Global report on primary immunodeficiencies: 2018 update from the Jeffrey Modell Centers Network on disease classification, regional trends, treatment modalities, and physician reported outcomes

Abstract

Primary immunodeficiencies (PI) are genetic defects of the immune system that result in chronic, serious, and often life-threatening infections, if not diagnosed and treated. Many patients with PI are undiagnosed, underdiagnosed, or misdiagnosed. In fact, recent studies have shown that PI may be more common than previously estimated and that as many as 1% of the population may be affected with a PI when all types and varieties are considered. In order to raise awareness of PI with the overall goal of reducing associated morbidity and mortality, the Jeffrey Modell Foundation (JMF) established a network of specialized centers that could better identify, diagnose, treat, and follow patients with PI disorders. Over the past decade, the Jeffrey Modell Centers Network (JMCN) has provided the infrastructure to accept referrals, provide diagnosis, and offer treatments. Currently, the network consists of 792 Expert Physicians at 358 institutions, in 277 cities, and 86 countries spanning 6 continents. JMF developed an annual survey for physician experts within the JMCN, using the categories and gene defects identified by the International Union of Immunological Societies Expert Committee for the Classification of PI, to report on the number of patients identified with PI; treatment modalities, including immunoglobulins, transplantation, and gene therapy; and data on gender and age. Center Directors also provided physician-reported outcomes and differentials pre- and post-diagnosis. The current physician-reported data reflect an increase in diagnosed patients, as well as those receiving treatment. Suspected patients are being identified and referred so that they can receive early and appropriate diagnosis and treatment. The significant increase in patients identified with a PI is due, in part, to expanding education and awareness initiatives, newborn screening, and the expansion of molecular diagnosis and sequencing. To our knowledge, this is the most extensive single physician report on patients with PI around the world.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

Abbreviations

PI:

Primary immunodeficiencies

JMF:

Jeffrey Modell Foundation

JMCN:

Jeffrey Modell Centers Network

SCID:

Severe combined immunodeficiency

IUIS:

International Union of Immunological Societies

HSCT:

Hematopoietic stem cell transplantation

CVID:

Common variable immunodeficiency

IG:

Immunoglobulin therapy

IVIG:

Intravenous immunoglobulin therapy

SCIG:

Subcutaneous immunoglobulin therapy

PEG-ADA:

Polyethylene glycol-conjugated adenosine deaminase

BM:

Bone marrow

PBSC:

Peripheral blood stem cell

Cord:

Cord blood

MUD:

Matched unrelated donor

mMUD:

Mismatched unrelated donor

MRD:

Matched related donor

NBS:

Newborn screening

HCUP:

Hospital Cost and Utilization Project

AHRQ:

Agency for Healthcare Research and Quality

HCCI:

Health Care Cost Institute

References

  1. 1.

    Modell V. The impact of physician education and public awareness on early diagnosis of primary immunodeficiencies. Immunol Res. 2007;38:43–7.

    Article  PubMed  Google Scholar 

  2. 2.

    Modell F. Immunology today and new discoveries: building upon legacies of Dr. Robert a. Good. Immunol Res. 2007;38:48–50.

    Article  PubMed  Google Scholar 

  3. 3.

    Cunningham-Rundles C, Ponda PP. Molecular defects in T- and B-cell primary immunodeficiency diseases. Nat Rev Immunol. 2005;5:880–92.

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    Cooper MA, Pommering TL, Koranyi K. Primary immunodeficiencies. Am Fam Physician. 2003;68:2001–8.

    PubMed  Google Scholar 

  5. 5.

    Bousfiha A, Jeddane L, Al-Herz W, Ailal F, Casanova JL, Chatila T, et al. The 2015 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol. 2015;35:727–38. https://doi.org/10.1007/s10875-015-0198-5.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

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

    Article  PubMed  Google Scholar 

  7. 7.

    Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol. 2007;27(5):497–502.

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Stray-Pedersen A, Sorte HS, Samarakoon P, Gambin T, Chinn IK, Coban Akdemir ZH, et al. Primary immunodeficiency diseases: genomic approaches delineate heterogeneous Mendelian disorders. J Allergy Clin Immunol. 2017;139(1):232–45. https://doi.org/10.1016/j.jaci.2016.05.042.

    Article  PubMed  Google Scholar 

  9. 9.

