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.
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
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 . 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 . 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 . 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 . 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 [5,6]. 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'.)
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 . Similar results were seen in a separate pair of trials that included a total of 1266 subjects and lasted 48 weeks . 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'.)
FOOD ALLERGY AND INTOLERANCE
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 . 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) . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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'.)
RHINITIS AND RHINOSINUSITIS
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 . 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'.)
URTICARIA AND ANGIOEDEMA
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 . 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'.)
VACCINES AND VACCINE HYPERSENSITIVITY
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 . 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 . 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'.)
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 . 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 2). (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'.)
OTHER GENERAL ALLERGY AND IMMUNOLOGY
Circulating influenza A H3N2 viruses in the United States (December 2014)
In December 2014, the 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 . 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. Influenza vaccination is still strongly recommended because it usually provides some cross-protection against drifted viruses and because influenza vaccines protect against other strains. 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) [25,26]. 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 . 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'.)
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 . 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 . 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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