November 2006 World Medical Journal Review
Reviewed by Richard F. Lockey, M.D., Editor-In-Chief
1. THE NATURAL HISTORY OF ASTHMA IN CHILDREN AND ADULTS BY DRS CHARLES REED & GAIL SHAPIRO
Dr. Reed lists six predictors of persistence and severity of adult asthma to include continued exposure to allergens, including occupational agents, older age onset, aspirin sensitivity, socioeconomic status, smoking and coexisting disease (COPD, bronchiectasis, etc.). For children, both Drs. Reed and Shapiro include a family history of atopy, early sensitization, and airway hyper-responsiveness. Dr. Shapiro also includes early onset; low lung function; female sex; smoking, passive smoking and smoking during pregnancy; and maternal asthma. Dr. Reed, for children, covers more frequent and severe asthma, onset during school age, increased serum IgE, increased URIs, lack of contact with other children, parenting problems and childhood psychological problems. Dr. Shapiro concludes, regardless of the prognosis of childhood wheezing, that parents of children with both low and high risk for persistent disease can be comforted and reassured if they follow an action plan for daily maintenance treatment and for acute exacerbations of asthma. Editor’s comment: Two outstanding articles discuss the vexing problem of who will and who will not have persistent childhood and adult asthma. Reed CE, J Allergy Clin Immunol 2006; 118: 543; the late Dr. Shapiro GG: 562.
2. THE EFFECTS OF A MONOCLONAL ANTIBODY DIRECTED AGAINST TUMOR NECROSIS FACTOR-α IN ASTHMA
Infliximab (I) (Remicade), a recombinant human-murine chimeric monoclonal antibody that specifically and potently binds and neutralizes the soluble TNF-α homotrimer and its membrane-bound precursor, was used in a DBPC, parallel-group study in 38 patients with moderate asthma treated with inhaled corticosteroids who were symptomatic during a run-in-phase. Lung function, symptoms and inhaled β2-agonist usage were monitored. There was no change in morning PEF, however, it was associated with a decrease in mean diurnal variation in PEF at wk 8 (p = 0.02). Likewise there was a decrease in exacerbations in the treatment group (p = 0.01) and an increased probability of freedom from exacerbation with time (p = 0.03). I decreases levels of TNF-α and other cytokines in sputum supernatants. No serious adverse events occurred. Editor’s comment: I looks like a promising therapy for moderate asthma. Erin EM, et al. Am J Respir Crit Care Med 2006; 174: 753.
3. URINE LEUKOTRIENE E4 LEVELS ARE ASSOCIATED WITH DECREASED PULMONARY FUNCTION IN CHILDREN WITH PERSISTENT AIRWAY OBSTRUCTION
This study was designed to assess the relationship between daily variability in urinary leukotriene E4 (LTE4) levels and daily lung function in 50 children with moderate to severe asthma primarily taking an inhaled corticosteroid (ICS) and long-acting β-agonist (LABA). Urinary LTE4, monitoring of FEV1, and albuterol use were measured. Daily variability in LTE4 levels is associated with clinically significant decreases in pulmonary function. In children who demonstrate a response associated with an increase in urinary LTE4 levels, leukotriene receptor antagonists protect against daily FEV1 decreases, which may be greatest in those with persistent airway obstruction despite the use of combined ICS and LABA therapy. Editor’s comment: Asthma is a complex disease and what is good for the goose may not be good for the gander. Rabinovitch N, et al. J Allergy Clin Immunol 2006; 118: 635.
4. THE COMPLEMENT INHIBITOR ECULIZUMAB IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
Patients (87) underwent randomization to receive either placebo (P) or eculizumab (E, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation) intravenously. Subjects were given 600 mg weekly for four weeks, followed one week later by a 900-mg dose and then 900 mg every other week through week 26. Stabilization of hemoglobin levels in the absence of transfusions was achieved in 49% of treated vs. P (P<0.001). During the study, no packed red cells were administered to the treatment group vs. 10 to the P group (P<0.001). E reduced intravascular hemolysis vs. P (P<0.001). There was a statistical improvement in quality of life in the treated group (P<0.001). There were no serious adverse events considered to be treatment-related. Editor’s comment: E is an effective therapy for PNH. Hillmen P, et al. N Engl J Med 2006; 355: 1233.
