Risk of anaphylaxis in cluster vs standard subcutaneous multiallergen immunotherapy.

BACKGROUND: Cluster schedules for subcutaneous allergen immunotherapy (AIT) require significantly fewer injections, but there have been conflicting reports regarding the risk of systemic reactions (SR). OBJECTIVE: To compare the incidence of SRs during the build-up stages of multiallergen standard vs cluster immunotherapy. METHODS: Data on SRs were collected prospectively from 91 urban adult patients who underwent either standard or cluster AIT at the Johns Hopkins Allergy and Asthma Center from 2014 to 2022. The SRs were recorded during the build-up phase and compared for both protocols using Pearson's χ2, Fisher exact test, and multivariate logistic regression models. RESULTS: Overall, SR rates were 21% for patients in the standard schedule and 37% for patients in the cluster immunotherapy schedule, which was not statistically different (P = .08). However, the SR rate for each injection was 0.69% per injection in the standard protocol and 2.29% per injection in the cluster schedule (incident rate ratio = 3.3). All SRs (100%) in both groups occurred in the second half of the build-up phase. Multivariate regression revealed that the target prescription protein nitrogen units and the number of allergens in the treatment vial did not influence SR rates (odds ratio = 1.00 and 1.06, respectively). CONCLUSION: The overall incidence of SR was not statistically different for cluster and standard AIT protocols. However, because cluster patients received approximately half the number of injections, the risk for SR per individual injection is more than 3-fold higher than that of standard immunotherapy.

Randomized double-blind pilot study of universal, species abundant, multiallergen subcutaneous immunotherapy for moderate-severe allergic rhinitis.

BACKGROUND: Allergic rhinitis affects approximately 10% to 20% of people living in industrialized nations leading to significant morbidity and large health care expenditures. Individualized high-dose, single-species allergen immunotherapy has been found to be effective in treating allergic rhinitis but can be associated with significant risks including anaphylaxis. Few studies have evaluated the safety and efficacy of universal low-dose multiallergen immunotherapy (MAIT). OBJECTIVE: To determine the efficacy and safety of a universal MAIT formula for the treatment of allergic rhinitis. METHODS: Patients with moderate-severe perennial and seasonal allergic rhinitis were randomized in a double-blind, placebo-controlled fashion to receive a novel, subcutaneous MAIT regimen containing a unique mixture of more than 150 aeroallergens, including several cross-reactive species. All patients received the exact same universal immunotherapy formula regardless of which specific skin tests were positive. Primary outcome measures at 8 and 12 weeks of therapy included validated clinical assessments, total nasal sinus score and mini-rhinoconjunctivitis quality of life questionnaire, and the use of rescue medications. RESULTS: A total of 31 patients (n = 31) were randomized to receive MAIT vs placebo. By week 12, MAIT resulted in a -4.6 (-58%) decrease in the combined total nasal sinus score and rescue medication score (daily combined score) compared with -1.5 (-20%) for placebo (P = .04). Likewise, MAIT resulted in a decrease in the mini-rhinoconjunctivitis quality of life questionnaire score of -34.9 (-68%) compared with -17 (-42%) for the placebo (P = .04). Mild adverse events were uncommon and with similar frequency among the groups. CONCLUSION: A novel, universal, and high-species abundant MAIT formula was well tolerated and resulted in significant improvement in symptoms of moderate-severe allergic rhinitis. The results of this pilot study should be considered preliminary, pending further randomized clinical trials.

Efficacy and safety of benralizumab in chronic rhinosinusitis with nasal polyps: A randomized, placebo-controlled trial.

