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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
Updated guidelines for chronic obstructive pulmonary disease (March 2017)
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published updated guidelines that focus on a combined assessment of an individual's symptoms and exacerbation history to guide therapy . Symptoms are assessed using standardized instruments, such as the COPD Assessment Tool (CAT) or the modified Medical Research Council (mMRC) dyspnea scale. Future exacerbation risk is based on the number of exacerbations and hospitalizations for exacerbations in the previous 12 months. (See "Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging", section on 'GOLD system'.)
Maternal fish oil supplementation and asthma in offspring (February 2017)
Maternal supplementation with fish oil, which consists of two n-3 long chain polyunsaturated fatty acids (docosahexaenoic acid [DHA]) and eicosapentaenoic acid [EPA]), has been proposed to improve a variety of pregnancy outcomes. In a placebo-controlled randomized trial of third-trimester maternal supplementation with fish oil 2.4 grams daily (55 percent EPA and 37 percent DHA), supplementation resulted in a 7 percent reduction in the absolute risk of persistent wheeze or asthma in offspring followed to age three to five years . Because of limitations in the design of this trial, UpToDate does not advise routine supplementation with this dose of fish oil, but continues to recommend that all pregnant women achieve DHA intake of at least 200 to 300 mg/day. (See "Fish consumption and docosahexaenoic acid (DHA) supplementation in pregnancy".)
Spirometry and asthma diagnosis (February 2017)
The importance of confirming reversible airflow limitation when making a diagnosis of asthma was illustrated in a study of 701 randomly selected adults who had a physician diagnosis of asthma in the previous five years . Current asthma was excluded in 33 percent and, among these, less than half had previous testing to confirm airflow limitation. This observation suggests that a clinical diagnosis of asthma, if not supported by spirometry, may be incorrect and reinforces guideline recommendations that spirometry pre- and post-bronchodilator be obtained at the time of an initial diagnosis of asthma.
Chest pain in patients with aspirin-exacerbated respiratory disease (November 2016)
Aspirin-exacerbated respiratory disease (AERD) describes patients with asthma and chronic rhinosinusitis with nasal polyposis who experience acute nasal symptoms and asthmatic reactions following the ingestion of aspirin and other nonsteroidal antiinflammatory drugs. Retrosternal chest pain may be another less common clinical feature of this syndrome. In a retrospective review of 153 individuals with AERD, 10 patients had been evaluated for chest pain that was variably associated with peripheral blood eosinophilia and vasospasm on angiography . The pain did not respond to angina treatments but did improve with glucocorticoids. Further study of this possible feature of AERD is needed. (See "Aspirin-exacerbated respiratory disease", section on 'Chest pain'.)
Controlled effectiveness trial of fluticasone furoate-vilanterol in COPD (November 2016)
One concern about randomized trials of chronic obstructive pulmonary disease (COPD) therapies is that their strict selection criteria exclude higher-risk patients and potentially miss adverse effects that could occur in routine clinical practice. A multicenter controlled effectiveness trial recruited almost 3000 patients with COPD who had had one or more exacerbations in the prior three years and assigned them to fluticasone furoate-vilanterol (100 mcg-25 mcg) once daily or usual care for one year . The fluticasone furoate-vilanterol group experienced approximately 8 percent fewer exacerbations. The trial did not demonstrate a significant difference in the incidence of pneumonia between the groups. (See "Management of stable chronic obstructive pulmonary disease", section on 'Efficacy'.)
Investigational interleukin-5 receptor antibody for asthma (November 2016)
Two trials found that an investigational anti-interleukin (IL)-5 receptor antibody, benralizumab, reduced exacerbations in patients with moderate to severe asthma who had elevated peripheral blood eosinophil counts.
●In the multicenter SIROCCO trial, about 1200 adolescent and adult patients with severe asthma and at least two exacerbations in the prior year despite high-dose inhaled glucocorticoids and a long-acting beta agonist were randomly assigned to subcutaneous benralizumab or placebo for 11 months . Benralizumab reduced exacerbations by approximately 50 percent in patients with a high peripheral blood eosinophil count (≥300/microL).
●In the CALIMA trial, approximately 1300 patients with moderate-to-severe asthma received benralizumab or placebo for 14 months . Among those with high peripheral blood eosinophil counts, the annual exacerbation rate was decreased in the benralizumab groups by 28 to 36 percent, compared with placebo.
