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Wednesday, October 22, 2014

Ray D. Owen (1915-2014)


Immunologist and geneticist Ray D. Owen, professor of biology, emeritus, at Caltech passed away on September 21. Owen's most significant contribution to immunology was his 1945 discovery of immunological tolerance in fraternal twin cattle. Using blood typing, he discovered that each twin had no immune response to the foreign antigens introduced from the other twin. His findings paved the way for the experimental induction of tolerance through immune suppression and for early tissue grafting—which initiated the era of organ transplantation. Owen's later work included studies on human antibodies, blood-group antigens, the evolution of immune systems, and the genetic analysis of the major histocompatibility complex—a large family of genes that plays an important role in the immune system and autoimmunity. Dr. Owen received his PhD in genetics from the University of Wisconsin and became an associate professor at Caltech in 1947; where he was promoted to full professor in 1953 and became professor emeritus in 1983. Not only was Owen a brilliant scientist, he was highly recognized for his extraordinary dedication to mentorship at Caltech, where he launched the effort to admit female undergraduate students; which ultimately allowed the first female undergraduates to enroll at the Institute in 1970. His accomplishments led Leonore Herzenberg, professor of genetics at the Stanford School of Medicine and pioneer of immunology, to write "Dr. Owen's belief in the genderlessness and color-blindness of intelligence and creativity has encouraged men and women to excel in their chosen fields," in a letter recommending Owen for a lifetime mentoring award.

Thursday, January 23, 2014

Sadly, gastroenterologist and immunologist Lloyd Mayer M. D., Head of the Division of Clinical Immunology, Icahn School of medicine at Mount Sinai, passed away September 5, 2013. Dr. Mayer was a highly esteemed colleague of the mucosal immunology community who made major contributions in the field. His passion was inflammatory bowel disease and among many scientific contributions he discovered that T cells secrete factors which control the class switching, activation, and proliferation of B cells. He applied himself to numerous organizations and held the highly esteemed position of Chairman of the National Scientific Advisory Committee of the Crohn's and Colitis Foundation of America. He was highly active in the Allergy/Immunology community as his research focused on mechanisms of oral tolerance and he was a key member of the NIH NIAID Consortium of Food Allergy Researchers (CoFAR). Anyone who knew Dr. Mayer describe him as a selfless person who despite all of his extraordinary accomplishments always remained humble and unassuming and was an irreplaceable friend to anyone who knew him.  For more details about his life and accomplishments, please view this memorial in the Journal of Clinical Immunology (published by Springer, Nov. 2013) 

Friday, December 27, 2013




The New Year is approaching, bringing huge changes in healthcare coverage for most Americans. This recent focus on healthcare costs has highlighted the extreme financial burden of rare diseases; effective therapies may have been developed, but the cost of R & D to the pharmaceutical companies is huge, compared to the number of potential users. Take Hereditary Angioedema; billions of dollars were spent on development of a very effective therapy, 95% of which was spent on unsuccessful drug trials. To recoup this investment, patent rights prevent generic alternatives, and the cost is passed on to the some 1 in 50,000. Each patient spends upwards of $100,000 per year to manage their condition. Perhaps this shake-up will force administrators to examine the real cost of healthcare, from pre-clinical trials to approval.


Tuesday, December 3, 2013

In recognition of an innovator in immunology: Leonard Herzenberg, inventor of the FACS machine.

Immunologist, geneticist, and philanthropist Dr. Leonard Herzenberg profoundly changed cell biology and immunology with the invention of the fluorescence-activated cell sorter  (FACS ) machine. Herzenberg created the biotechnology in 1970, driven by the need for quantification of cell types during his novel work with hybridomas, which are monoclonal antibody producing B cells fused with cancer cells.   The FACS, also referred to as a flow cytometer, allows scientists to sort, quantify, and identify different cells types, and has been vital to the field ever since its existence.  Not only did his seminal biotechnology and research significantly advance what is known about lymphocyte biology, he used the royalties from the FACS to further fund his own research.  Dr. Herzenberg’s ground breaking achievements earned him an array of awards, most notably the Kyoto Prize, a Japanese equivalent to the Nobel Prize. His priceless contributions will continue to impact basic science research indefinitely.

