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What's new in allergy and immunology
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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.

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.

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2015. | This topic last updated: Mar 02, 2015.

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.


Safety of inhaled long-acting beta agonist/glucocorticoid for asthma during pregnancy (February 2015)

An important clinical question for pregnant women with asthma is whether using a combination long-acting beta-agonist (LABA) plus inhaled glucocorticoid confers an increased risk for adverse fetal outcomes, compared with monotherapy using a higher dose of the inhaled glucocorticoid. In a study of 1302 pregnant women with asthma, the risk for a major congenital malformation was not increased when a LABA plus low dose inhaled glucocorticoid was compared with a medium dose inhaled glucocorticoid, or when a LABA plus medium-dose inhaled glucocorticoid was compared with a high-dose inhaled glucocorticoid [1]. (See "Management of asthma during pregnancy", section on 'Long-acting beta-adrenergic agents'.)

Safety of omalizumab for asthma during pregnancy (February 2015)

The safety of omalizumab exposure during pregnancy in humans has not been formally evaluated, but outcomes from an omalizumab registry have been published [2]. There were 169 pregnancies with known outcomes: 156 live births (160 infants), 1 fetal death/stillborn, and 11 spontaneous abortions. The rate of preterm birth was 14 percent, and 11 percent of infants were small for gestational age. Congenital anomalies were present in 13 percent, and 4 percent had a major anomaly. While the sample size is small, these results are similar to findings from other studies of pregnant women with asthma. Further data are needed to more fully characterize outcomes of omalizumab use in pregnancy. (See "Management of asthma during pregnancy", section on 'Anti-immunoglobulin E'.)

Novel glucocorticoid receptor agonist for asthma (February 2015)

The investigational agent AZD5423 is a nonsteroidal compound that binds to the glucocorticoid receptor in a different manner from that of traditional glucocorticoids. It suppresses production of proinflammatory proteins (like traditional glucocorticoids), but with reduced adverse effects in animal models. An inhaled dry powder formulation of AZD5423 was assessed in a trial that randomly assigned 20 subjects with mild allergic asthma to pretreatment with AZD5423, budesonide, or placebo for seven days followed by allergen-bronchoprovocation [3]. AZD5423 attenuated the fall in forced expiratory volume in one second (FEV1) during the late phase asthmatic response compared with budesonide or placebo, but did not affect the early decrease in FEV1. AZD5423 also decreased allergen-induced sputum eosinophilia and allergen-induced airway hyperresponsiveness at 24 hours and was well-tolerated. Additional studies are needed to determine the safety and efficacy of AZD5423 compared with inhaled glucocorticoids. (See "Alternative and experimental agents for the treatment of asthma", section on 'Novel glucocorticoid receptor agonist'.)

Aspirin therapy for aspirin-exacerbated respiratory disease (October 2014)

Aspirin desensitization followed by daily aspirin therapy is used in the treatment of aspirin-exacerbated respiratory disease (AERD). The utility of aspirin therapy in patients who have asthma and chronic polypoid rhinosinusitis but who tolerate aspirin has been unclear. In a small trial, 20 patients with AERD and 14 patients with asthma and CRS with nasal polyposis, but without aspirin intolerance, were randomized to receive aspirin therapy or placebo [4]. Aspirin therapy improved several asthma and rhinitis outcomes and led to lower maintenance doses of inhaled glucocorticoids in patients with aspirin intolerance, but was not beneficial in patients without aspirin intolerance. Although small, the findings of this trial support the clinical impression that aspirin's benefits are limited to patients with intolerance. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Efficacy of aspirin therapy in AERD'.)

Mepolizumab for severe asthma associated with peripheral blood eosinophilia (October 2014)

The anti-interleukin-5 monoclonal antibody mepolizumab has previously been shown to reduce exacerbations in patients with severe asthma and eosinophilic airway inflammation. Two additional trials validate using peripheral blood eosinophil counts to select patients with severe asthma who are likely to respond to mepolizumab, demonstrate comparable effects of intravenous and subcutaneous preparations, and show a glucocorticoid-sparing effect.

The larger multicenter trial (MEpolizumab as adjunctive therapy iN patients with Severe Asthma, MENSA) evaluated mepolizumab (given either intravenously or subcutaneously every four weeks) in patients with severe asthma and eosinophilic airway inflammation despite high-dose inhaled glucocorticoids [5]. At 32 weeks, exacerbations were reduced by approximately 50 percent for the groups using mepolizumab given by either route, compared with placebo.

