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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
Safety of inhaled glucocorticoid-LABA combination therapy in asthma (September 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 long-acting beta agonists (LABAs) in asthma. While concerning, the number of events was small, and it could not be determined if the potential risk of salmeterol could be mitigated by combining LABAs with inhaled glucocorticoids. Three large randomized trials including 30,000 children and adults found no increase in asthma-related adverse events or deaths among patients who used combination inhalers with salmeterol or formoterol plus an inhaled glucocorticoid versus glucocorticoid monotherapy [1-3]. These studies support the safety of these fixed-dose combination inhalers in patients with moderate-to-severe asthma. (See "Beta agonists in asthma: Controversy regarding chronic use", section on 'Potential risk mitigation'.)
Farm animals, asthma, and the innate immune response (September 2016)
Exposure to farm animals, particularly early in life, is negatively associated with the development of allergic disease. A recent study compared 60 children from Amish and Hutterite communities, two genetically similar, reproductively isolated farming populations in the United States . The Amish have traditional, single-family farms with exposure to horses and dairy cows, whereas the Hutterites live and work on large farms that are highly industrialized. Amish children have significantly lower rates of asthma and allergic sensitization than their Hutterite counterparts. Endotoxin levels were significantly higher in the Amish homes, and dust extracts from the Amish homes, but not the Hutterite homes, significantly blocked airway hyperresponsiveness and eosinophilia in a mouse model. In addition, in vitro studies showed an enhanced innate immune response in Amish, but not Hutterite, children. These findings suggest that the closer contact with farm animals in the Amish lifestyle may help prevent the development of asthma by altering the innate immune response. (See "Increasing prevalence of asthma and allergic rhinitis and the role of environmental factors", section on 'Farms, villages, worms, and other parasites'.)
Lack of association between acetaminophen and asthma in children (September 2016)
More frequent use of acetaminophen was associated with increased asthma-related complications in children in observational studies, leading to the recommendation by some for children with asthma to avoid acetaminophen. However, these findings were not replicated in a prospective, randomized trial comparing acetaminophen and ibuprofen use . In this trial, 300 children with mild persistent asthma were randomly assigned to as-needed treatment with acetaminophen or ibuprofen for fever or pain over a 48-week period. All children received standard controller therapy for asthma. There was no significant difference between the two groups in the number of asthma exacerbations requiring treatment with systemic glucocorticoids or in the number of asthma exacerbations. Thus, we do not advise restricting the use of acetaminophen in children with asthma. (See "Virus-induced wheezing and asthma: An overview", section on 'Acetaminophen use for febrile illnesses'.)
Evaluation of recurrent wheezing in children <2 years of age (August 2016)
The American Thoracic Society has developed guidelines for evaluation of children <2 years of age who have recurrent wheezing that is unresponsive to bronchodilators or inhaled or systemic glucocorticoids . Suggested evaluation includes one or more of the following: videofluoroscopic swallowing study (modified barium swallow) for possible swallowing dysfunction; 24-hour esophageal pH monitoring for assessment of gastroesophageal reflux; and/or flexible fiberoptic bronchoscopy bronchoalveolar lavage (BAL) to assess for lower airway bacterial infection. Our approach is consistent with these guidelines. (See "Approach to wheezing in infants and children", section on 'Radiography' and "Approach to wheezing in infants and children", section on 'Endoscopy' and "Approach to wheezing in infants and children", section on 'Evaluation for gastroesophageal reflux'.)
Omalizumab for allergic asthma in children 6 to 11 years of age (July 2016)
Omalizumab, a monoclonal antibody to immunoglobulin E (IgE), is an option for patients with moderate to severe persistent asthma and sensitization to perennial aeroallergens who are inadequately controlled on inhaled glucocorticoids. The US Food and Drug Administration (FDA) has now lowered the approved age range from 12 to 6 years of age, expanding the therapeutic options in step 5 asthma management in children . (See "Asthma in children younger than 12 years: Treatment of persistent asthma with controller medications", section on 'Step-up therapy' and "Asthma in children younger than 12 years: Treatment of persistent asthma with controller medications", section on 'Anti-IgE therapy' and "Anti-IgE therapy", section on 'Omalizumab therapy in asthma'.)
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 . 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'.)
Thrombotic microangiopathy from interferon (October 2016)
Drug-induced thrombotic microangiopathy (DITMA) has been described with a number of chemotherapeutic, immunosuppressive, and other drugs. Unlike thrombotic thrombocytopenic purpura (TTP), DITMA is not associated with severely reduced ADAMTS13 activity, and the principal treatment is drug discontinuation rather than plasma exchange. A new report has provided strong evidence for interferon as a cause of TMA . Patients receiving interferon who develop signs of a TMA should have the drug discontinued promptly before organ failure develops. (See "Drug-induced thrombotic microangiopathy", section on 'Immunosuppressive agents'.)
