Medical Journal Review

Reviewed by Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief and Guest Reviewer Gary Hellermann, PhD

1a. RESCUE USE OF BECLOMETHASONE (B) AND ALBUTEROL (A) IN A SINGLE INHALER FOR MILD ASTHMA
This is a 6-mo double-blind, double-dummy, randomized, parallel-group trial of 455 patients (18 to 65 yrs) with mild asthma [FEV1 of 2.96 liters (88.36% of the predicted value)]. After a 4-week run-in, patients were randomly assigned to one of four regimens: placebo (P) 2X/day plus B, 250 μg, and A, 100 μg, in a single inhaler prn; P 2X/day plus A, 100 μg, prn; B, 250 μg, 2X/day, and A, 100 μg, prn; or B, 250 μg, and A, 100 μg, in a single inhaler 2X/day plus A, 100 μg, prn. Morning PEF during the last two weeks of the 6-mo treatment was higher (P = 0.04) and the number of exacerbations during the 6-mo treatment lower (P = 0.002) in the as-needed combination therapy than in the prn A therapy group. However, the values in the prn combination therapy were not significantly different from regular B therapy or regular combination therapy. The authors conclude that the symptom driven use of prn inhaled B, 250 μg and A, 100 μg, in a single inhaler, is effective treatment and is associated with a lower 6-mo cumulation dose of inhaled corticosteroids. Papi A, et al. N Engl J Med 2007; 356: 2040.

1b. RANDOMIZED COMPARISON OF STRATEGIES FOR REDUCING TREATMENT IN MILD PERSISTENT ASTHMA
500 patients (six yrs or older) with mild asthma, well-controlled with inhaled fluticasone (F), 100 μg 2X/day, were randomly assigned to receive continued F, 100 μg 2X/day, montelukast (M), 5 or 10 mg each night, or F, 100 μg, plus salmeterol (S),50 μg, each night for 16 weeks in a DB study. Treatment failure was the primary outcome. 20% of patients assigned to receive F or F + S failed compared to 30.3% of those on M. The hazard ratio for both comparisons was 1.6 (95% CI, 1.1 to 2.6; P = 0.03). The % of asthma free days was similar across the three groups. The authors conclude that patients controlled with 2X/daily F can be switched to 1X/daily F + S without increased treatment failure. However, a switch to M results in an increased treatment failure and decreased asthma control, even though M treated patients remained free of symptoms on 78.7% of treatment days. Editor’s comment: Three physicians’ comments on various treatment options for mild, persistent asthma are included. One of the experts would use prn B and A in a combined inhaler, another, a leukotriene antagonist plus a prn rescue β-agonist, and the third, once daily inhaled corticosteroid plus a long-acting β-agonist in a single inhaler. William Osler, the Father of American Medicine, stated, “The practice of medicine is an art, based on science”. No single treatment may be absolutely correct to treat mild, persistent asthma. The American Lung Association Asthma Clinical Research Centers. N Engl J Med 2007; 356: 2027. Clinical Decisions. Kraft M: 2096. Israel E: 2097. O’Connor GT: 2098.
Full Text

2. REMODELING AND AIRWAY HYPERRESPONSIVENESS (AHR) BUT NOT CELLULAR INFLAMMATION PERSIST AFTER ALLERGEN CHALLENGE IN ASTHMA (A)
Fiberoptic bronchoscopy was performed at baseline, 24 hrs and seven days after allergen inhalational challenge of dual responders with mild-moderate asthma. At each time point, AHR, spirometry, and expression of tenascin (extracellular matrix protein), procollagen I, procollagen III, and heat shock protein (HSP)-47 (markers of collagen synthesis), and α-smooth muscle actin (myofibroblasts) were evaluated as markers of activation of airway remodeling. Likewise, numbers of mucosal major basic protein-positive eosinophils, CD68+ macrophages, CD3+, CD4+, CD8+ T cells, elastase-positive neutrophils, and tryptase-positive mast cells were assayed. AHR was increased from baseline at 24 hrs and seven days after allergen challenge. However, reticular basement membrane tenascin expression, elevated at 24 hrs, returned to baseline levels at seven days. Reticular basement membrane procollagen III expression was significantly elevated at seven days, and procollagen 1, HSP-47, and α-smooth muscle actin were all higher at seven days vs. 24 hrs. Eosinophil, macrophage, neutrophil, and CD3+ T cells increased at 24 hrs but returned to baseline by seven days. The authors conclude that the 24-hr increase after allergen challenge in dual responders with asthma in airway wall cellular inflammation resolves by seven days, whereas increases in AHR and markers of remodeling persist. Editor’s comment: AHR is associated with remodeling and not cellular inflammation. Kariyawasam HH, et al. Am J Respir Crit Care Med 2007; 175: 896.

