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
Early use of azithromycin to prevent lower respiratory tract illness in preschool children with recurrent wheezing (December 2015)
The potential utility of macrolide antibiotics in the treatment of recurrent
wheezing/asthma has been considered, given their antiinflammatory properties and antimicrobial effects against
Mycoplasma pneumonia and
Chlamydia pneumonia, although there is a paucity of data supporting their use in this setting. One multicenter trial examined whether the early use of azithromycin prevented lower respiratory tract illness (LRTI) in 607 preschool children with a history of severe recurrent wheezing [
1]. Treatment was initiated at the onset of respiratory illness in conjunction with
signs/symptoms that usually preceded the development of a severe LRTI specific to each child. Children were randomly assigned to oral azithromycin or placebo for five days in addition to albuterol. The risk of progressing to severe LRTI was significantly lower in the treatment group compared with the control, although there was no difference in urgent care utilization, emergency department visits, or hospitalizations. Although this study provides some evidence for the early use of azithromycin, given concerns regarding antibiotic resistance and adverse effects with widespread use, further study is warranted to define subpopulations who could most benefit from preventive therapy before recommendations can be made. (See
"Treatment of recurrent virus-induced wheezing in young children", section on 'Antibiotics'.)
New biologic therapy approved for severe eosinophilic asthma (November 2015)
Mepolizumab, a monoclonal antibody to interleukin (IL)-5, has been approved by the US Food and Drug Administration for add-on, maintenance treatment of severe asthma in patients who are age 12 or older, have frequent asthma exacerbations, and have an eosinophilic phenotype [
2]. One marker of an eosinophilic phenotype is an absolute eosinophil count in peripheral blood of
≥150/microL. Studies in patients with severe eosinophilic asthma have shown that mepolizumab reduces the rate of exacerbations [
3] and enables a reduction in the oral glucocorticoid dose. Mepolizumab is administered subcutaneously at four-week intervals. Based on a small increase in herpes zoster in treated adults, we suggest that patients who meet criteria for the varicella-zoster vaccine be immunized at least four weeks prior to initiation of mepolizumab. Mepolizumab will likely be commercially available in early 2016. (See
"Treatment of severe asthma in adolescents and adults", section on 'Anti-IL-5 therapy'.)
DRUG HYPERSENSITIVITY
Low allergic cross-reactivity between penicillins and carbapenems (May 2015)
Carbapenems (eg, imipenem, meropenem) share a common beta-lactam ring with penicillins and hence the potential for allergic cross-reactivity, and some drug information systems list penicillin allergy as a contraindication to the use of carbapenems (
figure 1). In the largest study to date, 212 patients with allergy to penicillins, confirmed by skin testing, were then tested with carbapenems [
4]. All subjects were negative to carbapenem skin testing and tolerated graded challenges to three different carbapenems. Based on this and other series, the rate of reactivity to carbapenems in patients with confirmed penicillin allergy is estimated at <1 percent. This supports our current recommendations on administration of carbapenems to patients reporting immediate-type penicillin allergy: Perform penicillin skin testing when available. If negative, patients may safely receive penicillins and carbapenems. If penicillin skin testing is positive or not available, carbapenems may be administered via a graded challenge. (See
"Penicillin-allergic patients: Use of cephalosporins, carbapenems, and monobactams", section on 'Carbapenems'.)
FOOD ALLERGY AND INTOLERANCE
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 [
5]. 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 [
6]. 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'.)
n-3 LCPUFA supplementation in pregnancy and allergies in offspring (November 2015)
It has been hypothesized that maternal intake of long chain polyunsaturated fatty acids (n-3 LCPUFA) during pregnancy may prevent development of allergies in offspring. However, a recent systematic review of randomized trials assessing the effect of n-3 LCPUFA supplementation during pregnancy
and/or breastfeeding on allergy outcomes in offspring found supplementation did not significantly reduce childhood allergic disease (food allergy, atopic dermatitis, allergic rhinitis, asthma) at 36 months of age compared with no
treatment/placebo [7]. (See
"Fish consumption during pregnancy", section on 'Other outcomes'.)
