. No swellings led to airway obstruction or respiratory compromise. No treatment-related anaphylactic shock, life-threatening, or serious treatment-related adverse events were reported for any MK-3641 dose. Of the 1,707 MK-3641-treated subjects, 1 systemic (anaphylactic) reaction was reported (0.06%). The 52-week long-term assessment was generally similar to the safety profile based on the 28-day assessment. CONCLUSION MK-3641 doses up to and including 12 Amb a 1-U were well tolerated, with no unexpected safety findings. Sublingual immunotherapy risks such as worsening asthma or airway swellings that could cause airway obstruction were not observed. Systemic reactions and use of epinephrine were uncommon. In these studies, after the first dose was administered in a health care setting, self-administration was well tolerated. TRIAL REGISTRATION clinicaltrials.gov Identifiers: NCT01469182, NCT00783198, NCT00770315, and NCT00978029.

Olopatadine ophthalmic solution adjunctive to loratadine compared with loratadine alone in patients with active seasonal allergic conjunctivitis symptoms.

BACKGROUND Olopatadine ophthalmic solution 0.1% (Patanol, Alcon Laboratories, Fort Woth, TX) is approved for the treatment of the signs and symptoms of allergic conjunctivitis. Loratadine 10 mg (Claritin, Schering-Plough, Madison, NJ) is a nonsedating oral antihistamine approved for the treatment of the signs and symptoms of allergic rhinitis. OBJECTIVE To compare the efficacy of olopatadine used adjunctively with loratadine versus loratadine alone in patients with seasonal allergic conjunctivitis. METHODS This three-center, observer-masked, treatment-controlled, randomized, parallel-group study involved patients aged 7 to 74 years with seasonal allergic conjunctivitis. Patients were treated for 7 days with either olopatadine twice daily adjunctive to loratadine once daily or only loratadine once daily. Efficacy variables (ocular itching and redness, physicians impression, patients impression, patient diary ratings of ocular redness and itching), and safety parameters were evaluated during the screening visit and on days 0, 3, and 7. Patients completed the rhinoconjunctivitis quality of life questionnaire on days 0 and 7. RESULTS Ninety-four patients received study drug. Patients receiving olopatadine twice daily in addition to loratadine once daily exhibited less ocular itching (P = 0.0436) and rated their ocular condition as more improved compared with those receiving loratadine alone (P < 0.0022). Twenty minutes after initial dosing, olopatadine plus loratadine relieved ocular itching and redness significantly better than loratadine alone (P = 0.001). Both treatment groups showed clinically meaningful improvements in overall quality of life in all but one of the rhinoconjunctivitis quality of life questionnaire domains. Overall, and in most domains, olopatadine plus loratadine also provided significantly better (P < 0.05) quality of life than loratadine alone at day 7. CONCLUSIONS Compared with loratadine alone, olopatadine adjunctive to loratadine provides greater relief of ocular itching and redness, a better quality of life, and is well tolerated in patients with seasonal allergic conjunctivitis.

Newer aspects in the treatment of pediatric and adult asthma: monoclonal anti-IgE

OBJECTIVE To review the results of the first anti-IgE agent to undergo clinical evaluation in the treatment of allergic asthma and allergic rhinitis. DATA SOURCES Treatment protocols conducted in Europe and the United States in moderate to severe allergic asthmatic patients who continued to show symptoms despite treatment with inhaled corticosteroids with the addition of monoclonal humanized anti-IgE treatment. STUDY SELECTION Double-blind, placebo-controlled studies, published and in press, are reviewed. RESULTS Treatment with anti-IgE allowed a decrease in inhaled corticosteroid and rescue medication use and significantly reduced the incidence and frequency of asthma exacerbations among these patients over a 28-week time period and a 6-month extension period. CONCLUSIONS Anti-IgE shows great promise as an adjunctive therapy in moderate to severe asthmatic patients.

