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What's new in allergy and immunology
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What's new in allergy and immunology
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2016. | This topic last updated: Jun 30, 2016.

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

House dust mite sublingual immunotherapy for allergic asthma (May 2016)

Injection allergen immunotherapy with house dust mite extract has demonstrated benefit in patients with asthma and house dust mite allergy, but is inconvenient and carries a small risk of serious allergic reactions. Sublingual immunotherapy tablets (SLIT-tablets) are a safer form of allergen immunotherapy with proven efficacy in allergic rhinoconjunctivitis, but studies in patients with allergic asthma are limited. In a randomized trial of over 800 house dust mite-sensitive adults with asthma not controlled by inhaled budesonide and short-acting beta-agonists, subjects were treated with house dust mite SLIT-tablets or placebo for 7 to 12 months, after which inhaled budesonide was gradually withdrawn and then stopped [1]. House dust mite SLIT significantly prolonged the time to first moderate or severe asthma exacerbation, reducing the absolute risk of an exacerbation during budesonide withdrawal from 32 to 25 percent with placebo and SLIT, respectively. However, clinically meaningful improvements in other measures of asthma symptoms were not clearly demonstrated. Thus, further study is needed to assess the effectiveness of SLIT-tablets in patients with allergic asthma. HDM SLIT-tablets are not yet available in the United States, but are available in Australia, Japan, and parts of Europe. (See "Sublingual immunotherapy for allergic rhinoconjunctivitis and asthma", section on 'Moderate-persistent asthma'.)

New guidelines regarding the endocrine effects of long-term inhaled glucocorticoids in children (April 2016)

The Pediatric Endocrine Society Drugs and Therapeutics Committee released guidelines regarding adrenal insufficiency in children on long-term inhaled corticosteroids (ICS) [2]. The guidelines recommend testing for adrenal insufficiency in children and adolescents who are taking long-term ICS (eg, >6 months) and have symptoms suggesting adrenal insufficiency (hypoglycemia, altered mental status, fatigue, weakness, anorexia, Cushingoid features, growth failure, or weight loss). The guidelines also suggest screening asymptomatic children and adolescents who are taking high-dose ICS. However, because of the rarity of clinically significant adrenal insufficiency, we prefer to follow an individualized determination of the need for screening, based on the presence of the following risk factors: >6 months' use of ICS at doses exceeding those considered "high," combined use of high-dose ICS and intranasal glucocorticoids or intermittent use of systemic glucocorticoids, and low body mass index (BMI) (eg, <15th percentile for age). The first step in screening for adrenal insufficiency is measurement of an 8 AM serum cortisol, followed by additional testing based on the result. (See "Major side effects of inhaled glucocorticoids", section on 'Children and adolescents'.)

A second monoclonal antibody against interleukin-5 approved for severe eosinophilic asthma (April 2016)

Reslizumab, a monoclonal antibody to interleukin (IL)-5, has been approved by the US Food and Drug Administration (FDA) for add-on maintenance therapy of severe asthma in patients who are age 18 or older and have an eosinophilic phenotype [3]. It is similar to mepolizumab, which was approved in late 2015. In clinical trials of reslizumab, an eosinophilic phenotype was defined as a peripheral blood absolute eosinophil count ≥400/microL. Studies in patients with severe eosinophilic asthma have shown that reslizumab reduces the rate of exacerbations by approximately 50 percent compared with placebo [4,5]. Reslizumab is administered intravenously at four-week intervals. The US FDA has added a boxed warning because anaphylaxis occurred in 0.3 percent of treated patients. (See "Treatment of severe asthma in adolescents and adults", section on 'Reslizumab'.)

