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BACKGROUND: Gefapixant is a P2X3 receptor antagonist that has shown promise for the treatment of refractory and unexplained chronic cough. The aim of this study was to evaluate the efficacy of gefapixant compared with placebo after 12 weeks of treatment for refractory chronic cough or unexplained chronic cough.METHODS: We did a 12-week, phase 2b, randomised, double-blind, placebo-controlled study in patients with refractory chronic cough or unexplained chronic cough aged 18-80 years who were recruited from 44 primarily outpatient pulmonologist or allergist sites in the UK and the USA. Eligible patients had refractory or unexplained chronic cough lasting 1 year or longer, no radiographic chest abnormality, and 40 mm or more on a 100-mm cough severity visual analogue scale at enrolment. Patients were randomly assigned to receive placebo or one of three doses (7·5 mg, 20 mg, or 50 mg) of oral gefapixant twice daily, every day, for 84 days; visits to investigative sites were on days 1, 28, 42, 56, 70, 84, and 85. The randomisation schedule was computer generated using a permuted block algorithm by Advance Research Associates (Santa Clara, CA, USA). Patients and all personnel involved in the conduct and interpretation of the study were masked to treatment assignment. The primary endpoint was placebo-adjusted change from baseline in awake cough frequency after 12 weeks, assessed in the full analysis set, which is a subset of the intention-to-treat population. Adverse events were monitored and safety was evaluated in all patients receiving one or more doses of study drug. This trial is registered with ClinicalTrials.gov, NCT02612610.FINDINGS: Between Dec 21, 2015, and July 26, 2016, 253 patients were randomly assigned to placebo (n=63), gefapixant 7·5 mg (n=64), gefapixant 20 mg (n=63), or gefapixant 50 mg (n=63) twice daily. The mean age of patients was 60·2 (SD 9·9) years and 193 (76%) were women. At 12 weeks, patients' geometric mean awake cough frequency was 18·2 coughs per h (geometric SD 3·1) with placebo, and 14·5 coughs per h (3·7) with 7·5 mg, 12·0 coughs per h (4·2) with 20 mg, and 11·3 coughs per h (2·8) with 50 mg gefapixant. Estimated percentage change relative to placebo was -22·0% (-41·8 to 4·6; p=0·097) with 7·5 mg, -22·2% (-42·0 to 4·3; p=0·093) with 20 mg, and -37·0% (95% CI -53·3 to -14·9; p=0·0027) with 50 mg gefapixant. Dysgeusia was the most common adverse event, occurring in three (5%) patients given placebo, six (10%) given 7·5 mg gefapixant, 21 (33%) given 20 mg gefapixant, and 30 (48%) given 50 mg gefapixant.INTERPRETATION: Targeting purinergic receptor P2X3 with gefapixant at a dose of 50 mg twice daily significantly reduced cough frequency in patients with refractory chronic cough or unexplained chronic cough after 12 weeks of treatment compared with placebo. Further development of gefapixant is warranted for the treatment of chronic cough.FUNDING: Afferent Pharmaceuticals (acquired by Merck & Co., Inc., Kenilworth, NJ, USA).

Introduction: There is a growing need to develop effective rehabilitation interventions for people presenting with stroke as healthcare services experience ever-increasing pressures on staff and re...

Background: The current treatment for patients with aspirin-exacerbated respiratory disease (AERD) who have uncontrolled asthma or chronic rhinosinusitis is aspirin desensitization. For patients who are unable to undergo or do not benefit from aspirin desensitization, treatment with biologics is an option, although efficacy data for AERD is scarce. Objective: We reported a series of patients with AERD who were started on omalizumab and measured the outcomes to assess improvement. Methods: Adult patients with AERD who were initiated on omalizumab from January 2007 to January 2018 were included. We compared outcomes 6-12 months before initiating biologic therapy and during the last 6-12 months while they were on biologic therapy. Our study investigated the number of oral steroid courses, short-acting beta-agonists (SABA), antibiotics for sinusitis or pneumonia, emergency department visits, hospitalizations, pulmonary function tests, and changes in controller medications. Results: Twenty-nine patients were placed on omalizumab. Sixty-two percent demonstrated a reduction in the number of steroid courses (p = 0.0014) and number of SABA canisters used (p = 0.0005) during their last 12 months while on omalizumab. Eighty-six percent of the patients with AERD and on omalizumab demonstrated either a decrease in the number of steroid courses or number of SABA canisters used in the last year of the study. The patients with AERD and with concomitant immunoglobulin E (IgE) mediated respiratory disease showed a statistically significant reduction in the number of steroid courses and number of SABA canisters used while on omalizumab for 1 year (p = 0.002 and p = 0.005, respectively), whereas those without concomitant IgE-mediated respiratory disease did not have a substantial reduction in steroids or SABA canisters used. Conclusion: Our case series reported that omalizumab could effectively be used as an adjunct treatment for AERD, but additional larger and longitudinal studies are needed to corroborate these findings.