3. A COMPREHENSIVE ANALYSIS OF ADVERSE OBSTETRIC AND PEDIATRIC COMPLICATIONS IN WOMEN WITH ASTHMA (A)
Outcomes for 37,585 pregnancies of women with A were compared to 243,434 without A. Risks of stillbirth and therapeutic abortion were similar; however, the risk of miscarriage was slightly higher (OR 1.10; 95% CI, 1.06 – 1.13). Risk of placental abruption, placental insufficiency, placenta previa, preeclampsia, hypertension, gestational diabetes, thyroid disorders in pregnancy, and assisted delivery were similar with the exception of increases in antepartum (OR, 1.20; 95% CI, 1.08-1.34) or postpartum (OR, 1.38; 95% CI, 1.21-1.57) hemorrhage, anemia (OR, 1.06; 95% CI, 1.01-1.12), depression (OR, 1.52; 95% CI, 1.36-1.69), and C-section (OR, 1.11; 95% CI, 1.07-1.16). Editor’s comment: Asthma is not a major risk factor in pregnancy. Tata LJ, et al. Am J Respir Crit Care Med 2007; 175: 991.

4. HERPESVIRUS LATENCY CONFERS SYMBIOTIC PROTECTION FROM BACTERIAL INFECTION
Reviewed by Gary Hellermann, PhD
Can herpesvirus infection be good for you? In this intriguing report, mice were infected with gamma herpesvirus (GHV) and the infection allowed to proceed to latency after which the animals were challenged with the intracellular pathogen, Listeria monocytogenes (L.m.). Mice without latent GHV suffered much greater susceptibility to L.m. infection than those previously infected with GHV. The mechanism for this enhanced antibacterial response may lie with subclinical reactivation of the virus producing sufficient viral antigen to maintain a prolonged increase in interferon gamma production. Editor’s comment: While this unusual type of latency-induced cross protection has not yet been shown in humans, this report demonstrates once again that in studying the immune system the rules are always subject to change. Barton ES, et al. Nature 2007; 447:326.

5. SMOKING AFFECTS RESPONSE TO INHALED CORTICOSTEROIDS OR LEUKOTRIENE RECEPTOR ANTAGONISTS IN ASTHMA (A)
44 nonsmokers and 39 light smokers with mild A were randomly assigned to treatment with inhaled beclomethasone (B) or once daily oral montelukast (M) in a multicenter, placebo-controlled, double-blind, double-dummy, crossover trial. The primary outcome was change in prebronchodilator FEV1 in smokers versus nonsmokers. Secondary outcomes include PF, PC20 methacholine, symptoms, QOL, and markers of airway inflammation. Subjects with A who smoked, had significantly more symptoms, worse QOL, and lower daily PF than nonsmokers. B significantly reduced sputum eosinophils and ECP in both smokers and nonsmokers but increased FEV1 (170 ml, P = 0.0003) only in nonsmokers. M significantly increased A.M. PF in smokers (12.6 L/min, P = 0.002) but not in nonsmokers. The authors conclude that in subjects with mild A who smoke, the response to B is attenuated and that M may be appropriate to treat smokers with A. They call for larger studies to confirm these data. Editor’s comment: Perhaps leukotrienne antagonists and not B will be more helpful for smokers than nonsmokers with A. Lazarus SC, et al. Am J Respir Crit Care Med 2007; 175:783.