Safety of fluticasone-salmeterol combination therapy in asthma (March 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 salmeterol in asthma. While concerning, the number of events was small, and the magnitude of the risk was unclear. In addition, it could not be determined if the potential risk of salmeterol could be mitigated by combining it with an inhaled glucocorticoid. The safety of salmeterol in combination with fluticasone has been assessed in a multicenter trial, in which almost 12,000 adolescents and adults with persistent asthma were randomly assigned to take inhaled fluticasone or the combination of inhaled fluticasone-salmeterol (in a single inhaler) for 26 weeks [6]. The rate of serious asthma-related adverse events was similar in the two groups, and no deaths occurred in either group. In addition, no difference was noted in the rate of asthma-related hospitalizations. Thus, for patients over age 12 who do not have a history of life-threatening asthma events, data are reassuring about the safety of fluticasone-salmeterol in a fixed-dose inhaler. (See "Beta agonists in asthma: Controversy regarding chronic use", section on 'Potential risk mitigation'.)

DRUG HYPERSENSITIVITY

Olanzapine linked to drug reaction with eosinophilia and systemic symptoms (DRESS) (May 2016)

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, potentially life-threatening, drug-induced hypersensitivity reaction that includes skin eruption, fever, hematologic abnormalities, lymphadenopathy, and internal organ involvement. Antiepileptic agents and allopurinol are the most frequently reported causes. In May 2016 the US Food and Drug Administration issued a warning that the antipsychotic drug olanzapine may cause DRESS, with 23 cases reported worldwide since 1996 [7]. A prolonged latency time (two to eight weeks) between drug exposure and development of symptoms is characteristic of DRESS. Prompt withdrawal of the offending drug and supportive measures are the mainstay of treatment. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)", section on 'Etiology and risk factors'.)

Low risk of anaphylaxis with intravenous iron (December 2015)

Many clinicians are reluctant to use intravenous (IV) iron due to concerns about anaphylaxis. We believe the risk is overestimated, largely due to experience with older products such as high molecular weight iron dextran (HMW ID), which is no longer used, and to the practice of aggressively treating non-allergic infusion reactions with diphenhydramine and other therapies that convert the reaction to a more serious event. A recent review addressed the frequency of anaphylaxis in nearly 700,000 older adults who received an IV iron product [8]. Overall risk of anaphylaxis was low (<0.07 percent), although some deaths were recorded. However, we believe this may overestimate serious reactions because the criteria for anaphylaxis were based on medical coding data that may not have distinguished adverse drug events from effects of premedications. The rates with iron dextran may also be an overestimate, since they included HMW ID. Further, findings from this population may not be directly applicable to younger patients. We continue to use IV iron in a variety of settings, and we do not premedicate with diphenhydramine (or in most cases, with any medications). (See "Treatment of iron deficiency anemia in adults", section on 'Risks/prevention'.)

FOOD ALLERGY AND INTOLERANCE

Failed food challenges and resolution of food allergy (May 2016)

Parents often express concern that a failed oral food challenge (OFC) will prolong their child's food allergy. An observational study examining this question demonstrated that neither food-specific immunoglobulin E (IgE) levels nor skin prick tests changed with either accidental or intentional exposures [9]. The absence of increased sensitization after OFCs that result in an allergic reaction suggests that these exposures will not alter the natural course or resolution of food allergy. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution", section on 'Role of avoidance'.)

Early introduction of highly allergenic foods in infancy (March 2016)

The Enquiring about Tolerance (EAT) trial examined whether early introduction of six highly allergenic foods (peanut, hen’s egg, cow's milk, sesame, whitefish, and wheat) beginning at three months of age, compared with exclusive breastfeeding until approximately 6 months of age, protected against the development of food allergy in over 1300 breastfed infants recruited from the general population [10]. Early food introduction did not reduce breastfeeding, although caregivers found the feeding regimen to be challenging, with only 43 percent of the participants in the early-introduction group adhering to the protocol. No difference was seen in the prevalence of food allergy at one and three years of age between the two groups in the intention-to-treat (ITT) analysis. However, in the per-protocol analysis, the prevalence of any food allergy, and peanut and egg allergy in particular, was lower in the early-introduction group compared with the standard-introduction group (2.4 versus 7.3 percent, respectively, for any food allergy). Thus, although the more rigorous ITT analysis did not show a benefit of introduction at three months and further research is needed, the results are consistent with our current recommendation to not withhold allergenic foods, and to introduce them as early as 4 to 6 months of age. (See "Introducing highly allergenic foods to infants and children", section on 'Introduction in the general population'.)

