Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.
ASTHMA AND COPD
Exhaled nitric oxide analysis and chronic cough (October 2017)
An increase in the fraction of exhaled nitric oxide (FENO) is a marker of eosinophilic airway inflammation. A potential role for measuring FENO in the diagnosis of cough-variant asthma (associated with eosinophilic inflammation) and nonasthmatic eosinophilic bronchitis (NAEB) was examined in a systematic review of over 2000 patients, in which FENO performed better to "rule in" cough-variant asthma and NAEB (as determined by a response to inhaled corticosteroids) than to exclude them, and performance was better for patients with cough-variant asthma than chronic cough without asthma . However, heterogeneity among studies was high, limiting the strength of the evidence. Further study is needed to clarify whether FENO measurement can help improve patient-important outcomes in chronic cough. (See "Exhaled nitric oxide analysis and applications", section on 'Cough variant asthma' and "Exhaled nitric oxide analysis and applications", section on 'Nonasthmatic eosinophilic bronchitis'.)
Global asthma mortality (October 2017)
Asthma ranks 32nd as a cause of death worldwide, but mortality varies among countries . Based on World Health Organization (WHO) data, age-standardized death rates per 100,000 individuals aged 5 to 34 years range from 17.16 in India and 1.65 in China to 0.88 in the United States and 0.24 in the Netherlands. In an analysis of the WHO database, asthma mortality was essentially unchanged from 2006 to 2012, after decreasing substantially from 1993 to 2006 . Lower mortality rates correlated with adoption of best practices and more widespread implementation of established asthma management strategies is needed. (See "Identifying patients at risk for fatal asthma", section on 'Mortality statistics'.)
Mepolizumab for eosinophilic granulomatosis with polyangiitis (August 2017)
Mepolizumab is a monoclonal anti-interleukin-5 antibody that is approved for use in severe eosinophilic asthma. In a multicenter trial, 136 patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA) were randomly assigned to receive mepolizumab 300 mg (three times the US Food and Drug Administration-approved dose of 100 mg) or placebo subcutaneously every four weeks for 52 weeks . Mepolizumab led to significantly more accrued weeks of remission and a lower frequency of relapse than placebo. Among mepolizumab-treated subjects, 44 percent were able to taper prednisolone to ≤4 mg/day, compared with 7 percent on placebo. While not all patients respond, high-dose mepolizumab may be an additional option for selected patients with EGPA. (See "Treatment and prognosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Anti-IL-5 antibodies'.)
Benralizumab and glucocorticoid-sparing effect in severe asthma (June 2017)
Benralizumab, an investigational anti-IL-5 receptor alpha antibody, appears to have a glucocorticoid-sparing effect in patients requiring oral glucocorticoids to control severe asthma. In a multicenter trial, 220 patients who had ≥150 eosinophils/mL in peripheral blood AND required daily oral glucocorticoids for the previous six months were randomly assigned to one of two benralizumab treatment arms or placebo . The oral glucocorticoid dose was reduced according to a predetermined program (2.5 to 5 mg every four weeks). After 28 weeks, the oral glucocorticoid dose decreased by 75 percent from baseline in the two benralizumab groups, compared with 25 percent in the placebo group. Exacerbation rates were lower in the benralizumab groups despite glucocorticoid tapering, and pulmonary function remained stable. (See "Investigational agents for asthma", section on 'Anti-IL-5 receptor alpha antibodies'.)
Cyclosporine for Stevens-Johnson syndrome/toxic epidermal necrolysis (November 2017)
Beyond supportive care, there are no established therapies for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), a severe and often life-threatening drug reaction. Immunosuppressive or immunomodulating therapies used in clinical practice include systemic corticosteroids, intravenous immune globulins, and cyclosporine. None has been adequately studied in randomized trials, but there is increasing evidence that cyclosporine may slow the progression of SJS/TEN. In a meta-analysis of observational studies including 134 patients with SJS/TEN treated with cyclosporine, the observed mortality rate was approximately 60 percent lower than that expected based upon the SCORTEN prognostic score at admission . We suggest cyclosporine in addition to supportive care for the treatment of SJS/TEN. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'Cyclosporine'.)
