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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
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'.)
Safety of inhaled glucocorticoid-LABA combination therapy in asthma (September 2016)
In early studies, a small increase in asthma-related deaths associated with salmeterol led the US Food and Drug Administration to place a boxed warning on the use of long-acting beta agonists (LABAs) in asthma. While concerning, the number of events was small, and it could not be determined if the potential risk of salmeterol could be mitigated by combining LABAs with inhaled glucocorticoids. Three large randomized trials including 30,000 children and adults found no increase in asthma-related adverse events or deaths among patients who used combination inhalers with salmeterol or formoterol plus an inhaled glucocorticoid versus glucocorticoid monotherapy [5-7]. These studies support the safety of these fixed-dose combination inhalers in patients with moderate-to-severe asthma. (See "Beta agonists in asthma: Controversy regarding chronic use", section on 'Potential risk mitigation'.)
Farm animals, asthma, and the innate immune response (September 2016)
Exposure to farm animals, particularly early in life, is negatively associated with the development of allergic disease. A recent study compared 60 children from Amish and Hutterite communities, two genetically similar, reproductively isolated farming populations in the United States . The Amish have traditional, single-family farms with exposure to horses and dairy cows, whereas the Hutterites live and work on large farms that are highly industrialized. Amish children have significantly lower rates of asthma and allergic sensitization than their Hutterite counterparts. Endotoxin levels were significantly higher in the Amish homes, and dust extracts from the Amish homes, but not the Hutterite homes, significantly blocked airway hyperresponsiveness and eosinophilia in a mouse model. In addition, in vitro studies showed an enhanced innate immune response in Amish, but not Hutterite, children. These findings suggest that the closer contact with farm animals in the Amish lifestyle may help prevent the development of asthma by altering the innate immune response. (See "Increasing prevalence of asthma and allergic rhinitis and the role of environmental factors", section on 'Farms, villages, worms, and other parasites'.)
Lack of association between acetaminophen and asthma in children (September 2016)
More frequent use of acetaminophen was associated with increased asthma-related complications in children in observational studies, leading to the recommendation by some for children with asthma to avoid acetaminophen. However, these findings were not replicated in a prospective, randomized trial comparing acetaminophen and ibuprofen use . In this trial, 300 children with mild persistent asthma were randomly assigned to as-needed treatment with acetaminophen or ibuprofen for fever or pain over a 48-week period. All children received standard controller therapy for asthma. There was no significant difference between the two groups in the number of asthma exacerbations requiring treatment with systemic glucocorticoids or in the number of asthma exacerbations. Thus, we do not advise restricting the use of acetaminophen in children with asthma. (See "Virus-induced wheezing and asthma: An overview", section on 'Acetaminophen use for febrile illnesses'.)
Evaluation of recurrent wheezing in children <2 years of age (August 2016)
The American Thoracic Society has developed guidelines for evaluation of children <2 years of age who have recurrent wheezing that is unresponsive to bronchodilators or inhaled or systemic glucocorticoids . Suggested evaluation includes one or more of the following: videofluoroscopic swallowing study (modified barium swallow) for possible swallowing dysfunction; 24-hour esophageal pH monitoring for assessment of gastroesophageal reflux; and/or flexible fiberoptic bronchoscopy bronchoalveolar lavage (BAL) to assess for lower airway bacterial infection. Our approach is consistent with these guidelines. (See "Approach to wheezing in infants and children", section on 'Radiography' and "Approach to wheezing in infants and children", section on 'Endoscopy' and "Approach to wheezing in infants and children", section on 'Evaluation for gastroesophageal reflux'.)
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
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'.)
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
Investigational oral agent for prophylaxis of hereditary angioedema (September 2016)
For patients with hereditary angioedema (HAE) due to C1 inhibitor deficiency, the only available oral agents for prophylaxis are androgens and tranexamic acid, which have significant adverse effects or limited efficacy, respectively. A new oral agent, avoralstat, which inhibits plasma kallikrein, was evaluated for prophylaxis in a placebo crossover trial of 24 patients with relatively severe HAE . Although angioedema episodes decreased during the avoralstat phase compared with the placebo phase (79 versus 123 over four weeks), results were not statistically significant, so it is not clear if this agent will be a viable option for prophylaxis. (See "Hereditary angioedema: General care and long-term prophylaxis", section on 'Investigational therapies'.)