BACKGROUND: Eosinophilic inflammation has been implicated in the pathogenesis, severity, and treatment responsiveness of chronic rhinosinusitis with nasal polyps (CRSwNP). OBJECTIVE: We sought to assess the efficacy and safety of benralizumab-mediated eosinophil depletion for treating CRSwNP. METHODS: The phase 3 OSTRO study enrolled patients with severe CRSwNP who were symptomatic despite treatment with intranasal corticosteroids and who had a history of systemic corticosteroid (SCS) use and/or surgery for nasal polyps (NP). Patients were randomized 1:1 to treatment with benralizumab 30 mg or placebo every 4 weeks for the first 3 doses and every 8 weeks thereafter. Coprimary end points were change from baseline to week 40 in NP score (NPS) and patient-reported mean nasal blockage score reported once every 2 weeks. RESULTS: The study population comprised 413 randomized patients (207 in the benralizumab group and 206 in the placebo group). Benralizumab significantly improved NPS and nasal blockage score compared to placebo at week 40 (P ≤ .005). Improvements in Sinonasal Outcome Test 22 score at week 40, time to first NP surgery and/or SCS use for NP, and time to first NP surgery were not statistically significant between treatment groups. Nominal significance was obtained for improvement in difficulty in sense of smell score at week 40 (P = .003). Subgroup analyses suggested influences of comorbid asthma, number of NP surgeries, sex, body mass index, and baseline blood eosinophil count on treatment effects. Benralizumab was safe and well tolerated. CONCLUSION: Benralizumab, when added to standard-of-care therapy, reduced NPS, decreased nasal blockage, and reduced difficulty with sense of smell compared to placebo in patients with CRSwNP. TRIAL REGISTRATION: ClinicalTrials.gov NCT03401229.

Time-dependent dual beneficial modulation of interferon-γ, interleukin 5, and Treg cytokines in asthma patient peripheral blood mononuclear cells by ganoderic acid B.

Th2 cytokines play a dominant role in the pathogenesis of allergic asthma. Interferon gamma (IFN-γ), a Th1 cytokine, links to therapeutic mechanisms of allergic asthma. Interleukin (IL)-10, a regulatory cytokine, is involved in the induction of immune tolerance. We previously demonstrated that Anti-Asthma Simplified Herbal Medicine Intervention (ASHMI) suppressed Th2 and increased IFN-γ in patients with asthma and in animal models, but its bioactive compound is unknown. Ganoderic acid beta (GAB) was isolated from Ganoderma lucidum (one herb in ASHMI). Human peripheral blood mononuclear cells (PBMCs) from adult patients with asthma were cultured with GAB or dexamethasone (Dex) in the presence of environmental allergens. The cytokine levels of IL-10, IFN-γ, IL-5, transcription factors T-bet, Foxp-3, and GATA3 were measured. Following 3-day culture, GAB, but not Dex, significantly increased IL-10 and IFN-γ levels by allergic patients' PBMCs. Following 6-day treatment, GAB inhibited IL-5 production, but IL-10 and IFN-γ remained high. Dex suppressed production of all three cytokines. GAB suppressed GATA3 and maintained Foxp-3 and T-bet gene expression, while Dex significantly suppressed GATA3 and T-bet expression. GAB simultaneously increased IL-10, IFN-γ associated with induction of T-bet and Foxp3, while suppressing IL-5, which was associated with suppression of GATA3, demonstrating unique beneficial cytokine modulatory effect, which distinguishes from Dex's overall suppression.

Benralizumab effect on severe chronic rhinosinusitis with nasal polyps (CRSwNP): A randomized double-blind placebo-controlled trial.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) can be a severe and debilitating disease associated with significant morbidity, loss of smell, sinus pressure and asthma exacerbations. Eosinophils play a role in the majority (85%) of patients. Benralizumab, an afucosylated monoclonal antibody directed against the IL-5 receptor, has powerful apoptotic effects on eosinophils. OBJECTIVE: We sought to investigate the therapeutic benefit of inhibiting the IL-5 receptor using benralizumab to treat severe rhinosinusitis with nasal polyps. METHODS: Patients with severe NP (defined by endoscopic grade 5 or more out of 8) with elevated eosinophils and a history of previous surgical or endoscopic polypectomy met entry criteria and were randomized in a double-blind fashion to receive 30 mg benralizumab SC or placebo. Endoscopic NP score was assessed at baseline and at treatment week 20. CT scan, SNOT-22 survey and UPSIT smell test score changes were also evaluated. RESULTS: Thirty-three patients were screened, and twenty-four (n = 24) were enrolled in the study. Compared with baseline, benralizumab significantly improved NP score (-0.9 ± 0.2, P = 0.004) whereas placebo did not (-0.3 ± 0.3, P = 0.166). Benralizumab induced polyp size reduction compared with placebo did not reach statistical significance (P = 0.103). Five of 12 benralizumab-treated patients (42%) had improvements in all major outcomes (polyp score, CT, SNOT-22 and smell test) versus 2 out of 12 placebo (17%). The ratio of blood eosinophil count to allergen skin test positivity correlated with polyp reduction. CONCLUSION: Benralizumab was well-tolerated and compared with baseline achieved a statistically significant reduction in nasal polyp size, sinus occupancy, symptoms and improved sensation of smell for most patients (83%).

