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What's new in allergy and immunology

Disclosures: Anna M Feldweg, MD Employee of UpToDate, Inc. Elizabeth TePas, MD, MS Employee of UpToDate, Inc.

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2014. | This topic last updated: Sep 19, 2014.

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.


Intermittent montelukast for acute wheezing episodes in young children (September 2014)

Several randomized trials have examined the intermittent use of leukotriene receptor antagonists (LTRAs) in preschool children with recurrent wheezing, with mixed results. The most recent trial adds to the data that do not favor this approach in most children, although specific subgroups based upon genotype may benefit. In this trial, over 1300 children aged 10 months to 5 years with a history of two or more wheezing episodes were randomly assigned to intermittent montelukast or placebo at the onset of any subsequent wheezing episode over a 12 month period [1]. No difference between the groups was seen in the frequency of unscheduled medical visits for wheezing episodes, although subgroup analysis suggested the response to montelukast was modified by arachidonate 5-lipoxygenase (ALOX5) genotype. Further study is needed to define and confirm these subpopulations. (See "Treatment of recurrent virus-induced wheezing in young children", section on 'Intermittent leukotriene-receptor antagonists'.)

Clusters of enterovirus D68 infections in the United States (September 2014)

Since August 2014, clusters of severe respiratory infections due to enterovirus D68 have been reported in several states in the United States [2,3]. These have occurred predominantly in children with a prior history of asthma and have been characterized by low-grade or absent fever with wheezing, dyspnea, hypoxia, and perihilar infiltrates. The possibility of enterovirus D68 should thus be suspected in cases of severe respiratory illnesses without alternative explanation, particularly in young children. Treatment is supportive and prevention relies on basic hygienic measures, including handwashing with soap and water. Alcohol-based sanitizers may be ineffective against enteroviruses. Enterovirus D68 had previously been implicated in smaller clusters of respiratory infections but was otherwise rarely reported. Additional surveillance information can be found on the CDC website. (See "Virus-induced wheezing and asthma: An overview", section on 'Enterovirus D68 infection' and "Clinical manifestations and diagnosis of enterovirus and parechovirus infections", section on 'Respiratory disease' and "Epidemiology, pathogenesis, treatment, and prevention of enterovirus and parechovirus infections", section on 'Serotypes and disease'.)

Long-acting beta agonist olodaterol for use in COPD (August 2014)

Olodaterol, a once-daily, long-acting beta agonist (LABA), is approved for the treatment of COPD in the United States, Canada, Russia, Denmark, and several other countries; it is not approved for use in asthma. In two trials that included a total of 1838 subjects with moderate-to-severe COPD, 24 weeks of olodaterol resulted in significant improvement in airflow limitation and quality of life, compared with placebo [4]. Similar results were seen in a separate pair of trials that included a total of 1266 subjects and lasted 48 weeks [5]. In all reports, adverse events with olodaterol were comparable to those of placebo. (See "Management of stable chronic obstructive pulmonary disease", section on 'Beta agonists'.)

Interplay between allergen and bacterial exposures in the development of asthma (June 2014)

Data have been conflicting about the role of allergen exposure in the development of asthma and recurrent wheeze in children. The Urban Environment and Childhood Asthma (URECA) study assessed allergen exposure in a large birth cohort at high risk for asthma, and also bacterial content of house dust in a nested study of 104 children [6]. Accumulated allergen exposure over the first three years of life was associated with increased allergic sensitization and with recurrent wheeze at age three, but exposure in the first year was negatively associated with recurrent wheeze. Moreover, the combination of early-life exposure to these allergens with high-level exposure to bacteria in house dust was associated with a further reduction in risk of recurrent wheeze by age three. These observations suggest that the effects of early life allergen exposure may differ from those of cumulative exposure and that the combination of high-level allergen and bacterial exposure in early-life may be protective against allergen sensitization and recurrent wheeze. (See "Risk factors for asthma", section on 'Influence of bacterial exposure'.)