New guidelines for the management of Stevens-Johnson/toxic epidermal necrolysis syndrome (August 2016)
The British Association of Dermatologists released new guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), a severe and potentially fatal mucocutaneous drug reaction . The guidelines provide evidence-based recommendations for the diagnosis, severity assessment, and management of SJS/TEN. Specific areas covered include initial management, supportive care, and therapies intended to reduce mortality, such as intravenous immune globulins, systemic corticosteroids, and cyclosporine. The treatment of eye involvement, including systemic therapies and amniotic membrane transplantation to prevent permanent ocular sequelae, as well as the management of oral, urogenital, and airway mucosal involvement are also addressed. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'General principles'.)
Mild skin-limited allergic reactions to antibiotics in children (June 2016)
It is not uncommon for young children to develop mild skin-limited reactions (eg, rash, hives) to antibiotics, particularly amoxicillin, during treatment for routine infections. Most of these reactions do not represent serious drug allergy, but IgE-mediated anaphylaxis can first present in this manner, so caution is necessary. In a new study of over 800 young children referred to an allergy clinic with past mild cutaneous reactions to amoxicillin, all children underwent a two-step challenge . Ninety-four percent had no reaction, 2 percent had mild immediate reactions (isolated hives), and 4 percent had mild delayed reactions. Skin testing was later performed on the subset with immediate initial reactions, and only 1 of 17 children had a positive result, indicating that skin testing would not have been useful in identifying these children before challenge. At present, we do not advocate this approach unless there is no alternative antibiotic and allergy referral is not available. However, this study provides valuable information about the pathophysiology of this common type of reaction and may allow for safe rechallenge protocols to be developed in the future for use in the primary care setting. (See "Penicillin allergy: Delayed hypersensitivity reactions", section on 'Children'.)
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 . 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'.)
FOOD ALLERGY AND INTOLERANCE
Extensively heated egg in children with egg allergy (July 2016)
The majority of children with egg allergy can tolerate extensively heated egg, and introduction of cooked egg can both improve quality of life and hasten resolution of egg allergy. A recent study examined whether various cooking methods affected tolerance and whether skin testing with the different cooked forms of the food was predictive of the oral food challenge (OFC) results . Fifty-four children with a history of egg allergy and positive skin testing to raw egg were tested with baked egg in a wheat matrix (cake), egg frittata (fried then baked, no wheat), and boiled egg. They were then challenged to the same forms of egg and pass rates were 88, 74, and 56 percent for baked in wheat matrix, fried/baked, and boiled egg, respectively. The OFC pass rates and higher internal temperatures for the cake and frittata compared with the boiled egg suggest that degree of cooking of the food is more important than the presence of a wheat matrix. Negative skin testing (ie, mean wheal diameters were <3 mm) with a given form of heated egg had a 100 percent negative predictive value for reacting to ingestion of that same form of egg. Although these results suggest that patients could introduce extensively heated egg without first undergoing an oral food challenge (OFC) if skin testing to the cooked form was negative, supervised OFCs are still recommended until these results have been confirmed in more patients, because of the lack of standardization with this type of testing and the risk of anaphylaxis with a failed challenge. (See "Egg allergy: Management", section on 'Extensively heated egg'.)
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 . 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'.)
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 . 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
Safety of intranasal triamcinolone for allergic rhinitis in pregnancy (July 2016)
Intranasal glucocorticoid sprays are highly effective for treatment of allergic rhinitis, but concerns remain about their use in pregnancy. The overall safety of intranasal glucocorticoids in pregnancy was supported by an observational cohort study of over 140,000 pregnant women, of whom 2502 were exposed to these medications during the first trimester . Exposure was not associated with increased rates of miscarriage or overall rates of major congenital malformations compared with non-exposure. Triamcinolone was the only intranasal glucocorticoid of potential concern; first trimester use was associated with abnormalities of the respiratory system and choanal atresia. Although these findings are not conclusive, we prefer to use other intranasal glucocorticoids in the first trimester, such as intranasal mometasone, fluticasone, or budesonide, pending further data . (See "Recognition and management of allergic disease during pregnancy", section on 'Glucocorticoid nasal sprays'.)
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 . 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'.)
URTICARIA AND ANGIOEDEMA
Investigational oral agent for prophylaxis of hereditary angioedema (September 2016)
For patients with hereditary angioedema (HAE) due to C1 inhibitor deficiency, the only available oral agents for prophylaxis are androgens and tranexamic acid, which have significant adverse effects or limited efficacy, respectively. A new oral agent, avoralstat, which inhibits plasma kallikrein, was evaluated for prophylaxis in a placebo crossover trial of 24 patients with relatively severe HAE . Although angioedema episodes decreased during the avoralstat phase compared with the placebo phase (79 versus 123 over four weeks), results were not statistically significant, so it is not clear if this agent will be a viable option for prophylaxis. (See "Hereditary angioedema: General care and long-term prophylaxis", section on 'Investigational therapies'.)