Reliability of allergy skin testing.

BACKGROUND: Percutaneous allergen skin testing remains an established benchmark for diagnosing atopic disease. The reliability of skin testing depends greatly on the performance of allergen extracts used, methods used, and the presence of antihistamine medications. OBJECTIVE: To determine the differential effect of cetirizine on 2 different concentrations of histamine control solution and 5 common allergens used for percutaneous skin testing. METHODS: Twelve individuals underwent skin testing with histamine (1 and 6 mg/mL), control diluent, and 5 common aeroallergens. Wheal and flare measurements were measured in a masked fashion by a single operator. Cetirizine was administered for 4 consecutive days to determine the effect on both histamine and allergen wheal and flare responses. RESULTS: A total of 384 skin tests were performed on 12 volunteers. Cetirizine began to suppress wheal and flare responses at 1 hour (P < .05), with maximum suppression at day 5 (P < .05). Wheal and flare responses returned to greater than 90% baseline within 4 days of not taking cetirizine. Suppression was more apparent with 1 vs 6 mg/mL of histamine (62% vs 33%). Four of the 12 individuals taking cetirizine had a positive skin test result using 6 mg/mL of histamine control when the 1-mg/mL histamine test result was negative. Importantly, twice as many individuals had false-negative allergen responses using 6 mg/mL of histamine vs the 1 mg/mL as a positive control, although this finding did not reach statistical significance. CONCLUSION: The use of a 6-mg/mL histamine control for some percutaneous skin test devices may result in more false-negative allergen responses because of the inability to detect the presence of antihistamines.

The Flavonoid 7,4'-Dihydroxyflavone Prevents Dexamethasone Paradoxical Adverse Effect on Eotaxin Production by Human Fibroblasts.

Eotaxin/CCL-11 is a major chemoattractant that contributes to eosinophilic inflammation in asthma. Glucocorticoids inhibit inflammation, but long-time exposure may cause paradoxical adverse effects by augmenting eotaxin/CCL-11production. The aim of this study was to determine if 7,4'-dihydroxyflavone (7,4'-DHF), the eotaxin/CCL11 inhibitor isolated from Glycyrrhiza uralensis, reduces in vitro eotaxin production induced by long-time dexamethasone (Dex) exposure, and if so, to elucidate the mechanisms of this inhibition. Human lung fibroblast-1 cells were used to identify the potency of 7,4'-DHF compared with other compounds from G. uralensis, to compare 7,4'-DHF with Dex on eotaxin production following 24-h short-time culture and 72-h longer-time (LT) culture, and to determine the effects of the 7,4'-DHF on Dex LT culture augmented eotaxin production and molecule mechanisms. 7,4'-DHF was the most potent eotaxin/CCL-11 inhibitor among the ten compounds and provided continued suppression. In contrast to short-time culture, Dex LT culture increased constitutively, and IL-4/TNF-α stimulated eotaxin/CCL11 production by human lung fibroblast-1 cells. This adverse effect was abrogated by 7,4'-DHF co-culture. 7,4'-DHF significantly inhibited Dex LT culture augmentation of p-STAT6 and impaired HDAC2 expression. This study demonstrated that 7,4'-DHF has the ability to consistently suppress eotaxin production and prevent Dex-paradoxical adverse effects on eotaxin production. Copyright © 2017 John Wiley & Sons, Ltd.

A case report and systematic literature review: insulin-induced type III hypersensitivity reaction.

Insulin-induced type III hypersensitivity reactions (HSRs) are exceedingly rare and pose complex diagnostic and management challenges. We describe a case of a 43-year-old woman with type 1 diabetes mellitus (DM), severe insulin resistance, and subcutaneous nodules at injection sites, accompanied by elevated anti-insulin IgG autoantibodies. Treatment involved therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIg) as bridge therapy, followed by long-term immunosuppression, which reduced autoantibody levels and improved insulin tolerance. Given the limited treatment guidelines, we conducted a comprehensive literature review, identifying 16 similar cases. Most patients were females with a median age of 36.5 years; 63% had type 1 DM, and 44% had concurrent insulin resistance (56% with elevated autoantibodies). Treatment approaches varied, with glucocorticoids used in 67% of cases. Patients with type 1 DM were less responsive to steroids than those with type 2 DM, and had a more severe course. Of those patients with severe disease necessitating immunosuppression, 66% had poor responses or experienced relapses. The underlying mechanism of insulin-induced type III HSRs remains poorly understood. Immunosuppressive therapy reduces anti-insulin IgG autoantibodies, leading to short-term clinical improvement and improved insulin resistance, emphasizing their crucial role in the condition. However, the long-term efficacy of immunosuppression remains uncertain and necessitates continuous evaluation and further research.

