July 2006 World Medical Journal Review
Reviewed by Richard F. Lockey, M.D., Editor-In-Chief
1. EFFECTS OF EARLY INTERVENTION WITH INHALED BUDESONIDE ON LUNG FUNCTION IN NEWLY DIAGNOSED ASTHMA
This randomized, double-blind study of 7,165 patients (5 to 66 yrs) with persistent asthma for < 2 years determined whether early intervention with low-dose inhaled budesonide (IB) prevents severe asthma-related events and decline in lung function. Patients received IB (200 µg qd for children < 11 years and 400 µg qd for others) or placebo for three years in addition to the usual asthma medications. IB treatment significantly improved pre- and post-bronchodilator FEV1 percentage of predicted and reduced the mean declines from baseline for bronchodilator FEV1 at one and three years: -0.62% and -1.79% for IB and -2.11% and -2.68% for placebo, respectively (p<0.001). The decline was more marked for males, active smokers, and subjects > 18 years. The smallest treatment effects occurred in adolescents. Editor's comment: This multinational study demonstrates that low-dose IB improves lung function in recent-onset persistent asthma and reduces the loss of lung function over time. O'Byrne PM, et al. Chest 2006; 129: 1478.
2. SENSITIZATION TO AEROALLERGENS AND AIRWAY HYPERRESPONSIVENESS (AHR) AT 7 YEARS OF AGE
One hundred thirty-one children at high risk for atopy underwent both skin-prick tests (SPT) to a panel of aeroallergens and a methacholine challenge test between 6.5 and 8.8 years (median-age 7.0 yr) of age to investigate the relationship between current and early life factors and AHR. Fifty-one percent (67) had at least one positive SPT and 28% (37) had AHR. After adjusting for relevant covariates, AHR was strongly associated with sensitization to at least four aeroallergens: cat, dust mite, cockroach, and ragweed. No relationship was found with early life exposure to perennial aeroallergens or other perinatal and first-year-of-life factors (daycare attendance, breastfeeding, tobacco exposure, and lower respiratory tract infection). The authors conclude that among young children at risk for atopy, sensitization to specific aeroallergens, but not early life exposures, is associated with increased AHR. Editor's comment: The major risk factor for AHR in this study was sensitization to cat, dust mite, cockroach, and ragweed. TePas EC, et al. Chest 2006; 129: 1500.
3. EARLY RISE IN EXHALED NITRIC OXIDE AND MAST CELL ACTIVATION IN REPEATED LOW-DOSE ALLERGEN CHALLENGE
Eight subjects with mild allergic asthma completed two 7-day repeated low-dose challenge periods with diluent and allergen, respectively. Subjects were symptom free at inclusion and were investigated when not exposed to specific allergen. Pulmonary function and symptoms were followed, and nitric oxide fraction (Fe,NO) and urinary mediators were correlated to changes in airway responsiveness to histamine and adenosine. There were no pulmonary function changes or asthma symptoms. Repeated allergen exposure, in contrast to diluent, caused significant increases in histamine responsiveness (2.3 doubling doses), an early and gradual increase in Fe,NO (up to a doubling from baseline) and a small increase in the mast cell marker 9α11β-prostaglandin F2 after adenosine challenge. Editor's comment: Serial low-dose allergen exposure causes airway inflammation. Ihre E, et al. Eur Respir J 2006; 27: 1152.
4. RAPID SUBCUTANEOUS IgG REPLACEMENT THERAPY IS EFFECTIVE AND SAFE IN CHILDREN AND ADULTS WITH PRIMARY IMMUNODEFICIENCIES – A PROSPECTIVE, MULTI-NATIONAL STUDY
Sixty patients (16 children, 44 adults) participated in this study to evaluate: (1) IgG levels when switching patients from intravenous IgG (IVIG) infusions in hospital to subcutaneous (SCIG) self-infusions at home using the same cumulative dose, (2) protections against infections, and (3) safety of a new, ready-to-use 16% IgG preparation. Ten adults who had been on SCIG therapy for years served as controls. In total, 2,297 infusions were given and 28 (1%) had systemic adverse reactions, none severe. SCIG administration was safe and high IgG levels were easily maintained resulting in protection against infections. Editor's comment: SCIG is safe and effective and could be more cost effective than IVIG. Gardulf A, et al. J Clin Immunol 2006; 26: 177.
5. PROGNOSTIC FACTORS OF ASTHMA SEVERITY: A 9-YEAR INTERNATIONAL PROSPECTIVE COHORT STUDY
The Global Initiative for Asthma categorization was used in 2002 to investigate severity of asthma in 856 subjects identified with asthma from 1991-93 in the European Community Respiratory Health Survey. The severity (remittent, intermittent, mild, moderate, severe), as measured at baseline, was a determinant of a patient's severity at follow-up. Moderate and severe persistent asthma are characterized by early deterioration of lung function. High IgE levels and persistent cough/mucus hypersecretion are strong markers of moderate/severe asthma. Remission occurs primarily in individuals with less severe asthma. Editor's comment: Severe asthma begets severe asthma. de Marco R, et al. J Allergy Clin Immunol 2006; 117: 1249.