5. CONCLUSIONS FROM THREE SEPARATE PAPERS FROM THE EUROPEAN HEALTH SURVEY
The first study determined cat allergen levels in approximately 3,000 mattresses during home visits in 22 communities. It showed that people who do not own cats may be exposed to high levels of cat allergen in their homes, particularly if they live in communities with high cat ownership. The second article determined that there are large qualitative and quantitative differences in house dust mite allergen levels partially explained by geographic and housing characteristics. They recommend that mite allergen levels could be reduced by replacing mattresses and increasing ventilation of the bedroom, particularly in the winter. The third article, perhaps the most interesting, determined that selective avoidance of cats subsequent to the onset of asthma and allergy was observed for childhood cat-keeping and adult cat acquisition, implying that part of the protective effects of childhood cats on asthma and allergy can be attributed to selective avoidance. Editor’s comment: Allergen avoidance is complex in spite of the best intentions of the physician and patient. Heinrich J, et al. J Allergy Clin Immunol 2006; 118: 674; Zock J, et al: 682; Svanes C, et al: 691.
Cat allergen level: Its determinants and relationship to specific IgE to cat across European centers
Distribution and determinants of house dust mite allergens in Europe: The European Community Respiratory Health Survey II
Do asthma and allergy influence subsequent pet keeping? An analysis of childhood and adulthood
6. PHARMACOLOGIC AND ANTI-IgE TREATMENT OF ALLERGIC RHINITIS ARIA UPDATE (IN COLLABORATION WITH GA2LEN)
This document updates the ARIA sections on the pharmacologic and anti-IgE treatment of allergic rhinitis literature published between January 2000 and December 2004. Oral H1-antihistamines, intranasal corticosteroids, intranasal H1-antihistamines, intranasal chromones, and anti-IgE mab achieved level evidence A, for seasonal and perennial rhinitis in children and adults. Anti-leukotrienes achieved an A level for seasonal rhinitis but not for perennial rhinitis for both groups. For “persistent rhinitis,” all treatments for both groups were either A or B except for the intranasal chromones which could not be rated. Editor’s comment: Physicians have a variety of different, proven treatments for seasonal and perennial rhinitis. Bousquet J, et al. Allergy 2006; 61: 1086.
7. A 10 YEAR ASTHMA PROGRAMME IN FINLAND: MAJOR CHANGE FOR THE BETTER
A National Asthma Program was undertaken in Finland from 1994-2004 to improve asthma care and prevent increased costs. Although the incidence of asthma is increasing, the number of hospital days fell by 54%, mortality decreased, and absolute numbers for disability pensions, allowances for days off work, and need for rehabilitation all decreased 30 to 50%. Most impressive was that there was an annual reduction in cost per patient of 50%. The authors conclude that diseases such as asthma require a multi-disciplinary action program with a broad commitment by the health care system and society. Editor’s comment: Optimal care and compliance led to decreased morbidity and mortality from asthma. Haahtela T, et al. Thorax 2006; 61: 663.
8. PERSISTENCE, ADHERENCE, AND EFFECTIVENESS OF COMBINATION THERAPY AMONG ADULT PATIENTS WITH ASTHMA
These authors compared persistence, adherence and effectiveness between patients with asthma, 16 to 44 yrs, using either a combination of an inhaled corticosteroid (ICS) and a long-acting β2-agonist (LABA) in one inhaler or the individual use of two different inhalers with similar medications. It is a retrospective 1-to-1 matched cohort of newly treated asthmatics selected from a database between 1999 and 2002. Using a variety of statistical models, persistence of use of medication fell to 10% and 5% after 12 months for combination and concurrent user, respectively. Combination users were found to be 17% less likely to stop their treatment, filled on average 0.9 more prescriptions per year, and were found to be 17% less likely to have a moderate to severe asthma exacerbation. Editor’s comment: When an ICS and LABA are used in one inhaler vs. two separate inhalers, compliance and outcomes improve. Marceau C, et al. J Allergy Clin Immunol 2006; 118: 574.