Context The morbidity potentially associated with unverified penicillin allergy in pregnant women, with and without group B streptococcus (GBS) infections, is unknown. Penicillin allergy testing is safe during pregnancy but is done infrequently. Objective To determine morbidity associated with antibiotic use in a large cohort of pregnant women, with and without an unverified history of penicillin allergy, and with and without GBS. Design Retrospective. All pregnant women who delivered live infants in Kaiser Permanente Southern California between January 1, 2009, and December 31, 2014, were identified. Main outcome measures Penicillin allergy status at delivery, delivery method, maternal and infant hospital utilization, peripartum antibiotic exposures, new antibiotic-associated adverse drug reactions, and new Clostridium difficile infections. Results There were 170,379 unique women who had 201,316 pregnancies during the study period. There were 16,084 pregnancies in women with an active, but unverified, penicillin allergy at delivery. There were 42,524 pregnancies in GBS-positive women, and 3500 also had a penicillin allergy. Women with a penicillin allergy, with or without GBS, had significantly (about 10%) higher cesarean section rates and spent significantly more (about 0.1) days in the hospital after delivery. Among GBS-positive women, those with an unverified penicillin allergy were exposed to significantly more cefazolin, clindamycin, vancomycin, and gentamicin and had significantly higher rates of adverse drug reactions associated with all antibiotic use. Conclusions Unverified penicillin allergy is associated with more hospital utilization and additional morbidity. Penicillin allergy testing of pregnant women with a history of penicillin allergy may help reduce these unwanted outcomes.

The Ronda peridotite massif of southern Spain exposes subcontinental lithospheric mantle that records pressure–temperature data and microstructures formed during exhumation beneath the rapidly extending Alboran domain. The peridotite is zoned from garnet- and spinel-bearing mylonites at the structural top, to spinel-bearing tectonites, to melt-percolated spinel-bearing granular peridotites, to plagioclase-bearing tectonites at the structural base. We find microstructural evidence of melt present in the spinel zones prior to the deformation event which exhumed the peridotites, and we therefore reinterpret the spinel tectonites as being a result of deformational overprinting of part of the granular domain. We also reinterpret garnet intergrown with spinel in the mylonite zone as part of the pre-mylonitic porphyroclast assemblage, rather than as a syn-mylonite assemblage. This places mylonite formation within the spinel field, rather than right on the garnet-spinel transition (18 kb). Two-dimensional thermal modeling indicates that these conditions require removal of lithospheric mantle below 100 km followed by exhumation along a low angle shear zone. Excision of material during exhumation is required to explain the steep thermal gradients observed. These results shed light on the mechanisms of back-arc extension, as well as the emplacement of orogenic lherzolites.

Background Accurate estimates of the incidence of anaphylaxis are limited. Current International Classification of Diseases, Ninth Revision ( ICD-9 ) codes complicate accurate diagnosis of anaphylaxis and assessment of appropriate epinephrine prescribing. Objective To quantify the incidence and demographic character of patients with anaphylaxis-related ICD-9 codes in a large health maintenance organization and analyze epinephrine prescribing and dispensing rates. Methods All patients included had at least 12 months of continuous membership over a 4-year period from January 1, 2008 to December 31, 2012 and were selected based on anaphylaxis-related ICD-9 codes (N = 159,172). This algorithm was extrapolated from a previous study that used expanded ICD-9 codes to identify more cases of anaphylaxis. Individual chart reviews found that many expanded ICD-9 codes represented unconfirmed cases of anaphylaxis and therefore were excluded, resulting in analysis of 52,405 patients. Results Incidence of anaphylaxis over 4 years was 2.07%, with female predominance (56.5%) over male predominance (43.5%). Epinephrine was prescribed in 16.2% of total cases. Highest rates of epinephrine prescription were for traditional ICD-9 codes 995.0 (other anaphylactic shock) and 995.60 to 995.69 (anaphylactic shock caused by food) at 49.3% and 58.6%, respectively. Of the cases in which an epinephrine auto-injector was prescribed, it was dispensed 95.9% of the time, independent of copayment amount. Conclusion Low epinephrine auto-injector prescribing rates in cases of anaphylaxis suggest the continued difficulty in the diagnosis of anaphylaxis and could result in suboptimal treatment of potential future episodes.

Objective We sought to determine the effect of treatment with topical tacrolimus on B- and T-cell immunity including the primary antibody response to pneumococcal polysaccharide vaccine in children with atopic dermatitis. Methods In this open-label, noncomparative study, 23 children aged 2 to 12 years with moderate to severe atopic dermatitis were treated with tacrolimus 0.03% ointment twice daily for 7 weeks, immunized with a 23-valent pneumococcal polysaccharide vaccine after 3 weeks of treatment, and had their antibody response measured (for 12 pneumococcal serotype antigens present in the vaccine) before and 4 weeks after vaccination. None had received pneumococcal vaccine before the study. Patient antibody and cellular immune responses were assessed at each study visit (baseline, week 3, and week 7). Results No significant changes in complete blood cell count, lymphocyte subsets, CD4/CD8 ratio, immunoglobulin levels, antibody titers to tetanus and Haemophilus influenzae , or lymphoproliferative responses were noted during the tacrolimus ointment treatment period. Tacrolimus blood levels were 1 ng/mL or less in all 23 children. Protective pneumococcal titers to all 12 serotypes were observed in 2 of 23 (9%) children prevaccination and in 16 of 23 (70%) children postvaccination. All 6 children who had protective titers to 0 to 5 of the 12 serotypes developed protective titers to an additional 5 to 11 serotypes. Of the patients, 91% had a greater than 4-fold increase in titer for at least 4 of 12 pneumococcal serotypes. Conclusion Topical application of tacrolimus ointment does not affect the serologic response to pneumococcal vaccine or interfere with preexisting T- and B-cell immune responses.