Transient transfer of food allergies in a blood product (September 2015)
A recent case report highlights the possibility of acquiring food allergies following transfusion of a blood product such as platelets [
8]. This may also occur after solid organ or hematopoietic cell transplantation. In the former case, the allergy is transient and is due to food-specific immunoglobulin E (IgE) in the blood product. In the latter case, the potential mechanism depends upon the type of transplant and can range from temporary allergy due to transferred mast cells or allergen-specific IgE, to longer-lasting or permanent allergy due to transfer of food allergen-specific lymphocytes or hematopoietic stem cells from the donor. Finally, an allergic reaction to a food can occur in an allergic recipient after receiving a blood product that contains intact allergen consumed by the donor. (See
"History and physical examination in the patient with possible food allergy", section on 'Questions related to contributory factors'.)
IMMUNODEFICIENCY
Updated guidelines for the diagnosis and management of primary immunodeficiency (November 2015)
A revised “Practice parameter for the diagnosis and management of primary immunodeficiency,” developed by the three national allergy and immunology societies in the United States, has been published to aid
allergy/immunology specialists and other practitioners in the recognition, diagnosis, and general management of these disorders [
9]. Highlights include screening and advanced laboratory tests for the different components of immune function, characteristic clinical manifestations and laboratory findings for a number of disorders, internet resources, antibiotic prophylaxis, and indications for hematopoietic cell transplantation or gene therapy. There are now more than 200 genetically distinct disorders of immune function that are classified using the system devised by the World Health Organization (WHO) and International Union of Immunological Societies (IUIS). Consultation with an immunology specialist with experience in diagnosing and managing primary immunodeficiencies is recommended. Our approach is consistent with that outlined in this practice parameter. (See
"Approach to the child with recurrent infections" and
"Laboratory evaluation of the immune system" and
"Medical management of immunodeficiency".)
Dedicator of cytokinesis 2 deficiency (June 2015)
Dedicator of cytokinesis 2 (DOCK2) deficiency is a newly recognized combined immunodeficiency (CID). Biallelic (homozygous or compound heterozygous) mutations in the
DOCK2 gene were identified through whole-exome sequencing in a group of unrelated patients with early-onset invasive bacterial and viral infections, lymphopenia, and defective T, B, and NK cell responses [
10]. DOCK2 deficiency results in impaired activation of RAC1 that leads to defects in actin polymerization, lymphocyte proliferation and migration, natural killer cell degranulation, and response to viral infections in fibroblasts and peripheral blood mononuclear cells. Other CIDs that are the result of defects in actin regulation include Wiskott-Aldrich syndrome and DOCK8 deficiency. (See
"Combined immunodeficiencies", section on 'Dedicator of cytokinesis 2 deficiency'.)
RHINITIS AND RHINOSINUSITIS
Systematic review of medical therapies for adults with chronic rhinosinusitis (September 2015)
A new systematic review of medical therapies for adults with chronic rhinosinusitis (CRS, both with and without nasal polyposis) concluded that topical glucocorticoids and high-volume nasal saline irrigations were the two therapies best supported by evidence [
11]. Evidence for the effectiveness of other therapies was conflicting, but the review supports the use of short courses (one to three weeks) of oral glucocorticoids, doxycycline, and leukotriene receptor antagonists for CRS with nasal polyposis, with which UpToDate largely agrees. The review also suggests a trial of long-term macrolide therapy for CRS without polyposis, although evidence for this is weak and UpToDate authors do not agree that benefits outweigh risks (drug resistance, costs, adverse effects) for most patients. More high-quality studies are needed for the optimal treatment of CRS. (See
"Chronic rhinosinusitis: Management", section on 'Oral glucocorticoids'.)
URTICARIA AND ANGIOEDEMA
Mechanism proposed for hereditary angioedema with normal C1 inhibitor and FXII mutations (August 2015)
Hereditary angioedema with normal C1 inhibitor is a rare disorder; normal complement studies distinguish this from other forms of hereditary angioedema. Defects in the gene for coagulation factor XII (FXII) are seen in some patients with hereditary angioedema with normal C1 inhibitor but a mechanism linking FXII defects and angioedema has been lacking. A new study proposes that one FXII mutation found in these patients affects a glycosylation site, resulting in increased autoactivation of FXII [
12]. Increased FXII autoactivation could lead to enhanced activation of the kallikrein-kinin pathway and excessive bradykinin formation. Thus, a potential mechanism has been identified for the pathogenesis of the hereditary angioedema in patients with normal complement studies and a FXII mutation. (See
"Hereditary angioedema with normal C1 inhibitor (type III HAE)", section on 'Mutations in the FXII gene'.)