Screening and prevention of hydroxychloroquine retinopathy (August 2016)
Antimalarial agents hydroxychloroquine (HCQ) and chloroquine are widely used for the treatment of systemic lupus erythematosus, rheumatoid arthritis, and other inflammatory and dermatologic conditions, and are generally thought to be safe. Retinal toxicity is a known risk, however, and measures to minimize this potential toxicity are necessary. Recently, the American Academy of Ophthalmology issued revised recommendations for screening and prevention of retinopathy . Key changes include the following:
●The maximum daily dose of HCQ should not exceed 5 mg/kg (previously 6.5 mg/kg), and the maximum daily dose of chloroquine should not exceed 2.3 mg/kg (previously 3 mg/kg).
●Real body weight should be used to calculate dose limits instead of ideal body weight.
In addition to exceeding the recommended daily dose, major risk factors for retinal toxicity include antimalarial use for greater than five years, renal disease, concomitant tamoxifen use, and the presence of macular disease. All patients should undergo a baseline eye examination before or within a year of beginning treatment with an antimalarial drug and, if normal, at least annually after five years of exposure for patients without major risk factors. For the treatment of rheumatic diseases, we typically use standard daily doses of HCQ (non-weight-based, eg, up to 400 mg) in individuals weighing 80 kg or more. In patients weighing less than 80 kg, we use a lower daily dose of HCQ up to the maximum of 5 mg/kg of real body weight. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Ocular health'.)
Acquired C1 inhibitor deficiency in lymphoma patients (August 2016)
Acquired C1 inhibitor deficiency is a rare disorder that causes episodes of angioedema that are unresponsive to epinephrine or antihistamines and can be fatal if the airway is compromised. In previous series of patients with acquired angioedema, 30 to 40 percent were found to have a malignancy of some type, most commonly a non-Hodgkin lymphoma (NHL). However, the overall prevalence of acquired C1 inhibitor deficiency in patients with lymphoma was unknown. In a new retrospective study of 131 patients with different types of lymphoma, patients were screened at the time of lymphoma diagnosis for deficiency and dysfunction of C1 inhibitor . Four patients (3 percent) were symptomatic with episodic swelling and all four had both functional tests and levels of C1 inhibitor that were below 50 percent of normal. Three of these four had splenic marginal cell lymphoma. Another 10 patients had abnormal C1 inhibitor function but had not developed angioedema. This study provides an initial estimate of the prevalence of acquired C1 inhibitor deficiency in lymphoma patients and suggests that those with splenic marginal cell lymphoma may be at particular risk. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis", section on 'Lymphoproliferative disorders and B cell malignancies'.)
OTHER GENERAL ALLERGY AND IMMUNOLOGY
Unclear role of montelukast in eosinophilic esophagitis (October 2016)
Initial experience suggested that montelukast may be helpful for symptom reduction in patients with eosinophilic esophagitis, but subsequent experience has been mixed. In a small randomized trial, patients with eosinophilic esophagitis were assigned to maintenance treatment with montelukast or placebo for 26 weeks following steroid-induced symptomatic remission . There were no significant differences in the proportion of patients that remained in remission between the two groups. Thus, the role of montelukast in eosinophilic esophagitis, if any, remains unclear. (See "Treatment of eosinophilic esophagitis", section on 'Montelukast'.)
Investigational topical therapy for atopic dermatitis (September 2016)
Crisaborole is a topical boron-based phosphodiesterase-4 inhibitor with limited systemic absorption, which is under investigation as a novel topical therapy for atopic dermatitis. In two identical, multicenter randomized trials, a total of 1522 patients ≥2 years old with mild to moderate atopic dermatitis were treated with crisaborole 2% ointment or vehicle twice daily for 28 days . More patients in the crisaborole groups than in the vehicle groups achieved the primary end point (an investigator’s global assessment score of 0 [clear] or 1 [almost clear] with a two-grade or more improvement from baseline). Improvement was noted in pruritus, skin inflammation, excoriation, and lichenification. Crisaborole-related adverse events occurred in 4.4 percent of patients and were mild and limited to burning or stinging at the site of application. Although crisaborole appears a promising nonsteroidal topical treatment for mild to moderate atopic dermatitis, studies of longer duration than four weeks are needed to evaluate its efficacy and safety. (See "Treatment of atopic dermatitis (eczema)", section on 'Crisaborole'.)
Midostaurin in systemic mastocytosis (June 2016)
Case reports have described dramatic responses in patients with systemic mastocytosis (SM) treated with the multikinase/KIT inhibitor midostaurin. Two prospective trials of midostaurin have now described responses in 60 to 70 percent of patients with advanced SM [24,25]. Treatment resulted in reversal of organ damage (cytopenias, liver dysfunction) and decreases in bone marrow mast cell burden and serum tryptase levels. Responses were observed regardless of KIT D816V status, prior therapy, or the presence of an associated hematologic neoplasm. Midostaurin is being evaluated by drug regulatory agencies, but is as yet unavailable. (See "Systemic mastocytosis: Treatment and prognosis", section on 'Midostaurin'.)
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) . 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 . 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 . (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults", section on 'Inpatients'.)
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