Overview of Allergy and Anaphylaxis.

Allergic reactions and anaphylaxis occur on a severity continuum from mild and self-limited to potentially life-threatening or fatal reactions. Anaphylaxis is typically a multiorgan phenomenon involving a broad range of effector cells and mediators. Emergency department visits for anaphylaxis are increasing, especially among children. There is a broad differential diagnosis for anaphylaxis, and the diagnosis of anaphylaxis can be aided by the use of the National Institutes of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network clinical diagnostic criteria. Risk factors for severe anaphylaxis include older age, delayed epinephrine administration, and cardiopulmonary comorbidities.

Overview of Allergy and Anaphylaxis.

Allergic reactions and anaphylaxis occur on a severity continuum from mild and self-limited to potentially life-threatening or fatal reactions. Anaphylaxis is typically a multiorgan phenomenon involving a broad range of effector cells and mediators. Emergency department visits for anaphylaxis are increasing, especially among children. There is a broad differential diagnosis for anaphylaxis, and the diagnosis of anaphylaxis can be aided by the use of the National Institutes of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network clinical diagnostic criteria. Risk factors for severe anaphylaxis include older age, delayed epinephrine administration, and cardiopulmonary comorbidities.

Anaphylaxis: Epidemiology and Differential Diagnosis.

Anaphylaxis-related emergency department (ED) visits and hospitalizations are increasing. Triggers for anaphylaxis include food, medications, and stinging insects. Idiopathic anaphylaxis accounts for 30% to 60% of cases of anaphylaxis in adults and up to 10% of cases in children with novel allergens such as galactose-α-1,3 galactose reclassifying these cases. Recent practice guidelines have recommended against the routine use of systemic corticosteroids and antihistamines for the prevention of biphasic reactions and recommend an extended observation, up to 6 hours, for those with risk factors for biphasic anaphylaxis and those with lack of access to epinephrine and to emergency medical services.

Global Trends in Anaphylaxis Epidemiology and Clinical Implications.

The true global scale of anaphylaxis remains elusive, because many episodes occur in the community without presentation to health care facilities, and most regions have not yet developed reliable systems with which to monitor severe allergic events. The most robust data sets currently available are based largely on hospital admissions, which are limited by inherent issues of misdiagnosis, misclassification, and generalizability. Despite this, there is convincing evidence of a global increase in rates of all-cause anaphylaxis, driven largely by medication- and food-related anaphylaxis. There is no evidence of parallel increases in global all-cause anaphylaxis mortality, with surprisingly similar estimates for case-fatality rates at approximately 0.5% to 1% of fatal outcomes for hospitalizations due to anaphylaxis across several regions. Studying regional patterns of anaphylaxis to certain triggers have provided valuable insights into susceptibility and sensitizing events: for example, the link between the mAb cetuximab and allergy to mammalian meat. Likewise, data from published fatality registers can identify potentially modifiable risk factors that can be used to inform clinical practice, such as prevention of delayed epinephrine administration, correct posturing during anaphylaxis, special attention to populations at risk (such as the elderly on multiple medications), and use of venom immunotherapy in individuals at risk of insect-related anaphylaxis.

Risk factors for recurrent anaphylaxis-related emergency department visits in the United States.

BACKGROUND: Anaphylaxis is a potentially life-threatening allergic reaction with a strong risk of recurrence. OBJECTIVE: To assess risk factors associated with recurrent anaphylaxis-related emergency department (ED) visits within 1 year of an ED visit for anaphylaxis in a large observational cohort study. METHODS: We used an administrative claims database to identify patients seen from 2008 through 2012 in the ED for anaphylaxis based on an International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code algorithm. Patients with at least 2 years of continuous enrollment in a health plan were included. Multivariable logistic regression analysis was used to determine associations with recurrence of anaphylaxis within 1 year. RESULTS: During the 5-year study period, 7,367 patients (median age, 42 years; <18 years old, 23.3%) met the inclusion criteria. The most common anaphylaxis trigger was unspecified (56.2%), followed by food (25.3%), medication (14.6%), and venom (3.9%). Overall, 3.0% of patients had an additional anaphylaxis-related ED visit within 1 year (3.61 episodes per 100 patient-years). On multivariable analysis, risk factors associated with anaphylaxis recurrence were food trigger (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.34-3.99), history of asthma (OR, 1.30; 95% CI, 1.13-1.51), and intensive care unit admission at the index anaphylaxis event (OR, 1.95; 95% CI, 1.41-2.69). CONCLUSION: In this contemporary cohort study, history of asthma, food trigger, and greater index anaphylaxis severity, as measured by intensive care unit admission, were associated with a higher likelihood of a recurrent anaphylaxis-related ED visit within 1 year.

