Dose Adjustment After Gaps in Administration of Subcutaneous Immunotherapy From a Past Survey: Work Group Report of the AAAAI Allergen Standardization and Allergy Diagnostics Committee.

The allergen immunotherapy practice parameters third update recommendations on dose adjustment after a gap in administration during the build-up are based solely on expert opinion, and no recommendations for gaps during maintenance are given. In a previous survey among American Academy of Allergy, Asthma & Immunology (AAAAI) members on subcutaneous allergen immunotherapy, this was addressed, but details were never published. Members of the Immunotherapy, Allergen Standardization, and Allergy Diagnostics Committee of the AAAAI convened a workgroup to address this issue and reanalyze results on the particular survey section. Build-up: many practitioners start dose-adjusting if a patient comes in 14.1/14 days (mean/median) after the last dose and restart immunotherapy after an interruption of 85/90 days. Dosing frequency during maintenance is generally every 3 (12%) to 4 weeks (73%). Maintenance: allergists start dose-adjusting if a patient comes in 5.1/5 weeks (mean/median) after the last dose and completely restart after an interruption of 16/12 weeks (some replied in days [90.4/90 days] or months [4.43/4 months]). Subgroups: physicians with ≥11 years in practice in nonacademic centers or rural/suburban settings tolerate longer gaps before restarting subcutaneous immunotherapy (SCIT). There is no uniform dose-adjustment protocol after gaps in SCIT administration. Prospective studies shall have to help find the best trade-off between safety (dose reduction) without giving in on efficacy (too much dose reduction).

Is immunotherapy safe for treatment of severe asthma.

PURPOSE OF REVIEW: The benefits of allergen immunotherapy (AIT), including subcutaneous allergen immunotherapy (SCIT) and sublingual allergen immunotherapy (SLIT), for IgE-mediated asthma are well established, especially for dust mite. This review will explore whether the benefits of AIT outweigh the risks in severe asthmatic patients. RECENT FINDINGS: Studies have mostly included mild and moderate asthmatic patients, but at least a few studies do show improvements in asthma symptoms and medication use in severe asthmatic patients. Asthma, and especially uncontrolled asthma, is a major risk factor for severe and fatal systemic reactions from SCIT. Uncontrolled asthma is an absolute contraindication for SCIT. It is less clear whether the benefits of SCIT and SLIT may outweigh the risks in well controlled, severe asthmatic patients, and further study is needed in this area. Asthma biologics, especially Omalizumab, may improve outcomes in severe, controlled asthmatic patients on SCIT, but further data are needed regarding timing of initiation and duration of treatment. SUMMARY: Although severe asthmatic patients may benefit from AIT, significant risks exist, especially in those with uncontrolled asthma. Further study is needed regarding optimal strategies to minimize risks.

Effectiveness of Hydroxychloroquine and Omalizumab in Chronic Spontaneous Urticaria: A Real-World Study.

BACKGROUND: Chronic spontaneous urticaria (CSU) not controlled by optimized doses of antihistamines is referred to as refractory CSU. Add-on therapies recommended by guidelines include omalizumab, immunosuppressive, and anti-inflammatory agents. OBJECTIVES: The objective of the study was to assess the real-world effectiveness of different add-on treatment options for refractory CSU in 2 large clinical practices. METHODS: A retrospective chart review was conducted in 264 patients with refractory CSU not adequately controlled for ≥6 weeks with optimized doses of second-generation histamine-1 blockers. Omalizumab and hydroxychloroquine were the most frequently prescribed add-on therapies, allowing comparisons of clinical outcomes for these 2 agents. Complete response included absent or infrequent urticaria and patient satisfaction with treatment. Partial response was reduced hives, but requiring a second add-on therapy. Sustained response was complete response to an add-on therapy for ≥1 year. RESULTS: Omalizumab add-on treatment was significantly more likely to be associated with a complete response versus hydroxychloroquine. Complete sustained response at 1 year was observed in 82% (111 of 134) of patients on omalizumab and 66% (73 of 111) on hydroxychloroquine as the first add-on therapy (P < .01). Patients with thyroid disease had a poorer response to add-on treatments (45% responded vs 63%; P = .03). In patients with incomplete responses to first add-on interventions (n = 45), 65% and 62% subsequently had complete responses to omalizumab and hydroxychloroquine, respectively. CONCLUSIONS: Although omalizumab was superior, hydroxychloroquine achieved a complete response in two-thirds of treated patients. Given a favorable safety profile, hydroxychloroquine should be considered as an add-on treatment for refractory CSU.