Identification of children with low-risk past penicillin reactions (August 2017)
Many children who have mild adverse reactions to penicillins, such as maculopapular rash, hives, or gastrointestinal symptoms, are not allergic and can safely receive this class of antibiotics in the future. In a study of children presenting to an urban emergency department with histories of past penicillin reactions, nearly 600 parents/caregivers completed a questionnaire about the child’s past reaction . The questionnaire included hives as a low-risk feature (for true allergy), but considered facial angioedema as a high-risk feature. One hundred of 434 patients with low-risk reactions were referred to an allergist for evaluation. Ninety-seven had negative skin tests, while three initially had positive skin tests that were negative upon later repeat testing. Ultimately, all 100 children passed oral challenge to amoxicillin. Despite these results, we consider both hives and angioedema as high-risk features and would advocate that children with past reactions involving either of these symptoms be referred to an allergy specialist to determine if penicillins can be safely used again. (See "Penicillin allergy: Delayed hypersensitivity reactions", section on 'Studies in children'.)
FOOD ALLERGY AND INTOLERANCE
Data limited for probiotic plus oral immunotherapy for peanut allergy (August 2017)
Oral immunotherapy (OIT) for foods is an investigational treatment for food allergies that can lead to temporary desensitization to a food, but the ability of OIT to induce permanent tolerance to the food is less clear. Adding an immunostimulatory adjuvant, such as a probiotic, to OIT may improve sustained unresponsiveness (SU) to the food allergen. In a follow-up study four years after completion of a randomized trial and cessation of treatment, patients treated with peanut OIT plus probiotic were more likely to still be eating peanut and to have SU after eight weeks of avoidance compared with patients treated with placebo only . However, there were significant flaws in the study design, and we await further data before recommending routine use of OIT (with or without an adjuvant). (See "Investigational therapies for food allergy: Oral immunotherapy", section on 'OIT plus adjuvant'.)
National Academies consensus report on food allergies (August 2017)
The National Academies of Sciences, Engineering, and Medicine consensus report on food allergies highlights a number of critical issues related to food allergy .
●Judicious use of food allergy testing, performed and interpreted in the context of the patient's clinical history
●Prompt treatment of anaphylaxis with epinephrine
●Primary prevention of peanut allergy through early dietary introduction
Our approach to the diagnosis and management of food allergies is consistent with the recommendations in this report. (See "Diagnostic evaluation of food allergy", section on 'Role of allergy tests in diagnosis' and "Food-induced anaphylaxis", section on 'Epinephrine' and "Introducing highly allergenic foods to infants and children", section on 'Suggested approach'.)
Four-food elimination diet for eosinophilic esophagitis (July 2017)
The traditional six-food (cow's milk, hen's egg, soy, wheat, peanut/tree nuts, and fish/shellfish) elimination diet for eosinophilic esophagitis (EoE) results in resolution of EoE in approximately three-quarters of children but is challenging and can have negative nutritional consequences. In a prospective study of four-food elimination (milk, soy, egg, wheat) in 78 children with EoE, histologic remission was achieved in 64 percent, with decreased symptoms in 91 percent . Thus, we now suggest either the four-food or six-food empiric elimination diet for most patients who opt for dietary management of EoE. (See "Dietary management of eosinophilic esophagitis", section on 'Elimination diets'.)
Introducing solids in infants with milk or soy FPIES (June 2017)
Food protein-induced enterocolitis syndrome (FPIES) is a nonimmunoglobulin E (IgE)-mediated gastrointestinal food hypersensitivity most commonly caused by cow's milk (CM) or soy protein. Recent international consensus guidelines from the American Academy of Allergy, Asthma & Immunology and the International FPIES Association advocacy group provide guidance on the introduction of solid foods in infants with CM or soy FPIES (table 1) . In accordance with these guidelines, for infants with CM or soy FPIES, we suggest introduction of vegetables and then fruits, rather than cereals, at four to six months of age, to reduce the risk of reactions to rice and other grains that may occur among infants with CM or soy FPIES. (See "Food protein-induced enterocolitis syndrome (FPIES)", section on 'Introduction of new foods'.)
