May 2006 World Medical Journal Review

Reviewed by Richard F. Lockey, M.D., Editor-In-Chief

1. LONG-TERM INHALED CORTICOSTEROIDS (ICS) IN PRESCHOOL CHILDREN AT HIGH RISK FOR ASTHMA
Two-hundred and eighty-five children, two or three years old, with a positive asthma predictive index were observed for one year and then given either fluticasone propionate (FP), 88µg 2x d, or placebo for two years. They were followed one additional year on no study medication or placebo. Treatment was associated with a significantly greater proportion of episode-free days, a lower rate of exacerbations, and less supplemental use of controller medications. At the end of the fourth year, the height increase was 0.7 cm less in the treatment group (P = 0.008). Even though the FP group did better during the two years of treatment, FP treatment did not alter the development of asthma or lung function during a third treatment-free year. Editor's comment: ICS are effective to treat pre-school children with asthma but do not alter long-term outcomes. Guilbert TW, et al. N Engl J Med 2006; 354: 1985. Gold DR, Fuhlbrigge AL, (editorial) 2058.

2. INTERMITTENT INHALED CORTICOSTEROIDS IN INFANTS WITH EPISODIC WHEEZING
Two-hundred and ninety-four infants were randomly assigned to receive budesonide or placebo at their first episode of wheezing. Proportion of symptom-free days was similar in both groups as was persistent wheezing. The outcomes were not affected by the presence or absence of atopic dermatitis, and the mean duration of the acute episodes was identical in both groups and independent of respiratory viral status. Height and bone mineral density were not affected in either group. Inhaled budesonide has no short-term benefit during episodes of wheezing during the first three years of life nor does it affect the progression from episodic to persistent wheezing. Editor's comment: Finding a way to prevent these episodes may be the best solution for early onset episodic wheezing. Bisgaard H, et al. N Engl J Med 2006; 354: 1998. Gold DR, Fuhlbrigge AL, (editorial) 2058.

3. EFFECT OF CODEINE ON OBJECTIVE MEASUREMENT OF COUGH IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
Twenty-one patients with physician-diagnosed stable COPD with cough (77% male; mean age, 68 years; mean predicted FEV₁, 53%; median smoking history, 43.5 pack-years) were studied in a DBPC crossover study. Cough frequency, cough seconds/hours, citric acid cough threshold, and subjective measurements were obtained. Codeine phosphate 60 mg or matched placebo was administered, in random order, at the start of each cough recording (0 and 12 hours). There were no significant differences in median time spent coughing, challenge thresholds, or subjective cough measures for codeine vs. placebo. Editor's comment: Codeine was no better than placebo to treat cough in patients with COPD. Smith J, et al. J Allergy Clin Immunol 2006; 117: 831.

4. SELF-ADMINISTRATION OF C1-INHIBITOR CONCENTRATE IN PATIENTS WITH HEREDITARY OR ACQUIRED ANGIOEDEMA (A) CAUSED BY C1-INHIBITOR DEFICIENCY
Thirty-one patients who had frequent A attacks participated in an hereditary or acquired C1-inhibitor deficiency study. Patients were trained to self-administer IV C1-inhibitor concentrate on-demand (31 patients) or prophylactically (12 patients). Mean follow-up was 3.5 years. Patients were able to self-administer the concentrate. The time between the onset of an attack and relief or complete resolution of symptoms in the on-demand group was shortened to 2.2 hours vs. 7.9 hours (baseline date) in the on-demand group. Prophylactic treatment decreased the A attack rate from 4.0 to 0.3 (baseline data) attacks per month. Editor's comment: Self-administered IV C1-inhibitor concentrate is effective both on-demand and prophylactically. Levi M, et al. J Allergy Clin Immunol 2006; 117: 904

5. RESPIRATORY SYNCYTIAL VIRUS (RSV), AIRWAY INFLAMMATION, AND FEV₁ DECLINE IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
RSV RNA was detected by PCR in 32.8% of 241 sputum samples collected quarterly over two years from 74 patients with stable COPD. Patients in whom RSV was more frequently detected (> than 50% of samples RSV PCR-positive, n = 18) had higher airway inflammation and faster FEV₁ decline over the study period compared with those with less frequent detection of RSV. This relationship was independent of smoking status, exacerbation frequency, and lower airway bacterial load. Persistent RSV in COPD is associated with airway inflammation and accelerated decline in FEV₁. Editor's comment: RSV infection may accelerate lung function decline in COPD. Wilkinson TMA, et al. Am J Respir Crit Care Med 2006; 173: 871.

6. HIGH LEVELS OF MEDICAL UTILIZATION BY AMBULATORY PATIENTS WITH VOCAL CORD DYSFUNCTION (VCD) AS COMPARED TO AGE- AND GENDER-MATCHED ASTHMATICS
Twenty-five ambulatory patients with VCD were gender matched to 25 control patients with moderate persistent asthma. Total physician visits and subspecialty care visits were significantly greater among the VCD vs. the asthma cohort. Both groups had comparable utilization of prescriptions, frequency of hospitalizations, and urgent care visits. The authors conclude that VCD patients use significantly more medical services and similar pharmaceutical assets compared to patients with moderate persistent asthma. Editor's comment: VCD must be ruled out in every patient who presents with symptoms of asthma. Mikita J, Parker J, Chest 2006; 129: 905. Christopher K, (editorial) 842.