6. FUNCTIONAL POLYMORPHISMS IN THE MANNAN-BINDING LECTIN (MBL) 2 GENE: EFFECT ON MBL LEVELS AND OTITIS MEDIA
Twelve genetic variants in the MBL2 gene and functional MBL serum levels were determined in a cohort of children with recurrent acute otitis media. Haplotypes were constructed and associated with functional MBL serum levels and the number of otitis episodes in the previous year. Single nucleotide polymorphisms in the promoter region, in exon 1, and in exon 4 of MBL2 were found to contribute to increased risk for otitis media in children younger than two years of age . Editor's comment: MBL is clinically important during early childhood when maternally derived antibodies and protective adaptive immunity is not fully developed. Wiertsema SP, et al. J Allergy Clin Immunol 2006; 117: 1344.
7. CHEMOKINES INDICATE ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA) IN PATIENTS WITH CYSTIC FIBROSIS
Levels of the Th2 chemokines thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) were measured in patients with CF and ABPA, asthma and ABPA, CF colonized with Aspergillus fumigatus, CF sensitized to A. fumigatus, atopic patients with CF, and non-CF atopic control subjects. Serum levels of TARC differentiate patients with CF or patients with asthma with ABPA with all others. Longitudinally, levels of TARC indicate ABPA exacerbations, suggesting TARC as a marker for identification and monitoring of ABPA in patients with CF. TARC vs IgE is a more sensitive marker for exacerbations for patients with CF and ABPA. Editor's comment: Perhaps TARC is a therapeutic target in patients with ABPA. Hartl D, et al. Am J Respir Crit Care Med 2006; 173; 1370.
8. MAJOR CONGENITAL MALFORMATIONS AFTER FIRST-TRIMESTER EXPOSURE TO ACE INHIBITORS
A cohort of 29,507 infants was studied between 1985 and 2000. Two hundred nine and 202 were exposed to ACE inhibitors and other antihypertensive medications, respectively, during the first trimester and compared to 29,096 controls. Infants with only first trimester exposure to ACE inhibitors, had an increased risk of major congenital malformations (risk ratio (RR), 2.71; 95% confidence interval (CI), 1.72 to 4.27), particularly of the cardiovascular and central nervous systems (RR, 3.72; 95% CI, 1.89 to 7.30). ACE inhibitors should be avoided during pregnancy. Editor's comment: All physicians should be aware that ACE inhibitors used during pregnancy are associated with congenital malformations. Cooper WO, et al. N Engl J Med 2006; 354: 2443.
9. RHINITIS MEDICAMENTOSA (RM)
RM is a condition induced by the overuse of nasal decongestants. The term RM, also called rebound or chemical rhinitis, is also used to describe the adverse nasal congestion that develops after using medications other than topical decongestants. Such medications include oral ß-adrenoceptor antagonists, antipsychotics, oral contraceptives, and antihypertensives. There are different mechanisms through which congestion is caused by topical nasal decongestants vs. oral medications. This article reviews rhinitis medicamentosa as well as drug induced rhinitis. It reviews its presentation, physiology of nasal congestion, mechanisms of action of nasal decongestants, pathophysiology of RM, histology of RM, treatment of RM, and the need for further research. Editor's comment: RM and drug induced rhinitis have to be first recognized before they can be treated. Ramey JT, et al. J Investig Allergol Clin Immunol 2006; 16: 148.
10. LOW-DOSE INHALED AND NASAL CORTICOSTEROID USE AND THE RISK OF CATARACTS
A matched nested case-control analysis was performed in a population-based cohort of elderly people who had been dispensed medications for airway disease through a universal drug benefit plan. Inhaled (lung) corticosteroid (IGC) use was associated with a dose-related increase in both the risk of all cataracts and severe cataracts requiring extraction, and the increase in risk of severe cataracts was apparent even at daily doses of < 500 µg. The authors conclude that among the elderly, even low-doses of IGC are associated with a small but significant excess risk of cataracts requiring extraction. This excess risk was not observed with nasal corticosteroids (NGC). Editor's comment: ICG and NGC should be used in the lowest possible doses to maintain disease control. Ernst P, et al. Eur Respir J 2006; 27: 1168.
11. REVIEW OF THE MAST CELL
This review contains articles by Chang TW et al, "Anti-IgE as a mast cell-stabilizing therapeutic agent"; Rivera J, et al, "Molecular regulation of mast cell activation"; Metcalfe DD, et al, "Mast cell biology in evolution"; Bradding P, et al, "The role of the mast cell in the pathophysiology of asthma"; Gurish MF, et al, "Mast cells: Ontogeny, homing, and recruitment of a unique innate effector cell". Editor's comment: The mast cell is an extraordinarily complex cell and remains the sentinel cell of allergic inflammation. J Allergy Clin Immunol 2006; 117: (6).