In both studies, effects were less consistent for patients with lower eosinophil counts. The subcutaneous drug was well tolerated and might be effective with dosing every eight weeks. Benralizumab is not commercially available. (See "Investigational agents for asthma", section on 'Anti-IL-5 therapy'.)
Rapid aspirin desensitization in patients with acute coronary syndrome (April 2017)
There are well-established protocols for elective desensitization to aspirin, but fewer studies of approaches in patients needing urgent treatment. In a multicenter observational study of 330 consecutive patients with acute coronary syndrome and past hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs), 95 percent were successfully desensitized to low-dose aspirin using a protocol that could be completed within six hours . The procedure was aborted in 5 percent because symptoms developed during the protocol. While useful, we prefer our own approach because it does not exclude patients who react during the protocol. (See "Diagnostic challenge and desensitization protocols for NSAID reactions", section on 'Our approach'.)
Thrombotic microangiopathy from interferon (October 2016)
Drug-induced thrombotic microangiopathy (DITMA) has been described with a number of chemotherapeutic, immunosuppressive, and other drugs. Unlike thrombotic thrombocytopenic purpura (TTP), DITMA is not associated with severely reduced ADAMTS13 activity, and the principal treatment is drug discontinuation rather than plasma exchange. A new report has provided strong evidence for interferon as a cause of TMA . Patients receiving interferon who develop signs of a TMA should have the drug discontinued promptly before organ failure develops. (See "Drug-induced thrombotic microangiopathy", section on 'Immunosuppressive agents'.)
FOOD ALLERGY AND INTOLERANCE
FPIES resolution and timing of challenges (March 2017)
An oral food challenge is used to determine whether food protein-induced enterocolitis syndrome (FPIES) has resolved before the food is reintroduced into the diet; however, optimal timing of challenges is uncertain. Studies have shown that resolution of FPIES is impacted by various factors including the type of food (cow's milk/soy versus a solid food), presence of concomitant immunoglobulin E (IgE) sensitization to the food, age at presentation and diagnosis, and the country/population [10,11]. While further studies are needed to determine the optimal timing of challenges, considering these factors may result in earlier successful reintroduction in some children and avoidance of failed reintroduction in others. (See "Food protein-induced enterocolitis syndrome (FPIES)", section on 'Solid-food FPIES natural history'.)
Risk of recurrence in anaphylaxis in children (January 2017)
Individuals who experience an initial episode of anaphylaxis are at risk for subsequent episodes. In the first prospective study to assess the risk of recurrent anaphylaxis, nearly 300 children treated for anaphylaxis (mostly food-induced) in the emergency department were followed for one year, during which 18 percent suffered another episode . Concomitant asthma and treatment of the initial episode with epinephrine were associated with an increased risk of recurrence. These results highlight the importance of prompt intervention (equipping patients/caregivers with epinephrine autoinjectors and referring to an allergist) after the initial episode. (See "Anaphylaxis: Emergency treatment", section on 'Risk of recurrence'.)
Guidelines on introduction of peanut to children (January 2017)
Formal guidelines from the National Institute of Allergy and Infectious Diseases for the introduction of peanut to children have been revised . The revised guidelines advise peanut introduction as early as four to six months of age, particularly in high-risk infants (eg, severe eczema, egg allergy), based upon the Learning Early about Peanut Allergy (LEAP) trial and other studies showing decreased rates of peanut allergy with early introduction. Testing for peanut allergy prior to introduction is indicated in high-risk populations. Our approach is consistent with these guidelines (algorithm 1). (See "Introducing highly allergenic foods to infants and children", section on 'Suggested approach'.)
Early introduction of egg for the prevention of egg allergy (December 2016)
Four recent randomized trials have examined introduction of egg for the prevention of egg allergy, with variable success. These studies are the Prevention of Egg Allergy with Tiny Amount Intake (PETIT) trial , the Starting Time of Egg Protein (STEP) trial , the Beating Egg Allergy Trial (BEAT) , and the Hen’s Egg Allergy Prevention (HEAP) trial . Each trial enrolled a slightly different population and introduced different doses and forms of egg at ages ranging from 4 to 6 months. The most successful trial (PETIT) involved infants with eczema given a low dose of heated egg starting at 6 months of age, which resulted in egg allergy at 12 months in 8 and 38 percent in the treatment and placebo groups, respectively. The other trials that used pasteurized raw egg and started dosing as early as 4 months were negative. Further studies are needed to determine the optimal timing, patient population, and form of egg to introduce. (See "Introducing highly allergenic foods to infants and children", section on 'Introduction in a high-risk population'.)