Objective : To describe the variability of the asthma phenotype in patients with mild persistent asthma enrolled in the Mild Asthma Montelukast versus Inhaled Corticosteroid (MIAMI) study. Methods : The variability of asthma rescue-free days, asthma symptoms, albuterol use, medical resource use, and exercise limitations among patients with documented mild persistent asthma was compared between the month before study enrollment and the last 2 weeks of the run-in period. Results : Patients eligible for randomization ( n =400), aged 15–85 years, exhibited symptoms (mean±sd) 3.6±1.3days/week, β -agonist use 3.5±1.3 days/week, and normal FEV 1 (94.0±9.9% predicted) during the last 2 weeks of the run-in period. In the year before enrollment, medical intervention for asthma flares was common: 38.5% made office visits, 15.8% had oral corticosteroids, and 8.3% required emergency room or hospitalized care. In the month before enrollment, 11.8% experienced daily symptoms, and 28.3% had limitations of normal activity. Patients with daily symptoms in the month before study enrollment, compared with those having less-than-daily symptoms, experienced fewer rescue-free days ( P =0.024) and had more days per week with symptoms ( P =0.008) and requiring albuterol ( P =0.048) during the run-in; FEV 1 was similar for both groups (93.1% vs. 94.2% predicted, respectively). Conclusion : Patients with mild persistent asthma reported a substantial disease burden in the year before enrollment. The asthma burden experienced by these patients both before and during the run-in period was of sufficient severity to support the recommendation that mild persistent asthma should be managed with daily controller therapy.

Background The skin prick test is the diagnostic procedure of choice for determination of immediate hypersensitivity. A wheal diameter of 3 mm or larger is generally accepted as the cutoff for a positive test result, although the validity of this assumption has not been rigorously demonstrated. Objective To determine the skin prick wheal size that best identifies clinical allergy to cat. Methods Forty-five patients referred for evaluation of rhinoconjunctivitis underwent determination of atopic status by skin testing using the Greer Dermapik device and a combination of other modalities, including history, in vitro determination of specific IgE level, and nasal challenge with standardized cat pelt extract. Parameters evaluated before and after nasal challenge included symptom score and nasal lavage tryptase and prostaglandin D 2 (PGD 2 ) levels. Results The widely accepted 3-mm wheal for a positive skin test result to cat is highly sensitive but only moderately specific for diagnosis of cat allergy as evaluated by history, specific IgE level, postchallenge symptom score, and tryptase and PGD 2 levels. Optimal cutoffs for a positive skin test result to cat based on receiver operating characteristic analysis and 95% positive predictive value were 5.5 mm or greater for each of these parameters. When a true-positive result for cat allergy was defined as a combination of positive history, specific IgE level, postchallenge symptom score, and tryptase and PGD 2 levels and a true-negative result as all of these parameters being negative, a 6-mm cutoff was able to distinguish cat allergic from cat nonallergic individuals. Conclusion In a potentially allergic population undergoing skin prick testing with the Greer Dermapik using standardized extracts, a 3-mm skin prick wheal will overestimate the presence of cat allergy. A 6-mm wheal appears to distinguish those individuals who are cat allergic from those who are not.

Background Hospital admission data indicate that the angioedema incidence has increased during the past several decades. Little is known about mortality trends. Objectives To count the number of deaths associated with angioedema in the United States, investigate correlations with age, sex, race, and other contributory causes, and analyze trends from 1979 to 2010. Methods All US death certificates in which angioedema was listed as an underlying or contributing cause of death during 1979 to 2010 were analyzed. Age-adjusted mortality rates were analyzed by age, sex, and race. Other conditions designated as the underlying cause of death were investigated. Results From 1979 to 2010, there were 5,758 deaths in which angioedema was listed as a contributing cause. The age-adjusted death rate for hereditary angioedema decreased from 0.28 (95% confidence interval [CI] 0.25–0.32) to 0.06 (95% CI 0.05–0.08) per million persons per year. Conversely, mortality for angioedema increased from 0.24 (95% CI 0.21–0.27) to 0.34 (95% CI 0.31–0.37) per million. Blacks constituted 55% of angioedema deaths that were associated with use of angiotensin-converting enzyme inhibitors. On death certificates that listed hereditary angioedema as the underlying cause of death, cancer (frequently lymphoma or leukemia) was the second most commonly listed cause. Conclusion Angioedema-associated deaths were very rare from 1979 to 2010. Hereditary angioedema deaths became even more so, whereas nonhereditary angioedema deaths increased. Risks associated with angiotensin-converting enzyme inhibitors were higher in blacks. Lack of specific coding for acquired angioedema most likely explains the observed association between cancer and hereditary angioedema. In the future, more granular coding systems may help distinguish hereditary from acquired angioedema.