    Rider NL, Kutac C, Hajjar J, Scalchunes C, Seeborg FO, Boyle M, et al. Health-related quality of life in adult patients with common variable immunodeficiency disorders and impact of treatment. J Clin Immunol. 2017;37(5):461–75. https://doi.org/10.1007/s10875-017-0404-8.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Quinti I, Di Pietro C, Martini H, Pesce AM, Lombardi F, Baumghartner M, et al. Health related quality of life in common variable immunodeficiency. Yonsei Med J. 2012;53(3):603–10. https://doi.org/10.3349/ymj.2012.53.3.603.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Casanova JL, Abel L, Quintana-Murci L. Immunology taught by human genetics. Cold Spring Harb Symp Quant Biol. 2013;78:157–72. https://doi.org/10.1101/sqb.2013.78.019968.

    Article  PubMed  Google Scholar 

  12. 12.

    Meyts I, Bosch B, Bolze A, Boisson B, Itan Y, Belkadi A, et al. Exome and genome sequencing for inborn errors of immunity. J Allergy Clin Immunol. 2016;138(4):957–69. https://doi.org/10.1016/j.jaci.2016.08.003.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. 13.

    Modell V, Gee B, Lewis DB, Orange JS, Roifman CM, Routes JM, et al. Global study of primary immunodeficiency diseases (PI)—diagnosis, treatment, and economic impact: an updated report from the Jeffrey Modell Foundation. Immunol Res. 2011;51:61–70.

    Article  PubMed  Google Scholar 

  14. 14.

    Modell F, Puente D, Modell V. From genotype to phenotype. Further studies measuring the impact of a physician education and public awareness campaign on early diagnosis and management of primary immunodeficiencies. Immunol Res. 2009;44(1–3):132–49.

    Article  PubMed  Google Scholar 

  15. 15.

    Picard C, Gaspar BH, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, et al. International Union of Immunological Societies: 2017 primary immunodeficiency diseases committee report on inborn errors of immunity. J Clin Immunol. 2018;38(1):96–128. https://doi.org/10.1007/s10875-017-0464-9.

    Article  PubMed  Google Scholar 

  16. 16.

    Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency 2015. J Clin Immunol. 2015;35(8):696–726. https://doi.org/10.1007/s10875-015-0201-1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. 17.

    Agency for Healthcare Research and Quality. http://www.hcup.ahrq.gov (2015).

  18. 18.

    Aetna Member Navigator. http://www.aetna.com (2015).

  19. 19.

    Bundorf KM, Royalty A, Baker LC. Health care cost growth among the privately insured. Health Aff. 2009;28(5):1294–304.

    Article  Google Scholar 

  20. 20.

    Truven Health Analytics. Healthcare Spending Index for Employer-Sponsored Insurance. 2014.

  21. 21.

    Centers for Medicare and Medicaid Services. Berenson-eggers type of service (BETOS). 2015. https://www.cms.gov/Medicare/Coding/HCPCSReleaseCodeSets/BETOS.html.

  22. 22.

    Centers for Medicare and Medicaid Services. Medicare current beneficiary survey (MCBS). 2015. https://www.cms.gov/Research-Statistics-Data-and-Systems/Research/MCBS/index.html?redirect=/mcbs.

  23. 23.

    Congressional Budget Office. Factors underlying the growth in medicare’s spending for physicians’ services. 2007. Retrieved 28 Apr 2010, from http://www.cbo.gov/ftpdocs/81xx/doc8193/06-06-MedicareSpending.pdf.

  24. 24.

    Fronstin P. Sources of health insurance and characteristics of the uninsured: analysis of the March 2013 current population survey, vol 390. EBRI (Employee Benefit Research Institute) Issue Brief No. 390, September 2013, Washington, DC; 2013. p. 1–36.

  25. 25.

    Chan K, Davis J, Pai SY, Bonilla FA, Puck JM, Apkon M. A Markov model to analyze cost-effectiveness of screening for severe combined immunodeficiency (SCID). Mol Genet Metab. 2011;104(3):383–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. 26.

    Health Care Cost Institute (HCCI) 2014 Health Care Cost and Utilization Report. 2015. http://www.healthcostinstitute.org/files/2014%20HCCUR%2010.29.15.pdf.

  27. 27.

    Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92(1):34–48.