Oral immunotherapy combined with omalizumab (October 2016)
Significant acute allergic reactions to oral immunotherapy (OIT) for food allergy are common and have led to the study of OIT combined with anti-immunoglobulin E (IgE), specifically omalizumab. In a small randomized trial of peanut OIT, combined therapy allowed for more rapid desensitization compared with OIT plus placebo . After 12 weeks, 77 and 12 percent of omalizumab- and placebo-treated subjects were able to tolerate 4 grams of peanut protein, respectively. Overall reaction rates during therapy were similar in both groups, although the omalizumab-treated subjects were exposed to much higher peanut doses. (See "Future therapies for food allergy", section on 'OIT plus anti-IgE'.)
Eosinophilic esophagitis and oral immunotherapy (October 2016)
A number of adverse effects are associated with oral immunotherapy (OIT) for food allergy. Up to 6 to 8 percent of children treated with OIT develop eosinophilic esophagitis (EoE) . Treatment with omalizumab does not appear to decrease the risk of developing EoE in patients receiving OIT . (See "Future therapies for food allergy", section on 'OIT plus anti-IgE' and "Future therapies for food allergy", section on 'Milk OIT'.)
Sustained unresponsiveness with oral immunotherapy (October 2016)
Most studies of oral immunotherapy (OIT) for food allergy have demonstrated sustained unresponsiveness in approximately 25 to 30 percent of patients. Two small studies suggest that earlier intervention with OIT (starting at 9 to 36 months of age rather than later in childhood)  and longer duration of OIT (up to 4 years versus <1 year)  are associated with higher rates of sustained unresponsiveness (78 percent and 50 percent, respectively). (See "Future therapies for food allergy", section on 'Peanut OIT' and "Future therapies for food allergy", section on 'Egg OIT'.)
Ustekinumab in leukocyte adhesion deficiency type I (March 2017)
Leukocyte adhesion deficiency type I (LAD I) is a primary immunodeficiency in which neutrophils cannot leave the vasculature to migrate into tissues under conditions of inflammation or infection. The simple absence of neutrophil killing was assumed to be responsible for the chronic skin and mucosal infections and ulcers seen in this disorder, but a case report described dramatic clinical improvement with ustekinumab, an agent known to downregulate inflammation . The observation that ustekinumab resulted in healing of chronic skin and mucosal lesions, rather than uncontrolled bacterial spread, suggests that a hyperinflammatory process is the primary reason for lack of healing. However, unchecked infection is a theoretical concern in more severe forms of LAD I, and longer-term studies are needed before the routine use of ustekinumab can be recommended. (See "Leukocyte-adhesion deficiency", section on 'Ustekinumab'.)
New form of SCID identified (December 2016)
A combination of newborn screening for severe combined immunodeficiency (SCID) and use of whole exome sequencing has identified a new disorder in a male infant with leaky SCID due to a heterozygous mutation in B cell chronic lymphocytic leukemia/lymphoma 11B (BCL11B) . BCL11B is involved in T cell development and migration of hematopoietic stem cells. The infant underwent successful hematopoietic cell transplantation prior to the onset of any infections, although his severe neurologic and skeletal abnormalities remain. (See "Severe combined immunodeficiency (SCID): Specific defects", section on 'B cell chronic lymphocytic leukemia/lymphoma 11B (BCL11B) defect'.)
RHINITIS AND RHINOSINUSITIS
Topical furosemide to retard growth of nasal polyps (December 2016)
Nasal polyposis is difficult to treat, and nonsteroid therapies to retard polyp growth are needed. Topical furosemide appears to interfere with edema formation by nasal polyp epithelial cells. In a randomized trial, in addition to low-dose glucocorticoid nasal spray in both groups, furosemide nasal spray was compared with placebo for two months following sinus surgery to remove polyps . At six months, the severity of polyposis was improved and regrowth of polyps decreased in the furosemide group. Although promising, further study is needed to determine optimal dosing, long-term safety and efficacy, and benefit relative to full-dose nasal glucocorticoids. (See "Chronic rhinosinusitis: Management", section on 'Therapies of uncertain benefit'.)
