February 2007 World Medical Journal Review
Reviewed by Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief
1. BUDESONIDE/FORMOTEROL MAINTENANCE PLUS RELIEVER THERAPY, A NEW STRATEGY IN PEDIATRIC ASTHMA
Asthma (A) Three hundred and forty-one (341) children (4-11 years) with A, uncontrolled with inhaled corticosteroids (ICS), were included in a 12-month, double-blind, randomized study to determine whether budesonide/formoterol (B/F) 80/4.5 µg qd maintenance plus prn inhalations versus B/F 80/4.5 µg qd maintenance or budesonide 320 µg qd reduced A exacerbations. The B/F qd plus prn use prolonged the time from first exacerbation versus fixed dose B (P = 0.02) and fixed dose combination (P< 0.001). Mild exacerbation days and awakenings were significantly lower with B/F qd plus prn use, and yearly growth improved by one centimeter versus B 320 µg qd (P< 0.01). B/F used daily plus prn use versus fixed dose B and fixed dose combination reduces exacerbation rates (both P<0.001). Editor's comment: Daily use of combination therapy plus prn use may become a new, accepted treatment for A. Bisgaard H, et al. Chest 2006; 130: 1733.
2. TYMPANOSTOMY TUBES AND DEVELOPMENTAL OUTCOMES AT 9 TO 11 YEARS OF AGE
Four hundred and twenty-nine (429) children, before 3 years, with persistent effusion were randomly assigned to undergo the insertion of tympanostomy tubes either promptly or up to nine months later if effusion persisted. In a previous report, the authors concluded that prompt versus delayed insertion did not result in improved cognitive language, speech or psychosocial development at 3, 4 or 6 years. They now assess literacy, attention, social skills and academic achievement in 391 of these children at 9 to 11 years and conclude that mean scores of 48 developmental measures in children who underwent early insertion of tympanostomy tubes did not differ significantly from the scores in the group that was assigned to undergo delayed insertion at the later age. Editor's comment: The authors suggest that watchful waiting for at least six additional months with bilateral infusions and for an additional nine months with unilateral infusions is the preferred management option in most cases. Recommendations should be individualized. Paradise JL, et al. N Engl J Med 2007; 356: 248. Editorial, Berman S. N Engl J Med 2007; 356: 300.
3. MULTIPLE CHEMICAL SENSITIVITIES (MCS): A SYSTEMATIC REVIEW OF PROVOCATION STUDIES
This is a review of provocation studies of persons reporting MCS from a database search from inception to May 2006. Most studies were insufficiently controlled. The authors conclude that persons with MCS react to chemical challenges; however, responses only occur when they can discern differences between active and sham substances. This suggests that the mechanism of action is related to expectations and prior beliefs rather than to the chemical itself. Editor's comment: Fortunately, humans are not as sensitive to a variety of different environmental agents as believed by some individuals and physicians. Das-Munshi J, et al. JACI 2006; 118: 1257.
4. LONG-TERM COMPARISON OF 3 CONTROLLER REGIMENS FOR MILD-MODERATE PERSISTENT CHILDHOOD ASTHMA (A) : THE PEDIATRIC A CONTROLLER TRIAL
This DB 48-week trial of 285 children (6-14 years) with A compared the efficacy of 3 treatment regimens: fluticasone 100 µg 2x/d (F2X), fluticasone 100 µg/salmeterol 50 µg (FS) in the A.M. and salmeterol 50 µg (S) in the P.M., and montelukast 5 mg (M) in the P.M. F2X and the FS and S were comparable but the F2X was superior for clinic-measured FEV1/FVC (P = .015), maximum bronchodilator response (P = .009), exhaled nitric oxide (P <.001), and methacholine PC20 (P<.001). F2X was superior to M for A control days (64.2% vs. 52.5%; P = .004) and other control outcomes. Growth over 48 weeks was not statistically different among groups. The study confirms the current guideline recommendations favoring inhaled glucocorticoid monotherapy in mild-moderate persistent A. Editor's comment: Inhaled glucocorticosteroids should be the primary treatment for mild-moderate persistent childhood A. Sorkness C, et al. J Allergy Clin Immunol 2007; 119: 64.
5. HISTAMINE H4 RECEPTOR (H4R) ANTAGONISTS ARE SUPERIOR TO TRADITIONAL ANTIHISTAMINES IN THE ATTENUATION OF EXPERIMENTAL PRURITUS
The authors demonstrate that scratching responses in mice, induced by histamine and selective H4R agonists, were almost completely attenuated in H4R knockout mice or by pretreatment with a selective H4R antagonist, JNJ 7777120. Pruritus induced by allergic mechanisms was also inhibited by the H4R antagonist or in H4R knockout mice. The inhibitory effect of JNJ7777120 was greater than with a histamine H1 receptor antagonist. The H4R pruritus was shown to be independent of mast cells or other hematopoietic cells and may result from actions on peripheral neurons. The authors conclude that the H4R is involved in pruritic responses in mice more so than the histamine H1 receptor. Editor's comment: Will this new agent provide an alternative and effective therapy for chronic pruritus? I hope so. Dunford PJ, et al. J Allergy Clin Immunol 2007; 119: 176.