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Chapel H, Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions. Br J Haematol. 2009;145(6):709–27. https://doi.org/10.1111/j.1365-2141.2009.07669.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. 29.

    de la Morena MT, Leonard D, Torgerson TR, Cabral-Marques O, Slatter M, Aghamohammadi A, et al. Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation. J Allergy Clin Immunol. 2017;139(4):1282–92. https://doi.org/10.1016/j.jaci.2016.07.039.

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    Merrill D. No one values your life more than the federal government. Bloomberg. October 19, 2017. https://www.bloomberg.com/graphics/2017-value-of-life/.

  31. 31.

    Menzin J, Sussman M, Munsell M, Zbrozek A. Economic impact of infections among patients with primary immunodeficiency disease receiving IVIG therapy. Clinicoecon Outcomes Res. 2014;6:297–302.

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Milner JD, Holland SM. The cup runneth over: lessons from the ever-expanding pool of primary immunodeficiency diseases. Immunology. 2013;13:635–48.

    PubMed  CAS  Google Scholar 

  33. 33.

    Puck J. Laboratory Technology for Population-based Screening for SCID in neonates: the winner is T-cell receptor excision circles (TRECs). J Allergy Clin Immunol. 2012;129(3):607–16. Published online 2012 Jan 29. https://doi.org/10.1016/j.jaci.2012.01.032.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Bharat ST, Alizadehfar R, Desrosiers M, Shuster J, Pant N, Tsoukasa CM. Adult primary immune deficiency: what are we missing? Am J Med. 2012;125(8):779–86.

    Article  Google Scholar 

  35. 35.

    Pollack A. Jennifer Doudna, a Pioneer Who Helped Simplify Genome Editing. Profiles in Science, NY Times. 2015. http://www.nytimes.com/2015/05/12/science/jennifer-doudna-crispr-cas9-genetic-engineering.html?_r=0. Accessed 13 May 2015.

  36. 36.

    Keller MD, Bollard CM, Hanley PJ, McCormack S, Heimall J, Bunin N, et al. Viral-specific T lymphocytes for treatment of viral infections in primary immunodeficiency. Biol Blood Marrow Trans. 2015;21(2):S229–30.

    Article  Google Scholar 

  37. 37.

    Naik S, Nicholas SK, Martinez CA, Leen AM, Hanley PJ, Gottschalk SM, et al. Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes. J Allergy Clin Immunol. 2016 May;137(5):1498–1505.e1. https://doi.org/10.1016/j.jaci.2015.12.1311.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. 38.

    Maffucci P, Filion CA, Boisson B, Itan Y, Shang L, Casanova JL, et al. Genetic diagnosis using whole exome sequencing in common variable immunodeficiency. Front Immunol. 2016;7:220. https://doi.org/10.3389/fimmu.2016.00220. eCollection 2016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. 39.

    Abolhassani H, Chou J, Bainter W, Platt CD, Tavassoli M, Momen T, et al. Clinical, immunologic, and genetic spectrum of 696 patients with combined immunodeficiency. J Allergy Clin Immunol. 2017;141:1450–8. https://doi.org/10.1016/j.jaci.2017.06.049.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank the Jeffrey Modell Center Directors for their generous support and continued commitment to the Jeffrey Modell Foundation and the global primary immunodeficiency communities. We thank Dr. Chaim Roifman, Founder, and Director of the Jeffrey Modell Centers Network, for his vision, and Dr. Jordan Orange for his expertise and guidance.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Fred Modell.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest except for the following:

Jordan Orange, MD, PhD: Shire Consultant, Grifols Consultant, CSL consultant, received speaking honoraria from Shire, ADMA Scientific Advisory Board, author of the chapter on IVIG in Up to Date for which he receives royalties.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Modell, V., Orange, J.S., Quinn, J. et al. Global report on primary immunodeficiencies: 2018 update from the Jeffrey Modell Centers Network on disease classification, regional trends, treatment modalities, and physician reported outcomes. Immunol Res 66, 367–380 (2018). https://doi.org/10.1007/s12026-018-8996-5

Download citation

Keywords

  • Primary immunodeficiencies (PI)
  • Jeffrey Modell Foundation (JMF)
  • Jeffrey Modell Centers Network (JMCN)
  • Awareness
  • Education
  • Diagnosis
  • Treatment
  • Gene discovery
  • Immunology