 Leonard Herzenberg (November 5, 1931 – October 27, 2013)

Tuesday, November 19, 2013

Claritin advertisements cause a placebo effect

It is well known that beliefs about the quality of a drug can enhance its physiological effect, but little is known of the impact of advertising of a branded drug. Kamenica et al (PNAS August 2013) conducted a clinical trial to measure the physiological impact of direct-to-consumer advertising of the antihistamine Claritin. The authors exposed subjects with or without allergies to a skin test of common allergens, and then subjects received Claritin, and viewed advertisements for Claritin or Zyrtec.  Regardless of allergy, all subjects experienced a wheal reaction to the skin test. In the allergy subpopulation, there was no significant change in beliefs associated with exposure to Claritin advertisements; however, in the subpopulation without allergies, exposure to Claritin advertisements increased the efficacy of Claritin (16% at 120 minutes).  This result suggests that advertising can have strong psychologically mediated physiological effects to a drug. 

It is unclear if the results were due to the positive effect of Claritin ads or a negative effect of Zyrtec ads.  A small pilot test included a group that did not receive advertisements, but the authors did not replicate this arm in the larger study.  A follow –up trial should be conducted to determine if positive or negative advertisements have a greater effect as well as a no advertisement control group.


The association of anaphylaxis and chronic pulmonary diseases on hospital outcomes

Mulla et al (BMJ open 2013) sought to determine if chronic pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD),  and cystic fibrosis adversely impacted outcomes  in hospitalized patients with various allergic conditions including anaphylaxis.  The authors used data collected from a statewide hospital discharge database, of which 2410 individuals had anaphylaxis. Asthmatics were found to have more than twice the odds of receiving mechanical ventilation and sufferers of chronic bronchitis and COPD had a prolonged hospitalization stay.  The unique analysis of a large database allowed the authors to determine that chronic pulmonary diseases increased the risk of adverse outcomes among hospitalized patients with anaphylaxis. 

The authors did not have access to the complete medical records of the patients, how could this have affected outcomes?


Could there be anaphylaxis coding inconsistencies in hospital databases especially in patients with pulmonary disease? 

Monday, April 22, 2013

World Primary Immunodeficiencies Week 2013

The week of April 22-29, 2013 is World Primary Immunodeficiencies Week. We are pleased to present the following editorial, submitted by Drs. Ricardo Sorensen, Amos Etzioni, Ahmed Bousfiha, and John Zeiger, on behalf of the World Primary Immunodeficiencies Week Steering Committee:

Ricardo Sorensen M.D.,1 Amos Etzioni, M.D.,2 Ahmed Aziz Bousfiha , M.D.,3 John B. Zeiger, M.D.4

1. Department of Paediatrics Children's Hospital, 200 Henry Clay Ave. New Orleans, LA, USA
2. Meyer Children's Hospital, Haifa, Israel
3. Clinical Immunology Unit, King Hassan II University, Averroes Hospital, Casablanca, Morocco
4. Sydney Children’s Hospital, Randwick, New South Wales, Australia



Introduction

World Primary Immunodeficiency Week (WPIW) 2013 runs from 22–29th April (www.worldpiweek.org). As this celebration and awareness campaign approaches, it is time to reflect on progress made and the challenges that remain for the primary immunodeficiency diseases (PID) community. In this article, representatives from leading PID societies evaluate the situation and plans for further progress in their respective areas of the world. It is hoped that this situation analysis will prompt further focus and enhanced collaboration on the gaps that remain in the pursuit of promoting early diagnosis and treatment of PIDs.

Europe

The European Society for Primary Immunodeficiency (ESID) is the oldest and largest professional organization focused on PIDs. Currently ESID has 800 members and almost 2000 individuals attended its last biennial meeting (Florence, October 2012). 