Safety of subcutaneous immunotherapy in patients with severe asthma.

BACKGROUND: Severe asthma (SA) has been identified as a risk factor for severe systemic reactions (SR) to allergen subcutaneous immunotherapy (SCIT). However, the incidence and characterization of SRs in SA in comparison to less severe or no asthma is not known. OBJECTIVE: The objective of this study was to characterize the incidence of SRs in patients with SA receiving SCIT in comparison to patients with no asthma or less SA. METHODS: A retrospective cohort study was performed on patients receiving SCIT from a multicenter national network of private allergy practices between January 2015 and December 2019. Demographics, asthma severity (International Classification of Diseases-10 codes), concomitant medications, aeroallergen skin testing, measures of asthma control with the asthma control test and forced expiratory volume in 1 second values, SCIT prescription, and an SR standardized form were assessed. RESULTS: A total of 65,855 patients, with 1072 patients having SA receiving SCIT, were included with a total of 4415 SRs (19.9 SR per 10,000 injection visits). Severe asthma had 23.9 SRs per 10,000 injection visits (incidence rate, 0.239; 95% confidence interval [0.189-0.298]). There were 155 grade III or IV SRs; 5 (3.2%) occurred in the SA group. There was no difference in rates of grade III or IV SRs between SA and no asthma and in rates of total SRs between SA and less SA. CONCLUSION: In a large cohort of patients with SA undergoing multiallergen SCIT drawn from a diverse outpatient allergy population, the diagnosis of SA was not associated with increased moderate-severe SRs compared with patients without asthma and any severity of asthma.

Safety of subcutaneous allergen immunotherapy.

Subcutaneous allergen immunotherapy (SCIT) is a unique treatment option for managing patients with allergic rhinitis, asthma, atopic dermatitis, and stinging insect allergy. Although systemic reactions to allergen injections are rare, near-fatal, and fatal anaphylactic reactions can occur. Patients with asthma are at greatest risk for more severe reactions as are those with previous systemic reactions. Treating allergists should institute best clinical practices to prevent and manage severe systemic reactions to SCIT, including the following: (1) prescreening patients with asthma for recent increases in asthma symptoms, (2) not prescribing SCIT to patients with severe and uncontrolled asthma, (3) instituting clinic protocols to prevent dosing errors, (4) considering modifying allergen doses during peak allergy seasons in patients at high risk, (5) instituting measures that require all patients on SCIT to be observed for at least 30 minutes after injections, and (6) regular training of all clinical staff in the recognition and expeditious treatment of anaphylaxis.

Systemic Allergic Reactions and Anaphylaxis Associated with Allergen Immunotherapy.

Subcutaneous allergen immunotherapy (SCIT) is a proven treatment of allergic rhinitis, asthma, atopic dermatitis, and prevention of Hymenoptera venom anaphylaxis. The known benefit of SCIT, however, must be considered in each patient relative to the potential risks of systemic allergic reactions (SRs). A mean of 1 SR per 1000 injection visits (0.1%) was estimated to occur between 2008 and 2018. Life-threatening anaphylactic events are estimated to occur in 1/160,000 injection visits. The factors that contribute to SRs and fatal reactions (FRs) are reviewed. Risk management strategies are proposed to prevent and decrease future SCIT associated with SRs, anaphylaxis, and FR.

Risk factors for fatal and nonfatal reactions to immunotherapy (2008-2018): postinjection monitoring and severe asthma.

BACKGROUND: Subcutaneous allergen immunotherapy (SCIT) is highly effective but risks exist. OBJECTIVE: To identify practices that influence systemic allergic reactions (SRs) to SCIT and SCIT-associated infections. METHODS: Members of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology completed an annual survey of SCIT-related SRs of varying severity (2008-2018). Injection-related infections were queried (2014-2018). Strategies to enforce postinjection waiting times and to reduce risks from asthma/severe asthma were queried (2016-2018). RESULTS: Data were gathered on 64.5 million injection visits. Ten confirmed fatalities occurred since 2008, including 3 new fatalities since 2017. One fatal reaction occurred per 7.2 million injection visits (2008-2018). No infections occurred. Practices that tracked the time after injections, and required checking out with office personnel, had significantly lower total (P < .001), grade 3 (severe) (P < .001), and grade 4 (very severe) SRs (P < .001). Having more individuals with asthma on SCIT was associated with more grade 3 SRs (P < .02). Not prescribing SCIT in individuals with uncontrolled asthma was associated with fewer grade 3 SRs (P = .02). Having individuals with more severe asthma on SCIT was associated with more total, grade 1, and grade 2 SRs (P < .001); 50% of grade 3 and 4 SRs occurred in individuals with severe asthma. CONCLUSION: SCIT-related fatalities have declined since 2008, with a slight increase in recent years. SCIT is not associated with an increased risk of infections. Tracking the time after injections and checking out with office staff confer significantly lower risks of severe SRs. Asthma, especially severe asthma, is a major risk factor for severe and fatal SRs. Strategies that reduce risks for individuals with asthma, such as not prescribing SCIT to patients with uncontrolled asthma, may lower the risks.

