Do we have biomarkers to improve control of asthma in children?

The level of asthma control incorporates current clinical control and exacerbations. Traditionally asthma treatments have been individualized using symptoms and spirometry or peak flow. Biomarkers hold promise for capturing complementary information, but need to be validated with regard to control. Two studies published online ahead of print in Thorax may help to give some guidance in clinical practice.

First, a systematic review evaluated the efficacy of tailoring asthma interventions based on inflammatory markers (sputum analysis and FeNO) as compared to clinical symptoms with or without pulmonary function tests in children and adults (Petsky et al. Thorax, 11 Oct 2010, epub ahead of print). The authors concluded that “tailoring of asthma treatment based on sputum eosinophils (3 studies in adults) is effective in decreasing asthma exacerbations in adults. However, tailoring of asthma treatment based on FeNO levels (2 studies in adults and 4 in children) has not been shown to be effective in improving asthma outcomes in children and adults.”

In the second article, a study was undertaken to investigate whether a strategy based on sputum eosinophils would be successful in 55 children with severe asthma (Fleming et al. Thorax, 8 August 2011, epub ahead of print). “Incorporating the control of sputum eosinophils into the management algorithm,” the authors concluded, “did not significantly reduce overall exacerbations or improve asthma control. Exacerbations were reduced in the short term, suggesting that more frequent measurements would be needed for a clinically useful effect and that controlling inflammation may have a role to play in subgroups of children with severe asthma.”

Do you agree that biomarkers are either not readily available or unavailable in most practice settings?

What do we really need to appraise the safety of combined long-acting ß2 agonists and inhaled corticosteroids in asthma?

The safety of LABAs has been questioned since their introduction in the early 1990s, and we do not have the answer yet. In an attempt to improve the safety of these drugs, the U.S. Food and Drug Administration (FDA) last year issued a requirement that labels for LABA-containing products should be changed with respect to asthma treatment. These changes state that LABAs are contraindicated without the concomitant use of an asthma controller medication, such as an inhaled corticosteroid. Furthermore, the revised labels recommend that LABAs are only to be used when they are necessary to achieve and maintain asthma control. While LABAs used by themselves increase the risk of serious adverse outcomes, it is still unclear whether there are similar risks when LABAs are added to inhaled corticosteroids. More studies are still needed to fully understand this key issue.

In a Perspective published in the New England Journal of Medicine (N Engl J Med 2011;364:2473-2475), Badrul Chowdhury and colleagues, from the FDA, provide some insights into the future studies that need to be carried out. This question cannot be answered through reanalysis of existing data, analyses of spontaneous reports of adverse events, or epidemiologic studies using existing databases; controlled clinical trials are necessary.

This April, the FDA issued a requirement that manufacturers of all LABAs marketed for asthma in the U.S. must conduct 5 controlled clinical trials to compare the safety of treatment with LABAs plus inhaled corticosteroids to treatment with inhaled corticosteroids alone. Even children as young as 4 will be enrolled in one of the trials. The 6-month trials will be multinational, randomized, and double-blind. The plan is to “mimic a real-world scenario,” and the FDA believes that “these clinical trials will provide data in a timely fashion that will clarify the safety risk associated with LABAs when used concurrently with inhaled corticosteroids and will inform the safe use of these medications for the treatment of asthma.”

What are your expectations for these trials? Are they going to change your practice?

The safety of tiotropium

“Safety of tiotropium: Indirect evidence suggests the Respimat inhaler is riskier than the Handihaler.” So states an editorial by Cates (BMJ 2011;342:d2970) that accompanies a recent BMJ article by Singh et al. (BMJ 2011;342:d3215). The authors systematically reviewed the risk of mortality associated with long-term use of tiotropium delivered using a mist inhaler for symptomatic improvement in COPD and found that 5 randomized controlled trials were eligible for inclusion. Tiotropium mist inhaler was associated with a significantly increased risk of mortality. The number needed to treat for a year with the 5 µg dose to see one additional death was estimated to be 151, based on the average control event rate from the long term trials. There is however considerable uncertainty around this estimate (95% confidence interval: 51 to 5556). However, this point estimate is considerably larger than that found for salmeterol in asthma.

Is everything clear? No. The same authors made a previous meta-analysis on tiotropium (Singh et al. JAMA 2008;300:1439-50) and showed that inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD. However, the publication of the large UPLIFT trial (Tashkin et al. N Engl J Med 2008;359:1543-54) did not confirm this meta-analysis. The FDA (Michele et al. N Engl J Med 2010;363(12):1097-9) did not support the conclusions of Singh et al. on tiotropium “because of the strengths of the UPLIFT data, the absence of a strong signal related to stroke or cardiovascular events with tiotropium and the potential methodologic limitations of the Singh meta-analysis.”
However, the conclusions of Cates are ambiguous since he wrote: “An ongoing trial will provide more certainty about the comparative safety of tiotropium inhaler devices” and concludes “if patients have a strong preference for the mist inhaler, the possible increased risk mortality will need to be shared with them.”