ESID developed the first clinical database for PIDs. Containing data from over 10,000 patients, this large registry has been used for many important projects and published studies (1-3). Furthermore, in 2012, ESID members collaborated in the publication of an updated PID diagnostic protocol for non-immunologists. This protocol incorporates newly defined PIDs and is designed to assist physicians caring for adults and children to promptly and cost-effectively screen and diagnose PIDs based on the clinical presentation and laboratory tests, with definitive tests subsequently performed in partnership with specialist immunologists (4).  


Aside from organizing the biennial meeting, ESID is involved in many other educational activities, such as a summer school for PID. A major objective of the organization is to increase awareness of PID through a new website and meetings with patient organizations. ESID also supports the wonderful ‘J project’, conducted by Prof. László Maródi (Hungary), which aims to develop PID awareness and expertise in eastern and central European countries (5).



In the upcoming year, ESID will focus on two main points for Europe:

* Implementation of neonatal screening for severe combined immunodeficiency (SCID). After the success of the program in several states in the USA, ESID will push for SCID screening to be established soon in many European countries.

* Provision of adequate treatment of the various PIDs across Europe. Unfortunately, in many countries the supply of intravenous immunoglobulin (IVIG) is inadequate and haematopoietic stem cell transplantation (HSCT) centres have yet to be developed in some countries, mainly in eastern Europe.



Although much has been achieved, there is still a long way to go in providing the early and precise diagnosis of PID, together with the appropriate treatment, to the many thousands of patients all over Europe and the world.



Latin America

Organised efforts towards improving the diagnosis and management of patients with PIDs in Latin America started in 1993 when a small group of immunologists from Argentina, Brazil, Chile and Colombia teamed up with Ricardo Sorensen, M.D., in the USA to create a joint patient reporting form under the auspices of an informal group called the Latin American Group for Primary Immunodeficiencies (LAGID). The goals of this organization were to include other Latin American countries and to create registries of patients with PIDs in each participating country. The group grew from the initial four to a total of 14 countries with a wide population range.



Many of the objectives set forth by LAGID have been accomplished, including: the development of patient and parent support groups in most participating countries; the creation of a website for members; the organization of 12 yearly scientific meetings held from 1995 to 2007; educational programmes and the education of paediatricians and general practitioners; and extensive collaborative efforts between member countries and between Latin American immunologists and their colleagues in Europe and the US. These efforts led to the creation of the first joint PID registry published by eight countries in 1998 (6).  A second report was published in 2007 (7)  



A second official electronic registry, following the model of the ESID registry, was established for all of Latin America in Sao Paulo, Brazil, with the assistance of ESID. Other actions have contributed to advancing the care of patients with PIDs in Latin America and have brought a new dynamic to diagnosis, treatment and research in the region (8,9).  These actions include the sponsored fellowship programme led by the Latin American Society for Immunodeficiencies (LASID), founded in 2009, which has assisted young immunologist in five countries to specialise in the diagnosis and care of PIDs, and the establishment of a network of Jeffrey Modell Diagnostic and Research Centers in Sao Paulo, Mexico City, Medellin, Chile and Buenos Aires. Created by the Jeffrey Modell Foundation, these centres offer enhanced diagnostic and treatment capabilities for PID across the world, including now in Latin America. Health authorities in several countries, including Mexico, Colombia, Argentina, Brazil and Chile, have now recognised PIDs as a special group of diseases and facilitated access to treatment. 


The present day challenges of PID in Latin America are two-fold: to continue to expand awareness and diagnosis and treatment possibilities to more areas in Latin America where there has been little or no progress, and to satisfy the desire of young Latin American immunologists to bring state-of-the-art advances in diagnosis and treatment to their patients. The encouraging experience gained from years of successful collaborative efforts allows LASID to look with great optimism to its future.



Africa and Middle East

PID diagnosis and care in Africa and the Middle East has developed tremendously over the past 2 years, but major efforts are still needed, especially in Sub-Saharan Africa.