Anti-IgE as a mast cell-stabilizing therapeutic agent
Molecular regulation of mast cell activation
Mast cell biology in evolution (No abstract available)
The role of the mast cell in the pathophysiology of asthma
Mast cells: Ontogeny, homing, and recruitment of a unique innate effector cell
12. EOSINOPHILS
Proceedings of a workshop in Tokyo, Japan, June 11, 2005 entitled "Eosinophils in Allergy and Related Diseases" is published in the International Archives of Allergy and Immunology. Papers included: Kishimoto S, et al, "Chemotaxis of Human Peripheral Blood Eosinophils to 2-Arachidonoylglycerol: Comparison with other Eosinophil Chemoattractants"; Itakura A, et al, "Interleukin 5 Plays an Essential Role in Elicitation of Contact Sensitivity through Dual Effects on Eosinophils and B-1 Cells"; Kushiya M, et al, "Differential Effects of Salbutamol and Montelukast on Eosinophil Adhesion and Superoxide Anion Generation"; Komiya A, et al, "Expression and Function of Toll-Like Receptors in Human Basophils"; Adachi T, et al, "The Role of Platelet-Derived Growth Factor Receptor in Eotaxin Signaling of Eosinophils"; Ueki S, et al, "Procaterol Upregulates Peroxisome Proliferator-Activated Receptor-γ Expression in Human Eosinophils"; Matsumoto K, et al, "CpG Oligodeoxynucleotide Prolongs Eosinophil Survival through Activation of Contaminating B Cells and Plasmacytoid Dendritic Cells in vitro"; Hashimoto T, et al, "IL-2-Induced IL-13 Production by Allergen-Specific Human Helper T Cell Clones"; and Mori A, et al, "Th2-Cell-Mediated Chemokine Synthesis Is Involved in Allergic Airway Inflammation in Mice". Editor's comment: This is a very interesting review of the advances in eosinophillic biology and their role in allergic diseases. Int Arch Allergy Immunol 2006; 140: 1-62.
Chemotaxis of Human Peripheral Blood Eosinophils to 2-Arachidonoylglycerol: Comparison with other Eosinophil Chemoattractants
Interleukin 5 Plays an Essential Role in Eliciatation of Contact Sensitivity through Dual Effects on Eosinophils and B-1 Cells
Differential Effects of Salbutamol and Montelukast on Eosinophil Adhesion and Superoxide Anion Generation
Expression and Function of Toll-Like Receptors in Human Basophils
The Role of Platelet-Derived Growth Factor Receptor in Eotaxin Signaling of Eosinophils
Procaterol Upregulates Peroxisome Proliferator-Activated Receptor-γ Expression in Human Eosinophils
CpG Oligodeoxynucleotide Prolongs Eosinophil Survival through Activation of Contaminating B Cells and Plasmacytoid Dendritic Cells in vitro
IL-2-Induced IL-13 Production by Allergen-Specific Human Helper T Cell Clones
Th2-Cell-Mediated Chemokine Synthesis Is Involved in Allergic Airway Inflammation in Mice
13. IN VIVO AND IN VITRO ALLERGY TESTING
The current issue of the journal of the Allergy Society of South Africa (ALLSA), Current Allergy & Clinical Immunology, is a review of in vivo and in vitro allergy testing. Articles included: Morris AJ, "To allergy test or not to test?"; Koshak E, "Do in vitro IgE tests have a role in identifying atopic asthma?"; Morris A, "Is allergy testing cost-effective?"; Potter PC, "Clinical indications and interpretation of the CAST"; Lopata AL, "Specialized in vitro diagnostic methods in the evaluation of hypersensitivity – an overview"; and Morris A, "ALLSA Position Statement: Allergen skin-prick testing." Editor's comment: An excellent review of allergy testing. Current Allergy & Clinical Immunology 2006; 19: 2-25.
To allergy test or not to test?
Do in vitro IgE tests have a role in identifying atopic asthma?
Is allergy testing cost-effective?
Clinical indications and interpretation of the CAST
Specialized in vitro diagnostic methods in the evaluation of hypersensitivity – an overview
ALLSA Position State: Allergen skin-prick testing
14. APPROACHES TO THE TREATMENT OF HYPEREOSINOPHILIC SYNDROMES: A WORKSHOP SUMMARY REPORT
Hypereosinophilic syndromes are a heterogeneous group of diseases characterized by the presence of marked peripheral blood eosinophilia, tissue eosinophilia, or both, which cause a wide variety of clinical manifestations. This group of clinicians discusses current and future approaches to therapy for 3 eosinophil-mediated disorders: hypereosinophilic syndrome, Churg-Strauss syndrome, and eosinophil-associated gastrointestinal disease. Editor's comment: Excellent workshop summary on hypereosinophilic syndromes. Klion AD, et al. J Allergy Clin Immunol 2006; 117: 1292.
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