We therefore think that you should be warned about this new controversy and we would be delighted to know what you think.

Omalizumab and severe uncontrolled asthma

The recommendations for patients with asthma that is not well-controlled are inhaled corticosteroids (ICS) and long-acting β(2)-agonists (LABAs). Many of these patients, however, continue to have inadequately controlled asthma. In a previous study (Humbert et al. Allergy 2005;60(3):309-16), it was found that the annualized rate of severe exacerbations was reduced by 29% in patients receiving omalizumab in addition to guideline-defined therapy. In a large study in 850 patients aged 12 to 75 years who had inadequately controlled asthma despite treatment with high-dose ICS plus LABAs, with or without other controllers, omalizumab reduced exaberbations by 25% over 48 weeks (Hanania et al. Ann Intern Med 2011;154: 573-8). Are you using omalizumab in patients with severe uncontrolled asthma? We want to hear about your experience.

Leukotriene Antagonists as Asthma-Controller Therapy

In the May 5, 2011, issue of the New England Journal of Medicine, Price et al. (N Engl J Med 2011; 364:1695-1707) http://www.nejm.org/doi/full/10.1056/NEJMoa1010846 report on two parallel, multicenter trials that compared the real-world effectiveness of a leukotriene-receptor antagonist (LTRA) with either an inhaled glucocorticoid being used as a first-line asthma-controller therapy, or a long-acting beta-agonist (LABA) being used as an add-on therapy in patients who were already being given inhaled glucocorticoids. The authors assigned patients to 2 years of open-label therapy. After 2 months, the efficacy of the LTRA was equivalent to the use of an inhaled glucocorticoid as first-line controller therapy and to LABA as an add-on therapy. However, equivalence after 2 years was not proven. The two groups did not show a significant difference in either rate of exacerbations or ACQ scores. Is this what you find in your practice?

World PI (Primary Immunodeficiencies) Week

This week is World PI (Primary Immunodeficiencies) Week. Dr. Amos Etzioni, Professor of Pediatrics and Immunology at Meyer Children's Hospital in Haifa, Israel, has sent us the following editorial on the behalf of the World PI Week Steering Committee. We asked Dr. Etzioni to tell us about the launch of this movement:

JACI: How did the World Primary Immunodeficiencies Week movement get started?
Dr. Etzioni: The foundations of the Day of Immunology (DoI) were established on April 29th 2005 by the European Federation of Immunological Societies (EFIS) to raise awareness amongst the public, the press, politicians and decision makers about the critical importance of the immune system in everybody’s everyday life. The success of the European awareness-raising programme has led to the International Day of Immunology being celebrated worldwide since 2007. In addition, the United States Congress declared April 22-29 National Primary Immunodeficiency (PI) Awareness Week with PID activities taking place all week and culminating in World Day of Immunology (WDI) on 29 April. The opportunity therefore exists to continue to leverage the work that has been done to date and unite all stakeholders around the common objective of driving early diagnosis and optimal care for PID across Europe. ASID, CIS, EFIS, ESID, INGID, IPOPI, JMF and LASID have all partnered to support World PI Week. World PI Week may be the best vehicle to achieve continued success and keep everyone united and working towards common goals.

JACI: What are the Steering Committee's goals for this inaugural week?
Dr. Etzioni: World PI Week’s overarching mission is to raise awareness of the importance of primary immunodeficiency (PI) diseases globally and stimulate efforts to improve the recognition, diagnosis, treatment and the quality of life for people with PI world-wide. WPIW seeks to create a ‘global’ movement around PI and a central platform for local and national players, and seek to bring together, empower and engage all global stakeholders in the PI cause (patients, nurses, physicians, scientists, allied health professionals, and industry).
The first World PI Week will be celebrated on 22-29 April 2011 and will focus on increasing the understanding of these diseases and promoting optimal diagnosis.
World PI Week therefore offers a crucial, visible opportunity to inform and educate health policy-makers, schools and families, and the general public about primary immunodeficiencies (PI) to drive the earliest possible diagnosis and optimal treatment. Through events and activities promoting the warning signs of PI, seminars, public lectures, video-diaries, and press conferences, the global PI community can unite to bring about positive changes in healthcare systems and practices around the world in support of people living with PI.

