Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: The Year in Human and Medical Genetics: Inborn Errors of Immunity Ten warning signs of primary immunodeficiency: a new paradigm is needed for the 21st century Peter D. Arkwright1 and Andrew R. Gennery2 1Department of Paediatric Allergy and Immunology, Royal Manchester Children’s Hospital, University of Manchester, Manchester, United Kingdom. 2Department of Paediatric Immunology, University of Newcastle upon Tyne, Newcastle, United Kingdom Address for correspondence: Peter D. Arkwright, Senior Lecturer in Paediatric Immunology, Department of Paediatric Allergy and Immunology, Royal Manchester Children’s Hospital, Oxford Road, Manchester M13 9WL. [email protected] The 10 warning signs of primary immunodeficiency are being promoted as a screening tool for use by both the general public and physicians. A recent study, however, shows that except for family history, need for intravenous antibiotics and failure to thrive, the 10 warning signs are not a useful screen of primary immunodeficiency diseases (PIDs). Over the last few decades, there has been a revolution in our understanding of PID. The 10 warning signs do not take into account the fact that PIDs now include diseases that present with sporadic infections, autoimmunity, autoinflammation, and malignancy. This review focuses on the advances in our understanding of PID, the current limitations of the 10 warning signs, and recommendations to ensure that patients with PID are diagnosed in a timely fashion in the future. Keywords: primary immunodeficiency; autoimmunity; atopic dermatitis; cancer; family history Preferred citation: Arkwright, P.D. & A.R. Gennery. 2011. Ten warning signs of primary immunodeficiency: a new paradigm is needed for the 21st century. In “The Year in Human and Medical Genetics: Inborn Errors of Immunity I.” Jean-Laurent Casanova, Mary Ellen Conley & Luigi Notarangelo, Eds. Ann. N.Y. Acad. Sci. 1238: 7–14. First studies characterizing primary serious, recurrent, or unusual infections. Changes to immunodeficiency diseases the way we promote awareness of PID among the medical profession and sectors of the general public The first primary immunodeficiency diseases are required if premature death and serious mor- (PIDs) were identified 50–60 years ago, at a time bidity due to late diagnosis of the wider spectrum when immunoglobulin was first measured and iso- , of PID are to be avoided. lated from serum1 2 and the function of lymphocytes as an important component of the immune system 3 The development of the 10 warning signs was recognized. The earliest PID to be described of primary immunodeficiency included disorders of neutrophils (chronic gran- ulomatous disease),4 Tlymphocytes(severecom- The first PIDs to be discovered were manifest by bined immunodeficiency [“Swiss-type”]),5 Wiskott a propensity to recurrent severe or unusual infec- Aldrich syndrome,6 and B lymphocytes (Bruton’s tions. Attending physicians learned to recognize agammaglobulinemia).7 Along with this expan- patterns of clinical disease that suggested the pa- sion in our understanding of the immune basis of tient may have an underlying primary immune PID, new therapies were being developed, including defect.9–11 Over the last few decades, the number the introduction of immunoglobulin replacement of clinicians and scientists involved in the diag- (1952) and bone marrow transplantation (1957).8 nosis and management of PID has expanded ex- The molecular etiology of 150 different PIDs have ponentially, initially in western Europe (European now been defined. The spectrum of clinical presen- Society for Immunodeficiencies) and the United tations of PID is now recognized to include autoin- States (United States Immunodeficiency Network; flammation, autoimmunity, and neoplasia as well as http://www.usidnet.org/), and more recently in doi: 10.1111/j.1749-6632.2011.06206.x Ann. N.Y. Acad. Sci. 1238 (2011) 7–14 c 2011 New York Academy of Sciences. 7 Ten warning signs of PID in the 21st century Arkwright & Gennery eastern Europe (J Project),12 the Middle East Table 1. Ten warning signs of primary immunodeficiency (Asian Society for Primary Immunodeficiency), ≥ northern Africa (African Society for Immunode- 1 4 ear infections in one year ≥ ficiency), South America (Latin American Group 2 2 serious sinus infections in one year ≥ for Primary Immunodeficiencies), and other parts 3 2 pneumonias in one year of the world. Better training of physicians has led to 4 Recurrent, deep skin or organ abscesses diagnosis of more patients with PID.13 The preva- 5 Persistent thrush in mouth or fungal lence of PID is currently estimated to be 1/10,000 infection on skin ≥ people in the Western world. 