In a group of patients with severe asthma requiring systemic glucocorticoids, the SteroId ReductIon with mepolizUmab Study (SIRIUS) compared subcutaneous mepolizumab, given every four weeks, with placebo [6]. At 20 weeks, mepolizumab allowed a median reduction in the systemic glucocorticoid dose of 50 percent, decreased the number of asthma exacerbations, and improved control of asthma symptoms.

Mepolizumab is not commercially available at present, although it is under review by regulatory agencies. (See "Alternative and experimental agents for the treatment of asthma", section on 'Anti-IL-5 antibodies'.)

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 [7]. 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 across the continental United States [8,9]. These have occurred predominantly in children with a prior history of asthma and have been generally characterized by low grade or absent fever with wheezing, dyspnea, hypoxia, and perihilar infiltrates. Infection has also been associated with rare cases of limb weakness with spinal cord lesions on imaging. 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'.)


Oat cereal for thickening infant bottle feeds (February 2015)

For healthy infants with problematic gastroesophageal reflux who are bottle-fed, thickening feeds with infant cereal slightly improves symptoms. Although rice cereal has traditionally been used for this purpose, oat cereal is now preferred because of concerns about possible contamination of rice cereal with arsenic [10-12]. The US Food and Drug Administration (FDA) is investigating to determine if there are clinically significant traces of arsenic in rice cereal. (See "Gastroesophageal reflux in infants", section on 'Thickening feeds'.)

2014 Food allergy practice parameter update (December 2014)

The American Academy of Allergy, Asthma & Immunology, the American College of Allergy, Asthma & Immunology, and the Joint Council of Allergy, Asthma & Immunology have updated their practice parameter for food allergy that covers multiple aspects of patient care [13]. Recommendations are largely consistent with those presented in UpToDate. One area highlighted was the utility of component-resolved diagnostic testing for peanut allergy. (See "Component testing for pollen-related, plant-derived food allergies", section on 'Peanut testing approach' and "Component testing for pollen-related, plant-derived food allergies", section on 'Overview'.)

Role of exercise in food-dependent exercise-induced anaphylaxis (November 2014)

Food-dependent exercise-induced anaphylaxis (FDEIAn) is a disorder in which patients have a food allergy that is believed to cause symptoms only when food ingestion is followed by physical exercise in the ensuing few hours. Although exercise has been viewed as an essential trigger, a new study has raised the question of whether various factors, other than exercise, could also trigger symptoms when combined with food. In this study, 16 patients with wheat-dependent FDEIAn were challenged with increasing amounts of the causative allergen, alone or combined with aspirin and/or alcohol (both associated with more severe reactions in this disorder) [14]. Fourteen of the 16 patients developed symptoms with various combinations of these factors, with only two requiring exercise. These findings suggest that FDEIAn may be more accurately viewed as a food allergy that requires one or more augmenting factors, of which one may be exercise, to cause a clinically-significant reaction. (See "Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, pathogenesis, and diagnosis", section on 'Wheat-dependent FDEIAn'.)

Infant feeding practices and risk of celiac disease (October 2014)

In the past, epidemiologic studies suggested that an infant's risk for developing celiac disease might be reduced by introducing gluten gradually between four and six months of age, ideally while breast feeding. This hypothesis was not confirmed by two new randomized trials, which found no association between the timing and manner of gluten introduction and celiac disease risk. One study included 944 infants in eight European countries who were at high risk for celiac disease because of their genetic profile. The infants were randomized to receive a small amount of gluten daily from 16 to 24 weeks of age, versus placebo [15]. There was no difference in celiac disease prevalence at three years of age, and the prevalence did not vary with exposure to breast feeding. A second study included 832 infants from Italy with high risk for celiac disease who were randomized to dietary introduction of gluten at six months of age versus 12 months of age [16]. Early introduction of gluten was associated with higher risk for celiac autoimmunity and overt celiac disease at two years of age, but there was no difference between the groups by five years of age, and no association with breast feeding was found. (See "Clinical manifestations and diagnosis of celiac disease in children", section on 'Infant feeding practices'.)