National trends in emergency department visits and hospitalizations for food-induced anaphylaxis in US children.

BACKGROUND: Food is the leading cause of anaphylaxis in children seen in emergency departments in the United States, yet data on emergency department visits and hospitalizations related to food-induced anaphylaxis are limited. The objective of our study was to examine national time trends of pediatric food-induced anaphylaxis-related emergency department visits and hospitalizations. METHODS: We conducted an observational study using a national administrative claims database from 2005 through 2014. Participants were younger than 18 years with an emergency department visit or hospitalization for food-induced anaphylaxis. Outcome measures of our study included time trends of pediatric food-induced anaphylaxis-related emergency department visits and hospitalizations, including observations (in an emergency department or a hospital unit), inpatient admissions, and intensive care unit admissions. RESULTS: During the study period, participants had 7310 food-induced anaphylaxis-related emergency department visits. Emergency department visits for food-induced anaphylaxis increased by 214% (P < .001); the highest rates were in infants and toddlers (age 0-2 years). Rates of emergency department visits significantly increased in all age-groups, with the highest increase in adolescents (age 13-17 years: 413%; P < .001). Peanuts accounted for the highest rates (5.85 per 100 000 in 2014) followed by tree nuts/seeds (4.62 per 100 000 in 2014). The greatest increase in rates of emergency department visits for food-induced anaphylaxis occurred with tree nuts/seeds (373.0% increase during the study period). CONCLUSIONS: The incidence of food-induced anaphylaxis has significantly increased over time in children of all ages. Food-induced anaphylaxis in children is an important national public health concern.

Outcomes of Emergency Department Anaphylaxis Visits from 2005 to 2014.

BACKGROUND: Although the incidence of anaphylaxis appears to be increasing, trends in anaphylaxis-related health care utilization are not well understood. OBJECTIVE: To better understand the potential increasing health care burden, we analyzed the changes in anaphylaxis-related health care utilization, including emergency department (ED) discharges, observation stays, inpatient admissions, intensive care unit admissions, and endotracheal intubations. METHODS: We conducted an observational study examining outcomes of anaphylaxis-related ED visits between January 1, 2005, and December 31, 2014. We analyzed administrative claims data from OptumLabs Data Warehouse, which includes more than 100 million Medicare Advantage and privately insured enrollees in the United States. We studied trends in the proportions of ED-related anaphylaxis visits based on demographic characteristics, triggers, and ED disposition for our study population. RESULTS: Among 56,212 anaphylaxis-related ED visits during a 10-year period, the proportion of patient observation/inpatient admissions increased by 37.6% (P = .02), from 13.2% of anaphylaxis-related ED visits in 2005 to 18.2% in 2014. The proportion of patients admitted to the intensive care unit increased by 27.4% (P = .001), from 4.5% in 2005 to 5.8% in 2014. Proportions of endotracheal intubation increased by 145.2% (P < .001). CONCLUSIONS: The increasing proportions of observation/inpatient admissions, intensive care unit admissions, and endotracheal intubations suggest an increase in anaphylaxis severity. Enhanced awareness of these trends among patients, practitioners, and the community is necessary to create effective strategies to prevent anaphylaxis and decrease associated adverse consequences.

Risk factors for severe anaphylaxis in the United States.