9. IMMUNOTHERAPY WITH A RAGWEED-TOLL-LIKE RECEPTOR 9 AGONIST VACCINE FOR ALLERGIC RHINITIS
These authors conducted a randomized DBPC trial of a vaccine consisting of Amb a 1, conjugated to a phosphorothioate oligodeoxyribonucleotide immunostimulatory sequence of DNA (AIC) in 25 ragweed allergic subjects. They received six weekly injections of AIC vs. placebo before the ragweed season. The vaccine did not reduce the albumin level in nasal-lavage fluid but had positive effects on peak season rhinitis scores (P=.0006), peak-season daily nasal symptoms scores (P=0.02), and midseason overall quality-of-life (P=0.05). It also induced a transient increase in Amb a 1-specific IgG antibody and suppressed the seasonal increase in Amb a 1-specific IgE antibody. Some clinical benefits and seasonal specific IgE antibody responses were observed in the subsequent ragweed season. Editor’s comment: More studies are needed but AIC may be useful to treat allergic rhinitis. Creticos PS, et al. N Engl J Med 2006; 355: 1445.
10. KILLED MYCOBACTERIUM VACCAE SUSPENSION IN CHILDREN WITH MODERATE-TO-SEVERE ATOPIC DERMATITIS: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL
This multi-centered study determined the effects of intradermal injection of killed M. vaccae (0.1 or 1 mg) on patients, aged 5-16, with moderate to severe AD. The primary end point was change in severity at 12 weeks using a six area, six sign, atopic dermatitis score. Secondary end points included changes in disease extent, patient’s global assessment and children’s dermatologic QOL index. In 166 randomized patients, M. vaccae was no more effective than placebo in ameliorating the severity of AD. Editor’s comment: Decreased exposure to mycobacterial infection does not seem to be a reason for the increased incidence of atopic dermatitis. Berth-Jones J, et al. Clinical and Experimental Allergy 2006; 36: 1115.
11. PROBIOTICS IN THE PREVENTION OF ANTIBIOTIC-ASSOCIATED DIARRHEA (AAD) IN CHILDREN: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS
Six randomized, placebo-controlled trials (766 children) were included in this meta-analysis to determine whether or not treatment with probiotics vs. placebo reduced the risk of AAD. The results show that such treatment reduced the risk of AAD from 28.5% to 11.9% (RR, 0.44, 95% CI 0.25 to 0.77, random effect model). Reduction of risk was associated with the use of Lactobacillus GG, S. boulardii or B.lactis & Str. thermophilus. The authors conclude that for every seven patients that would develop AAD while on antibiotics, one fewer would occur if they also received probiotics. Editor’s comment: Give cultured yogurt or probiotics. They decrease AAD in children. Szajewska H, et al. J Pediatr 2006; 149: 367.
12. PSYCHIATRIC ADVERSE EFFECTS OF CORTICOSTEROIDS
Two large meta-analyses found that severe reactions occurred from systemic corticosteroids in nearly 6% of patients and mild to moderate reactions in about 28%. Side effects include mood, cognition, sleep and behavior problems (frank delirium or even psychosis). The most common are euphoria and hypomania. Dosage seems to be most related to the incidence of adverse effects. In severe cases, where these drugs cannot be reduced, antipsychotics or mood stabilizers may be required. Editor’s comment: An excellent review of a problem that allergists/immunologists face all the time. Warrington TP, Bostwick JM. Mayo Clin Proc 2006; 81: 1361.