VACCINES AND VACCINE HYPERSENSITIVITY
Adjuvanted influenza vaccine approved for elderly adults in the United States (November 2015)
There has been interest in using adjuvants in influenza vaccines in elderly individuals, who have reduced immune responses to influenza vaccines; adjuvants are substances that amplify the immune response to an antigen. In November 2015, an adjuvanted trivalent inactivated influenza vaccine (Fluad) was approved for use in individuals ≥65 years of age in the United States [
13]. It is the first adjuvanted seasonal influenza vaccine to be approved in the United States, but it has been approved already in >35 other countries. The vaccine is formulated with the adjuvant MF59, an oil-in-water emulsion of squalene oil. Studies have shown that the MF59-adjuvanted vaccine has comparable [
13] or higher immunogenicity compared with unadjuvanted vaccines [14-16]. Until further data are available, we continue to suggest the non-adjuvanted high-dose inactivated vaccine for individuals ≥65 years of age. (See
"Seasonal influenza vaccination in adults", section on 'Adjuvanted vaccine' and
"Seasonal influenza vaccination in adults", section on 'Vaccine formulations'.)
Statins and influenza vaccine immunogenicity and effectiveness (November 2015)
Statins are used commonly in older adults with hyperlipidemia and are known to have immunomodulatory effects, which could affect vaccine responses. In an observational study conducted in the context of a randomized trial that evaluated influenza vaccines in individuals >65 years of age, hemagglutination inhibition (HAI) geometric mean titers to various influenza strains were substantially lower in those receiving chronic statin therapy than in those not receiving it [
17]. In addition, in the adjusted analysis of a large retrospective cohort study, statin use was associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness [
18]. The observed associations between statin use and vaccine effectiveness could be due to confounding, as patients receiving statins are likely to be at differing baseline risk of influenza from those not receiving statins. Although these studies raise the possibility that older patients receiving statins are less likely to be protected by the influenza vaccine, such individuals should still receive statins, when indicated, as well as an influenza vaccine annually. (See
"Seasonal influenza vaccination in adults", section on 'Efficacy'.)
Revised schedule for pneumococcal vaccination in older adults (September 2015)
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 2014, the United States Advisory Committee on Immunization Practices (ACIP) began also recommending the 13-valent pneumococcal conjugate vaccine (PCV13) for adults ≥65 years of age [
19]. In September 2015, the ACIP changed the recommended interval between administration of PCV13 and PPSV23 for immunocompetent adults ≥65 years of age from 6-12 months to ≥1 year to simplify the administration schedule (
algorithm 1) [
20]. In patients who have already received PPSV23, at least 1 year should elapse before they are given PCV13. (See
"Pneumococcal vaccination in adults", section on 'Schedule for dual vaccination'.)
OTHER GENERAL ALLERGY AND IMMUNOLOGY
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 [
21]. 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'.)
Dupilumab for moderate to severe atopic dermatitis in adults (November 2015)
Dupilumab is an investigational monoclonal antibody directed against the IL-4 receptor alpha subunit, which blocks the downstream signaling of IL-4 and IL-13. These cytokines are believed to be drivers of the Th2-mediated inflammation in atopic dermatitis. In an industry-sponsored phase IIb randomized trial, over 300 adult patients with chronic moderate to severe atopic dermatitis were treated with dupilumab, at five different doses and schedules, or placebo [
22]. At 16 weeks, patients in all the dupilumab treatment groups had a greater improvement in the eczema area and severity score (EASI) compared with baseline than patients in the placebo group, and improvement was dose-dependent. The most common adverse events associated with dupilumab were upper respiratory tract infection and exacerbation of atopic dermatitis. These results suggest that dupilumab may be a promising treatment for long-standing atopic dermatitis in adults. However, due to both the high attrition rate in the dupilumab groups and the short duration of the trial, further studies are needed to evaluate the long-term efficacy and safety of dupilumab for the treatment of atopic dermatitis. (See
"Treatment of atopic dermatitis (eczema)", section on 'Experimental agents'.)