Peanut avoidance and loss of peanut tolerance in children (March 2016)

The Learning Early About Peanut allergy (LEAP) trial, in which introduction of peanut to high-risk infants at 4 to 11 months of age led to a decreased risk of peanut allergy by 5 years of age, was the first randomized trial to show benefit of early introduction of a major food allergen. In a follow-up study (LEAP-On), which included 550 of the 640 participants from the primary trial, both groups were asked to avoid peanut for 12 months until the age of 6 years [11]. Peanut allergy continued to be more common in the early peanut avoidance group than in the early peanut consumption group (18.6 versus 4.8 percent, respectively). Three children in the consumption group who were previously tolerant developed peanut allergy during the 12-month avoidance period. Loss of tolerance in children who cease consumption is consistent with data on peanut allergy recurrence in patients who had outgrown their peanut allergy but did not go on to eat it regularly after a successful oral food challenge. (See "Introducing highly allergenic foods to infants and children", section on 'Introduction in a high-risk population'.)

Hypoallergenic formulas to prevent allergic disease in high-risk infants (March 2016)

We currently suggest that high-risk infants who cannot be exclusively breastfed receive a partially hydrolyzed formula (pHF) or extensively hydrolyzed formula (eHF) in preference to a conventional cow’s milk (CM) or soy formula for the purpose of preventing allergic diseases, particularly eczema. However, a 2016 meta-analysis examining the use of conventional and hydrolyzed CM formulas in infants at high risk for developing allergic disease found limited efficacy with regard to prevention of atopic disease [12]. Of note, there were a number of limitations with the available data, including a wide variation in study design and criteria for diagnosis of atopic diseases, as well as publication and methodologic biases. The Australasia Society of Clinical immunology and Allergy (ASCIA) no longer recommends a pHF or eHF over a conventional CM formula. Although we have not yet modified our suggested approach, guidelines in Europe and the United States are in the process of revision and recommendations may be changing in the near future. (See "Introducing formula to infants at risk for allergic disease", section on 'Formula selection for the high-risk infant'.)

Omalizumab and oral immunotherapy for food allergy (January 2016)

Investigational protocols of oral immunotherapy (OIT) for food allergy have been complicated by high rates of allergic reactions during treatment. There has been interest in co-treating patients with anti-IgE (omalizumab) to prevent these reactions, although omalizumab is expensive. Results from a randomized, multicenter trial suggest that treatment with anti-IgE before and during the build-up phase of OIT may be a more cost-effective approach than continuing anti-IgE for the duration of OIT therapy. In this trial, 57 children and adults were assigned to omalizumab or placebo for four months before and throughout the build-up and maintenance phases of open-label milk OIT [13]. The median percentages of doses per subject to cause symptoms in the omalizumab and placebo groups were 2.1 and 16.1 during build-up, and 0 and 3.4 during maintenance, respectively. There were no significant differences in the percent of patients desensitized (>70 percent) or with sustained unresponsiveness to milk (>36 percent). Thus, omalizumab treatment improved the safety, but did not impact the efficacy of OIT. Because most reactions occurred during the build-up phase, omalizumab could be limited to that phase of treatment to reduce cost. (See "Future therapies for food allergy", section on 'Oral immunotherapy combined with anti-IgE'.)