An anti-thymic stromal lymphopoietin monoclonal antibody shows promise in allergic asthma (June 2014)

Thymic stromal lymphopoietin (TSLP) is an epithelial-cell-derived cytokine that may play a role in allergic inflammation. In a proof-of-concept study, 31 patients with allergic asthma were randomly assigned to receive the anti-TSLP monoclonal antibody (AMG 157) or placebo intravenously, once a month for three doses [7]. On day 84, patients who received AMG 157 demonstrated significant blunting in their response to inhaled allergen, when compared with those who received placebo. This study provides support for anti-TSLP as a novel therapy for allergic asthma; further studies are planned. (See "Alternative and experimental agents for the treatment of asthma", section on 'Anti-thymic stromal lymphopoietin'.)

Pediatric health effects of public smoking bans (June 2014)

Policies that ban indoor smoking in workplaces and public places have been associated with long-term health benefits in adults. Smoking bans also appear to be associated with immediate health benefits in children. In a meta-analysis of quasi-experimental observational studies, public smoking bans were associated with reductions of approximately 10 percent in preterm births and hospital admissions for asthma [8]. Some of the effects may be mediated through home smoking bans, which often are prompted by public smoking bans. Additional studies are necessary to determine the effects of smoking bans on respiratory tract infections and other child-health outcomes. (See "Control of secondhand smoke exposure", section on 'Public smoking bans'.)

Statin therapy does not reduce COPD exacerbations (June 2014)

In observational studies of chronic obstructive pulmonary disease (COPD), statins have been associated with a reduced rate and severity of exacerbations, rate of hospitalizations, and mortality. However, these beneficial effects were not supported in a trial that randomly assigned 885 participants with COPD, but without other indications or contraindications for statin therapy, to simvastatin or placebo for up to 36 months [9]. Simvastatin did not reduce the rate of exacerbations or the time to first exacerbation. (See "Management of exacerbations of chronic obstructive pulmonary disease", section on 'Ineffective interventions'.)

Breastfeeding and development of asthma (May 2014)

Studies of breastfeeding are invariably subject to confounding, and data regarding the effects of breastfeeding on the prevention of asthma have been conflicting. In a systematic review and meta-analysis, the strongest protective effect of breastfeeding was seen in the birth to two years age group, in which rates for both "recent asthma" and "asthma ever" were consistently reduced, regardless of duration or exclusivity of breastfeeding [10]. This protective effect decreased with age, which is consistent with findings from individual studies that followed children until adolescence and found that breastfeeding was ultimately not protective against asthma in the highest risk children. The early reduction in asthma-type symptoms is probably due in part to the decreased number of clinically significant respiratory tract infections seen in breastfed infants. (See "The impact of breastfeeding on the development of allergic disease", section on 'Breastfeeding and asthma'.)

Dexamethasone for acute asthma exacerbations in children (March 2014)

Oral, rather than intravenous or intramuscular, administration of glucocorticoids for acute asthma exacerbations in children is preferred because it is less invasive, equally effective, and can be more easily discontinued in the setting of intolerance. However, vomiting of orally administered prednisone/prednisolone has been an issue. A meta-analysis comparing a five-day course of oral prednisolone or prednisone to one to two doses of oral or intramuscular dexamethasone for asthma exacerbations managed in the emergency department (ED) found that the treatments were similarly effective, but dexamethasone by either route caused less vomiting [11]. However, most of the trials included in the meta-analysis used older prednisone formulations and more palatable formulations have since been developed. Thus, either the newer formulations of oral prednisone/prednisolone or oral dexamethasone are good options for ED therapy. (See "Acute asthma exacerbations in children: Emergency department management", section on 'Systemic glucocorticoids'.)


HLA-B*1502 testing prior to oxcarbazepine therapy (June 2014)

The HLA-B*1502 allele is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis due to carbamazepine, and screening for this allele is recommended prior to initiating therapy in patients with Asian ancestry, who are more likely to carry the allele. Although data are weaker for the relationship between oxcarbazepine-induced hypersensitivity reactions and the HLA-B*1502 allele, the two drugs have similar chemical structures, and preclinical data have shown a direct interaction between oxcarbazepine and the HLA-B*1502 protein. For these reasons, the US Food and Drug Administration has revised the oxcarbazepine label to suggest testing for the HLA-B*1502 allele in genetically at-risk populations (ie, those with Asian ancestry) before initiating treatment with oxcarbazepine [12]. (See "Pharmacology of antiepileptic drugs", section on 'Oxcarbazepine'.)