Efficacy of sublingual immunotherapy tablets for allergic rhinitis (October 2016)
The relative efficacy of sublingual immunotherapy tablets (SLIT-tablets) compared with various medical therapies for allergic rhinitis has not been extensively studied, and head-to-head studies are lacking. In an indirect analysis, 10 trials of SLIT-tablet for seasonal (grass and ragweed pollen) and perennial (house dust mite) allergic rhinitis were compared with 24 trials of monotherapy with full-strength mometasone nasal spray, desloratadine, or montelukast . SLIT-tablet treatment resulted in an overall improvement in total nasal symptom scores (TNSS) of 16 to 17 percent, whereas mometasone nasal spray resulted in improvements in TNSS of 22 and 11 percent for seasonal allergic rhinitis and perennial allergic rhinitis, respectively, and the other pharmacotherapies were inferior to SLIT. While the indirect nature of the analysis limits the conclusions that can be drawn, this study suggests that SLIT-tablets and glucocorticoid nasal sprays may have similar efficacy. (See "Sublingual immunotherapy for allergic rhinoconjunctivitis and asthma", section on 'Efficacy compared with pharmacotherapy'.)
URTICARIA AND ANGIOEDEMA
Subcutaneous C1 inhibitor for hereditary angioedema (April 2017)
Patients with hereditary angioedema (C1 inhibitor deficiency) suffer attacks of angioedema affecting the skin, gastrointestinal tract, and airway, which can be prevented with intravenous infusions of C1 inhibitor, typically given twice weekly. Subcutaneous administration would significantly facilitate self-treatment. In a randomized multicenter trial of 90 children and adults, participants injected a subcutaneous formulation of C1 inhibitor or placebo twice weekly for 16 weeks . Therapy was well tolerated and attack rates were reduced by approximately 90 percent relative to placebo. This preparation is not currently available outside of clinical trials, although approval in the future is anticipated. (See "Hereditary angioedema: General care and long-term prophylaxis", section on 'Subcutaneous C1 inhibitor'.)
VACCINES AND VACCINE HYPERSENSITIVITY
High-dose influenza vaccine in older adults (March 2017)
For influenza vaccination of adults ≥65 years of age, we recommend the high-dose inactivated influenza vaccine, which has previously been shown to be more immunogenic and modestly more effective at preventing influenza infection than the standard-dose vaccine. In a study of United States Medicare beneficiaries ≥65 years of age, the high-dose vaccine was more effective than the standard-dose vaccine for preventing postinfluenza death during the 2012-2013 influenza season, a season when circulation of H3N2 influenza A (a strain associated with severe disease) was common . In contrast, it was not more effective for preventing postinfluenza death during the following season, when H1N1 influenza A (a strain associated with mild disease) predominated. This difference was likely due to the difficulty in demonstrating benefit during a mild influenza season, when death is a rare outcome. The high-dose vaccine was associated with a reduced risk of hospitalization during both seasons. (See "Seasonal influenza vaccination in adults", section on 'High-dose vaccine'.)
OTHER GENERAL ALLERGY AND IMMUNOLOGY
Nemolizumab for atopic dermatitis (March 2017)
Some patients with atopic dermatitis do not experience disease control with topical treatments. In a phase 2 trial, 264 patients with moderate to severe atopic dermatitis not controlled by topical corticosteroids or topical calcineurin inhibitors were randomly assigned to monthly subcutaneous nemolizumab, an investigational humanized monoclonal antibody against interleukin-31, at three different doses or to placebo . At 12 weeks, pruritus was reduced by 44, 60, and 63 percent, in the low, medium, and high dose groups, respectively, versus 21 percent in the placebo group. However, nemolizumab did not reduce the body surface area affected by atopic dermatitis. Adverse effects occurred in approximately 70 percent of patients in all study groups and were generally mild, with the most frequent being exacerbation of atopic dermatitis and respiratory tract infections. Although nemolizumab appears to be a promising treatment for pruritus associated with atopic dermatitis, larger studies of longer durations are needed to confirm its efficacy and safety. (See "Treatment of atopic dermatitis (eczema)", section on 'Nemolizumab'.)
Immunotherapy for stinging insect hypersensitivity in adults (February 2017)
Venom immunotherapy (VIT) for the treatment of patients with anaphylactic reactions to stings of Hymenoptera insects (eg, bees, yellow jackets, wasps, hornets, and fire ants) is highly effective in preventing future anaphylactic reactions. However, in an updated practice parameter from the American Joint Task Force, VIT is no longer suggested for adults with systemic reactions limited to the skin (ie, generalized erythema, pruritus, urticaria, or angioedema) as studies suggest these patients are at low risk for serious future systemic reactions . This change brings the American approach into closer alignment with guidelines of other countries and is similar to the existing recommendation for children. Despite this revision, VIT may be appropriate for certain adults with cutaneous systemic reactions (eg, those with underlying medical conditions or medications that could affect the outcome of a systemic reaction, frequent unavoidable exposure to Hymenoptera, or impaired quality of life due to fear of future stings). (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action", section on 'Patients with past cutaneous systemic reactions'.)