Genetic modification of foods to reduce allergen content (December 2015)

There has been interest in genetically modifying foods to lower the content of specific allergenic proteins, and an apple line has been modified by RNA interference to reduce the content of Mal d 1, an allergen important in pollen-food allergy syndrome (PFAS, also called oral allergy syndrome). In a proof-of-concept study of 21 adults with PFAS, single-blind oral challenges of two lines containing the lowest amount of this allergen produced no symptoms in 43 and 63 percent of subjects, respectively, and only mild symptoms in nearly all the others [14]. The apple lines produced for this study are not commercially available. (See "Management and prognosis of oral allergy syndrome (pollen-food allergy syndrome)", section on 'Genetically-modified foods'.)

IMMUNODEFICIENCY

Virus-specific T cell infusions for patients with primary immunodeficiencies and hematopoietic cell transplant (June 2016)

Viral infections, particularly with cytomegalovirus, Epstein-Barr virus, and adenovirus, are a leading cause of death in patients with severe combined immunodeficiency (SCID) and other forms of moderate-to-severe primary immunodeficiency (PID), both before and after hematopoietic cell transplantation (HCT). Investigational infusions of virus-specific T cells (VST) from either stem cell donors or third-party donors have been evaluated to treat and/or prevent these life-threatening viral infections. One retrospective series examined 26 patients with a PID requiring HCT who had at least one documented serious viral infection and were treated with VST either before or after HCT [15]. Complete or partial antiviral response was seen in 76 to 100 percent of patients, depending upon the particular virus. An additional 10 patients were treated preventively with VST prior to HCT. Of these, eight remained free of the most common serious viral infections. This therapy is still experimental, but commercial entities are developing these cellular products and they may be available for more widespread use in a few years. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Treatment'.)

RHINITIS AND RHINOSINUSITIS

Restriction of fluoroquinolone use in uncomplicated infections (May 2016)

The US Food and Drug Administration (FDA) has stated that the serious adverse effects associated with fluoroquinolones generally outweigh the benefits for patients with uncomplicated acute sinusitis, acute bronchitis, and urinary tract infections who have other treatment options [16]. For patients with these infections, fluoroquinolones should be reserved for those who have no alternative treatment options. This announcement was based on an FDA safety review showing that systemic fluoroquinolone use is associated with disabling and potentially permanent serious side effects, including those involving the tendons, muscles, joints, nerves, and central nervous system. (See "Fluoroquinolones", section on 'Restriction of use for uncomplicated infections'.)

Anti-IL-4 receptor antibodies for chronic rhinosinusitis with nasal polyposis (February 2016)

Chronic rhinosinusitis with nasal polyposis (CRS with NP) is a disorder that significantly impacts quality of life and often requires sinus surgeries to control. Dupilumab, an investigational monoclonal antibody to the alpha subunit of the interleukin-4 (IL-4) receptor, blocks the signaling of cytokines important in allergic inflammation. In a randomized trial, 51 patients with CRS with NP refractory to glucocorticoid nasal spray were randomized to dupilumab or placebo, while the glucocorticoid spray was continued [17]. By week 16, patients receiving dupilumab, compared with those receiving placebo, showed significant improvement in symptoms and endoscopic nasal polyp scores. Further studies are needed to compare the safety and efficacy of this therapy directly with other treatments, particularly endoscopic sinus surgery. (See "Chronic rhinosinusitis: Management", section on 'Dupilumab'.)

URTICARIA AND ANGIOEDEMA

Cholinergic urticaria with anaphylaxis (April 2016)

Cholinergic urticaria is a form of inducible physical urticaria, in which patients develop skin erythema with small 1 to 2 mm hives, characteristically triggered by sudden increases in body temperature. Typical triggers include high heat and humidity, exertion, emotional stress, and hot showers. In most patients, symptoms are limited to the skin, but a few isolated cases have been reported of systemic reactions. In the largest series to date, 19 patients with cholinergic urticaria and anaphylaxis were described [18]. Most were young women whose anaphylaxis episodes were triggered by typical cholinergic triggers, but diagnosis was often delayed by several years because clinicians were seeking other allergic causes to account for the anaphylactic presentation. Clinicians should be aware that cholinergic urticaria can involve systemic symptoms. (See "Physical urticarias", section on 'Cholinergic urticaria'.)