Obstructive sleep apnea screening in children with asthma.

RATIONALE: Obstructive sleep apnea is highly prevalent in children with asthma, particularly in obese children. The sleep-related breathing disorder screening questionnaire has low screening accuracy for obstructive sleep apnea in children with asthma. Our goal was to identify the questions on the sleep-related breathing disorder survey associated with obstructive sleep apnea in children with asthma. METHODS: Participants completed the survey, underwent polysomnography and their body mass index z-score was measured. Participants with survey scores above 0.33 were considered high risk for obstructive sleep apnea and those with an apnea-hypopnea index ≥ 2 events/h classified as having obstructive sleep apnea. Logistic regression was used to examine the association of each survey question and obstructive sleep apnea. Positive and negative predictive values were calculated to estimate screening accuracy. RESULTS: The prevalence of obstructive sleep apnea was 40% in our sample (n = 136). Loud snoring, morning dry mouth, and being overweight were the survey questions associated with obstructive sleep apnea. The composite survey score obtained from all 22 questions had positive and negative predictive values of 51.0% and 65.5%, while the combined model of loud snoring, morning dry mouth, and being overweight had positive and negative predictive values of 60.3% and 77.6%. On the other hand, the body mass index z-score alone had positive and negative predictive values of 76.3% and 72.2%. CONCLUSIONS: The body mass index z-score is useful for obstructive sleep apnea screening in children with asthma and should be applied routinely given its simplicity and concerns that obstructive sleep apnea may contribute to asthma morbidity.

High Histamine Control Concentration Leads to False Negative Allergy Skin Testing.

BACKGROUND: Allergy skin test reliability depends on the reagents and controls selected. Histamine is used at 1 mg/ml and 6 mg/ml concentration but few studies address the rationale for selecting one versus the other and how this may impact diagnostic accuracy. OBJECTIVE: To determine the rate of false negative allergen skin tests responses between UniTest PC (using the 1 mg/mL histamine) and Quintip devices (using 6 mg/mL) for 4 common aeroallergens. METHODS: Subjects aged 18-65 with symptoms of allergy to cat and/or ragweed received skin testing with 4 aeroallergens (dust mite mix, timothy grass, ragweed, cat), histamine and control diluent. Those individuals who tested positive to cat or ragweed with one skin prick test (SPT) device but not the other then proceeded to nasal allergen challenge (NAC). The primary outcomes were the aeroallergen false negative rates and sensitivities of the skin test devices followed by nasal allergen (NAC). RESULTS: Twenty-five individuals were recruited and underwent a total of 300 SPTs. SPT to allergens (ragweed, dust mite, cat, and timothy grass) resulted in a statistically significant difference in wheal size among the two skin testing devices (p value <0.0001, 0.0001, 0.0006, and 0.0053 respectively). Six NAC procedures were performed to cat/ragweed and 5 of 6 (83% were positive). The overall allergen sensitivity rate for UniTest and Quintip were 97% and 78% respectively with most false negatives due to the use of 6 mg/ml histamine control reagent. CONCLUSION: Our study shows that 6 mg/ml concentration of histamine control reagent may contribute to a false interpretation of aeroallergen skin prick test results.

Sophora flavescens Alkaloids and Corticosteroid Synergistically Augment IL-10/IL-5 Ratio with Foxp3-Gene-Epigenetic Modification in Asthma PBMCs.