Indeed, we have witnessed the creation of PID networks and the release of multicentre studies on these conditions. In particular, two workshops bringing together experts from the North Africa and Middle East were held in Athens in 2012 and in Dubai in 2013. These led to the sharing of solutions between experts and to the building of cooperative bridges in training and research. In 2011, Ridha Barbouche and colleagues published a profile of PIDs in North Africa (Morocco, Tunisia and Egypt), (10) while Saleh Al Muhsen and colleagues published on the epidemiology of PID in the Middle East (11). Both regions are characterised by high rates of in-breeding (20–60%) and they have a comparable distribution of PID causes, with a high incidence of SCID and founder mutations. Teams in the Middle East, including Saudi Arabia, have published excellent results on HSCT and have contributed to internationals research on PID specific cases (12). PID treatment has been slower to develop in North Africa, with difficulties existing in IVIG access and HSCT being introduced only timidly. 


These advances allow high hopes for patients with PIDs in the aforementioned regions. However, with the exception of South Africa — where the situation is comparable to that in North Africa — progress is lagging in the rest of the African countries. Indeed, there seems to be little or no activity in the PID field in over 40 of the 54 countries of this continent. To address this issue, the African Society for Immunodeficiencies (ASID), created in Casablanca in 2008, opted for regional actions to educate paediatricians and other healthcare professionals and to promote cross-country initiatives to allow the exchange of expert experience and education. ASID’s achievements are already palpable: Africa has a spokesperson for PID scientific and social societies, and schools to provide education about PIDs have involved a dozen countries in each region of Africa.

However, challenges remain in Africa, whose population has this year exceeded 1 billion citizens, and urgent international actions are necessary in this continent. These should aim not only to increase awareness of PIDs among physicians, nurses and other healthcare professionals, but in particular to bring the attention of the authorities and the general public to this large group of rare diseases and their significant effect on infant mortality. Indeed, PIDs are more common than is generally thought. It is estimated that up to 900,000 people in Africa may have a PID, whereas only around 1000 cases are currently registered (13). 


The two regions of North Africa and the Middle East have rightly decided to work together to improve PID diagnosis and care. Corresponding joint efforts are also needed in the rest of Africa to enable the work of patient groups, doctors and nurses to bring a positive change for PID patients.



Australia

There is an active immunodeficiency community in Australia, with many of the major interactions revolving around the PID Committee of the Australasian Society of Clinical Immunology and Allergy (ASCIA) and the now well-established triennial Asia Pacific Primary Immune Deficiency (APPID) Summer School. While geographical constraints make large PID centres difficult to envisage, there are a number of major centres seeing patients with complex immunodeficiency disorders and the first Australian Jeffrey Modell Foundation Center will soon open at Sydney Children's Hospital, Randwick. The outcomes amongst the five centres currently performing HSCT for PIDs in Australia compare favourably to those from other parts of the world (14).
 

From a research perspective there has been an effort to form collaborative research partnerships across the country, initially through the Australian PID registry (15) and more recently through the antibody deficiency orientated Australia and New Zealand Antibody Deficiency Allele (ANZADA) study, which has now being joined by the more paediatric-orientated CIRCA group.

As in other (but not all) countries with similar economies, IVIG use is increasing by more than 10% per annum. In Australia most IVIG use is funded by the federal government (16) and distributed through the Red Cross Blood Service. A study in New South Wales is interrogating the Red Cross database to improve our understanding of the factors driving these changes. Subcutaneous immunoglobulin (SCIG) is becoming increasing popular among PID patients. SCIG appears to require lower overall immunoglobulin doses and some centres report that more patients are now using SCIG rather than IVIG. Although three products have been approved by regulatory authorities for SCIG use, and SCIG has been endorsed in the Australian criteria for the clinical use of immunglobulin (http://www.nba.gov.au/ivig/index.html), national funding of SCIG use is still awaited.  



Conclusion

The last 10 years has seen an unprecedented improvement in PID care in many areas of the world, including some areas where provision was seriously lacking. These improvements have resulted from collaborative efforts involving immunologists, non-specialist physicians, nurses’ associations, health providers, policymakers, and patient organisations. Such collaborations offer a model for further efforts to promote early diagnosis and therapy in order to extend and improve the lives of people with PIDs, especially in areas of greatest need.