New guidelines for management of peanut and tree nut allergies (June 2017)
The most straightforward approach in managing any food allergy is complete avoidance of the culprit food and all similar foods, particularly for peanut and tree nuts. However, some patients may find this approach too burdensome. Reflecting a shift in clinical practice, the recent British Society of Allergy and Clinical Immunology guidelines permit, with certain restrictions, consumption of similar foods after confirming that they are safe, if the patient and family prefer this approach . This guideline for the management of peanut and tree nut allergy is consistent with our approach. (See "Peanut, tree nut, and seed allergy: Management", section on 'Clinical scenarios'.)
Consensus statement on granulomatous and lymphocytic interstitial lung disease (August 2017)
Granulomatous and lymphocytic interstitial lung disease (GLILD) is the most common cause of diffuse parenchymal lung disease in patients with common variable immunodeficiency, but the literature to date has been limited to case reports and small series. The British Lung Foundation and UK Primary Immunodeficiency Network published a consensus statement summarizing the experience of approximately 30 physicians caring for over 100 patients with GLILD . It includes a proposed definition for the disorder, as well as several statements about diagnosis and first-line therapy, and is intended to provide preliminary guidance for care and future research. (See "Pulmonary complications of primary immunodeficiencies", section on 'Granulomatous and lymphocytic interstitial lung disease'.)
URTICARIA AND ANGIOEDEMA
Recombinant C1 inhibitor for prevention of hereditary angioedema attacks (October 2017)
Conestat alfa (Ruconest in the United States and Europe, Rhucin in other countries) is a recombinant human C1 inhibitor (rhC1INH) preparation that has been available for acute treatment of hereditary angioedema attacks. It has a much shorter half-life than plasma-derived C1INH, and its efficacy for prophylaxis had not been studied. A multicenter randomized trial of 26 patients with high attack rates demonstrated that rhC1INH given intravenously twice weekly resulted in a mean of 2.7 attacks per month, compared with 7.2 attacks with placebo . The recombinant product has the advantages of a stable supply chain and no risk of transmission of bloodborne infections, compared with the plasma-derived product, but its shorter half-life may limit its prophylaxis effectiveness and it has not been approved for this indication. In most situations, plasma-derived C1INH is preferred for prophylaxis, although if not available, rhC1INH provides another option. (See "Hereditary angioedema: General care and long-term prophylaxis", section on 'Intravenous recombinant C1 inhibitor'.)
Mixed data regarding icatibant in ACE inhibitor-induced angioedema (August 2017)
Although the bradykinin receptor antagonist icatibant has proven efficacy in hereditary angioedema, particularly when given soon after onset of symptoms, evidence is mixed regarding its utility in angiotensin-converting enzyme inhibitor-associated angioedema (AceIA). In a randomized trial of 121 patients with AceIA of the head or neck, icatibant did not decrease the time to discharge relative to placebo . Therefore, careful airway management, rather than icatibant, remains the primary intervention for most cases of AceIA, although icatibant may have a role in rare instances when patients present very early. (See "ACE inhibitor-induced angioedema", section on 'Icatibant'.)
New mutation in hereditary angioedema with normal C1 inhibitor (July 2017)
Most patients with hereditary angioedema have deficiency or dysfunction of C1 inhibitor, but a subset have no identifiable complement abnormalities. Within this subgroup, mutations in the gene for factor XII account for the disease in some families, while pathogenesis in the remainder has been unexplained. Now, a mutation has been identified in the gene encoding angiopoietin-1 (ANGPT1), a glycoprotein that inhibits bradykinin-induced plasma leakage, in one Italian family . The mutation was present in four symptomatic women and absent in seven asymptomatic relatives. Understanding of the genetic basis of this disease is gradually expanding, and other mutations potentially leading to the hereditary angioedema phenotype will likely be found over time. (See "Hereditary angioedema with normal C1 inhibitor", section on 'Other mutations'.)