Safety of allergen immunotherapy in North America from 2008-2017: Lessons learned from the ACAAI/AAAAI National Surveillance Study of adverse reactions to allergen immunotherapy.

In 2004, it was estimated that one fatal anaphylactic reaction (FR) occurred in every 2.4 million subcutaneous immunotherapy (SCIT) injection visits. Uncontrolled asthma was the most commonly cited factor that contributed to FRs. Results of the annual American College of Allergy, Asthma, and Immunology/American Academy of Allergy, Asthma and Immunology sponsored survey conducted among practicing allergists suggest that one nonfatal systemic reactions (SR) occurred in 0.15% of injection visits and in 0.7% of patients who were treated. Analysis of recent data indicated that FRs are 3.75-fold less frequent. Life-threatening grade 4 anaphylactic reactions are estimated to occur in 0.005% of patients who receive SCIT (or 1/160,000 injection visits). Analysis of data from annual surveys identified the following possible risk factors for SRs: a history of SRs to SCIT, the administration of injections in patients with uncontrolled asthma, use of accelerated buildup regimens, and never adjusting doses during the height of the allergy season. Delayed-onset SRs beginning >30 minutes after injections represented 15% of all SRs in clinics with 30-minute observation periods. The safety profile of sublingual immunotherapy is favorable, with no FRs yet identified for sublingual tablet or liquid formulations. Risk management should focus mainly on patients with uncontrolled asthma by withholding injections in such patients, with recent worsening in asthma symptoms and lung function (e.g., peak expiratory flow rate). Because nearly all FRs and SRs occur within 30 minutes of injections, a 30-minute observation period is recommended. Routinely prescribing epinephrine for all patients did not prevent severe SRs, likely due to poor adherence when SRs occurred. Also, no local or systemic infections were identified in 2.3 million patients attending 24.5 million injection visits, which allayed concerns over infections associated with compounding of allergen extracts by practicing allergists.

AAAAI/ACAAI Subcutaneous Immunotherapy Surveillance Study (2013-2017): Fatalities, Infections, Delayed Reactions, and Use of Epinephrine Autoinjectors.

BACKGROUND: Subcutaneous allergen immunotherapy (SCIT) is highly effective but safety risks exist. OBJECTIVE: The aims of this study were to: (1) identify clinical practices that could influence fatal and nonfatal systemic allergic reactions (SRs) to SCIT, and (2) identify SCIT-associated infections. METHODS: From 2008 to 2016, 27% to 51% of American Academy of Allergy, Asthma, and Immunology/American College of Allergy, Asthma, and Immunology members completed an annual survey of SCIT-related SRs of varying severity. Injection-related local cutaneous and systemic infections were queried for 2014-2016. For 2014-2016, respondents were queried about timing of onset of SRs, postinjection waiting times, and prescription/use of epinephrine autoinjectors. RESULTS: Data were gathered on 54.4 million injection visits (2008-2016). Two confirmed fatalities from SCIT occurred between 2008 and 2014. An additional 5 confirmed fatalities occurred between 2015 and 2017. No infections occurred in 17.3 million injection visits (2014-2016). Among practices monitoring patients for at least 30 minutes, 15% of SRs occurred after 30 minutes. Practices prescribing an epinephrine autoinjector >90% of the time (29% of practices) did not experience lower rates of delayed grade 3/4 SRs. Of patients experiencing grade 3/4 delayed SRs, 26% and 8% used prescribed self-injectable epinephrine devices during 2014-2015 and 2015-2016, respectively. CONCLUSIONS: There is an unexplained slight increase in SCIT-related fatalities for 2015-2017, although mean annual reported events over 9 years (0.8 fatal reactions per year) have declined. SCIT-related infections were not identified during 2 years of surveillance. The 15% incidence of delayed-onset SRs (>30 minutes) is similar to a prior annual survey. Prescribing epinephrine autoinjectors for SCIT does not appear to improve outcomes, possibly due to low rates of self-administration.

