Medical Journal Review

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

1. SALMETEROL (S) AND FLUTICASONE PROPIONATE (FP) AND SURVIVAL IN CHRONIC OBSTRUCTIVE PLUMONARY DISEASE (COPD)
This is a randomized, double-blind trial comparing S 50 µg plus FP 500 µg in a single inhaler two times daily with placebo, S 50 µg alone, or FP 500 µg alone for 3 yrs to treat COPD. The primary outcome was death from any cause. Secondary outcomes included frequency of exacerbation, spirometric values and health status. 6,112 patients were included, and 875 died within 3 yrs, 12.6% in the combination–therapy group, 15.2% in the placebo group, 13.5% in the S group, and 16.0% in the FP group, corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5% (P=0.052). S alone or FP alone did not differ significantly from placebo. Compared with placebo, the combination regimen reduced annual exacerbation rates from 1.13 to 0.85 and improved health status and spirometric values (P<0.001 for all comparisons with placebo). Pneumonia as an adverse event was higher among patients receiving medications containing FP (19.6% in the combination-therapy group and 18.3% in the F group) vs. placebo (12.3%, P<0.001 for comparisons between these treatments and placebo). The reduction in deaths from all causes did not reach statistical significance; however, there are significant benefits in other outcomes with the combined therapy. Editor’s comment: Combination-therapy reduced annual exacerbation rates and improved health status and spirometric values (secondary outcomes) but had no statistical effect on mortality (primary outcome). Calverley PMA, et al. N Engl J Med 2007; 356: 775. Editorial, Rabe KF. N Engl J Med 2007; 356; 851.

2. VANCOMYCIN-INDUCED IMMUNE THROMBOCYTOPENIA
Vancomycin-dependent, platelet-reactive IgG or IgM antibodies were identified in 34 patients suspected of having vancomycin-induced thrombocytopenia. Clinical follow-up information on 29 patients revealed a mean nadir platelet count of 13,600 per mm3 and severe bleeding in 10 patients (34%). Platelet levels returned to baseline in all 26 surviving patients when vancomycin was stopped. Vancomycin-dependent antibodies were not found in 25 controls given vancomycin without thrombocytopenia. The authors conclude that severe bleeding occurs in vancomycin-induced immune thrombocytopenia and the diagnosis can be confirmed by the detection of vancomycin-dependent antiplatelet antibodies. Editor’s comment: Add vancomycin to the list of drug-induced thrombocytopenia. Von Drygalski A, et al. N Engl J Med 2007; 356: 904. Editorial, Warkentin TE. N Engl J Med 2007; 356: 891.

3. A BRIEF HISTORY OF TH17, THE FIRSTS MAJOR REVISION IN THE TH1/TH2 HYPOTHESIS OF T CELL-MEDIATED TISSUE DAMAGE
This author reviews the evolution of several hypotheses which dominated thinking in cell-to-cell regulation and interaction and the pathogenesis of disease. First was the concept of T-helper and T-suppressor cells which was replaced by the concept that cytokines produced by the TH1 cells could negatively regulate the function of TH2 cells and vice versa. The TH1/TH2 hypothesis is being replaced by newer data which indicate that a pathway named TH17 is now credited for causing and sustaining tissue damage in diverse situations such as organ-specific autoimmunity in the brain, heart, synovium and intestines, allergic disorders of the lung and skin, and microbial infections of the intestines and nervous system. It is likely to become established that no single cytokine can regulate a vital process like tissue damage and that it is a constellation of cytokines, tuned in concert, which ultimately produces a complex phenotype like “tissue damage” or “recovery from tissue damage”. Editor’s comment: This is a very lucid article summarizing the newest information on T-helper cell differentiation and regulation. Must reading for everyone. Steinman L. Nature Medicine 2007; 13: 139.