BACKGROUND: Anaphylaxis is an acute systemic allergic reaction and may be life-threatening. OBJECTIVE: To assess risk factors associated with severe and near-fatal anaphylaxis in a large observational cohort study. METHODS: We analyzed administrative claims data from Medicare Advantage and privately insured enrollees in the United States from 2005 to 2014. Severe anaphylaxis was defined as anaphylaxis resulting in hospital or intensive care unit (ICU) admission, requiring endotracheal intubation, or meeting criteria for near-fatal anaphylaxis. RESULTS: Of 38,695 patients seen in the emergency department for anaphylaxis during the study period, 4,431 (11.5%) required hospitalization, 2,057 (5.3%) were admitted to the ICU, 567 (1.5%) required endotracheal intubation, and 174 (0.45%) were classified as having a near-fatal episode. Multivariable analysis revealed that medication-related anaphylaxis (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.38-1.63; P < .001), age of 65 years or older (OR, 3.15; 95% CI, 2.88-3.44; P < .001), and the presence of cardiac disease (OR, 1.56; 95% CI, 1.50-1.63; P < .001) or lung disease (OR, 1.23; 95% CI, 1.16-1.30; P < .001) were associated with increased odds of severe anaphylaxis requiring any hospital admission, ICU admission, or intubation or being a near-fatal reaction. CONCLUSION: In this large contemporary cohort study, 11.6% of patients had severe anaphylaxis. Age of 65 years or older, medication as a trigger, and presence of comorbid conditions (specifically cardiac and lung disease) were associated with significantly higher odds of severe anaphylaxis. Additional studies examining risk factors for severe anaphylaxis are needed to define risk assessment strategies and establish a framework for management.

Temporal Trends in Epinephrine Dispensing and Allergy/Immunology Follow-up Among Emergency Department Anaphylaxis Patients in the United States, 2005-2014.

BACKGROUND: Anaphylaxis is a potentially life-threatening allergic reaction; measures including prescription of an epinephrine autoinjector (EAI) and allergy/immunology (A/I) follow-up may prevent future morbidity. OBJECTIVE: The objective of this study was to evaluate trends in outpatient management of anaphylaxis by studying EAI dispensing and A/I follow-up among patients seen in the emergency department (ED) for anaphylaxis from 2005 through 2014. METHODS: We analyzed administrative claims data from the OptumLabs Data Warehouse database using an expanded International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code algorithm. RESULTS: The study cohort comprised 18,279 patients with a mean age of 39 years; 58% were female, and 86% were discharged from an ED. Within 1 year after discharge, 46% had filled an EAI prescription and 29% had A/I follow-up. Overall, from 2005 to 2014, annual rates of filled EAI prescriptions and A/I follow-up did not change. Among children (aged <18 years), rates increased for filled EAI prescriptions (16.1% increase; P = .02 for trend) and A/I follow-up (18.8% increase; P = .048 for trend). Rates decreased for A/I follow-up among adults (15.4% decrease; P = .002 for trend). Overall rates of filled EAI prescriptions were highest in those with venom-induced (73.9 per 100 ED visits) and food-induced anaphylaxis (69.4 per 100 ED visits); the lowest rates were among those with medication-related anaphylaxis (18.2 per 100 ED visits). CONCLUSIONS: Over the past decade, rates of EAI dispensing and A/I follow-up after an ED visit for anaphylaxis have remained low, suggesting that patients may not be prepared to manage future episodes.

Predictors of granulomatous lymphocytic interstitial lung disease in common variable immunodeficiency.

BACKGROUND: A subset of patients with common variable immunodeficiency (CVID) develop granulomatous lymphocytic interstitial lung disease (GLILD), which is associated with early mortality. OBJECTIVE: To determine a set of clinical and/or laboratory parameters that correlate with GLILD. METHODS: A retrospective, nested case-control (patients with CVID diagnosed with GLILD compared with patients with CVID without a diagnosis of GLILD) medical record review was undertaken at Mayo Clinic, Rochester, MN. Network and univariate analysis was used to identify clinical and laboratory parameters at the time of diagnosis that are associated with GLILD. RESULTS: Twenty-six cases with radiologic evidence of GLILD were included in this study. Eighteen cases (69%) cases had coexistent splenomegaly with lower IgA levels (P = .04) compared with the controls. Patients with low IgA levels (<13 mg/dL) also had percentage expansion of low CD21 B cells (CD21low >5%) (P = .007). Univariate analysis revealed that splenomegaly (odds ratio [OR], 17.3; 95% confidence interval [CI], 3.9-74.5), history of immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia (AIHA) (OR, 4.8; 95% CI, 1.1-20.2), low IgA level (OR, 3.6; 95% CI, 1.2-11.9), and percentage expansion of CD21low (OR, 5.8; 95% CI, 1.6-24.7) were independently associated with GLILD. Logistic regression analysis revealed that splenomegaly, history of ITP or AIHA, low IgA level, and percentage expansion of CD21low B cells are highly sensitive in predicting presence of GLILD (area under the receiver operating curve of 0.86). CONCLUSION: Presence of splenomegaly, history of ITP or AIHA, low serum IgA level, and percentage expansion of CD21low B cells may be useful to identify a group of patients at high risk for development of GLILD.