Recurrence of Stevens-Johnson syndrome/toxic epidermal necrolysis (June 2014)

Although there are reports of recurrence of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), the overall risk of recurrence is unknown. In a 10-year population-based cohort of 708 patients hospitalized for a first episode of SJS or TEN, 7.2 percent of 581 survivors were hospitalized for a second episode and 1.4 percent had multiple recurrences; lack of direct access to medical records precluded information about medication exposures [13]. The median time to first recurrence was 315 days. The high risk of recurrence after a first episode of SJS/TEN may reflect a long-lasting vulnerability or a genetic predisposition to severe drug reactions. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'Recurrence'.)


Oral immunotherapy for food allergy (March 2014)

Data continue to accumulate regarding the efficacy and limitations of oral immunotherapy (OIT) for childhood food allergies. Important developments of several phase 1/pilot studies include safe administration of OIT with multiple foods simultaneously [14], ability to perform OIT in high-risk patients and reach maintenance more quickly with concomitant anti-immunoglobulin E therapy [15], and unresponsiveness to the allergenic food in some patients for one to six months after discontinuing successful OIT [16,17]. OIT is associated with a greater risk of anaphylaxis compared with avoidance [18,19], although despite this, parents assess their children’s quality of life as higher with OIT [20]. Additional studies, particularly randomized trials, are still needed to determine if the benefits outweigh the risks for most food-allergic children. (See "Future therapies for food allergy", section on 'Oral immunotherapy' and "Future therapies for food allergy", section on 'OIT combined with anti-IgE'.)

Maternal intake of highly allergenic foods during pregnancy (March 2014)

To date, most studies have found that maternal avoidance of highly allergenic foods during pregnancy does not reduce the incidence of allergic disease in infants and children at risk for these disorders. However, participants in such studies are often from "high risk" atopic families and thus may not be representative of the general population. A new cohort study in over 1200 unselected mother-child pairs examined the association between maternal intake of common allergenic foods during pregnancy and the development of allergic disorders in the offspring [21]. Data from mid-childhood visits found that diets lower in allergenic foods were not associated with reduction in the incidence of food allergy, asthma, allergic rhinitis, or atopic dermatitis, and in some situations, higher intake in early pregnancy appeared to have a protective effect. These findings support our current suggestion that women not restrict their diets during pregnancy for the purpose of reducing allergic disease in their children. (See "Primary prevention of allergic disease: Maternal avoidance diets in pregnancy and lactation", section on 'Definitions'.)


Inheritance patterns in hemophagocytic lymphohistiocytosis (August 2014)

Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome of excessive immune activation seen in patients of all ages, predominantly infants and children. Gene mutations affecting cytotoxic lymphocyte function are often found. Genetic testing in a series of 2701 patients has now revealed a previously unappreciated mode of inheritance in HLH. In addition to homozygosity or compound heterozygosity for mutations in a single HLH gene, the disease can also be caused by digenic inheritance, in which separate mutations in two different HLH genes are found [22]. The specific genes involved appear to affect the age of disease onset. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Genetics'.)

Donor source and transplantation outcomes for severe combined immunodeficiency (August 2014)

Historically, HLA-matched related donors have been the preferred donor source for hematopoietic cell transplantation (HCT) in patients with severe combined immunodeficiency (SCID) and other primary immunodeficiencies, but most patients do not have such a donor available. Results from a series of 240 infants with SCID who had undergone HCT show that excellent survival is possible with any donor type if the transplantation occurs in the first 3.5 months of life and before the onset of infection [23]. Survival at 5 years was high regardless of donor type among infants transplanted at ≤3.5 months of age (94 percent) and among older infants who had not yet developed infection (90 percent) or whose infections had resolved (80 percent). (See "Hematopoietic cell transplantation for primary immunodeficiency", section on 'Early identification' and "Hematopoietic cell transplantation for primary immunodeficiency", section on 'Donor source'.)


Diagnostic criteria for mucous recirculation syndrome (July 2014)

Mucous recirculation syndrome is an acquired disorder of impaired mucous clearance in which mucus draining through a sinus ostium re-enters the sinus through a different ostium and recirculates, rather than draining out through the nasopharynx. It is a cause of refractory chronic rhinosinusitis (CRS). Based upon a cohort of 12 patients and review of the literature including an additional 44 cases, researchers have proposed diagnostic criteria for mucous recirculation syndrome and described various recirculation patterns [24]. Proposed diagnostic criteria are: CRS not responding to oral or topical therapies, visualization of mucous recirculation between two or more ostia by rhinoscopy, and resolution of symptoms with surgical treatment. (See "Management of chronic rhinosinusitis", section on 'Mucous recirculation syndrome'.)