6. OSTEOPONTIN HAS A CRUCIAL ROLE IN ALLERGIC AIRWAY DISEASE THROUGH REGULATION OF DENDRITIC CELL SUBSETS
Reviewed by Gary Hellermann, PhD
Osteopontin (Opn), also known as early T lymphocyte activation-1 (Eta-1) factor, is a cytokine that wears many hats. Bone researchers found that it assists osteoclasts in localizing to bone matrix while cancer researchers reported Opn is involved in tumor suppression. Opn-1 is produced in abundance by activated T lymphocytes and binds to the cell adhesion receptor, CD44, affecting homing and attachment of lymphocytes and other immune system cells. New research now implicates the secreted form of the cytokine, Opn-s, in differential regulation of the allergic immune response through actions on dendritic cells. In this report on a mouse model, Opn-s proved to be pro-inflammatory during allergen sensitization, but anti-inflammatory during challenge. Editor’s comment: The demonstration of both pro- and anti-inflammatory activities in the same molecule emphasizes the need for great care in the design and evaluation of clinical trials of cytokines such as Opn. Xanthou G, et al. Nature Medicine 2007, 13:570.

7. A WEB-BASED, TAILORED ASTHMA (A) MANAGEMENT PROGRAM FOR URBAN AFRICAN-AMERICAN HIGH SCHOOL STUDENTS
This study was developed and evaluated as a multimedia, web-based A management program which specifically targeted urban high school students in an attempt to alter their behavior as it related to A outcome. High school students were randomized to receive the treatment website vs a sham website on school computers. At 12 mo, treatment students reported fewer symptom-days, symptom-nights, school days missed, restricted activity days, and hospitalizations for asthma when compared to controls (RR and 95% CIs all significant). Editor’s comment: Education, which leads to compliance, is a key to improved asthma outcomes in all populations. Joseph CLM, et al. Am J Respir Crit Care Med 2007; 175: 888.

8. ADENOTONSILLECTOMY (AT) IMPROVES SLEEP, BREATHING, AND QUALITY OF LIFE (QOL) BUT NOT BEHAVIOR
This retrospective cohort study was designed to obtain parental perspectives on changes in sleep, breathing, QOL, and neurobehavioral outcomes after AT was performed for obstructive sleep apnea syndrome (OSAS) from 1993 to 2001. Children who underwent AT were compared to children who did not. 138 of the 166 questionnaires returned (35%) from parents of 473 children were complete. Compared to controls, parents of children who had AT reported improvements in sleep, breathing and QOL but not in concentration, school performance, and intellectual or developmental progress. Both short and long term, there were no significant effects of AT on any of the Conners’ Parent Rating Scale-Revised behavior subscales. The authors conclude that AT improves sleep, breathing, and QOL but not neurobehavioral outcomes. Editor’s Comment: Neurobehavioral outcomes did not improve in this study following AT for sleep apnea in children. More data are necessary. Constantin E, et al. J Peds 2007; 150: 540.

9. BASAL SERUM TRYPTASE (T) LEVEL CORRELATES WITH SEVERITY OF HYMENOPTERA STING AND AGE
109 patients, 63 wasp venom and 46 honey bee venom-allergic, had basal serum T levels measured. T levels were elevated in 12 (11%) and increased from a mean of 5.14 to 6.98 μg/L for patients with sting reactions from grades I through IV, (Mueller classification). Serum T levels correlated significantly with the sting reaction severity (r = 0.2752; P = .004) and with age (r = 0.2906; P = .002). Sting reaction severity also correlated with age (r = 0.3654; P = .001). The authors conclude that serum T levels correlate with both sting severity and age. Editor’s comment: This is another paper which indicates that basal levels of serum T probably influence outcomes of sting induced anaphylaxis. Kucharewicz I, et al. J Investig Allergol Clin Immunol 2007; 17: 65.