Current Evidence on Safety and Practical Considerations for Administration of Sublingual Allergen Immunotherapy (SLIT) in the United States.

Liquid sublingual allergen immunotherapy (SLIT) has been used off-label for decades, and Food and Drug Administration (FDA)-approved grass and ragweed SLIT tablets have been available in the United States since 2014. Potentially life-threatening events from SLIT do occur, although they appear to be very rare, especially for FDA-approved products. Practice guidelines that incorporate safety precautions regarding the use of SLIT in the United States are needed. This clinical commentary attempts to address unresolved issues including controversy regarding the FDA mandate for the prescription of epinephrine autoinjectors for patients on SLIT; how to approach polysensitized patients; optimal timing and duration of SLIT administration; how to address gaps in therapy; whether antihistamines can prevent local reactions, if certain patient populations (such as persistent asthmatics) should not receive SLIT; and when to instruct patients to self-administer epinephrine. Key points are that physicians should focus on educating patients regarding: (1) when not to administer SLIT; (2) how to recognize a potentially serious allergic reaction to SLIT; and (3) when to administer epinephrine and seek emergency care.

Risk factors for fatal and nonfatal reactions to subcutaneous immunotherapy: National surveillance study on allergen immunotherapy (2008-2013).

BACKGROUND: In 2008, an annual surveillance study of systemic reactions (SRs) from subcutaneous immunotherapy (SCIT) injections was initiated in North America. OBJECTIVE: To define the incidence of SRs to SCIT. METHODS: From 2008 to 2013, 27% to 51% of American Academy of Allergy, Asthma, and Immunology and American College of Asthma, Allergy, and Immunology members completed an annual survey of SCIT-related SRs of varying severity. From 2012 to 2013, data were collected regarding SRs with off-label sublingual immunotherapy (SLIT), selection of patients with asthma for SCIT, and strategies for dose adjustment during pollen seasons. RESULTS: From 2008 to 2013, data were gathered on 28.9 million injection visits, including 344,480 patients for 2012 to 2013. Since 2008, a total of 2 confirmed fatalities were directly reported that occurred under the care of allergists. Two additional fatalities occurred under the care of nonallergists. The rate of SRs from SCIT remained stable, occurring in 1.9% of patients, with 0.08% and 0.02% experiencing grade 3 and 4 SRs. SRs occurred in 1.4% of patients receiving off-label SLIT, including 0.03% with grade 3 SRs. There were no SLIT-related grade 4 SRs or fatalities. Practices that never administered SCIT in patients with uncontrolled asthma (Asthma Control Test score <20) had significantly fewer grade 3 and 4 SRs (odds ratio, 0.7; 95% confidence interval, 0.5-1.0, and odds ratio, 0.3; 95% confidence interval, 0.1-0.8, respectively). Lowering doses during pollen seasons for patients with highly positive skin tests reduced SRs of all severity grades (P < .05). CONCLUSIONS: SCIT-related fatality rates may be decreasing, but continued vigilance regarding modifiable risk factors, including careful patient selection, is needed. Dose adjustment during pollen seasons for highly sensitive patients may reduce risks. Potential risk for SRs from off-label SLIT exists.

Significant predictors of poor quality of life in older asthmatics.

BACKGROUND: Morbidity and mortality from asthma are high in older adults and quality of life (QOL) might be lower, although standardized measurements of QOL have not been validated in this population. OBJECTIVE: To determine predictors of asthma-related QOL in older adults. METHODS: Allergy and pulmonary outpatients (n = 164) at least 65 years old with an objective diagnosis of asthma completed the Mini-Asthma Quality of Life Questionnaire (mAQLQ). Demographics, medical history, and mean value for daily elemental carbon attributable to traffic, a surrogate for diesel exposure, were obtained. Regression analysis was used to determine predictors of mAQLQ scores. RESULTS: Total mAQLQ (mean ± SD 5.4 ± 1.1) and symptom, emotional, and activity domain scores were similar to those of younger populations, whereas environmental domain scores (4.4 ± 1.7) appeared lower. Poorer mAQLQ scores were significantly associated with emergency department visits (adjusted ß [aß] = -1.3, where ß values indicate the strength and direction of association, P < .0001) and with poorer scores on the Asthma Control Questionnaire (aß = -0.7, P < .0001). Greater ECAT exposure (aß = -1.6, P < .02), female sex (aß = -0.4, P < .006), body mass index of at least 30 kg/m(2) (aß = -0.4, P < .01), gastroesophageal reflux (aß = -0.4, P < .01), nonatopic status (aß = -0.5, P < .002), and asthma onset before 40 years of age (aß = -0.5, P < .004) were significantly associated with poorer mAQLQ scores. CONCLUSION: The mAQLQ scores in older adults with stable asthma were similar to those in younger populations and were predictive of other measurements of asthma control, verifying that the mAQLQ is an appropriate tool in older adults with asthma. Traffic pollution exposure was the strongest predictor of poorer asthma-related QOL in older adults with asthma.