Prevalence and Impact of Nighttime Symptoms in Adults and Children With Asthma: A Survey

Abstract Background The frequency of nighttime asthma symptoms is an important measure of asthma severity. This study was designed to determine the prevalence of daytime and nighttime symptoms in adults and children with asthma and to evaluate the impact of nighttime symptoms on sleep and daytime activities. Methods: An online survey was conducted among adults (> 18 years) and mothers of children aged 2 to 17 years with asthma. The survey included questions on daytime and nighttime asthma symptoms and asthma controller medication. Invitations to complete the survey were sent to 6349 members of a global opinion panel who were identified as having asthma. Data collection was from April to May 2005. Results: A total of 1600 invited panelists responded to the survey. Overall, 61 % of participants reported nighttime asthma symptoms and 74% reported daytime asthma symptoms. Asthma-related sleep difficulties occurred approximately 4 times per week in adults and approximately 3 times per week in children. A significantly greater proportion of adults than children reported bothersome symptoms in the morning on awakening. Wheezing and difficulty breathing were reported in a greater proportion of adults, whereas coughing was reported in a greater proportion of children. A greater proportion of adults than children reported feelings of tiredness and impaired activity on days after experiencing nighttime symptoms. Absenteeism and lateness were more commonly reported by mothers of children with asthma than by other adults. Conclusions: The prevalence of reported asthma symptoms, particularly nighttime symptoms, and the effects of nighttime symptoms on sleep and daytime activities indicates that survey participants had poorly controlled asthma.

Current standards and future directions in immunotherapy: perspectives on challenges and opportunities for the allergist

S A t w m l i m T e INTRODUCTION This year marks the 100th anniversary of immunotherapy and the publication of the third update of the Practice Parameters for Immunotherapy.1 During the 2010 Annual Meeting of the American College of Allergy, Asthma and Immunotherapy (ACAAI), the ACAAI brought together a panel of nationally recognized experts to share their perspectives on these milestones and on the current and future practice of immunotherapy in the United States. The panelists discussed current standards for immunotherapy; the advent of sublingual immunotherapy (SLIT) in Europe and elsewhere, and its implications for potential future use in the United States; novel immunotherapy delivery methods, including intranasal, epicutaneous, and intralymphatic; and needed research and unanswered questions. This perspective looks at the opportunities and challenges that these issues present to the practicing allergist.

Tissue loss with subcutaneous immunotherapy--Nicolau syndrome.

Considering the number of subcutaneous allergy immunotherapy injections given in the United States each year and around the world, minor local adverse reactions are common. A rare but distinctive injection reaction, termed Nicolau syndrome, is worth consideration for the practicing allergist because early recognition and treatment can prevent significant tissue loss. A 16-year-old female with a history of allergic rhinoconjunctivitis and intermittent asthma presented for her 94th routine maintenance dose subcutaneous immunotherapy injection, without any history of significant local or systemic adverse events. Injection volume and contents were as follows: 0.3 mL of (1:200 wt/vol) extract containing cottonwood, cedar elm, mountain cedar, oak mix, Bermuda grass, Johnson grass, timothy grass, sour dock, English plantain, marsh elder, mugwort, ragweed, and sagebrush in normal saline with 0.4% phenol diluent. The injection was given using standard aseptic injection technique with aspiration before injection. She experienced immediate pain radiating to her hand upon injection and a small trickle of blood with removal of the needle. Within 30 minutes, she experienced dyspnea and an impressively large local wheal and flare lesion. Somewhat uncharacteristic of other allergic local reactions were her pain and the central bluish hue to the wheal. She was treated for early anaphylaxis, receiving subcutaneous epinephrine above the injection site and a second injection in the contralateral deltoid region. Ice was applied, but no tourniquet. Other adjunct medications included albuterol, cetirizine, and 40 mg of prednisone designed for 3-day use. On follow-up the next day, there was resolution of wheal and flare reaction, with residual appearance considered to be suggestive of a hematoma or bruise. She continued to complain of intermittent discomfort at the site and was followed by telephone daily. Five days after injection, she was reevaluated because of a complaint of exquisite tenderness at the site. Because of her underlying pain and lesion appearance, an urgent magnetic resonance imaging was performed, showing a small stellate region of signal change in the deep subcutaneous tissue overlying the triceps muscle (<2 cm in area and <5 mm in thickness) consistent with small postinjection deep subcutaneous fibrotic/ granulation tissue. The radiologist assisted in describing a bluish, localized discoloration of the skin with well-defined sharp and angular margins in the area of livid discoloration, suggesting, both by physical examination and by magnetic resonance imaging, the Nicolau syndrome. Subsequent evaluation by plastic surgery and dermatology resulted in conservative wound care and pain control without surgical debridement or graft, but the pain was so intense as to require both opiates and gabapentin. Hyperbaric oxygen therapy was offered, but not pursued by the patient. Through a lengthy course of wound care, local sloughing and some resultant scarring of the upper extremity occurred. Although initially quite dramatic in appearance, the end result was a small keloid formation over the original injection site, requiring no grafting or surgical procedures (Figure 1). A review of the literature for Nicolau syndrome using EMBASE and MEDLINE produced 111 articles, mostly case reports and series. The syndrome (also referred to as embolia cutis medicamentosa and livedoid dermatitis) was first described in the 1920s with the injection of bismuth salts for the treatment of syphilis by Freudenthal and Nicolau. It is thought to be a rare iatrogenic event associated with injection and is characterized by immediate pain at the site, livid discoloration, and varying degrees of tissue damage and necrosis. It has been variously reported with multiple medication classes such as nonsteroidal anti-inflammatory drugs, corticosteroids, antibiotics, antihistamines, and vaccines, and not considered a specific immunologic event. In some cases, extensive tissue damage results in grafting over large areas as the extent of the damage becomes apparent and compartment syndrome, and even death has been reported. This adverse event has been described only once in association with subcutaneous pollen extract injection (allergy shots) in a single case report in the Polish literature. The mechanism of tissue destruction is not well understood. Given the association with multiple medications of varying chemical properties and routes, the most widely accepted mechanism is rooted in perivascular injection, resulting in blood vessel damage, spasm, thrombus, and subsequent tissue damage. The site of the injection in this patient was appropriate in an area of the arm relatively low in both nervous system and arterial involvement. Although Nicolau syndrome is a rare event with a high degree of unpredictability and unavoidability, early recognition is the key to management because vascular and tissue injuries likely occur acutely and are sustained. The most characteristic early signs for the allergist are uncharacteristic pain with injection and bruising. The usual management of a large local reaction will not prevent the sequelae. Although there is no standard treatment, early recognition and treatment with vasoactive and antiinflammatory agents such as subcutaneous heparin, oral pentoxifylline, and corticosteroids, or even early use of hyperbaric techniques could reduce tissue loss. Conservative treatment also includes pain control, antibiotics, and dressings with possible surgical methods if necrosis is extensive. Knowledge of this potential adverse event may have relevance in consideration for