JACI: What do you see as the biggest challenge(s) facing the Primary Immunodeficiencies community?
Dr. Etzioni: As we move forward in our understanding the immune system it is quite clear today that defects in the immune system are much more common than thought in the past. I believe that we should continue to increase the knowledge about possible defects leading to increase susceptibility to infections. Early treatment, due to increase awareness, is crucial for decreasing mortality and morbidity in these conditions. Furthermore, a lot of effort should be given to research in order to fully understand the pathopysiology of many of the PIDs which eventually will bring new therapeutic options .


Editorial:
Primary Immunodeficiencies (PI) used to be considered rare conditions, affecting 1 in approximately 10,000, adults and children. As will be outlined in this communication, we believe that today, the incidence and prevalence is much greater.

The late Dr. Fred Rosen, many years ago, pointed out that immunodeficiency is a pediatric emergency. The early recognition of any of the various forms of PI, quite clearly, improves outcomes. As an example, performing Stem Cell Transplantation in patients with Severe Combined Immune Deficiency (SCID), during the first 3 months of life, will increase survival to more than 95% in a condition that in the past was always lethal. Using new genetic techniques the number of genes found to cause defects in the immune system is growing every day, with more than 200 different entities described so far. This has a huge impact on the patients and their families for several reasons. First and most importantly, we can offer better and adequate treatment for the patients. Gene therapy has already been successfully performed for children with SCID due to RAG Mutations or ADA Deficiency. Secondly, many children in whom the diagnosis was not clear now can have a definitive diagnosis followed by appropriate therapy. Defining a genetic defect in the family can help the family planning their future and there is the possibility of prenatal diagnosis.

The new Neo-natal Screening, using a technique developed by Dr. Jennifer Puck, using the TREC Assay, has already been recommended by the United States Secretary of Health. Newborn Screening will help discover the patients even before any serious infectious events occur. Increased awareness of PI has had a major impact on the consequences of patients suffering from such diseases. It is well known that lung infections are very common in these cases. Delay in the diagnosis and thus recurrent pneumonia, will often lead to bronchoectasis, which may lead to lung failure. Some of us still remember the time we had to treat our patients with intramuscular immunoglobulin, which was extremely painful and with side effects. In the last 30 years, the use of Intravenous Immunoglobulins (IVIG) became the standard of care and recently, Subcutaneous Immunoglobulins (SCIG) are gaining popularity. This will encourage the possibility of home treatment, which will increase patient's compliance.

Until recently, we studied the adaptive (T and B lymphocyte) immune defects. The focus now is aimed also at the innate immune system. The tremendous contribution made by Dr. Jean-Laurent Casanova has identified many more defects in the innate immune system. Dr. Casanova described children with severe infectious episodes, who might need intensive care treatment. These are cases where no defect in the immune system was found. These severe illnesses could be described as cases of "bad luck" but are more likely, "bad genes", still to be discovered and identified. Furthermore, polymorphism in many genes may also contribute to increased susceptibility to infections. This will lead eventually to new therapeutic biological agents aiming at the specific defect.

The increased effort to improve the knowledge of physicians all over the world and awareness of the general population is ongoing. It is the continuous work done by the patient organizations, mainly the Jeffrey Modell Foundation (JMF), the International Patient Organization for Primary Immunodeficiency (IPOPI), as well as several physician organizations, such as the European Society for Immune Deficiency (ESID), and the Clinical Immunology Society (CIS), and all the World PI Week founding organizations.

The upcoming World Primary Immunodeficiency Week (WPIW) is an excellent opportunity to try to achieve our goal that the medical community and the public will understand more about PI and encourage earlier diagnosis and better treatment. There is evidence to support better outcomes with earlier diagnosis. We believe very much in what the late Dr. Robert A Good, father of Clinical Immunology, said when the first molecular genetic defects in PI were discovered:

"This is not the beginning of the end but just the end of the beginning of the field of PI"

Prof. Amos Etzioni MD on behalf of the WPIW steering committee

Treatment of chronic rhinosinusitis with nasal polyposis with oral steroids followed by topical steroids

Chronic rhinosinusitis (CRS) with nasal polyposis is a common problem resulting in nasal blockage, facial pain, and hy- posmia. Responses to therapy are frequently incomplete, and relapses are common. Although oral steroids are recommended when specialty care is required, little is known about their efficacy. In a study reported in the Annals of Internal Medicine, 60 adults with CRS and moderate-sized or larger nasal polyps who were referred by their primary physicians for specialty care received oral prednisolone, 25 mg/d, or placebo for 2 weeks, followed in both groups by fluticasone propionate nasal drops, 400 µg twice daily, for 8 weeks and then fluticasone propionate nasal spray, 200 µg twice daily, for 18 weeks. Initial oral steroid therapy followed by topical steroid therapy seems to be more effective over 6 months than topical steroid therapy alone in decreasing polyp size and improving olfaction in patients referred for specialty care of CRS with at least moderate nasal polyposis.

Will this study modify your practice?