Hereditary vibratory urticaria (February 2016)

Vibratory urticaria is a rare form of physical urticaria in which patients develop urticaria/angioedema in areas of skin that are exposed to vibratory forces, such as the palms after holding the handle of a lawn mower or steering wheel. The disorder can be hereditary or sporadic. In two families with autosomal dominant vibratory urticaria, a gain-of-function mutation in the gene ADGRE2 has been implicated [19]. ADGRE2 encodes a cell surface receptor that is normally inhibitory on mast cells, but the mutated form renders the cell susceptible to degranulation following exposure to vibration. This receptor may be a component of an innate immune response to noxious physical stimuli. (See "Physical urticarias", section on 'Pathogenesis'.)

OTHER GENERAL ALLERGY AND IMMUNOLOGY

Water hardness and risk of atopic dermatitis (June 2016)

Epidemiologic evidence has linked high levels of calcium carbonate in domestic water (ie, “hard” water) with increased prevalence of atopic dermatitis in children. A population-based cross-sectional study including 1303 three-month-old infants found that high levels of calcium carbonate, but not of chlorine, in household water were associated with a nearly doubled risk of visible atopic dermatitis compared with low calcium carbonate levels, after adjusting for potential confounders (presence of filaggrin mutation, sex, ethnicity, and maternal age) [20]. However, the results of this study should be interpreted with caution, because residual confounding from unmeasured factors, such as changes in skin care practices associated with presence of eczema or dry skin, cannot be excluded. Further studies are needed to evaluate this association. (See "Pathogenesis, clinical manifestations, and diagnosis of atopic dermatitis (eczema)", section on 'Risk factors'.)

Etiology of community-acquired pneumonia (April 2016)

Multiple studies of patients with community-acquired pneumonia (CAP) have identified an etiologic agent in fewer than half of cases. In a study of hospitalized adults with CAP in the United Kingdom that used both bacterial cultures and comprehensive multiplex molecular testing for bacteria and viruses of lower respiratory tract specimens, a pathogen was identified in 87 percent of cases by molecular methods [21]. Culture-based methods detected a pathogen in only 39 percent of cases. Haemophilus influenzae and Streptococcus pneumoniae were the most common agents detected, followed by a wide variety of pathogens. Viruses were present in 30 percent of cases; 82 percent of these were detected in specimens that also tested positive for bacteria. A caveat is that contamination of specimens with upper respiratory tract secretions could cause false positive results [22]. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults", section on 'Inpatients'.)

Treatment of unexplained chronic cough with pregabalin (March 2016)

Like gabapentin, pregabalin is thought to act centrally to inhibit neurotransmitter release. Evidence for its use in chronic cough comes from a randomized trial in which 40 adults with chronic refractory cough were assigned to take pregabalin daily or placebo combined with speech pathology treatment for 14 weeks [23]. Baseline cough frequency was 24 coughs/hour in both groups; spirometry was normal. Both groups experienced a reduction in cough severity and cough frequency, and improvements in cough-related quality of life (QOL). The pregabalin group experienced greater improvement in cough severity and QOL. Adverse effects in the pregabalin group included dizziness in 45 percent and cognitive changes in 30 percent, although these did not lead to discontinuation of the study drug. Four weeks after withdrawal of study medication, there was no deterioration in symptom control. To minimize sedation and dizziness, pregabalin is initiated at a low dose and gradually increased as tolerated over a week. Of note, the American College of Chest Physicians (ACCP) guidelines do not include pregabalin because this study was published after the guidelines were prepared. (See "Treatment of subacute and chronic cough in adults", section on 'Gabapentin and pregabalin'.)