Systemic symptoms in patients with chronic idiopathic urticaria (June 2017)
Patients with chronic idiopathic urticaria (CIU) sometimes report accompanying systemic symptoms, although the prevalence of such symptoms has not been specifically examined. In a study of 155 CIU patients presenting to a referral allergy clinic, 66 percent reported systemic symptoms, including headache, fatigue, joint pain or swelling, wheezing, flushing, gastrointestinal symptoms, and palpitations . Patients with systemic symptoms had a greater disease burden compared with those without symptoms. Although this study population was probably skewed towards more severe disease, it is helpful to recognize that systemic symptoms are not uncommon in CIU. (See "Chronic urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Systemic symptoms'.)
VACCINES AND VACCINE HYPERSENSITIVITY
2017-2018 influenza immunization recommendations for the United States (September 2017)
The Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) have released recommendations for influenza immunization for the 2017-2018 season in the United States [18,19]. Routine influenza immunization with a licensed, age-appropriate vaccine (table 2) is recommended for all persons ≥6 months of age. Live attenuated influenza vaccine is not recommended for the 2017-2018 season. Pregnant women and persons with egg allergy of any severity can receive any licensed, age-appropriate inactivated influenza vaccine with standard immunization precautions. Although neither the ACIP nor the AAP provide a preference for a particular formulation, we favor a quadrivalent vaccine when available for adults <65 years and we recommend the high-dose vaccine for those ≥65 years. (See "Seasonal influenza in children: Prevention with vaccines", section on 'Types of vaccine' and "Seasonal influenza vaccination in adults", section on 'Choice of vaccine formulation' and "Influenza and pregnancy", section on 'Vaccination' and "Influenza vaccination in individuals with egg allergy", section on 'Safety of vaccines in patients with egg allergy'.)
OTHER GENERAL ALLERGY AND IMMUNOLOGY
Probiotics ineffective for the prevention of early childhood eczema (October 2017)
Two meta-analyses in 2012 and 2014 suggested that there was a modest protective effect of probiotics used in late pregnancy/early infancy on the development of eczema within the first two years of life, although subsequent trials did not confirm these findings. A recent randomized trial provides further evidence of the lack of effectiveness of probiotics for eczema prevention . In this trial, 184 high-risk infants received either Lactobacillus rhamnosus GG plus inulin or inulin alone for the first six months of life. Eczema was diagnosed by age two in approximately 30 percent of the children in both groups. We suggest not giving probiotics during pregnancy and infancy for the prevention of eczema. (See "Prebiotics and probiotics for prevention of allergic disease", section on 'Efficacy'.)
Midostaurin for advanced systemic mastocytosis (August 2017)
Cytoreductive treatment of advanced systemic mastocytosis (SM) can mitigate organ dysfunction, improve quality of life, and limit disease progression until a suitable donor for allogeneic hematopoietic cell transplant is identified. Midostaurin is a multikinase inhibitor that is effective against SM with wild type or mutant KIT (eg, KIT D816V). A recent phase II study found that midostaurin was associated with improved measures of organ damage (eg, cytopenias, liver function studies) in two-thirds of patients with advanced SM, with median overall survival >3 years , confirming similar findings from an earlier trial . The drug was well tolerated, with primarily grade 1 to 2 nausea/vomiting or modest cytopenias. The US Food and Drug Administration approved midostaurin for treatment of advanced SM earlier this year. We now suggest midostaurin for initial systemic therapy of advanced SM. (See "Systemic mastocytosis: Management and prognosis", section on 'Choice of therapy'.)
Countering the high cost of epinephrine autoinjectors (June 2017)
Physicians and patients in the United States have been struggling with the high cost of epinephrine autoinjectors, and alternatives, as well as ways to maximize the utility of expensive devices, have begun to appear:
●A prefilled syringe (Symjepi) containing 0.3 mg epinephrine per dose was approved by the US Food and Drug Administration (FDA) in June 2017 and should offer a more affordable alternative to autoinjectors . It will be available in upcoming months in just one dose, labeled for use in patients weighing ≥30 kg (66 lbs). (See "Prescribing epinephrine for anaphylaxis self-treatment", section on 'Prefilled syringes'.)
●A study of 31 expired autoinjectors (EpiPens) found that devices as much as four years past the expiration date still contained 84 to 88 percent of the intended epinephrine dose . Thus, patients should understand that expired devices retain most of their potency and that if anaphylaxis develops, using an outdated device is preferable to not injecting epinephrine at all. (See "Prescribing epinephrine for anaphylaxis self-treatment", section on 'Use of expired autoinjectors'.)