7. CYSTEINYL LEUKOTRIENE RECEPTOR 1 PROMOTER POLYMORPHISM IS ASSOCIATED WITH ASPIRIN-INTOLERANT ASTHMA (AIA) IN MALES
Cysteinyl Leukotrienes (CysLTs) are important in the pathogenesis of AIA. Three CysLTR 1 promoter single nucleotide polymorphisms (SNPs) were associated with AIA risk in males, and males with AIA had significantly higher frequencies of the minor alleles (T,C,G) at the three SNPs than male control subjects. Moreover, the two common three-SNP haplotypes were also associated with AIA risk in males. The ht1 [C-A-A] haplotype was associated with decreased risk and ht2 [T-C-G] haplotype with increased risk. Males were younger than females in the AIA group. Male AIA patients carrying ht2 [T-C-G] may be at greater risk to develop AIA at an earlier age. There were no significant associations of CysLTR1 genotypes or three-SNP haplotypes with AIA risk in female patients. Genetic variants of CysLTR 1 are associated with AIA in a Korean population and may modulate CysLTR 1 expression. Editor's comment: Understanding the genetics of AIA will go along way in understanding its pathogenesis. Kim S-H, et al. Clin Exp Allergy 2006; 36: 433.

8. SAFETY OF SPECIFIC IMMUNOTHERAPY (SIT) USING A FOUR-HOUR ULTRA-RUSH INDUCTION SCHEME IN BEE AND WASP ALLERGY
Sixty-seven Hymenoptera allergic individuals received 80 outpatient courses of ultra-rush SIT. In 78 courses (97.5%), the maintenance dose of 111.1 µg was reached within four hours and was tolerated in 82.5% without any adverse reaction. Allergic reactions were observed in 17.5% (n = 14), all of which were local reactions and none of which was life-threatening. Ultra-rush IT to Hymenoptera (wasp and honeybee venoms) was safe, convenient,and completed within 4 hours in an outpatient setting. Editor's comment: Venom immunotherapy using a four-hour-ultra-rush IT schedule was safe. Roll A, et al. J Investig Allergol Clin Immunol 2006; 16: 79.

9. INTRANASAL DELIVERY OF THE CYTOPLASMIC DOMAIN OF CTLA-4 USING A NOVEL PROTEIN TRANSDUCTION DOMAIN PREVENTS ALLERGIC INFLAMMATION
CTLA-4 is a negative regulator of T-cell activation. CTLA-4 was fused to a novel protein-transduction domain in human transcriptional factor Hph-1 to suppress allergic inflammation. The Hph-1-ctCTLA-4 fusion protein (FP) inhibited the production of IL-2 and downregulated CD69 and CD25. Intranasal administration of the FP, reduced infiltration of inflammatory cells, secretion of T_H2 cytokines, serum IgE levels, and airway hyper-responsiveness in a mouse model of allergic airway inflammation. Thus, CTLA-4 might block the T_H2 cell-polarized T-cell activation and potentially could be used intranasally to treat allergic asthma. Editor's comment: Another molecule which could possibly be used intranasally to downregulate allergic inflammation. Choi J, et al. Nature Medicine 2006.

10. AN ANTIBODY-DEFICIENCY SYNDROME DUE TO MUTATIONS IN THE C19 GENE and INHERITED AND SOMATIC CD3ζ IN A PATIENT WITH T-CELL DEFICIENCY
Four patients with mutations in the CD19 gene had increased susceptibility to infection, hypogammaglobulinemia, and normal numbers of B-cells. The CD19 gene is responsible for generating CD19, a protein on the B-cell surface which forms a complex with other proteins that participate in activation of B-cells by antigens. In a SECOND article a child with greatly increased susceptibility to viral, bacterial, and fungal infections was found to have inherited a homozygous germ-line mutation of the CD3ζ gene. CD3ζ is a component of the CD3 T-cell-receptor complex and is essential for T-cell activation. These articles are accompanied by a superb editorial entitled, "Disabled Receptor Signaling and New Primary Immunodeficiency Disorders." Editor's comment: These articles and the editorial are must reading for physicians who do not understand the multiple defects that cause T-cell and B-cell immunodeficiencies. van Zelm MC, et al. N Engl J Med 2006; 354: 1901, Rieux-Laucat F, et al. 1913, Rudd CE, (editorial) 1874.

11. REVIEW OF THE USE OF INTRAVENOUS GAMMA GLOBULIN (IGIV) IN HUMAN IMMUNODEFICIENCY DISEASES
This is an evidence-based review of the use of IGIV for primary immunodeficiency, secondary immunodeficiency, autoimmune diseases, asthma, and neurological disorders. Editor's comment: Article is full of wonderful tables and references and is excellent reading. Orange JS, et al. J Allergy Clin Immunol 2006; 117: S525

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