Poster 33: Triamcinolone Acetonide Aqueous Nasal Spray does not Alter Adrenocortical Function in Children with Allergic Rhinitis

used as controls. The characteristics of the glycoprotein and the mitotic activity of the olfactory epithelial cells were investigated using eight kinds of lectins and BrdU (50 mg/ kg), which was injected an hour before sacrifice. The results were as follows: 1. In experimental groups the olfactory epithelium showed degenerative changes such as atrophy and squamous metaplasia, which were observed until 2 weeks after the inhalation. 2. The olfactory epithelium started to recover in 3 weeks and showed a similar state compared with the control group in 4 weeks after the inhalation. 3. In the control group, positive reactions appeared in the supporting cells to PNA, SBA, WGA, ECL, and PHA-L; in the olfactory cells to PNA, SBA, WGA, and UEA; and in the proper basal cells to GS-I, SBA, WGA, and PHA-L. In the experimental groups the positive reaction increased in the supporting cells to SBA, ECL, and PHA-L and in Bowmans gland to all used lectins, except ECL and GS-I. 4. The number of BrdU-labeled cells in the olfactory epithelium was 14.83 _+ 1.21/ram in the control group. The mitotic activities were decreased to 4.8 _+ 0.8/mm in 2 weeks and recovered within 3 weeks after the inhalation. 5. The double-labeling immunostaining method was performed with proper basal cell-specific lectins (GS-I or PHAL) and BrdU to find the stem cells of olfactory receptor cells. In BrdU-labeled cells containing positive reactions to these specific lectins, the proper basal cells occupied 18% in control groups and 60.7% in lesioned groups (4 days to 2 weeks after inhalation) and 44.5% in recovery groups (3 to 6 weeks after inhalation). In conclusion, formaldehyde gas inhalation causes atrophy and squamous metaplastic changes of olfactory epithelium and the proper basal cells take charge of more active mitotic activity in the regeneration of the olfactory epithelium rather than globose basal cells after the cytotoxic damage of formaldehyde gas.