Medical Journal Review

Reviewed by Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief

1. INVARIANT NATURAL KILLER T CELLS (NK) IN ASTHMA (A) AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
These authors studied the frequency of NK in the airways of subjects with mild (8 not treated with inhaled corticosteroids) and moderate (16 treated with inhaled corticosteroids) A, 10 subjects with COPD and 10 controls. NK were enumerated with flow cytometry with the use of CD1d tetramers loaded with α-galactosylceramide and antibodies specific to the NK receptor in samples of BAL, induced sputum, and bronchial-biopsy specimens. Real-time PCR analysis was performed on bronchoalveolar-lavage cells for evidence of gene expression of the NK receptor. The authors found that fewer than 2% of the T cells obtained from all subjects were similar and no expression of messenger RNA for the NK-receptor domains Vα24 and Vβ11 were present. NK are found in low numbers in the airways of subjects with asthma, COPD, and controls. Editor’s comment: More studies are needed to determine a possible role for NK in asthma. Vijayanand P, et al. N Engl J Med 2007; 356: 1410. Editorial, Ho LP: 1466.

2. OPIATE THERAPY IN CHRONIC COUGH (CC)
27 patients with CC enrolled into a randomized DBPC study using four weeks of slow-release morphine sulfate (MS) 5 mg 2X/day and a corresponding period of matched placebo. An open-labeled extension of the core study allowed dose escalation to MS 10 mg 2X/day. CC was assessed using the Leicester Cough Questionnaire (LCQ), daily symptom diary and citric acid cough challenge (CACC). A significant improvement of 3.2 points over baseline was noted on the LCQ (p < 0.01). A rapid reduction of 40% in CC scores was noted in subjects on slow-release MS ( p < 0.01). CACC test results did not show any significant changes. Two-thirds of the 18 patients in the extension study opted to increase the MS to 10 mg 2X/day, and at the end of three mo, there was a similar improvement in CC between the 5- and 10-mg groups. MS is an effective antitussive in CC at doses of 5 to 10 mg twice daily. Editor’s comment: The risk (side-effects, dependence and sedation) – benefits (decreased cough) have to be weighed when prescribing MS for CC. Morice AH, et al. Am J Respir Crit Care Med 2007; 175: 312.

3. OVERWEIGHT, OBESITY, AND INCIDENT ASTHMA–A META-ANALYSIS OF PROSPECTIVE EPIDEMIOLOGIC STUDIES
This is an online bibliographic database search for studies evaluating body mass index (BMI) and incident asthma in adults. Independent observers extracted data from studies meeting predetermined criteria [defined categories of normal weight (BMI < 25), overweight (BMI, 25-29.9), and obesity (BMI ≥ 30)]. Seven studies of 333,102 subjects met inclusion criteria. Overweight and obesity conferred increased odds of incident asthma, with an OR of 1.51 (95% CI, 1.27 – 1.80). A dose-response effect was observed. The observations were present in both men (OR, 1.46; 95% CI, 1.05 – 2.02) and women (OR, 1.68; 95% CI, 1.45 – 1.94; p = 0.232 for the comparison). The authors conclude that overweight and obesity are a dose-dependent risk in the odds of incident asthma. Editor’s comment: This is the best review available indicating that overweight and obesity are risk factors for asthma. Beuther DA, et al. Am J Resp Crit Care Med 2007; 175: 661.

4. SAFETY OF ANTI-IMMUNOGLOBULIN E THERAPY WITH OMALIZUMAB (O) IN ALLERGIC PATIENTS AT RISK OF GEOHELMINTH INFECTION (GI)
137 subjects (12 -30 years) at high risk of GI were included in a randomized DBPC trial. All received pre-study anthelminthic treatment followed by 52 weeks’ treatment with O or placebo (P). 50% (34/68) of the O subjects experienced at least one intestinal GI vs. 41% (28/69) of P subjects [OR 1.47, 95% CI 0.74 – 2.95, one-sided p = 0.14; OR (adjusted for study visit, baseline infection status, gender and age) 2.2 (0.94 – 5.15); one-sided p = 0.035], providing some evidence for a potential increased incidence of this form of infection in subjects on this medication. Infection severity and response to anthelminthics appeared to be unaffected by O therapy. The authors conclude in this exploratory study that O therapy may be associated with a modest increase in the incidence of GI. However, such therapy was safe and well tolerated. Editor’s comment: More information is needed to determine whether anti-IgE therapy is associated with an increased risk of intestinal helminth infections. Cruz AA, et al. Clin Exp Allergy 2007; 37: 197.

5. SHORT-COURSE MONTELUKAST (M) FOR INTERMITTENT ASTHMA (IA) IN CHILDREN–A RANDOMIZED CONTROLLED TRIAL
220 children (aged 2 – 14 yr) with IA were randomized in this multicenter, DBPC clinical trial over 12 months, 107 to M and 113 to placebo (P), to determine whether a short course of M in children with IA would modify the severity of an asthma episode. There were 681 treated episodes (345 M, 336 P) provided by 202 patients. The M group had 163 unscheduled health care resource utilizations for A compared with 228 in the P group (OR, 0.65; 95% CI, 0.47 – 0.89). There was a nonsignificant reduction in specialist attendances and hospitalizations, duration of episode, and ß-agonist and prednisolone use. Symptoms were reduced by 14% and nights awakened by 8.6% (p = 0.043), days off from school or childcare by 37% and parent time off from work by 33% (p < 0.0001 for both). The authors conclude that M introduced at the first signs of an A episode results in a modest reduction in acute health care resource utilization, symptoms, time off from school, and parental time off from work in children with IA. Editor’s comment: More studies are necessary to determine the effects of M on viral respiratory tract infections, particularly when M is used to prevent viral infections. Robertson CF, et al. Am J Respir Crit Care Med 2007; 175: 323.