BACKGROUND: It has been demonstrated that ASHMI (antiasthma-simplified herbal medicine intervention) can improve airway function and reduce inflammation in human asthmatic patients with high safety and tolerability. In addition, ASHMI significantly suppresses Th2 cytokine production and increases Th1 cytokine production in treating asthma. OBJECTIVE: Allergic asthma is associated with dysregulation of cytokines. We focused on IL-5 and IL-10 as signature Th2 and Treg cytokines to characterize ASHMI immunomodulatory components. METHODS: The effects of ASHMI and individual herbal constituents on IL-5 and IL-10 production by PBMCs from asthmatic subjects were determined ex vivo. Sophora flavescens (SF)-F2, containing alkaloid compounds, effects on PBMC IL-10 and IL-5 production in the presence or absence of dexamethasone (Dex), and on DNA methylation levels at the foxp3 gene promoter were determined. RESULTS: The ratio of anti-CD3/CD28 stimulated IL-10/IL-5 production by PBMCs from asthmatic subjects was significantly reduced compared to healthy subjects. In PBMCs from asthmatic subjects, ASHMI significantly reduced IL-5 production and increased IL-10 secretion in a dose-dependent manner (p < 0.05-0.01). SF-F2 was most effective in increasing IL-10, whereas SF-F4 (flavonoid compounds) was most effective in suppressing IL-5 production. Dex-treated PBMCs from asthma subjects showed a trend of increasing ratio of IL-10/IL-5 while demonstrating reduced levels in both IL-5 and IL-10 (p < 0.05). Co-culture with Dex and SF-F2 significantly prevented Dex suppression of IL-10, while retained Dex-suppression of IL-5 production, and increased IL-10/IL-5 ratio by Dex. Co-culture with SF-F2 and Dex significantly reduced DNA methylation levels at the foxp3 gene promoter at CpG-126. CONCLUSION: The SF alkaloid-rich fraction may be responsible for ASHMI induction of IL-10 production by PBMCs and plays a synergistic effect with Dex for augmenting IL-10/IL-5 ratio.

Interferons modulate Fc epsilon RI-dependent production of autoregulatory IL-10 by circulating human monocytoid dendritic cells.

BACKGROUND: Immature human blood monocytoid dendritic cells (mDCs) express high-affinity receptors for IgE (Fc epsilon RI), yet their exact function and regulation remain poorly understood. OBJECTIVE: We sought to characterize Fc epsilon RI-dependent cytokine responses and their regulation in circulating human blood mDCs. METHODS: Fc epsilon RI-dependent cytokine responses of circulating mDCs were studied by using anti-Fc epsilon RI alpha stimulation. Plasmacytoid dendritic cell (pDC) cross-regulation through Toll-like receptor 9 on these responses was investigated by examining the effects of exogenous IFN-alpha pretreatment and by coculturing pDCs and mDCs stimulated with CpG. Culture supernatants were analyzed by means of ELISA to determine cytokine levels. Cell markers were determined by means of flow cytometry. RESULTS: mDCs express marked levels of Fc epsilon RI (net mean fluorescence intensity, 196 +/- 49; n = 4). After Fc epsilon RI-dependent activation in mDCs, TNF-alpha (2189 +/- 864 pg/10(6) mDCs, n = 3) levels were upregulated within 4 hours, whereas IL-10 (112 +/- 47 pg/10(6) mDCs, n = 3) levels were detectable only after 24 hours of incubation. After adding IL-10-neutralizing antibody, TNF-alpha Fc epsilon RI-dependent responses were significantly augmented (3903 +/- 197 pg/10(6) mDCs, P < .01, n = 3). Conversely, recombinant IL-10 dose-dependently inhibited Fc epsilon RI-mediated TNF-alpha responses up to 86% +/- 3% (n = 3, P < .001). Pretreatment of mDCs with IFN-alpha (100 U/mL) enhanced Fc epsilon RI-dependent secretion of IL-10 by 3.2-fold (183 +/- 11 pg/10(6) mDCs, n = 4) compared with that seen in untreated cells (57 +/- 33 pg/10(6) mDCs, P < .001, n = 4). In pDC/mDC cocultures pretreated with CpG, Fc epsilon RI-dependent IL-10 secretion by mDCs was similarly augmented by 3-fold. CONCLUSIONS: Autocrine secretion of IL-10, a critical autoregulator of Fc epsilon RI-dependent proinflammatory responses in mDCs, is cross-regulated by IFN-alpha, a major product of Toll-like receptor 9 responses in pDCs that normally promotes T(H)1 immunity.

Performance and Pain Tolerability of Current Diagnostic Allergy Skin Prick Test Devices.