Based on the recommendations of The Decade of Discovery in Astronomy and Astrophysics — a report from the National Research Council’s Astronomy and Astrophysics Survey Committee (chaired by John Bahcall) — NASA’s Astrophysics Division crafted a strategic plan consisting of missions and other programme elements to begin development within the next ten years. NASA’s challenge in developing this ten-year plan was to implement the Bahcall report recommendations within the very constrained fiscal climate. The resulting strategic plan was approved by the science community and presented to the Space Science and Applications Advisory Committee (SSAAC), NASA’s highest level science advisory group, at a week long strategic planning retreat. SSAAC combined the Astrophysics plan with the needs of the rest of the space science community and recommended a single, fiscally responsible plan for NASA space science missions from 1994 through 1998.

Fractional exhaled nitric oxide (FENO) is a marker of airway inflammation. Its role in assessing asthma burden in clinical practice needs more study.To determine whether higher FENO levels are associated with greater asthma burden.This was a multicenter cross-sectional retrospective study of atopic 12- to 56-year-old persistent asthmatics on inhaled corticosteroids (ICS). Questionnaire and 1-year retrospective administrative data were used to analyze by unadjusted and adjusted robust Poisson regression (relative risks) and negative binomial regression [incidence rate ratios (IRRs)] the associations of masked FENO levels (NIOX MINO®) to short-acting beta-agonist (SABA) dispensings and oral corticosteroid (OCS) use in the past year independent of spirometry and an asthma control tool [Asthma Control Test (ACT)].FENO levels ranged from 7-215 ppb (median 28 ppb) in 325 patients. Higher FENO levels significantly correlated with more SABA dispensings and OCS courses in the past year, lower FEV(1)% predicted levels, but not ACT score. FENO highest (≥48 ppb) versus lowest (≤19 ppb) quartile values were associated independently in the past year with ≥7 SABA canisters dispensed (relative risk=2.40, 95% CI=1.25-4.62) and total number of SABA canisters dispensed (IRR=1.46, 95% CI=1.12-1.99) and with ≥1 OCS course (relative risk=1.48, 95% CI=1.06-2.07) and total number of OCS courses (IRR=1.71, 95% CI=1.09-2.66). The significant independent relationship of higher FENO levels to increasing SABA dispensings and OCS courses was confirmed by linear trend analyses.Independent and clinically meaningful associations between higher FENO levels and greater asthma burden during a prior year in persistent asthmatics on ICS suggest that FENO measurement may be a complementary tool to help clinicians assess asthma burden.

Epinephrine can be lifesaving in episodes of anaphylaxis, yet it is underprescribed and underused. Tracking of epinephrine refills over time for patients with a diagnosis of anaphylaxis has not been reported. This study reports on the refill history of 14,677 patients in a large HMO who received an initial dispensing of EpiPen (Dey Pharma, Basking Ridge, NJ) or EpiPen Jr between 2000 and 2006. A total of 6,776 (46%) refilled at least once. Twenty-five percent of the patients who were in the cohort for 5 years or more refilled multiple times, and 11% refilled consistently at all expected refill times. Infants through children 12 years of age were more likely to receive a refill dispensing (63%) compared with teenagers and adults (40%). The most common ICD-9 codes that were linked to the initial epinephrine dispensing were allergic disorder (37%), miscellaneous anaphylaxis/angioedema (23%), hymenoptera/insect bite or sting (14%), and specific or nonspecific food allergy (11%). A total of 79% of patients with a food-related ICD-9 code and 59% of patients with an insect sting-related ICD-9 code refilled epinephrine at least once. An opportunity exists to identify system-based as well as personal barriers in an ongoing effort to provide patients at risk with the tools and empowerment that could reduce their risk during life-threatening anaphylactic reactions.

A summary is presented of plans for the future NASA astrophysics missions called SIRTF (Space Infrared Telescope Facility), SOFIA (Stratospheric Observatory for Infrared Astronomy), SMIM (Submillimeter Intermdiate Mission), and AIM (Astrometric Interferometry Mission), the Greater Observatories, and MFPE (Mission From Planet Earth). Technology needs for these missions are briefly described.

Objective. To determine hip joint pain referral patterns. Design. Retrospective analysis. Setting. Multicenter. Patients. Fifty-one consecutive patients meeting clinical criteria of a symptomatic hip joint. Interventions. Fluoroscopically guided intra-articular hip joint injection. Outcome Measures. Anatomic pain map before hip injection and visual analog scale both before and after hip injection. Results. The hip joint was shown to cause pain in traditionally accepted referral areas to the groin and thigh in 55% and 57% of patients, respectfully. However, pain referral was also seen in the buttock and lower extremity distal to the knee in 71% and 22%, respectively. Foot and knee pain were seen in only 6% and 2% of patients, respectively, while lower lumbar spine referral did not occur. Fourteen pain referral patterns were observed. Conclusions. Buttock pain is the most common pain referral area from a symptomatic hip joint. Traditionally accepted groin and thigh referral areas were less common. Hip joint pain can occasionally refer distally to the foot. Lower lumbar spine referral did not occur.