Oral fluoroquinolone use and serious arrhythmia (March 2016)

QT interval prolongation and torsades de pointes have been associated with fluoroquinolone use, but the degree to which fluoroquinolones block cardiac potassium channels and thereby cause QT prolongation varies by agent. The risk of serious arrhythmia during fluoroquinolone therapy was evaluated in a cohort of adults aged 40 to 79 years of age in Denmark and Sweden; arrhythmic events were compared for 909,656 courses of fluoroquinolones (ciprofloxacin in 83 percent, norfloxacin in 12 percent, ofloxacin in 3 percent, moxifloxacin in 1 percent, other in 1 percent) and 909,656 courses of penicillin, an antibiotic not associated with arrhythmia [24]. There was no increase in the risk of serious arrhythmia with fluoroquinolones compared with penicillin. This finding conflicts with results from earlier studies, and may be explained in part by the predominant use of ciprofloxacin in this cohort, with its smaller impact on QT prolongation. (See "Fluoroquinolones", section on 'QT interval prolongation and arrhythmia'.)

Abbreviated skin testing protocol for Hymenoptera venom allergy (February 2016)

A small number of publications have described abbreviated protocols for Hymenoptera venom skin testing. The most recent was a retrospective review of 300 patients evaluated for venom allergy in a single practice [25]. Patients with all severities of sting reactions (24 percent had severe anaphylaxis) were included, and all were tested with an identical protocol consisting of a single intradermal dose of a 1 microgram/mL concentration of five separate commercial bee and vespid venom extracts. All patients had at least one positive skin test. There were no generalized immediate reactions to testing, and just one delayed reaction (hours later) consisting of diffuse urticaria. This testing approach appears to be safe, although the total number of patients now reported as having been tested with this and other abbreviated protocols is under 1000, and these findings have not yet been incorporated into practice parameters. For clinicians who wish to begin using an abbreviated venom testing protocol, it may be prudent start with patients who experienced milder sting reactions, while awaiting more definitive data. (See "Diagnosis of Hymenoptera venom allergy", section on 'Technique and interpretation'.)

Association between atopic eczema and anemia (January 2016)

An analysis of caregiver-reported and self-reported data on over 200,000 children and adolescents from the United States National Health Interview Survey 1997-2013 found an increased risk of anemia in children with a history of atopic disorders, including eczema, asthma, hay fever, or food allergy [26]. The risk was much higher in children with all four disorders. Using laboratory data from the National Health and Nutrition Examination Survey 2014-2015 on over 30,000 children, the authors found that children with a current history of atopic eczema or asthma had an approximately twofold increased risk of anemia, particularly microcytic anemia. Whether anemia in atopic children is related to chronic inflammation or malnutrition secondary to dietary restrictions for suspected food allergies is unknown. Further studies are needed to confirm this association and clarify the underlying mechanisms. (See "Pathogenesis, clinical manifestations, and diagnosis of atopic dermatitis (eczema)", section on 'Anemia'.)

Classification of cutaneous manifestations of mastocytosis (December 2015)

Mastocytosis is characterized by the expansion of a clonal mast cell population and can be limited to the skin or systemic. Skin lesions may be present in the systemic form of the disease. An international consensus report proposed revised definitions and diagnostic criteria for different skin lesions [27]. The most common skin finding, urticaria pigmentosa, is now called maculopapular cutaneous mastocytosis (MPCM). MPCM is divided into two types: a monomorphic type typically seen in adults, consisting of multiple uniform, small, brownish-red lesions; and a polymorphic type usually seen in infants and children, consisting of larger, more heterogeneous lesions. Childhood polymorphic MPCM usually improves or regresses by puberty, but children who present with monomorphic MCPM appear to have a higher risk of the disease persisting into adulthood and involving extracutaneous organs. (See "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in adults" and "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in children", section on 'Skin examination'.)

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REFERENCES

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