Differences in anaphylaxis treatment by age (February 2017)
Epinephrine given by intramuscular (IM) injection is the treatment of choice for anaphylaxis, but clinicians are sometimes reluctant to administer it, particularly to older adults. In a retrospective study of nearly 500 children and adults with anaphylaxis presenting to the emergency department, patients >50 years of age were less likely to receive epinephrine (36 versus 61 percent) compared with younger patients . In addition, among patients who were given epinephrine, older adults were more likely to receive excessive doses when epinephrine was administered intravenously (IV). IM epinephrine was well-tolerated by patients of all ages, while IV administration was associated with a higher rate of cardiovascular complications. These findings support our recommendations to administer epinephrine by IM injection whenever possible and reserve IV administration for refractory cases. (See "Anaphylaxis: Emergency treatment", section on 'Situations requiring caution'.)
Masitinib in indolent and smoldering systemic mastocytosis (February 2017)
There are limited treatment options for indolent and smoldering systemic mastocytosis (ISM and SSM, respectively). Masitinib is a tyrosine kinase with activity against at least three mast cell signaling molecules. In a phase III trial of 135 severely symptomatic patients with ISM or SSM, oral masitinib reduced symptoms, tryptase levels, and urticaria pigmentosa lesions compared with placebo, although it was associated with side effects requiring discontinuation in 24 percent . The drug is under regulatory review, and further data about the safety and efficacy are needed before its use can be recommended. (See "Systemic mastocytosis: Management and prognosis", section on 'Clinical trials'.)
Topical crisaborole for atopic dermatitis (December 2016)
A topical preparation containing 2% crisaborole, an investigational boron-based, small-molecule, phosphodiesterase-4 inhibitor, was approved by the US Food and Drug Administration in December 2016 for the treatment of mild to moderate atopic dermatitis in patients two years of age and older . In four-week clinical trials, topical crisaborole was more effective than placebo in reducing pruritus, skin inflammation, excoriation, and lichenification. However, trials comparing topical crisaborole with other topical treatments for atopic dermatitis are lacking. (See "Treatment of atopic dermatitis (eczema)", section on 'Crisaborole'.)
E-cigarette use and respiratory symptoms in adolescents (November 2016)
Use of e-cigarettes has been rising among adolescents in the United States, and the long-term health consequences of e-cigarette use are unknown. A survey of 11th and 12th grade students in California found an association between self-reported chronic bronchitic symptoms (chronic cough, phlegm, bronchitis in the past year) and current or past e-cigarette use that remained after adjustment for confounders such as cigarette smoking or secondhand smoke exposure; risk of respiratory symptoms increased with frequency of current use of e-cigarettes . (See "E-cigarettes", section on 'Adverse health effects'.)
Persistence of pediatric atopic dermatitis (November 2016)
Atopic dermatitis (AD) is a chronic disease with a highly variable course. Although most children are thought to “outgrow” it before adolescence, little is known about the factors associated with its persistence into adulthood. A meta-analysis including over 110,000 subjects found that 20 percent of children with AD had persistent disease eight years after the diagnosis, and less than 5 percent had persistent disease 20 years later . Children who developed AD before two years of age had a much lower risk of persistent disease than those who developed AD later in childhood or during adolescence. Other predictors of persistent AD were severity and duration of AD and female sex, whereas hypersensitivity to one or more allergens at disease onset did not seem to influence the persistence of disease. (See "Pathogenesis, clinical manifestations, and diagnosis of atopic dermatitis (eczema)", section on 'Clinical course and complications'.)
Dupilumab for moderate to severe atopic dermatitis in adults (October 2016)
Two 16-week phase III trials of identical design, including nearly 1400 adults, evaluated the efficacy of dupilumab, an investigational monoclonal antibody that targets interleukin 4 and 13, for the treatment of atopic dermatitis not controlled by topical therapies . The primary end point was the proportion of patients to achieve a "clear" or "almost clear" rating, which occurred in approximately 40 and 10 percent of patients receiving dupilumab and placebo, respectively. The drug was well tolerated. Dupilumab is not yet available for clinical use. (See "Treatment of atopic dermatitis (eczema)".)
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