Sublingual tablet immunotherapy for pollen-induced rhinitis (April 2014)

Sublingual immunotherapy has been used for decades in Europe to treat allergic rhinoconjunctivitis, although products specifically designed for oral use and proven effective in high-quality studies had not been available in the United States. Two products, a five-grass sublingual tablet (Oralair), and a single-grass tablet (Grastek) were approved by the US Food and Drug Administration in early April 2014 [25,26] based on earlier randomized trials demonstrating efficacy. A third product (Ragwitek) for allergic rhinitis (with or without conjunctivitis) due to short ragweed pollen was approved in late April [27]. Sublingual tablet immunotherapy expands the available treatment options for patients with seasonal nasal and ocular allergies. The first dose should be administered under medical supervision. The most common adverse effects are oral or pharyngeal pruritus, but systemic allergic reactions are rare. (See "Sublingual immunotherapy for allergic rhinitis", section on 'Availability'.)


Recombinant C1 inhibitor for hereditary angioedema (August 2014)

Recombinant human C1-esterase inhibitor (conestat alfa) has been approved by the US Food and Drug Administration for treatment of acute attacks of hereditary angioedema in adolescents and adults [28]. This agent has been available in some other countries since 2011. It is collected from the milk of transgenic rabbits, and all patients should be screened for allergy to rabbit before receiving this agent, because severe allergic reactions have been reported in patients with pre-existing rabbit allergy. Studies directly comparing recombinant to plasma-derived C1 esterase inhibitor are lacking, although available data suggest that they are similarly effective. The recombinant product has a shorter half-life, requiring higher doses to achieve adequate plasma levels. (See "Hereditary angioedema: Treatment of acute attacks", section on 'Efficacy and adverse effects'.)

Omalizumab for refractory chronic urticaria (April 2014)

Omalizumab, a recombinant humanized monoclonal antibody that binds immunoglobulin E (IgE), was approved by the US Food and Drug Administration in March 2014 for the treatment of chronic urticaria (CU) that is not controlled with H1 antihistamine therapy in patients 12 years of age and older [29]. Approval was based on several randomized trials published in recent years, in which most patients responded within the first few weeks of therapy. Two doses were approved: 150 mg or 300 mg injected subcutaneously every four weeks. Omalizumab has a superior safety profile to many of the other agents used in the treatment of refractory CU, although it is the most expensive and does not appear to have a long-term disease modifying effect. Studies directly comparing omalizumab to other treatments for refractory CU are needed to determine the optimal use for omalizumab in the management of this disorder. (See "Chronic urticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)

Chronic idiopathic urticaria and food/drug additives (March 2014)

Although food and drug additives are felt to cause chronic urticaria only rarely, if at all, many patients with chronic urticaria believe that additives are partly or entirely to blame. In a referral center study of 100 patients with chronic urticaria, including 43 who suspected they were sensitive to one or more additives, subjects were systematically challenged with common food and drug additives [30]. In an initial challenge with a combination of 11 additives, two patients had significant worsening of symptoms. Neither patient reacted to a series of subsequent double-blind placebo-controlled challenges with each additive. Thus, none of the 100 patients was sensitive to any of the additives tested. This study should prove helpful in communicating with patients who suffer from this vexing disorder, while research into its true etiology(ies) continues. (See "Allergic and asthmatic reactions to food additives", section on 'Patients with chronic urticaria'.)


ACIP recommendations for the 2014-2015 influenza season (August 2014)

In August 2014 the United States Advisory Committee on Immunization Practices (ACIP) released updated recommendations for the prevention of seasonal influenza with vaccines [31]. Important changes from previous recommendations include:

A preferential recommendation for the nasal spray vaccine (live attenuated influenza vaccine, LAIV) over the intramuscular injection (inactivated influenza vaccine, IIV) for children two through eight years of age who do not have specific contraindications to the nasal vaccine (eg, asthma, egg allergy, diabetes, immunosuppression). UpToDate agrees with this recommendation, but also prefers LAIV for children older than eight years. If LAIV is not immediately available, IIV should be administered to avoid missing an opportunity for influenza immunization. (See "Seasonal influenza in children: Prevention with vaccines", section on 'LAIV compared with IIV'.)