6. IMPACT OF SALMETEROL/FLUTICASONE PROPIONATE VERSUS SALMETEROL ON EXACERBATION IN SEVERE COPD
After a 4-week, run-in period, 994 clinically stable patients were randomized to one of two treatment groups, 507 received the salmeterol/fluticasone combination 50/500 µg 2x/d (SFC) and 487 received salmeterol 50 µg 2x/d (S) for 44 weeks. There were 334 exacerbations in the SFC and 464 in the S (P <0.0001). The annualized rate of moderate and severe exacerbations per patient was 0.92 in the SFC and 1.4 in the S group (35% decrease). Mean time to first exacerbation in SFC was significantly longer versus S (128 vs. 93 d, p<0.0001). QOL, PEF and use of rescue medication were significantly improved in the SFC group. The authors conclude that SFC is better than monotherapy with S for severe COPD. Editor's comment: SFC reduces exacerbation frequency in high risk patients with severe COPD. Kardos P, et al. Am J Respir Crit Care Med 2007; 175: 144.
7. ANTIBIOTIC (AB) TREATMENT OF EXACERBATIONS OF COPD; A RANDOMIZED, CONTROLLED TRIAL COMPARING PROCALCITONIN (P)-GUIDANCE WITH STANDARD THERAPY
Serum levels of P increase rapidly in the presence of infection. Two hundred and eight (208) consecutive COPD patients requiring hospitalization for COPD exacerbation were randomized to P-guided or standard AB therapy. Those receiving P-guided therapy were treated with AB according to serum P levels; standard-therapy patients received AB according to the attending physician. The primary outcome was the AB exposure at the index exacerbation and subsequent AB requirements for COPD exacerbation within six months. Secondary outcomes were clinical recovery, symptom scores, length of hospitalization, need for ICU stay, death, lung function, exacerbate rate, and time to the next exacerbation. P-guidance reduced AB prescriptions (P< 0.0001), AB exposure (RR, 0.56; 95% CI, 0.43 to 0.73; P <0.0001), and permitted significant reduction in total AB exposure for up to 6 months (RR, 0.76; 95% CI, 0.64 to 0.92; P = 0.004). Outcomes at 14 days to 6 months did not differ, neither did the exacerbation rate, re-hospitalization rate or the mean time to next exacerbation. The authors conclude that P-guidance reduces AB use for up to 6 months with a number-needed-to-treat of 3. Editor's comment: P levels seem to indicate whether AB will or will not benefit patients with a COPD exacerbation. Stolz D, et al. Chest 2007; 131: 9.
8. FEATURES OF SEVERE ASTHMA IN SCHOOL-AGE CHILDREN: ATOPY AND INCREASED EXHALED NITRIC OXIDE
This study identified features of severe versus mild-to-moderate asthma in school children by assessing lung function, presence of atopy and airway inflammation. A total of 75 children with asthma had lung volume testing, methacholine challenge, allergy evaluation and offline measures of exhaled nitric oxide (FENO). The severe asthma sub-group (N=39) required high doses of inhalational corticosteroids (ICS). These 39 children had more symptoms, greater airway obstruction, more gas trapping, increased methacholine sensitivity, higher concentrations of FENO, and greater sensitization to aeroallergens. Both the reduction of FEV1 and increased FENO persisted in the severe versus mild-to-moderate group throughout the study. Despite adjustments in ICS, the number of exacerbations was significantly higher in subjects with severe (83%) versus the mild-to-moderate group (43%). Editor's comment: Repeated exacerbations, greater allergen sensitization, increased airflow obstruction, and increased FENO all characterized more severe asthma in children. Fitzpatrick AM, et al. JACI 2006;118:1218.
9. EGG (E) ORAL IMMUNOTHERAPY (OIT) IN NONANAPHYLACTIC CHILDREN WITH E ALLERGY
E allergic subjects (positive ingestion hx. within 6 months of beginning the study with a + serum CAP of 7 kU/L or greater (2 kU/L or greater for subjects =2 years) or with a + allergic reaction to E within 6 months of beginning the study without a history of anaphylaxis to E underwent a 24-month E OIT involving modified rush, build-up and maintenance phases. DBPC food challenges were performed at study conclusion and E-specific IgE and IgG concentrations measured. E-specific IgG increased significantly, whereas E-specific IgE did not change in the seven subjects who completed the protocol. All tolerated significantly more E protein than at study onset. Two subjects demonstrated oral tolerance. The authors conclude that allergen-specific OIT to protect subjects with food allergy may represent a significant advancement in treatment. Editor's comment: Double-blind control studies with placebo and E oral therapy are now necessary. Buchanan AD, et al. J Allergy Clin Immunol 2007; 119: 199.
10. REPEATED MEASUREMENTS OF MITE AND PET ALLERGEN LEVELS IN HOUSE DUST OVER A TIME PERIOD OF 8 YEARS
The authors investigated the variability of house dust mites (Der p 1, Der f 1) and cat (Fel d 1) allergens in Dutch homes. Mite allergen concentrations for the child's mattress, the parents' mattress and the living room floor were moderately correlated between time-points. Agreement was better for cat vs. mite allergens. They conclude that over a period of 4 years, mite and cat allergens measured in house dust are sufficiently stable to use single measurements with confidence in epidemiologic studies. The within home variance was larger when samples were taken 8 years apart, so that over a longer period, repetition sampling is recommended. Editor's comment: Dust mite and pet allergen levels in homes vary little for at least 4 years. Antens CJM, et al. Clin Exp Allergy 2006; 36: 1525.
11. COMPARATIVE PHARMACOLOGY OF THE H1 ANTIHISTAMINES
This supplement begins with a review of the discovery of histamine and antihistamines. It contains chapters on comparative pharmacology, effects on the cardiovascular system, the central nervous system and their interactions. It concludes with a section on H1 antihistamines and their effects on psychomotor performance and driving. Editor's comment: A complete and excellent review of this subject. del Cuvillo A, et al. J Investig Allergol Clin Immunol 2006; 16: Supplement 1.