4. META-ANALYSIS: INTRAVENOUS IMMUNOGLOBULIN (IVIG) IN CRITICALLY ILL ADULT PATIENTS WITH SEPSIS
All randomized controlled trials of critically ill adults with sepsis, severe sepsis or septic shock who received IVIG or placebo or no intervention were reviewed. 20 trials (n=2621) met eligibility criteria and were analyzed. IVIG was associated with an overall survival benefit (RR, 0.74 [95% CI, 0.62 to 0.89) compared with placebo or no intervention. The authors suggest that a large randomized, controlled trial of IVIG therapy be performed because of the methodological limitations of the current literature review. Editor’s comment: IVIG seems to be helpful in adult patients with sepsis, but a large controlled trial is necessary. Turgeon AF, et al. Ann Intern Med 2007; 146: 193.

5. CLINICAL TRIAL OF LOW-DOSE THEOPHYLLINE (T) AND MONTELUKAST(M) IN PATIENTS WITH POORLY CONTROLLED ASTHMA (A)
This is a randomized, double-masked, placebo-controlled trial of 489 subjects with poorly controlled A randomly assigned to placebo, T (300 mg/d), or M (10 mg/d). Participants were monitored for 24 wk to measure rate of episodes of poor A control (EPACs) defined by decreased peak flow (PEF), increased β-agonist use, increased oral corticosteroid (CS) use, or unscheduled health care visits. Results show there was no significant difference in EPACs compared with placebo: low-dose T, 4.9 (95% CI, 3.6-6.7; not significant); M, 4.0 (95% CI, 3.0-5.4; not significant) and placebo, 4.9 (95% CI, 3.8-6.4). M and T caused small improvements in prebronchodilator FEV1 of borderline significance. Either treatment improved A symptoms or QOL. In subjects not receiving inhaled CS, additional T significantly (p<0.002) improved asthma control and symptoms as well as lung function. The authors conclude that neither M nor low-dose T lowered EPACs in patients with poorly controlled A despite improved lung function. For patients not using inhaled CS, low-dose T improves A symptom control more than M or placebo and provides a safe and low-cost alternative A treatment. Editor’s comment: T is still a good cost-effective drug to use for A. The American Lung Association Asthma Clinical Research Centers. Am J Respir Crit Care Med 2007; 175: 235.

6. COMBINATION THERAPY WITH A LONG-ACTING β-AGONIST AND A LEUKOTRIENE ANTAGONIST IN MODERATE ASTHMA
192 subjects (12 to 65 yr) with moderate asthma were enrolled in a randomized, placebo-controlled study comparing the clinical efficacy of treatment for 14 wks with montelukast (M) and salmeterol (S) compared to beclomethasone (B) and S. The primary outcome was time to treatment failure. M and S was inferior to B and S as judged by protection against asthma treatment failures (p =0.0008), lung function (26 L/min difference in A.M. PEF, P = 0.011), asthma control score (0.22 difference in Asthma Control Questionnaire score, p = 0.038), and markers of inflammation and airway reactivity. The authors conclude that M and S should not be substituted for inhaled corticosteroid (ICS) and LABA. Editor’s comment: ICS (with or without a long-acting β-agonist) remains the first treatment of choice for moderate asthma in this age group. Deykin A, et al. Am J Respir Crit Care Med 2007; 175: 228.

7. LIVE ATTENUATED (LAIV) VS. INACTIVATED INFLUENZA VACCINE (IIV) IN INFANTS AND YOUNG CHILDREN
Approximately, 8,000 children, 6 to 59 months of age, without a recent episode of wheezing illness or severe asthma, were randomly assigned in a 1:1 ratio to receive either cold-adapted trivalent IAIV intranasally or trivalent IIV in a double-blind manner. Influenza-like illness was monitored with cultures throughout the 2004-05 influenza season. There were 54.9% fewer cases of cultured-confirmed influenza in the group that received LAIV than in the group that received IIV (153 vs. 338 cases, P<0.001). Among previously unvaccinated children, wheezing within 42 days of the administration of dose 1 was more common with LAIV than IIV, primarily among children 6 to 11 months of age (P=0.076). Rates of hospitalization for any cause during the 180 days were higher among the LAIV recipients who were 6 to 11 months of age (6.1%) vs. the recipients of IIV in this age group (2.6%, P=0.002). The authors conclude that LAIV had significantly better efficacy than IIV and should be a highly effective, safe vaccine for children 12 to 59 months of age without a history of asthma or wheezing. Editor’s comment: LAIV is more effective than IIV but should not be used in children with asthma. Belshe RB, et al. N Engl J Med 2007; 356: 685. Editorial, Cox NJ, Bridges CB. N Engl J Med 2007; 356: 729.