Auvi-Q and Allerject epinephrine autoinjectors recalled by manufacturer (October 2015)
A manufacturer's recall was issued in October 2015 of all Auvi-Q epinephrine autoinjectors in the United States, as well as all Allerject devices in Canada, including both the 0.15 and 0.3 mg strengths, due to potentially inaccurate dose delivery [
23,24]. Patients should be provided with a prescription for an alternate epinephrine device and return Auvi-Q and Allerject autoinjectors to their pharmacy for replacement and instruction on how to use the new device. Patients should only use Auvi-Q or Allerject if no other device is available in a severe allergic reaction and then immediately contact 9-1-1 or emergency medical services. (See
"Prescribing epinephrine for anaphylaxis self-treatment", section on 'Types of autoinjectors'.)
Prediction model for eosinophilic esophagitis (September 2015)
The distinction between eosinophilic esophagitis and gastroesophageal reflux disease is often difficult to make. A prediction model that incorporated eight clinical and endoscopic features (younger age; male sex; presence of dysphagia and food allergies; presence of esophageal rings, furrows, and plaques; and lack of a hiatal hernia) predicted eosinophilic esophagitis with an accuracy, sensitivity, and specificity of 84, 97, and 92 percent, respectively [
25]. However, additional studies are needed to validate this model. (See
"Clinical manifestations and diagnosis of eosinophilic esophagitis", section on 'Distinction from GERD'.)
Stevens-Johnson syndrome outbreak associated with M. pneumoniae (August 2015)
Stevens-Johnson
syndrome/toxic epidermal necrolysis
(SJS/TEN) is a rare, severe blistering mucocutaneous reaction, most commonly triggered by medications, characterized by extensive necrosis and detachment of the epidermis and mucosa.
Mycoplasma pneumoniae and cytomegalovirus infections are the next most common trigger of
SJS/TEN, particularly in children. Between September and November 2013, an outbreak of eight pediatric cases of
M. pneumoniae-associated
SJS/TEN was reported in Colorado, likely related to high levels of
M. pneumoniae infection in the region [
26]. All children had severe oropharyngeal mucositis; the conjunctiva was involved in seven children and the genital mucosa in five. (See
"Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Infection'.)
Influenza vaccine recommendations for 2015-2016 influenza season (August 2015)
In August 2015, the Advisory Committee on Immunization Practices released recommendations for the prevention and control of influenza during the 2015-2016 influenza season in the United States. As in previous seasons, seasonal influenza vaccination is recommended for everyone ≥6 months of age [
27]. Changes for the 2015-2016 season include:
●Different influenza A H3N2 and influenza B (Yamagata lineage) antigens than were in the 2014-2015 vaccines
●A simplified dosing algorithm for children six months through eight years (
algorithm 2)
●Availability of a quadrivalent intradermal vaccine for adults 18 through 64 years of age (
table 1)
Predictors of the need for repeat epinephrine doses in anaphylaxis (August 2015)
Epinephrine is the first-line therapy for anaphylaxis, and retrospective studies suggest that up to one-third of patients may require a second dose. However, predictive factors for requiring more than one dose are not well defined. In a prospective cohort study of over 500 patients (all ages) treated for anaphylaxis in a tertiary care emergency department, 14 percent of those requiring any epinephrine required more than one dose [
28]. Patients with a history of previous anaphylaxis, and those presenting with flushing, diaphoresis, or dyspnea, were more likely to require multiple doses of epinephrine to control symptoms. Anaphylaxis is an inherently unpredictable disorder, but this study provides some insight into predictors of a more complicated treatment course and may help clinicians managing such patients. (See
"Anaphylaxis: Rapid recognition and treatment", section on 'Dosing and administration'.)
Acute worsening of atopic dermatitis due to aeroallergen exposure (July 2015)
Environmental allergens are a trigger of atopic dermatitis (AD) in a small subset of children and adults. Patients who have environmental allergies as a trigger of AD have persistent disease with chronic exposure to an allergen in the environment. A small study of adults with AD demonstrated that exposure to grass pollen in an environmental challenge chamber for two consecutive days resulted in a significant worsening of AD on exposed skin for the five days after challenge compared with exposure to clean air (placebo) [
29]. This study shows that an isolated exposure to an aeroallergen can cause an acute flare of AD in sensitized individuals. (See
"Role of allergy in atopic dermatitis (eczema)", section on 'Aeroallergens'.)