Hypogammaglobulinemia following rituximab therapy (November 2014)

Rituximab, a monoclonal antibody used in the treatment of hematologic malignancies and several autoimmune and rheumatologic disorders, depletes B cells and may cause hypogammaglobulinemia in some patients. Early clinical trials suggested that hypogammaglobulinemia following rituximab administration was transient and not associated with serious infections. However, subsequent reports have described persistent hypogammaglobulinemia associated with significant infections in a small subset of patients. A retrospective review of 19 patients with persistent, symptomatic hypogammaglobulinemia included patients who had received rituximab for periods ranging from one month to four years for hematologic malignancies or autoimmune or rheumatologic disorders [17]. Most patients experienced sinopulmonary infections, but three had enteroviral meningoencephalitis (with one fatality). All but one required immune globulin replacement to prevent infections. Clinicians should be aware of this complication, particularly in patients receiving multiple courses of rituximab, although risk factors for and incidence of hypogammaglobulinemia remain poorly defined. (See "Secondary immunodeficiency induced by drugs and biologic therapies", section on 'Hypogammaglobulinemia'.)

Hyaluronidase-facilitated subcutaneous immune globulin (November 2014)

Subcutaneous immune globulin is usually given in weekly doses, because the amount of solution that can be comfortably infused in the subcutaneous space is limited. To circumvent this, a solution of hyaluronidase can be administered immediately before the immune globulin, to increase dispersion. HyQvia is a 10 percent immune globulin preparation (Gammagard) packaged together with a fixed dose of recombinant human hyaluronidase in a separate vial. It was introduced in Europe in 2013, and was recently approved by the US Food and Drug Administration (FDA) for adults but not pregnant women or children under 18 years of age [18]. It can be given in doses similar to intravenous immune globulin (IVIG) every three to four weeks, and may be particularly useful for patients with difficult venous access. A seven-week "ramping up" protocol is recommended when initiating therapy with HyQvia (table 1). (See "Subcutaneous and intramuscular immune globulin therapy", section on 'Hyaluronidase-facilitated SCIG'.)

CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI) disease (October 2014)

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an inhibitory receptor expressed on regulatory T (Treg) cells. Based on studies of four unrelated families, haploinsufficiency of CTLA-4 has been shown to result in an autoimmune lymphoproliferative syndrome (ALPS)-like disorder with dysregulation of Treg cells and hyperactivation of effector T cells. Patients demonstrated lymphoproliferation, lymphocytic infiltration of nonlymphoid organs, autoimmune cytopenias, and B cell abnormalities with hypogammaglobulinemia [19]. A similar spectrum of clinical complications can result from CTLA-4-blocking agents (eg, ipilimumab, abatacept) that are used in patients with cancer and autoimmune disease. (See "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis", section on 'CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI) disease'.)

Modified retrovirus vector for X-linked SCID gene therapy (October 2014)

Gene therapy is an effective treatment for primary immunodeficiencies such as X-linked severe combined immunodeficiency (SCID). However, it is associated with leukemia due to retroviral vectors preferentially integrating into proto-oncogenes. A self-inactivating retrovirus vector, in which the long terminal repeats containing viral enhancer sequences have been deleted, is under study for the treatment of X-linked SCID [20]. Seven of nine infants have been successfully treated using this vector, with decreased clustering of insertion sites within lymphoid proto-oncogenes and no reported cases of leukemia during the median 29.1 months of follow-up. Longer-term follow-up is necessary to confirm lack of leukemogenesis with this modified vector. (See "Gene therapy for primary immunodeficiency", section on 'X-linked SCID'.)

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 [21]. The specific genes involved appear to affect the age of disease onset. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Genetics'.)


Sensitivity to nonsteroidal antiinflammatory drugs in children with chronic urticaria (February 2015)

In many patients with chronic spontaneous urticaria (CSU), nonsteroidal antiinflammatory drugs (NSAIDs) exacerbate symptoms. NSAID sensitivity has been demonstrated in 20 to 40 percent of adults with CSU and typically presents as an increase in urticaria lesions appearing one to four hours after ingestion. However, data in children have been limited. In a new study of 68 children with CSU and no history of previous reactions to NSAIDs, subjects underwent single-blind challenge with aspirin, and 10 to 24 percent developed increased symptoms, with the majority experiencing isolated lip angioedema [22]. Clinicians should inform patients with CSU (and their caretakers) about potential sensitivity to NSAIDs. (See "Chronic urticaria: Standard management and patient education", section on 'Avoidance of exacerbating factors'.)