Increasing Emergency Department Visits for Anaphylaxis, 2005-2014.

BACKGROUND: Anaphylaxis is a potentially life-threatening systemic allergic reaction. Studies suggest that the incidence of anaphylaxis is increasing; however, recent trends in emergency department (ED) visits for anaphylaxis in the United States have not been studied. OBJECTIVE: To examine trends in the incidence and rates of anaphylaxis-related ED visits from 2005 through 2014. METHODS: We retrospectively analyzed data from a national administrative claims database including commercially insured and Medicare Advantage patients. We identified all ED visits for anaphylaxis and calculated rates as number of anaphylaxis-related ED visits per 100,000 enrollees. Rates were compared over time and by age and trigger. RESULTS: During the 10-year time period, 56,212 ED visits for anaphylaxis were identified. The median (interquartile range) age was 36 (17-52 years) years, and 58% were female. Most cases (57%) were due to unspecified triggers, 27% were associated with food, 12% were medication related, and 4% were due to insect venom. The overall rate of anaphylaxis per 100,000 enrollees increased by 101%, from 14.2 in 2005 to 28.6 in 2014 (P < .001). Rates of ED visits for anaphylaxis increased in all age groups, but the greatest increase was in children aged 5 to 17 years (196% increase; P < .001). The rate of food-related anaphylaxis increased by 124% (P < .001), and the rate of medication-related anaphylaxis increased by 212% (P < .001). CONCLUSIONS: ED visits for anaphylaxis increased between 2005 and 2014. Increases in ED visits were greatest among children.

Autoinjectors Preferred for Intramuscular Epinephrine in Anaphylaxis and Allergic Reactions.

INTRODUCTION: Epinephrine is the treatment of choice for anaphylaxis. We surveyed emergency department (ED) healthcare providers regarding two methods of intramuscular (IM) epinephrine administration (autoinjector and manual injection) for the management of anaphylaxis and allergic reactions and identified provider perceptions and preferred method of medication delivery. METHODS: This observational study adhered to survey reporting guidelines. It was performed through a Web-based survey completed by healthcare providers at an academic ED. The primary outcomes were assessment of provider perceptions and identification of the preferred IM epinephrine administration method by ED healthcare providers. RESULTS: Of 217 ED healthcare providers invited to participate, 172 (79%) completed the survey. Overall, 82% of respondents preferred the autoinjector method of epinephrine administration. Providers rated the autoinjector method more favorably for time required for training, ease of use, convenience, satisfaction with weight-based dosing, risk of dosing errors, and speed of administration (p<0.001 for all comparisons). However, manual injection use was rated more favorably for risk of provider self-injury and patient cost (p<0.001 for both comparisons). Three participants (2%) reported a finger stick injury from an epinephrine autoinjector. CONCLUSION: ED healthcare providers preferred the autoinjector method of IM epinephrine administration for the management of anaphylaxis or allergic reactions. Epinephrine autoinjector use may reduce barriers to epinephrine administration for the management of anaphylaxis in the ED.

Prospective Validation of the NIAID/FAAN Criteria for Emergency Department Diagnosis of Anaphylaxis.