- Song WJ, Kim HJ, Shim JS, et al. Diagnostic accuracy of fractional exhaled nitric oxide measurement in predicting cough-variant asthma and eosinophilic bronchitis in adults with chronic cough: A systematic review and meta-analysis. J Allergy Clin Immunol 2017; 140:701.
- www.worldlifeexpectancy.com/cause-of-death/asthma/by-country (Accessed on September 22, 2017).
- Ebmeier S, Thayabaran D, Braithwaite I, et al. Trends in international asthma mortality: analysis of data from the WHO Mortality Database from 46 countries (1993-2012). Lancet 2017; 390:935.
- Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med 2017; 376:1921.
- Nair P, Wenzel S, Rabe KF, et al. Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma. N Engl J Med 2017; 376:2448.
- González-Herrada C, Rodríguez-Martín S, Cachafeiro L, et al. Cyclosporine Use in Epidermal Necrolysis Is Associated with an Important Mortality Reduction: Evidence from Three Different Approaches. J Invest Dermatol 2017; 137:2092.
- Vyles D, Adams J, Chiu A, et al. Allergy Testing in Children With Low-Risk Penicillin Allergy Symptoms. Pediatrics 2017; 140.
- Hsiao K-C, Ponsonby A-L, Axelrad C, et al. Long-term clinical and immunological effects of probiotic and peanut oral immunotherapy after treatment cessation: 4-year follow-up of a randomised, double-blind, placebo-controlled trial. The Lancet Child & Adolescent Health 2017.
- Sicherer SH, Allen K, Lack G, et al. Critical Issues in Food Allergy: A National Academies Consensus Report. Pediatrics 2017.
- Kagalwalla AF, Wechsler JB, Amsden K, et al. Efficacy of a 4-Food Elimination Diet for Children With Eosinophilic Esophagitis. Clin Gastroenterol Hepatol 2017; 15:1698.
- Nowak-Węgrzyn A, Chehade M, Groetch ME, et al. International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: Executive summary-Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol 2017; 139:1111.
- Stiefel G, Anagnostou K, Boyle RJ, et al. BSACI guideline for the diagnosis and management of peanut and tree nut allergy. Clin Exp Allergy 2017; 47:719.
- Hurst JR, Verma N, Lowe D, et al. British Lung Foundation/United Kingdom Primary Immunodeficiency Network Consensus Statement on the Definition, Diagnosis, and Management of Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2017; 5:938.
- Riedl MA, Grivcheva-Panovska V, Moldovan D, et al. Recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial. Lancet 2017; 390:1595.
- Sinert R, Levy P, Bernstein JA, et al. Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema. J Allergy Clin Immunol Pract 2017; 5:1402.
- Bafunno V, Firinu D, D'Apolito M, et al. Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema. J Allergy Clin Immunol 2017.
- Doong JC, Chichester K, Oliver ET, et al. Chronic Idiopathic Urticaria: Systemic Complaints and Their Relationship with Disease and Immune Measures. J Allergy Clin Immunol Pract 2017; 5:1314.
- Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2017-18 Influenza Season. MMWR Recomm Rep 2017; 66:1.
- COMMITTEE ON INFECTIOUS DISEASES. Recommendations for Prevention and Control of Influenza in Children, 2017 - 2018. Pediatrics 2017; 140.
- Cabana MD, McKean M, Caughey AB, et al. Early Probiotic Supplementation for Eczema and Asthma Prevention: A Randomized Controlled Trial. Pediatrics 2017; 140.
- DeAngelo DJ, George TI, Linder A, et al. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia 2017.
- Chandesris MO, Damaj G, Canioni D, et al. Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med 2016; 374:2605.
- Approval letter: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/207534Orig1s000ltr.pdf (Accessed on June 19, 2017).
- Cantrell FL, Cantrell P, Wen A, Gerona R. Epinephrine Concentrations in EpiPens After the Expiration Date. Ann Intern Med 2017; 166:918.