Icatibant for ACE-inhibitor associated angioedema (February 2015)

Angiotensin-converting enzyme (ACE) inhibitors cause episodic, bradykinin-mediated angioedema in less than 1 percent of recipients, but this accounts for approximately one-third of angioedema cases presenting to emergency departments in countries where these medicines are widely used. The most common approach to management of severe episodes affecting the airway has been discontinuation of the ACE inhibitors and supportive care, which may involve intubation and even tracheotomy. Icatibant, a bradykinin receptor antagonist approved for use in hereditary angioedema, has now been shown to be effective for ACE inhibitor-associated angioedema [23]. In a randomized trial of 27 adults presenting to the emergency department with angioedema of the upper aerodigestive tract while taking an ACE inhibitor, patients received one dose of icatibant or standard therapy (an intravenous glucocorticoid plus an antihistamine). Symptoms in the icatibant group resolved in a median of 8 hours, compared with 27 hours in the glucocorticoid/antihistamine group, and icatibant was well tolerated. Icatibant is most likely to be effective if given in the first few hours of an angioedema attack when the swelling is still increasing. (See "ACE inhibitor-induced angioedema", section on 'Icatibant'.)


Pneumococcal conjugate vaccine in adults ≥65 years of age (September 2014)

The 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been recommended for many years in the United States for all adults ≥65 years of age. In September 2014, the United States Advisory Committee on Immunization Practices (ACIP) began also recommending the pneumococcal conjugate vaccine (PCV13) for all adults ≥65 years of age [24]. Current recommendations for individuals ≥65 years of age who have not previously received either PCV13 or PPSV23 are to administer PCV13 followed 6 to 12 months later by PPSV23 (algorithm 1). In patients who have already received PPSV23, at least one year should elapse before they are given PCV13.

The ACIP revision was prompted by results from the CAPiTA trial. This randomized placebo-controlled trial, including approximately 85,000 adults ≥65 years of age in the Netherlands, demonstrated the efficacy of PCV13 against vaccine-type pneumococcal pneumonia, vaccine-type nonbacteremic pneumococcal pneumonia, and vaccine-type invasive pneumococcal disease [25]. However, some concern has been raised that since this trial began before PCV13 was used routinely in infants in the Netherlands, it might not answer the question of whether its use in adults is efficacious in countries that routinely vaccinate infants. (See "Pneumococcal vaccination in adults", section on 'Indications'.)


Safety of calcineurin inhibitors for treatment of atopic dermatitis in children (February 2015)

Topical calcineurin inhibitors can be used as an alternative to topical corticosteroids for the treatment of mild to moderate atopic dermatitis. In 2005, based upon case reports, animal studies, and the known risks with systemic calcineurin inhibitors, the US Food and Drug Administration (FDA) issued boxed warnings about a possible link between the topical calcineurin inhibitors and cancer. An analysis of data from 7500 children enrolled between 2004 and 2014 in the Pediatric Eczema Elective Registry (PEER), an ongoing post-marketing cohort study, found a trend toward increased risk for lymphoma and leukemia that was not statistically significant compared with incidence in the general population based on the SEER database [26]. The small sample size and wide confidence intervals for these data may not exclude all risk. While awaiting data from a larger study, it seems prudent to use topical calcineurin inhibitors only as second-line therapy for the management of atopic dermatitis in areas at high risk for skin atrophy when treated with topical corticosteroids. (See "Treatment of atopic dermatitis (eczema)", section on 'Long-term safety concerns'.)

Caustic ingestions mimicking anaphylaxis in young children (February 2015)

Accidental ingestion of caustic liquids by young children may be mistaken for anaphylaxis because both may present with nausea, vomiting, difficulty swallowing, and swelling of the lips, tongue, or pharynx. In a report of two cases and review of the literature, clinical clues to the diagnosis of caustic ingestion include the lack of a history of food allergy or other allergic disease and failure to respond to treatment for anaphylaxis [27]. Caretakers may not have witnessed the ingestion, or may not report it for fear of reprisal. Careful visualization of the affected areas with endoscopy or microlaryngoscopy can distinguish caustic ingestion from anaphylaxis by identifying ulceration and mucosal damage to the upper airway and esophagus. Preparations should be in place to intubate, if necessary, when manipulating a compromised airway. (See "Differential diagnosis of anaphylaxis in children and adults", section on 'Caustic ingestion (young children)' and "Caustic esophageal injury in children".)