Background The epidemiology of anaphylaxis is uncertain, especially its geographic distribution. Objective To address this deficit, we examined regional rates of EpiPen prescriptions in the United States. Methods EpiPen prescriptions in 2004 were obtained for all 50 states and Washington, DC, from NDCHealth, Pharmaceutical Audit Suite (Alpharetta, Ga). Data included the number of total filled prescriptions, including refills, and the actual number of EpiPens prescribed. Several data sets were used to obtain state-specific populations, as well as multiple demographic, health, and weather characteristics. State population was used to calculate the average number of prescriptions written per person. Results Overall, there were 1,511,534 EpiPen prescriptions filled during 2004. These prescriptions accounted for 2,495,188 EpiPens. On average, there were 5.71 EpiPens prescribed per 1000 persons. Massachusetts had the highest number of prescriptions per 1000 persons (11.8), whereas Hawaii had the lowest (2.7). In addition to state-to-state variation, there was an obvious regional difference: New England (Connecticut, Rhode Island, Massachusetts, Vermont, New Hampshire, Maine) had the highest values, with 8 to 12 EpiPen prescriptions per 1000 persons, whereas the southern states (between and including California and Mississippi) had only 3 prescriptions per 1000 persons. The New England finding persisted even when controlling for all available factors (eg, population demographic characteristics, number of health care providers, prescriptions for other medications). Conclusion A strong north-south gradient was observed for the prescription of EpiPens in the United States, with the highest rates found in New England. Clinical implications The regional differences in EpiPen prescribing may provide important etiologic clues (vitamin D status) and merit further investigation.

Purpose To determine whether montelukast is as effective as fluticasone in controlling mild persistent asthma as determined by rescue-free days. Subjects and methods Participants aged 15 to 85 years with mild persistent asthma (n = 400) were randomized to oral montelukast (10 mg once nightly) or inhaled fluticasone (88 μg twice daily) in a year-long, parallel-group, multicenter study with a 12-week, double-blind period, followed by a 36-week, open-label period. Results The mean percentage of rescue-free days was similar between treatments after 12 weeks (fluticasone: 74.9%, montelukast: 73.1%; difference=1.8%, 95% confidence interval [CI]: −3.2% to 6.8%) but not during the open-label period (fluticasone: 77.3%, montelukast: 71.1%; difference=6.2%, 95% CI: 0.8% to 11.7%). Although both fluticasone and montelukast significantly improved symptoms, quality of life, and symptom-free days during both treatment periods, greater improvements occurred with fluticasone in lung function during both periods and in asthma control during open-label treatment. Post hoc analyses revealed a difference in rescue-free days favoring fluticasone in participants in the quartiles for lowest lung function and greatest albuterol use at baseline. Conclusion In patients with mild persistent asthma, rescue-free days and most asthma control measures improved similarly with fluticasone or montelukast over the short term, but with prolonged open-label treatment, asthma control improved more with fluticasone. Improved asthma control with fluticasone appeared to occur in those with decreased lung function and greater albuterol use at baseline. In the remaining patients, the two treatments appeared to be comparable. These results suggest that classification criteria for mild persistent asthma may need to be re-evaluated.

HISTORY The patient was first admitted to the hospital at the age of 6 months for croup. After discharge from the hospital, he developed a left arm abscess at an intravenous catheter site associated with Staphylococcus aureus bacteremia, and was readmitted. During this second hospitalization, he developed influenza A pneumonia and rotavirus gastroenteritis, and was found to be neutropenic. His neutrophil count varied over the next 10 months, with absolute neutrophil counts (ANCs) as low as 100 cells/mm (Fig 1). At the age of 9 months he experienced an episode of fever, otitis media, and Staphylococcus pneumoniae bacteremia, associated with an ANC of 5,820 cells/mm3. His growth was below average, with height ranging from the 10th to 15th percentile for age, and weight ranging from 5th percentile to the 15th percentile for age. He has had a total of four episodes of otitis media, five episodes of gastroenteritis with diarrhea, and recurrent oral aphthous ulcers. All episodes of otitis media responded to antibiotics. He has had no history of meningitis, osteomyelitis, chronic diarrhea, pneumonia, or sinusitis. He has not received any blood transfusions. He has no history of asthma or rhinitis. There is a history of a mild, scaly skin rash, treated successfully with moisturizing creams only. Past medical history is otherwise remarkable for anemia that resolved with iron supplementation. He is not using any regular medications and has no known medication allergies. His immunizations are up to date for age. Family history is remarkable for asthma in the father and in numerous family members on the mother’s side. Family history is negative for recurrent infections. The parents have no HIV risk factors, and both have tested negative for HIV.