Screening and prevention of hydroxychloroquine retinopathy (August 2016)
Antimalarial agents hydroxychloroquine (HCQ) and chloroquine are widely used for the treatment of systemic lupus erythematosus, rheumatoid arthritis, and other inflammatory and dermatologic conditions, and are generally thought to be safe. Retinal toxicity is a known risk, however, and measures to minimize this potential toxicity are necessary. Recently, the American Academy of Ophthalmology issued revised recommendations for screening and prevention of retinopathy . Key changes include the following:
●The maximum daily dose of HCQ should not exceed 5 mg/kg (previously 6.5 mg/kg), and the maximum daily dose of chloroquine should not exceed 2.3 mg/kg (previously 3 mg/kg).
●Real body weight should be used to calculate dose limits instead of ideal body weight.
In addition to exceeding the recommended daily dose, major risk factors for retinal toxicity include antimalarial use for greater than five years, renal disease, concomitant tamoxifen use, and the presence of macular disease. All patients should undergo a baseline eye examination before or within a year of beginning treatment with an antimalarial drug and, if normal, at least annually after five years of exposure for patients without major risk factors. For the treatment of rheumatic diseases, we typically use standard daily doses of HCQ (non-weight-based, eg, up to 400 mg) in individuals weighing 80 kg or more. In patients weighing less than 80 kg, we use a lower daily dose of HCQ up to the maximum of 5 mg/kg of real body weight. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Ocular health'.)
Acquired C1 inhibitor deficiency in lymphoma patients (August 2016)
Acquired C1 inhibitor deficiency is a rare disorder that causes episodes of angioedema that are unresponsive to epinephrine or antihistamines and can be fatal if the airway is compromised. In previous series of patients with acquired angioedema, 30 to 40 percent were found to have a malignancy of some type, most commonly a non-Hodgkin lymphoma (NHL). However, the overall prevalence of acquired C1 inhibitor deficiency in patients with lymphoma was unknown. In a new retrospective study of 131 patients with different types of lymphoma, patients were screened at the time of lymphoma diagnosis for deficiency and dysfunction of C1 inhibitor . Four patients (3 percent) were symptomatic with episodic swelling and all four had both functional tests and levels of C1 inhibitor that were below 50 percent of normal. Three of these four had splenic marginal cell lymphoma. Another 10 patients had abnormal C1 inhibitor function but had not developed angioedema. This study provides an initial estimate of the prevalence of acquired C1 inhibitor deficiency in lymphoma patients and suggests that those with splenic marginal cell lymphoma may be at particular risk. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis", section on 'Lymphoproliferative disorders and B cell malignancies'.)
OTHER GENERAL ALLERGY AND IMMUNOLOGY
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)", section on 'Dupilumab'.)
Unclear role of montelukast in eosinophilic esophagitis (October 2016)
Initial experience suggested that montelukast may be helpful for symptom reduction in patients with eosinophilic esophagitis, but subsequent experience has been mixed. In a small randomized trial, patients with eosinophilic esophagitis were assigned to maintenance treatment with montelukast or placebo for 26 weeks following steroid-induced symptomatic remission . There were no significant differences in the proportion of patients that remained in remission between the two groups. Thus, the role of montelukast in eosinophilic esophagitis, if any, remains unclear. (See "Treatment of eosinophilic esophagitis", section on 'Montelukast'.)
Investigational topical therapy for atopic dermatitis (September 2016)
Crisaborole is a topical boron-based phosphodiesterase-4 inhibitor with limited systemic absorption, which is under investigation as a novel topical therapy for atopic dermatitis. In two identical, multicenter randomized trials, a total of 1522 patients ≥2 years old with mild to moderate atopic dermatitis were treated with crisaborole 2% ointment or vehicle twice daily for 28 days . More patients in the crisaborole groups than in the vehicle groups achieved the primary end point (an investigator’s global assessment score of 0 [clear] or 1 [almost clear] with a two-grade or more improvement from baseline). Improvement was noted in pruritus, skin inflammation, excoriation, and lichenification. Crisaborole-related adverse events occurred in 4.4 percent of patients and were mild and limited to burning or stinging at the site of application. Although crisaborole appears a promising nonsteroidal topical treatment for mild to moderate atopic dermatitis, studies of longer duration than four weeks are needed to evaluate its efficacy and safety. (See "Treatment of atopic dermatitis (eczema)".)
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