6. PREVALENCE OF VIRAL RESPIRATORY TRACT INFECTIONS IN CHILDREN WITH ASTHMA (A)
Respiratory specimens from children aged 2 to 17 years with A exacerbations (case patients, n = 65) and with well-controlled A (control subjects, n = 77), frequency matched by age and season of enrollment, were tested for rhinoviruses, enteroviruses, respiratory syncytial virus, human metapneumovirus, coronaviruses 229E and OC43, parainfluenza viruses 1 to 3, influenza viruses, adenoviruses, and human bocavirus. Respiratory viruses were associated with A exacerbations (63.1% in case patients vs. 23.4% in control subjects; OR, 5.6; 95% CI, 2.7 – 11.6). Rhinoviruses were the most prevalent viruses (60% among case patients vs. 18.2% among control subjects) and the only ones significantly associated with exacerbations (OR, 6.8; 95% CI, 3.2 – 14.5). The authors conclude that rhinoviruses should be a target for therapies as a means to decrease asthma exacerbations. Editor’s comment: This article confirms that rhinoviruses are the most important viruses associated with asthma exacerbations in children. Khetsuriani N, et al. JACI 2007; 119: 31.

7. CORRELATION BETWEEN BRONCHODILATOR RESPONSIVENESS AND QUALITY OF LIFE (QOL) IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
63 subjects with COPD, mean age 71.7 yr, were investigated to determine the relationship between reversibility and QOL. Post-bronchodilator FEV1, % predicted, was positively correlated with both the total scores of 2 different QOL questionnaires (p < .0001 and p < 0.006). For the most part, reversibility of FVC was also positively correlated. The reversibility of FEV1 was neither correlated with the total score nor any other items in the scales. The authors conclude that patients who have a FVC that respond to a bronchodilator at rest might result in improvement of QOL after Rx. Editor’s comment: Bronchodilators probably improve the QOL in patients with COPD primarily because of increased respiratory function. Omata M, et al. Allergol Internatinal 2007; 56: 15.

8. ASYMMETRIC T LYMPHOCYTE DIVISION IN THE INITIATION OF ADAPTIVE IMMUNE RESPONSES
Reviewed by Gary Hellermann, Ph.D.
T cell activation through interaction with MHC-peptide at the immunological synapse is the key feature of adaptive immunity, but it is only part of the picture. Activation also produces memory T cells that generate a rapid response when faced with the same antigen. In this intriguing article, the authors hypothesize that polarization of specific proteins between the synapse and the opposite pole in T cells during prolonged contact with antigen-presenting cells results in an asymmetric cell division producing two daughter cells--one an effector T cell bearing markers from the synapse side and the other a memory T cell with markers from the distal pole. Editor’s comment: The reason for the extended interaction between T cells and antigen-loaded dendritic cells appears to be co-generation of effector and memory T cells by asymmetric cell division. Chang JT et al. Science 2007, 315:1687. Editorial, Littman DR, et al.: 1673.

9. A POOLED ANALYSIS OF FEV1 DECLINE IN COPD PATIENTS RANDOMIZED TO INHALED CORTICOSTEROIDS (ICS) OR PLACEBO (P)
This is a pooled study of patient-level data from seven long-term randomized controlled trials of ICSs vs. P lasting ≥ 12 mo in patients with moderate-to-severe COPD. 3,911 randomized participants (29.2% female) were included in the analysis. In the first six mo after randomization, ICS use was associated with a significant mean (± SE) relative increase in FEV1 of 2.42 ± 0.19% compared with P (p < 0.01). However, from 6 to 36 months, there was no significant difference between P and ICS therapy in terms of FEV1 decline (-0.01 ± 0.09%; p = 0.86). The authors conclude that ICS therapy is more effective in ex-smokers than in current smokers with COPD and that women have larger responses to ICS than men. However, this effect only lasts for approximately six months, and thereafter, does not modify the decline in FEV1. Editor’s comment: Is it possible there are phenotypes within this cohort with reversible airways disease that responds better and over a longer period than others who have minimal or no reversibility? Soriano JB, et al. Chest 2007; 131: 682.

10. EVIDENCE-BASED SELECTION OF INHALED CORTICOSTEROID (ICS) FOR TREATMENT OF CHRONIC ASTHMA
This is an excellent evidence-based article on the published literature comparing various ICSs. There is considerable heterogeneity in the published results on these medications and their efficacy, and side-effects depend on their formulation, dosing, device used, and the subjects’ age, severity of asthma, and inhaler technique. Each medication is reviewed and the pros and cons of using it elaborated upon. The article is 12 pages with 137 citations. Editor’s comment: This is a nice review on a subject of importance to every physician who treats asthma. Abdullah AK, et al. J Asthma 2007; 44: 1

11. UPDATE IN ASTHMA 2006
Drs. Moore and Peters update asthma 2006. New concepts discussed include long-acting beta-agonists, risk, and the genetics of the β₂-adrenergic receptor. They also review the pros and cons of whether early inhalational corticosteroids prevent development of asthma in transient wheezing infants. Anti-tumor necrosis factor-α is discussed as a potential new asthma medication. In addition, gene-environment interactions, pharmacogenomics, endotoxin and ozone, remodeling in asthma (vascular remodeling and remodeling in children), and ADAM33, the gene that best exemplifies the increasing significance of extracellular matrix proteins and mesenchymal cells in asthma pathogenesis, are discussed. Editor’s comment: Great review for physicians who care for patients with asthma. Moore W et al. Am J Resp Crit Care Med 2007; 175: 649.

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