Over the past few years, the classic idea that no new nerve cells are born in the adult mammalian brain has finally and conclusively been refuted by the scientific community. Yet, the first indications that neurogenesis occurs in the brain of adult mammals were obtained using light and electron microscopy over two decades ago. Why this went unrecognized is described in a personal account by the researcher who pioneered those studies: Michael Kaplan.

Boguniewicz M, Zeichner JA, Eichenfield LF, et al. J Pediatr . 2008;152(6):854–859 PURPOSE OF THE STUDY. To examine the safety and efficacy of MAS063DP (Atopiclair [Graceway Pharmaceuticals, Bristol, TN]), a topical nonsteroidal antiinflammatory agent, in the management of mild-to-moderate atopic dermatitis in infants and children. STUDY POPULATION. Infants and children ( N = 142) between the ages of 6 months and 9 years with mild-to-moderate atopic dermatitis affecting ≥5% of body surface area and scores of ≥40 of 100 on a visual analog scale (VAS) for pruritus. METHODS. Subjects were randomly assigned to apply MAS063DP or vehicle cream 3 times per day to affected areas, as …

Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD. Lancet. 2008;372(9643):1058–1064 PURPOSE OF THE STUDY. To estimate the contributions of gender and early life factors to newly diagnosed and persistent asthma in young adults. STUDY POPULATION. The study evaluated 849 enrollees of the Tucson Children's Respiratory Study who had adult data at 22 years of age. METHODS. The cohort was derived from all healthy infants born in Tucson, Arizona, between 1980 and 1984. Shortly after birth, the parents completed a questionnaire on demographic data and were instructed to see a collaborating pediatrician at the first sign of lower respiratory illness. Physician-diagnosed asthma or wheezing was assessed at 2, 3, 6, 8, …

Because of the common nature of asthma and the attention this disease has been given in recent years, it is important to consider the possibility of other disorders that may present in a similar manner to asthma. Failure to consider alternative diagnoses often leads to inappropriate treatment with medications such as systemic corticosteroids that result in untoward morbidity. This review will discuss several diseases originating not only in the tracheobronchial tree but also in extrapulmonary sites, such as the gastrointestinal tract, that may be mistakenly diagnosed as asthma. Newly described entities such as irritant vocal cord dysfunction and exercise-induced hyperventilation syndrome are discussed in this article, as is new information pertaining to well-established diseases such as Churg-Strauss syndrome and sarcoidosis.

Conn KM, Halterman JS, Lynch K, Cabana MD. Pediatrics. 2007;120(3). Available at: www.pediatrics.org/cgi/content/full/120/3/e521 PURPOSE OF THE STUDY. To evaluate how parents’ beliefs about asthma medications can influence their adherence to their child's prescribed therapy and assess whether race/ethnicity is an independent predictor of medication adherence. STUDY POPULATION. The authors conducted a cross-sectional survey of parents of children with asthma in southeast Michigan who were on ≥1 preventive asthma medication between April 2004 and February 2005. Parents (n = 1858) were selected from rural, suburban, and urban areas from 40 primary care pediatric offices, of which 1322 agreed to participate in the telephone survey (response rate: 71.2%). There were 622 patients who completed the survey and met the study criteria. METHODS. To assess parents’ positive and negative attitudes about their child's medications, a previously validated 10-item Beliefs About Medications Questionnaire was used. A necessity-concern differential score was calculated and separated the study population into 3 groups: greater concern than necessity; equal to concern; and greater necessity than concern. To measure medication adherence, a 4-item parent-report scale Medication Adherence Score was used. RESULTS. Only 14% of the parents reported full compliance with their child's medications. Among 77% of the parents, necessity scores outweighed concern scores. For 17%, concerns outweighed necessity, and 6% had equal scores. Nonminority parents were more likely to have necessity scores that exceeded concern scores (79% vs 68%; P = .03). Other factors associated with parents having a higher concern than need score were parents who used alternative therapies (P = .03), parents whose children were taking CONCLUSIONS. When parents’ positive and negative beliefs about medications are weighed against each other, most felt greater need for their child's medications than concern, and this was independently associated with better adherence scores. Nonminority status was independently linked with better medication adherence scores. REVIEWER COMMENTS. The question that was not answered with this study is whether physician-directed patient education regarding asthma and asthma medications affects parents’ beliefs and subsequent adherence to their child's asthma medications. It would be interesting to explore the basis for parental concern, addressing the concerns and reinforcing the perception of need through education, and then measure the impact of the intervention on change in adherence.

Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A; IFWIN Study Team. Lancet. 2006;368:754–762 PURPOSE OF THE STUDY. To determine if the early use of inhaled fluticasone propionate in wheezy infants helps to prevent loss of lung function and progression of asthma later in childhood. STUDY POPULATION. High-risk children (N = 1073) identified by having 1 atopic parent were followed prospectively until 2 wheezing episodes occurred or there was 1 wheezing episode longer than 1 month. Of these patients, 206 who met the inclusion criteria were randomly assigned: 104 to placebo and 102 to treatment. The median age was 1.2 years (range: 0.5–4.9 years). Eighty-six percent continued to be followed by their fifth birthday. METHODS. Children were excluded if they had wheeze caused by bronchiolitis, were preterm ( RESULTS. There was no significant difference between those in the treatment group versus placebo in the proportion of children with current wheeze, physician-diagnosed asthma, use of asthma medication, or current wheeze, even when factoring the addition of those participants who added open-label medication. There was also no significant difference in FEV1 (baseline or postbronchodilator), sRAW, or airway reactivity at 5 years of age in these groups. The 2 groups were similar in the number of children who required, and in the length of time to adding, open-label drug. Symptom scores, use of reliever medication, and unscheduled visits to the family doctor were similar until the third month, when children in the treatment group had lower median daily symptom scores, a trend toward less reliever medication, and significantly fewer visits than those in the placebo group. In the 2 open-label drug groups, there was a greater risk of current wheeze, current use of asthma medications, and current wheeze with asthma medications compared with those in the placebo group, although there was no difference in baseline or postbronchodilator FEV1. However, there was a significantly higher sRAW in the treated groups, which represented decreased lung function. CONCLUSIONS. The use of ICS in young children at risk for asthma with the earliest sign of recurrent wheezing had no significant effect on the natural history of wheezing, lung function, or airway reactivity by 5 years of age and only showed a small improvement on symptom scores and unscheduled physician visits after the third month of the study. Higher postbronchodilator sRAW showing reduced lung function was seen in children in the treated group compared with those in the placebo group. REVIEWER COMMENTS. Evidence for the efficacy of ICS in infants and very young children remains unclear. It has been suggested that early use of ICS could be detrimental to the lung development on the basis of the sRAW scores of ICS-treated patients. However, children in both the treatment and placebo groups required the addition of fluticasone equally, which suggests that perhaps those in the treatment group had worse disease. Prestudy lung function was not tested, and individual atopic status was not assessed to determine if these 2 groups were truly equivalent. Studies are needed to determine if atopy is a confounding factor and whether controlling for allergen exposure in addition to ICS has an effect on asthma outcomes. This study and other similar studies suggest that ICS can improve asthma symptoms, but early use does not modify the disease.

Purpose of the Study. To determine if a standardized citywide asthma management program delivered by primary care providers (PCPs) would increase adherence with the National Asthma Education and Prevention Program guidelines and whether this would improve medical service utilization. Study Population. Children between 6 months and 18 years of age (n = 8324) who presented for care at any of 6 primary care clinics in Hartford, Connecticut, between 1998 and 2002 and had enrolled in either Medicaid or the State Children’s Health Insurance Plan (SCHIP). Methods. Enrollment in the Easy Breathing asthma management program for PCPs included completing a survey regarding the child’s clinical history, provider assessment of asthma severity, and a written asthma treatment plan for the caregiver. Providers underwent training in the Easy Breathing curriculum. Data regarding demographics for enrolled patients were obtained from the survey and compared with all resident children in Hartford. Claims data were obtained. Utilization of medical services and prescriptions was examined. Children were continuously enrolled in the program during the 4-year analysis period. Relative rates of utilization (in event/child-months) were compared for the same children before and after enrollment. Results. Of the 1799 children with persistent asthma, only 38% were treated with antiinflammatory therapy before Easy Breathing; after enrollment, this improved to 96%, with 85% of those treated specifically with an inhaled corticosteroid. After enrollment in Easy Breathing, the rate of hospitalization for all children with asthma decreased 35% (P < .006), and the decrease was sustained over 3 years. There was a 27% overall decrease in emergency department (ED) visits for asthma (P < .01) and less seasonal variation in hospitalizations. Adjusted relative rates for total and asthma-specific ED and hospital visits decreased significantly for children with persistent asthma. Decreases in adjusted rates of outpatient visits after enrollment were also found for children overall (19%; P < .0001). This was true for children with intermittent asthma (22%; P < .001) and persistent asthma (18%; P < .001). Conclusions. Adherence to National Asthma Education and Prevention Program guidelines by PCPs managing asthma for low-income minority children decreased their total number of hospitalizations and asthma-specific ED visits and outpatient visits. The authors believe that contributors to the success of the program include the standardized approach to therapy, including inhaled corticosteroids when indicated, as well as the development of a written, individualized asthma treatment plan. The benefits of the program continued through the 3 years. Reviewer Comments. Despite a few limitations (nonrandomized, use of claims data), this study strongly reinforces the idea that improving asthma management relies not only on patient adherence but also physician review and faithful implementation of the current guidelines. PCPs managing asthma in low-income, urban, minority children would benefit the community by participating in such standardized programs that are focused on diagnosis and treatment. This not only decreases the morbidity related to asthma in these children but also alleviates the financial burden involved in excessive utilization of medical services.