Adjunctive glucocorticoids for hospitalized patients with community-acquired pneumonia (January 2015)

There has been interest in using glucocorticoids as adjunctive therapy to antibiotics in hospitalized patients with community-acquired pneumonia (CAP) in an attempt to reduce the inflammatory response, which is likely to contribute to the morbidity of the disease. There are conflicting data on this approach, but the largest randomized trial suggests a modest benefit. In the trial, which included 785 hospitalized adults with CAP, prednisone 50 mg daily for seven days shortened the time to clinical stability by approximately one day compared with placebo, without an increase in complications [28]. Pending the results of a large trial evaluating mortality rates in severe CAP, we do not favor the routine use of adjunctive glucocorticoids in adults with CAP. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Glucocorticoids'.)

Circulating influenza A H3N2 viruses and influenza vaccine effectiveness in the United States (December 2014, MODIFIED January 2015)

In December 2014, the United States Centers for Disease Control and Prevention (CDC) released a health advisory stating that more than half of influenza A H3N2 viruses collected and analyzed in the United States in October and November 2014 were antigenically different (drifted) from the H3N2 antigen included in this season's influenza vaccines [29]. Most isolated influenza viruses to date have been H3N2 strains. During previous seasons in which influenza A H3N2 viruses have predominated, higher hospitalization and mortality rates have been reported among older people, very young children, and individuals with certain medical conditions. In seasons where predominant circulating influenza viruses have antigenically drifted, decreased vaccine effectiveness has been observed. Nevertheless, vaccination typically provides some cross-protection against drifted viruses and should still reduce hospitalization and death. As of early January 2015, overall vaccine effectiveness against laboratory-confirmed influenza associated with medically attended acute respiratory illness was only 23 percent [30]. Influenza vaccination is still highly recommended [29]. The CDC health advisory was issued to reemphasize the importance of the use of neuraminidase inhibitors (eg, oseltamivir, zanamivir) when indicated for the treatment and prevention of influenza infection as an adjunct to vaccination. (See "Seasonal influenza vaccination in adults", section on 'Drifted H3N2 viruses during the 2014 to 2015 influenza season' and "Seasonal influenza in children: Prevention with vaccines", section on 'Drifted H3N2 viruses during the 2014 to 2015 influenza season'.)

Emollient therapy from birth and incidence of atopic dermatitis (October 2014)

Epidermal barrier dysfunction is a key factor in the initiation and progression of atopic dermatitis. Two randomized trials, one performed in Japan and the other in the United States and United Kingdom, found that enhancement of the skin barrier with daily application of emollient reduced the incidence of atopic dermatitis at six to eight months of age in infants at increased risk (ie, those with a parent or sibling with atopic dermatitis) [31,32]. Although the long-term efficacy of this treatment needs to be evaluated in larger studies with extended follow-up, emollient therapy from birth is a simple, inexpensive, and safe intervention that may prevent the onset of atopic dermatitis in the first year of life. (See "Treatment of atopic dermatitis (eczema)", section on 'Prevention'.)

Hematopoietic stem cell transplant for advanced systemic mastocytosis (October 2014)

Some advanced forms of systemic mastocytosis (SM), specifically SM with an associated hematologic nonmast cell lineage disorder (SM-AHNMD), mast cell leukemia (MCL), and aggressive systemic mastocytosis (ASM), have carried poor prognoses. However, allogeneic hematopoietic cell transplant (allo-HCT) has been performed with increasing frequency for these disorders. The largest series to date evaluated outcomes of 57 patients who were treated with allo-HCT, using different types of donors and conditioning regimens [33]. Overall, 70 percent of patients responded, and nearly one-third demonstrated complete remission. Survival at three years was 74, 43, and 17 percent for SM-AHNMD, ASM, and MCL, respectively, which was significantly greater than historical controls, particularly for patients with SM-AHNMD. Myeloablative conditioning regimes were superior to reduced intensity regimens. Thus, these preliminary results are encouraging and further prospective trials are needed. HCT is not appropriate for indolent or cutaneous forms of SM. (See "Treatment and prognosis of systemic mastocytosis", section on 'Hematopoietic cell transplantation'.)

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