Changes to the dosing schedule for children six months through eight years of age (algorithm 1). (See "Seasonal influenza in children: Prevention with vaccines", section on 'Schedule'.)

Recommendations for adults are largely unchanged. (See "Seasonal influenza vaccination in adults", section on 'Overview'.)

Efficacy of high-dose influenza vaccine in elderly adults (August 2014)

Due to concern that standard-dose influenza vaccines may be less effective in elderly adults than in younger adults, a high-dose influenza vaccine, Fluzone high-dose, has been developed. In a trial that included more than 30,000 adults ≥65 years of age, Fluzone high-dose was modestly more effective than standard-dose Fluzone [32]. Among individuals in the high-dose group, 1.4 percent had laboratory-confirmed influenza associated with an influenza-like illness compared with 1.9 percent in the standard-dose group (relative efficacy 24.2 percent). The rates of serious adverse events were similar with the high-dose and standard-dose vaccines. For individuals ≥65 years of age, we prefer Fluzone high-dose when available rather than a standard-dose inactivated vaccine. However, the United States Advisory Committee on Immunization Practices has not stated a preference for Fluzone high-dose over the standard-dose inactivated influenza vaccine in older adults [31,33]. (See "Seasonal influenza vaccination in adults", section on 'High-dose vaccine' and "Seasonal influenza vaccination in adults", section on 'Choice of vaccine formulation'.)

Influenza vaccine administration by needle-free jet injector (June 2014)

Needle-free vaccine technology could be useful for immunizing needle-phobic patients and reducing the risk of needlestick injuries. In August 2014, the US Food and Drug Administration (FDA) approved an intramuscular inactivated influenza vaccine (Afluria) for use with a jet injector device (PharmaJet Stratis needle-free injection system) for adults between 18 and 64 years of age [34]. The jet injector uses a high-pressure narrow jet of liquid vaccine to penetrate tissue [35]. In a randomized trial in healthy adults, the immune response to influenza vaccine was comparable when administered by jet injector device or needle and syringe. The jet injector device was associated with a higher frequency of local injection site reactions. (See "Seasonal influenza vaccination in adults", section on 'Needle-free jet injector'.)


STING-associated vasculopathy with onset in infancy (August 2014)

Autoinflammatory diseases are due to pathogenic inflammation that arises through aberrant, antigen-independent activation of the immune system. A new autoinflammatory disease in children, stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI), has been identified [36]. SAVI is caused by gain-of-function mutations in the gene encoding STING (TMEM173, transmembrane protein 173). Patients present in early infancy with tachypnea and/or rashes (telangiectasia, pustules, and/or blisters) and develop marked vascular inflammation limited to the capillaries. Most patients also have recurrent low-grade fevers. Patients have not responded to the usual drugs used to treat rheumatologic disease, but blockade of interferon signaling is a potential therapeutic strategy. (See "Periodic fever syndromes and other autoinflammatory diseases: An overview", section on 'Chronic recurrent multifocal osteomyelitis'.)

Dupilumab for atopic dermatitis (July 2014)

Dupilumab is a fully human monoclonal antibody that inhibits downstream signaling of IL-4 and IL-13, cytokines of type 2 helper T lymphocytes (Th2) that are believed to play a key role in atopic diseases, including asthma and atopic dermatitis. Dupilumab was evaluated in four small, industry-sponsored randomized trials in adult patients with moderate to severe atopic dermatitis [37]. In the largest study, 109 patients received weekly subcutaneous injections of dupilumab 300 mg or placebo. At 12 weeks, patients in the dupilumab group had a greater reduction in the Eczema Area and Severity Index score, body surface area affected, and pruritus than patients in the placebo group. Nasopharyngitis and headache were the most frequent adverse events. Although the results suggest that dupilumab may be a promising treatment for atopic dermatitis, additional studies are needed to evaluate its long-term efficacy and safety. (See "Treatment of atopic dermatitis (eczema)", section on 'Experimental agents'.)

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