8. DETECTION OF AN ALERGEN IN DOG DANDER THAT CROSS-REACTS WITH THE MAJOR CAT ALLERGEN, Fel d 1
These authors took a recombinant (rFel d 1) with the same immunologic properties as natural Fel d 1 and used it for quantitative (CAP) IgE competition experiments performed with sera obtained from 36 cat-allergic patients. They found that a Fel d 1 cross-reactive dog allergen was characterized by one- and two-dimensional immunoblotting using rFel d1 for IgE inhibition experiments and with monospecific, polyclonal rabbit anti-recombinant Fel d 1 antibodies. In 25% of Fel d 1-reactive cat-allergic patients, more than 50% inhibition of IgE reactivity to dog allergens was achieved with rFel d 1. A Fel d 1 cross-reactive 20 kDa allergen with a pI of approximately 3.4 was detected in dander extracts of several different dog breeds. They conclude that a Fel d 1-like allergen in dog dander extracts exist and may be responsible for double positivity to cat and dog in serology, and provide evidence that dog and cat dander, besides Can f 3/Fel d 2 (albumin) and perhaps Fel d 4 (lipocalin), contain other cross-reactive antigens. Editor’s comment: This is additional evidence that cat and dog allergens cross-react. Reininger R, et al. Clin Exp Allergy 2007; 37: 116.

9. A HUMAN INTERLEUKIN-12/23 MONOCLONAL ANTIBODY (MA) FOR THE TREATMENT OF PSORIASIS
320 patients (age > 18 yr) with moderate-to-severe plaque psoriasis underwent randomization in this double-blind placebo-controlled trial for treatment with the MA or placebo. 64 patients were randomly assigned to each group. There was at least 75% improvement in the psoriasis area-and-severity index at wk 12 (the primary end point) in 53% of patients who received 45 mg of the MA vs. placebo. Higher doses achieved even better results (P < 0.001). There was no statistical difference in adverse or serious adverse events. The authors conclude that this study demonstrates the therapeutic efficacy of a MA for psoriasis and provides further evidence of a role of the interleukin-12/23 p40 cytokines in the pathophysiology of this disease. Editor’s comment: Aberrant type I immune responses are linked to the pathogenesis of psoriasis and interleukin-12 and IL-23 seem to be the appropriate therapeutic targets. Krueger GG, et al. N Engl J Med 2007; 356: 580.

10. NFkB IN BREAST CANCER (BC) CELLS PROMOTES OSTEOLYTIC BONE METASTASIS BY INDUCING OSTEOCLASTOGENESIS VIA GMCSF
Reviewed by Gary Hellermann, Ph.D.
Persons with BC have a high incidence of bone metastases because BC cells have an affinity for bone but also because they secrete factors that stimulate osteoclasts which are responsible for bone resorption. These authors reasoned that since the transcription factor NF-kappaB (nuclear factor-kappa B) regulates genes involved in tumor invasion and metastasis, it may also be involved in the osteolytic bone metastases seen in some BC patients. They found that a cancer cell line highly metastatic for bone had significantly higher NF-kappaB activity than one that was weakly metastatic. Using mice as a model they showed that blocking NF-kappaB reduced the size and number of osteolytic lesions, in some cases preventing them completely. A potential connection with NF-kappaB was made when it was discovered that the increased activity of NF-kappaB correlated with an increase in GM-CSF (granulocyte macrophage-colony stimulating factor) which stimulates osteoclast differentiation. Editor’s comment: NF-kappaB is a ubiquitous proinflammatory factor and this study demonstrates that anti-NF-kappaB treatment may prove to be effective in preventing cancer metastasis. Park et al. Nature Med 2007; 13: 62.