References

1. Eades-Perner AM, Gathmann B, Knerr V, Guzman D, Veit D, Kindle G, Grimbacher B; ESID Registry Working Party. The European internet-based patient and research database for primary immunodeficiencies: results 2004-06. Clin Exp Immunol 2007;147:306–12

2. Gathmann B, Grimbacher B, Beauté J, Dudoit Y, Mahlaoui N, Fischer A, Knerr V, Kindle G; ESID Registry Working Party. The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008. Clin Exp Immunol 2009;157 Suppl 1:3–11

3. Gathmann B, Binder N, Ehl S, Kindle G; ESID Registry Working Party. The European internet-based patient and research database for primary immunodeficiencies: update 2011. Clin Exp Immunol 2012;167:479–91

4. de Vries E; European Society for Immunodeficiencies (ESID) members. Patient-centred screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update. Clin Exp Immunol 2012;167:108–19

5. Maródi L, J Project Study Group. The creation and progress of the J Project in Eastern and Central Europe. Ann NY Acad Sci 2011;1238:65-73



6. Zelazko M, Carneiro-Sampaio M, Cornejo de Luigi M, Garcia de Olarte D, Porras Madrigal O, Berrón Perez R, et al. Primary immunodeficiency diseases in the Latin America: first report from eight countries participating in LAGID. J Clin Immunol 1998; 18: 161–166

7. Leiva LE, Zelazco M, Oleastro M, Carneiro-Sampaio M, Condino-Neto A, Costa-Carvalho BT, et al. Primary immunodeficiency diseases in Latin America: the second report of the LAGID registry. J Clin Immunol 2007;27:101–8

8. Errante PR, Franco JL, Espinosa-Rosales FJ, Sorensen R, A Condino-Neto. Advances in primary immunodeficiency diseases in Latin America: epidemiology, research, and perspectives. Ann N Y Acad Sci 2012;1250:62–72

9. Condino-Neto A, Franco JL, Espinosa-Rosales FJ, Leiva LE, King A, Porras O, et al. Advancing the management of primary immunodeficiency diseases in Latin America: Latin American Society for Immunodeficiencies (LASID) Initiatives. Allergol Immunopathol (Madr) 2012;40:187–93

10. Barbouche MR, Galal N, Ben Mustapha I, Jeddane L, Mellouli F, Ailal F, et al. Primary immunodeficiencies in highly consanguineous North African populations. Ann N YAcad Sci 2011;1238:42–52

11. Al-Muhsen S, Alsum Z. Primary immunodeficiency diseases in the Middle East. Ann N Y Acad Sci 2012;1250:56–61

12. Hassan A, Booth C, Brightwell A, Allwood Z, Veys P, Rao K, et al. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency. Blood 2012;120:3615–24

13. Bousfiha AA, Jeddane L, Ailal F, Benhsaien I, Mahlaoui N, Casanova JL, Abel L. Primary immunodeficiency diseases worldwide: more common than generally thought. J Clin Immunol 2013;33:1–7



14. Mitchell R, Nivison-Smith I, Anazodo A, Tiedemann K, Shaw P, Teague L, et al. Outcomes of hematopoietic stem cell transplantation in primary immunodeficiency: a report from the Australian and New Zealand Children's Haematology Oncology Group and the Australasian Bone Marrow Transplant Recipient Registry. Biol Blood Marrow Transplant 2013;19:338–43

15. Kirkpatrick P, Riminton S. Primary immunodeficiency diseases in Australia and New Zealand. J Clin Immunol 2007;27:517–24

16. National Blood Authority National Report on the Issue and Use of Intravenous Immunoglobulin (IVIg) for 2010–2011. Canberra; National Blood Authority [www.nba.gov.au/ivig/ivig-report-10-11_amended_dec2012.pdf; last accessed 5 March 2013]