Optimum predictors of childhood asthma: persistent wheeze or the Asthma Predictive Index?

BACKGROUND: The Asthma Predictive Index (API) and persistent wheezing phenotypes are associated with childhood asthma, but previous studies have not assessed their ability to predict objectively confirmed asthma. OBJECTIVE: To determine whether the University of Cincinnati API Index (ucAPI) and/or persistent wheezing at age 3 can accurately predict objectively confirmed asthma at age 7. METHODS: Data from the Cincinnati Childhood Allergy and Air Pollution Study, a high-risk prospective birth cohort, was used. Asthma was defined as parent-reported or physician-diagnosed asthma objectively confirmed by a change in FEV1 of ≥12% after bronchodilator or a positive methacholine challenge (PC20 ≤ 4 mg/mL); or as prior treatment with daily asthma controller medication(s). Multivariate logistic regression was used to investigate the relationship between confirmed asthma at age 7 and a positive ucAPI (adapted and modified from prior published API definitions) and persistent wheezing at age 3. RESULTS: At age 7, 103 of 589 children (17.5%) satisfied the criteria for asthma. Confirmed asthma at age 7 was significantly associated with a positive ucAPI (adjusted odds ratio [aOR] 13.3 [95% CI, 7.0-25.2]; P < .01) and the persistent wheezing phenotype (aOR 9.8 [95% CI, 4.9-19.5]; P < .01) at age 3. Allergic persistent wheezing was associated with a significantly higher risk of asthma (aOR 10.4 [95% CI, 4.1-26.0]; P < .01) than nonallergic persistent wheezing (aOR 5.4 [95% CI, 2.04-14.06]; P < .01). CONCLUSION: Both a positive ucAPI and persistent wheeze at age 3 were associated with objectively confirmed asthma at age 7; however, the highest risk was associated with ucAPI. These results demonstrate the ucAPI as a clinically useful tool for predicting future asthma in school-age children.

AAAAI/ACAAI surveillance study of subcutaneous immunotherapy, years 2008-2012: an update on fatal and nonfatal systemic allergic reactions.

BACKGROUND: Before 2002, there were an estimated 3.4 fatal reactions per year to subcutaneous allergen immunotherapy (SCIT). Recent incidences of SCIT-related systemic allergic reactions (SR) and fatal reactions are not well defined. OBJECTIVE: To define the incidence of and clinical practices associated with SRs to SCIT and skin testing. METHODS: From 2008 to 2012, 27% to 49% of the American College of Allergy, Asthma, and Immunology and American Academy of Allergy, Asthma, and Immunology members completed an annual survey of SCIT-related fatal and nonfatal SRs of varying severity. A shortened version of the World Allergy Organization (WAO) classification system for SRs was adopted in 2011 (grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, very severe). From 2011 to 2012, data were collected regarding nonfatal SRs to skin testing and strategies to lower the risk of SRs from SCIT. RESULTS: Between 2008 and 2012, data were gathered on 23.3 million injection visits. One confirmed fatality occurred in 2009. Overall SR rates remained stable at 0.1%. The rate of very severe, WAO grade 4, SRs was similar to previously reported rates of near-fatal reactions (1 in 1 million injections). Although almost one-third of practices experienced at least 1 SR from skin testing, no WAO grade 3 or 4 SRs from skin testing were reported. A lower target dose during cluster buildup before transitioning to maintenance may be associated with a lower risk of WAO grade 3 SRs (P = .07). Dose adjustment during pollen seasons was associated with fewer WAO grade 3 or 4 SRs (P < .001). CONCLUSIONS: Although SR rates have remained stable and fatalities appear to be declining, continued vigilance regarding SCIT safety is recommended. Additional surveillance and study regarding methods to decrease the risk of severe SRs is warranted.