10. THE VARIABILITY OF REGIONAL AIRFLOW OBSTRUCTION WITHIN THE LUNGS OF PATIENTS WITH ASTHMA: ASSESSMENT WITH HYPERPOLARIZED HELIUM-3 MAGNETIC RESONANCE (H3HeMR) IMAGING
Using hyperpolarized helium-3 magnetic resonance (H3HeMR) imaging, airspaces are depicted and focal areas of airflow obstruction are shown as “ventilation defects”. The authors investigate the regional changes in airflow obstruction with time and repeated bronchoconstriction. H3HeMR and spirometry were performed before and immediately after methacholine challenge in 10 patients (18-35 yrs) with asthma on two days that were 7-476 days (mean, 185.3 ± 37.2 days) apart. Pair-wise image comparisons demonstrate that 41% ± 10% and 69% ± 5% (P = .017) of defects , respectively, were in the same location, and of those, 69% ± 12% and 43% ± 5% (P = .022), respectively, did not change size. Comparing premethacholine vs. postmethacholine images, 58% ± 9% of defects were in the same location on day one and 73% ± 7% (P = .088) on day two. The authors conclude that ventilation defects persist or recur in the same locations in asthmatics and suggest that regional changes of the airflow obstruction are relatively fixed. Editor’s comment: There is tremendous variability in asthma, even in different areas of the lung of the same subject. deLange EE, et al. JACI 2007; 119:1072.

11. STRUCTURAL INSIGHT INTO PRE-B CELL RECEPTOR FUNCTION
Reviewed by Gary Hellermann, PhD
B cells, like T lymphocytes, undergo constant scrutiny by regulatory cells to ensure that self-tolerance is maintained. One checkpoint is at the stage where the pre-B cell receptor contains an intermediate known as the surrogate light chain (SLC). Only those B cells in which the SLC can pair with the newly expressed heavy chain are allowed to go on to clonal expansion. In this report, the human pre-B cell receptor was crystallized and the structure of the SLC examined. Editor’s comment: Structural analysis at the submolecular level reveals significant new information about the interaction of the SLC with the heavy chain and suggests how this binding affects the yea or nay decision on B cell survival. Bankovich, AJ et al. Science 2007; 316:291.

12. ONCE-YEARLY ZOLEDRONIC ACID (ZA) FOR TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS (O)
This is a 3-year DBPC trial of 3889 patients (mean age, 73 yrs) randomly assigned to receive a single 15-minute infusion of ZA, 5 mg, or 3876 placebo (P) at baseline, 12 mo, and 24 mo. They were followed until 36 mo. Primary end points were new vertebral fracture (in patients not taking concomitant osteoporosis medications) and hip fracture (all patients). Secondary end points included bone mineral density (BMD), bone turnover markers, and safety outcomes. Treatment with ZA reduced the risk of vertebral fracture by 70% compared to P (3.3% in ZA vs 10.9% in P, relative risk, 0.30; 95% CI, 0.24 to 0.38) and reduced the risk of hip fracture by 41% (1.4% in ZA vs 2.5% in P; hazard ratio, 0.59; 95% CI, 0.42 to 0.83). Non-vertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and 77%, respectively (P<0.001 for all comparisons). ZA was associated with improvement in BMD and bone metabolism markers. Atrial fibrillation occurred more frequently in the ZA group (50 vs 20 patients, P<0.001), without serious consequences. Once a year infusion of ZA significantly reduces the risk of vertebral, hip, and other fractures. Editor’s comment: Once a year treatment for osteoporosis is on its way. Black DM, et al. N Engl J Med 2007; 356: 1809. Editorial, Compston J: 1878.

13. EXERCISE-INDUCED BRONCHOSPASM (EIB): DIAGNOSIS AND TREATMENT
This CME article is an excellent review of the subject of EIB asthma (A). EIB is usually suspected from the clinical history; a methacholine, exercise, or eucapnic voluntary hyperventilation challenge can be helpful in its diagnosis. First-line pharmacologic treatment is a short-acting β-agonist. However, regularly used inhaled corticosteroids, leukotriene inhibitors, long-acting β-agonists and mast cell stabilizers are all effective treatments. Editor’s comment: EIB often goes unrecognized, untreated, and interferes with exercise. Bruns AS and Parsons JP. JCOM 2007; 14: 211.

© 2000-2008 WAO.
All rights reserved.
Disclaimer