Purpose of the Study. Seventy-five percent of the asthma care in the United States is provided by primary care generalists. The National Asthma Education and Prevention Program guidelines recommend spirometry to assess management once the peak flow has stabilized. The purpose of this study was to assess how pulmonary-function tests (PFTs) performed during a patient encounter influence management decisions beyond the history and physical examination alone. Study Population. A total of 367 asthmatic patients were enrolled during their visit to a pediatric pulmonary clinic. The patients were 4 to 18 years old (mean: 10.4 years), and 60% were male. Patients were excluded if PFTs could not be performed on them, if they had a pulmonary diagnosis other than asthma, or if they had used albuterol within 4 hours. Methods. History of asthma symptoms was obtained, and a physical examination was performed. Spirometry was performed before the provider assessment. Peak expiratory flow rate (PEF) was also obtained. The results of the PFTs were not known to the provider at the time of the assessment and initial decision-making. The provider then reviewed the spirometry results and revised the initial recommendations if necessary. Changes in management were analyzed with respect to demographic data and spirometry. The diagnostic accuracy of PEF to detect abnormal lung function was determined. Results. Eight percent of the patients had mild intermittent asthma, 21% mild persistent asthma, 57% moderate persistent asthma, and 14% severe persistent asthma. Spirometry results were normal in 55% of the visits. Abnormal spirometry occurred equally in boys and girls. Sixty percent of the abnormal results were new compared with previous baseline measurements. The likelihood of an abnormal PFT increased with increasing severity classification. Ten percent of those in the group with mild intermittent asthma had abnormal PFTs, compared with 74% of those with severe persistent asthma. PFT results changed management in 15% of the visits. When spirometry did not change the treatment, the providers were more likely to have already decided to maintain therapy (58%). When spirometry did change treatment, providers were more likely to increase medications (75%). PEF was moderately inaccurate in detecting abnormal spirometry. Conclusions. In a clinical setting, even asthma care experts tended to overestimate the degree of asthma control as measured by airway obstruction. Spirometry results in this study were just as likely to be abnormal in patients with a normal history and physical examination. Reviewer Comments. The next logical question is: Does decision-making enhanced by spirometry result in better outcomes such as decreased symptoms, improved functioning and sleep, fewer exacerbations requiring steroid rescue, and less use of urgent asthma care services? When assessing asthma control, one should always consider comorbidities and adherence issues before stepping up therapy.

Laubereau B, Brockow I, Zirngibl A, et al. J Pediatr . 2004;144:602–607 Most studies have shown a protective effect of breastfeeding on atopic disease, but some have shown an increased risk. This study examined the impact of exclusive breastfeeding for the first 4 months of infancy on the prevalence of atopic dermatitis (AD) during the first 3 years of life. A large birth cohort of healthy term neonates in Germany enrolled between 1995 and 1998 for a study designed to investigate risk factors for and course and prevention of allergic disease. …

Veenhoven R, Bogaert D, Uiterwaal C, et al. Lancet . 2003;361:2189–2195 To determine whether pneumococcal conjugate vaccine can prevent acute otitis media (AOM) among older children who have experienced previous episodes of AOM. A total of 383 children (1–7 years of age) with ≥2 episodes of AOM in the year before study entry were studied. Children recruited from a Netherlands general hospital and tertiary care hospital were randomized to receive either 7-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide …

Chauhan AJ, Inskip HM, Linaker CH. Lancet. 2003;361:1939–1944 Nitrogen dioxide (NO2) exposure has been linked to respiratory tract illness. This study examined the relationship between the level of personal exposure to NO2 and the severity of asthma exacerbations caused by respiratory viral infections. The subjects were 114 asthmatic children, 8 to 11 years of age (63 male subjects and 51 female subjects). The cohort of 114 children collected daily upper and lower respiratory tract symptom scores and peak expiratory …

Background Few studies have focused on weight loss programs implemented in community-based primary care settings. The objective of this analysis was to evaluate the effectiveness of a weight loss program and determine whether physicians in primary care practices could achieve reductions in body weight and body fat similar to those obtained in weight loss clinics. Methods Analyses were performed on chart review data from 413 obese participants who underwent weight loss at a primary care (n=234) or weight loss (n=179) clinic. Participants received physician-guided behavioral modification sessions and self-selected a diet plan partially or fully supplemented by meal replacements. A repeated-measures analysis of covariance was conducted with age and sex serving as covariates; significance was set at P ≤.05. Results In 178 subjects (43%) completing 12 weeks of the program, primary care clinics were as effective as weight loss clinics at achieving reductions in body weight (12.4 vs 12.1 kg) but better with regard to reduction in body fat percentage (3.8% vs 2.7%; P ≤.05). Regardless of location, participants completing 12 weeks lost an average of 11.1% of their body weight. Participants selecting full meal replacement had greater reductions in weight and body fat percentage (12.7 kg, 3.5%) compared with participants selecting a partial meal replacement plan (8.3 kg, 2.3%). Conclusion Primary care physicians can successfully manage and treat obese patients using behavioral modification techniques coupled with meal replacement diets.

Summary Two patients with clinically significant immunoglobulin E (IgE) mediated reactions to cow's milk which occur only under special circumstances are described. Although double-blind, placebo-controlled food challenges or open food challenges are generally very helpful, certain patients who react only under special circumstances might be missed when these office tests are used. The two reported incidences occurred in older children who seemed to outgrow their cow-milk allergy but still had clinically significant allergic reactions under certain circumstances.