BACKGROUND: Anaphylaxis diagnostic criteria were proposed at the Second Symposium on the Definition and Management of Anaphylaxis. These criteria were 97% sensitive and 82% specific when retrospectively validated. OBJECTIVE: To prospectively evaluate the diagnostic accuracy of the National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria for diagnosis of anaphylaxis in the emergency department (ED). METHODS: We conducted a prospective observational study of patients seen in our institution's ED from April 2010 to March 2013. Patients seeking care for an allergic reaction and possible anaphylaxis were enrolled. Patients and providers completed questionnaires regarding onset, trigger, and signs and symptoms. Records were reviewed independently and blindly by 2 board-certified allergist-immunologists, and their final diagnosis (anaphylaxis vs no anaphylaxis) was used as the reference standard. Two-by-two tables were built, and test characteristics were calculated. RESULTS: Among the 174 enrolled patients, 91 (52%) met the NIAID/FAAN criteria for anaphylaxis. The allergist-immunologists diagnosed 61 cases of anaphylaxis (35%), of which 58 (95%) also satisfied the NIAID/FAAN criteria. The interrater agreement between allergist-immunologists was substantial (κ = 0.7). Test characteristics (95% CIs) of the NIAID/FAAN criteria were as follows: sensitivity, 95.1% (85.4%-98.7%); specificity, 70.8% (61.4%-78.8%); positive predictive value, 63.7% (52.9%-73.4%); negative predictive value, 96.4% (89.1%-99.1%); positive likelihood ratio, 3.26; and negative likelihood ratio, 0.07. CONCLUSIONS: Prospectively, the NIAID/FAAN criteria continued to be highly sensitive (95%) but had lower specificity (71%) than on retrospective assessment. These criteria are likely to be useful for the diagnosis of anaphylaxis in the ED.

Longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation.

PURPOSE: To measure longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation (HSCT). PATIENTS AND METHODS: Body mass index (BMI) was analyzed in 179 survivors by category (underweight, healthy-weight, overweight, and obese) and by z score. Fat and lean body mass measured by dual-energy x-ray absorptiometry was analyzed as z scores. RESULTS: Over a median 6.6 years of follow-up, BMI z scores diminished significantly (0.32 pre-HSCT v -0.60 at 10 years post-HSCT; P < .001). Mean z scores for fat mass stayed within population norms, but those for lean mass remained below normal levels and diminished significantly over time (P = .018). Pre-HSCT BMI category and/or z score were strongly predictive of post-HSCT BMI (P < .001) and of fat and lean mass z scores (both P < .001). Survivors with extensive chronic graft-versus-host disease were more likely than others to have low BMI (P = .004) and low lean mass (P < .001) post-HSCT. Older age at HSCT (P = .015) and T-cell-depleted graft (P = .018) were predictive of lower post-HSCT BMI. Female patients had higher body fat (P = .002) and lower lean mass (P = .013) z scores than male patients, and black patients had higher fat mass z scores than white patients (P = .026). CONCLUSION: BMI declines significantly after allogeneic HSCT for childhood hematologic malignancies, reflecting primarily a substantial decrease in lean mass but not fat mass. Monitoring and preservation of BMI and lean mass are vital, especially in those with the identified risk factors.

Pulmonary function after whole lung irradiation in pediatric patients with solid malignancies.

BACKGROUND: Although whole lung irradiation is used to treat pulmonary metastases of pediatric solid malignancies, few studies have addressed its long-term pulmonary consequences. METHODS: The authors conducted a retrospective study of longitudinal changes in 171 pulmonary function tests (PFTs) and their relation with clinical features in 48 survivors of pediatric malignant solid tumors treated with whole lung irradiation. RESULTS: Although active respiratory symptoms were seen in only 9 patients (18.8%), abnormalities in forced vital capacity (FVC; 58.3%), forced expiratory volume in 1 second (FEV(1) ; 64.6%), total lung capacity (TLC; 72.9%), and diffusion capacity of the lung for carbon monoxide corrected for hemoglobin (DLCO(corr) ; 70.8%) were common. At a median follow-up of 9.7 years after whole lung irradiation, FVC, FEV(1) , and TLC significantly declined longitudinally (P = .04, .03, and .02, respectively). Focal pulmonary boost irradiation was significantly associated with abnormal FEV(1) /FVC (P = .03), forced expiratory flow between 25% and 75% forced vital capacity (P = .005), residual volume (RV; P = .005), and RV/TLC (P = .002). Ten patients had baseline PFTs, and FVC, FEV(1) , TLC, and DLCO(corr) worsened immediately after radiation, followed by transient improvement but subsequent decline. Thirteen of 32 (40.6%) patients aged >18 years were smokers. CONCLUSIONS: Pulmonary dysfunction was prevalent after whole lung irradiation and worsened over time, although most patients were asymptomatic. Boost irradiation impaired pulmonary function, and a significant proportion of patients were smokers. Further studies are planned to assess the predictors and clinical consequences of progressive PFT abnormalities and to evaluate educational interventions.