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?

Ragweed pollen season is earlier and longer

Climate change will have enormous effects on human health. It may profoundly modify exposure to pollens of invasive species and therefore modify allergic diseases with anticipated increases in prevalence and severity. A new study published in the Proceedings of the National Academy of Sciences finds that the length of the ragweed season in some northern U.S. states has grown by more than two weeks since 1995, and the length of the ragweed season in some areas of Canada has been extended by nearly a month. According to lead author Lewis Ziska (Agricultural Research Service, U.S. Department of Agriculture), as quoted in a U.S. News & Report article about the study, "This study is a confirmation of what the Intergovernmental Panel on Climate Change has been projecting. We've gone from a theoretical projection of changes in the timing of ragweed season, to boots on the ground starting to see it happen." This increased length of the season might be associated with increased prevalence in allergy.

Is this apparent in your clinical practice?

The asthma epidemic has still not abated in the U.S.

Some epidemiologic studies suggest that asthma prevalence and severity are decreasing in high-income countries. However, it appears that there is a large heterogeneity among populations.

The U.S. National Center for Health Statistics’ report "Asthma Prevalence, Health Care Use, and Mortality: United States, 2005-2009" (January 12, 2011) presents recent figures for the US. In 2009, current asthma prevalence was 8.2% of the U.S. population (24.6 million people); within population subgroups it was higher among females, children, persons of non-Hispanic black and Puerto Rican race or ethnicity, persons with family income below the poverty level, and those residing in the Northeast and Midwest regions. In 2008, persons with asthma missed 10.5 million school days and 14.2 million work days due to their asthma. In 2007, there were 1.75 million asthma-related emergency department visits and 456,000 asthma hospitalizations.

It is therefore of great importance to consider asthma as a major public health problem, in particular in underserved populations.

Anti-TNF-alpha in asthma: Myth or reality

TNF-alpha has been widely studied in asthma and proposed as a possible target for the treatment of severe asthma. Unfortunately, toxic effects of monoclonal antibodies against TNF-alpha have precluded their use in patients with severe disease. Moreover, the clinical benefits have always been very small.

A new trial assessed the efficacy and safety of ethanercept, a biologic against TNF-apha (fusion protein of TNF-alpha receptor), in moderate-to-severe persistent asthma. In a 12-week, randomized, double-blind, placebo-controlled, phase 2 trial, 132 subjects with asthma received subcutaneous injections of etanercept or placebo twice weekly.

Clinical efficacy of etanercept was not shown in any of the outcomes studied over 12 weeks. However, etanercept treatment was well-tolerated.

The authors propose that studies in specific subsets of patients with asthma with longer-term follow-up may be needed to fully evaluate the clinical efficacy of etanercept in asthma.

Is Bisphenol A a risk factor for allergy in children?

Exposure to environmental toxicants is associated with numerous disease outcomes, many of which involve underlying immune and inflammatory dysfunction. The U.S. government declared Bisphenol A (BPA) a hazardous substance in October 2008 and has since placed it on its list of toxic substances. Triclosan (2,4,4’ –trichloro-2’-hydroxydiphenyl ether) is a chlorinated aromatic anti-microbial agent under review by the U.S. Environmental Protection Agency (EPA) using the new National Health and Nutrition Examination Survey (NHANES) 2003-2006 data.

Using data from the 2003-2006 NHANES, a study in the journal Environmental Health Perspectives compared urinary BPA and triclosan with diagnoses of allergies or hayfever in U.S. adults and children age ≥ 6 years.

Triclosan, but not BPA, showed a positive association with allergy/hayfever diagnosis. In the under-18 age group, higher levels of triclosan were associated with greater odds of having been diagnosed with allergies or hayfever (p<0.01).

Although additional studies should be done to investigate these interesting findings, shall we further restrict the use of BPA ?

Osteopontin implicated in maintenance of chronic allergic contact dermatitis

Acute allergic contact dermatitis (ACD) has been previously linked to secreted osteopontin (sOPN), a glycoprotein with cytokine and chemokine functions. OPN is known to attract myeloid dendritic cells (mDCs) to activate naïve T cells in draining lymph nodes in the skin and induce a TH1 phenotype.

Seier et al. (Am J Path 2010, 176:246-258) follow up on their work identifying osteopontin as a principal player in acute ACD with investigations into the pathophysiology that leads to the chronic condition, which is associated with severe eczema. They discover that OPN attracts memory T cells, monocytes, macrophages, and DCs to the skin in acute exposure. Cytokine function of OPN specifically induces IL-12 secretion and suppresses IL-10 production in macrophages. Then, OPN-related IL-12 production establishes Th1 conditions by skewing mDCs toward IL-12 production, which in turn, augments further OPN secretion. The authors also find that IFN-γ from antigen-specific T cells is critical for activation of OPN production in keratinocytes. The Th1 environment in the epidermis is maintained through cybernetic mechanisms involving OPN, IL-12, and antigen-specific T cells, which support persistent, chronic inflammatory conditions in the skin.

Seier et al. also report that anti-OPN antibody treatment can suppress response in established chronic ACD, suggesting possible prevention and intervention possibilities.

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