BACKGROUND: Allergen skin prick testing remains an essential tool for diagnosing atopic disease and guiding treatment. Sensitivity needs to be defined for newly introduced devices. OBJECTIVE: Our aim was to compare the performance of 10 current allergy skin prick test devices. METHODS: Single- and multiheaded skin test devices (n = 10) were applied by a single operator in a prospective randomized manner. Histamine (1 and 6 mg/mL) and control diluent were introduced at 6 randomized locations onto the upper and lower arms of healthy subjects. Wheal and flare reactions were measured independently by 2 masked technicians. RESULTS: Twenty-four subjects provided consent, and 768 skin tests were placed. Mean wheal diameter among devices differed from 3.0 mm (ComforTen; Hollister-Stier, Spokane, Wash) to 6.8 mm (UniTest PC; Lincoln Diagnostics, Decatur, Ill) using 1 mg/mL histamine (P < .001) and 4.8 mm (GREER Pick; Greer, Lenoir, NC) to 8.4 mm (Duotip-Test II; Lincoln Diagnostics, Decatur, Ill; and Sharp-Test; Panatrex, Placentia, Calif) using 6 mg/mL histamine (P < .001). The false-negative rates ranged from 0% to 45% with 1 mg/mL histamine. The analytical specificity was 100% for all devices tested. All devices were well tolerated, with average pain score of less than 4 on a 10-point visual analog scale. Pain scores were higher among women, but this did not reach statistical significance. The Multi-Test PC and the UniTest PC had the lowest pain scores compared with the other devices. CONCLUSIONS: All 10 skin prick test devices displayed good analytical sensitivity and specificity; however, 3 mm cannot arbitrarily be used as a positive threshold. The use of histamine at 1 mg/mL is unacceptable for certain devices but may be preferable for the most sensitive devices. On average, there was no pain score difference between multiheaded and single-head devices.

Ganoderic acid C1 isolated from the anti-asthma formula, ASHMI™ suppresses TNF-α production by mouse macrophages and peripheral blood mononuclear cells from asthma patients.

Asthma is a heterogeneous airway inflammatory disease, which is associated with Th2 cytokine-driven inflammation and non-Th2, TNF-α mediated inflammation. Unlike Th2 mediated inflammation, TNF-α mediated asthma inflammation is generally insensitive to inhaled corticosteroids (ICS). ASHMITM, aqueous extract of three medicinal herbs-Ganoderma lucidum (G. lucidum), Sophora flavescens Ait (S. flavescens) and Glycyrrhiza uralensis Fischer (G. uralensis), showed a high safety profile and was clinically beneficial in asthma patients. It also suppresses both Th2 and TNF-α associated inflammation in murine asthma models. We previously determined that G. uralensis flavonoids are the key active compounds responsible for ASHMITM suppression of Th2 mediated inflammation. Until now, there are limited studies on anti-TNF-α compounds presented in ASHMITM. The objective of this study was to isolate and identify TNF-α inhibitory compounds in ASHMITM. Here we report that G. lucidum, but not the other two herbal extracts, S. flavescens or G. uralensis inhibited TNF-α production by murine macrophages; and that the methylene chloride (MC)-triterpenoid-enriched fraction, but not the polysaccharide-enriched fraction, contained the inhibitory compounds. Of the 15 triterpenoids isolated from the MC fraction, only ganoderic acid C1 (GAC1) significantly reduced TNF-α production by murine macrophages (RAW 264.7 cells) and peripheral blood mononuclear cells (PBMCs) from asthma patients. Inhibition was associated with down-regulation of NF-κB expression, and partial suppression of MAPK and AP-1 signaling pathways. Ganoderic acid C1 may have potential for treating TNF-α mediated inflammation in asthma and other inflammatory diseases.

Allergic rhinitis.

Allergic rhinitis is a costly disease associated with significant morbidity. It impacts the quality of life of millions of individuals, particularly in industrialized nations, and it is on the rise. Lost productivity and total healthcare expenditure exceeds several billion dollars annually in the United States, with an estimate of >$6 billion spent on prescription medications alone. It is also associated with asthma and other atopic conditions, sinusitis, otitis media, and sleep apnea. Primary care physicians should be well adept at recognizing and initiating empiric first-line therapy for chronic rhinitis. Allergen avoidance, topical nasal steroids, and antihistamines may be sufficient for some patients. In most cases, referral to a board-certified allergy specialist for skin testing and targeted management is indicated. It is essential to make sure that patients abstain from using antihistamines at least 1 week prior to reporting to the allergist for skin testing in order to avoid false-negative results. Traditional subcutaneous allergen immunotherapy, when performed by an experienced allergist, affords relief in >75% of cases. The growing armament of treatment options for refractory allergic rhinitis includes oral and sublingual immunotherapy, recombinant allergens, conjugated DNA vaccines, and anti-immunoglobulin E monoclonal antibody.