6 2 deep-seated infections including A number of nonprofit organizations (Jeffery septicemia ≥ Modell Foundation, International Patient Organ- 7 2 months on antibiotics with little isation for Primary Immunodeficiencies, Primary effect Immunodeficiency Association) provide valuable 8 Need for intravenous antibiotics to clear support for families with PID as well as health infections care professionals looking after these patients. Re- 9 Failure of an infant to gain weight or cently, these organizations have become increas- grow normally ingly vocal in promoting public awareness of PID 10 Family history of primary at a government level as well as among the gen- immunodeficiency eral public. The 10 warning signs of primary im- Note: If you or someone you know is affected by ≥2 munodeficiency, based largely on clinical presen- warning signs, speak to a physician about the possible tation of antibody immunodeficiencies in adults14 presence of an underlying primary immunodeficiency; and expert opinion, are now heavily promoted as www.info4pi.org/aboutPI/index.cfm?section=aboutPI& a way of making people aware of PID, most re- content=warningsigns, accessed July 18, 2011. cently through World Primary Immunodeficiency Week 2011 (www.worldpiweek.org/). The clinical was a family history, with use of intravenous antibi- features focus on the occurrence of recurrent upper otics for sepsis in children with neutrophil PID and and lower respiratory tract infections (sinus, ear, failure to thrive in children with T lymphocyte PID and chest), persistent superficial fungal infections, of secondary importance. Using these three signs, or more deep-seated infections (localized abscesses 96% of patients with neutrophil and complement or disseminated blood-borne infections). The need deficiencies and 89% of children with T lympho- for intravenous antibiotics or prolonged courses of cyte PID could be correctly identified. The results oral antibiotics, failure to thrive in infancy, and a indicated that as well as hospital physicians, educa- family history of PID are also included (Table 1). tion and particularly genetic counseling of families who have had a child with a PID are important. Validity of the 10 warning signs in The 10 warning signs leaflet advises that if two or predicting the likelihood of PID in children more warning signs are present, PID should be con- It remains the role of specialists who treat patients sidered. Wetherefore performed additional analyses with PID to ensure that promotional material is to determine whether two or more warning signs are accurate and up to date in relation to the rapid ad- more common in children with defined PID com- vances in the field of immunodeficiency. As the ef- pared with those where no PID is found. Two or fectiveness of the 10 warning signs as a screening test more warning signs identified children with neu- of PID had not previously been formally assessed, trophil PID but not those with complement, B cell early in 2011 we evaluated the presenting symptoms or T cell PID (Table 2). of 563 children attending two tertiary pediatric im- Evolving concepts of infectious diseases munology centers in the north of England.15 Ninety- that may herald PID six percent of the children with PID were referred by hospital clinicians, indicating that the most im- It is now recognized that PID may not only present portant group to target regarding awareness and with recurrent or unusual infections, but that one- education of PID are hospital doctors who are most off infections with common pathogens may also her- likely to be called on to manage children at presen- ald a life-threatening PID. To delay considering the tation. The strongest identifier of PID in our study diagnosis of PID for the appearance of subsequent 8 Ann. N.Y. Acad. Sci. 1238 (2011) 7–14 c 2011 New York Academy of Sciences. Arkwright & Gennery Ten warning signs of PID in the 21st century Table 2. Frequency (percentage) of ≥2 warning signs in cytosis, hereditary angioedema, immunodysregu- children with and without PID lation polyendocrinopathy enteropathy X-linked [IPEX], IL-10 receptor deficiency, and periodic fever Relative risk syndromes). Thus, in our north of England cohort, (95% CI) at least one in five patients with PID would be missed < ≥ 2 Warning 2 Warning compared if the 10 warning signs were used as a screen. signs signs with no PID To illustrate this point further, a classic exam- ple of a PID disease, where presentation is usu- No PID 70 (52%) 63 (48%) – ∗ ally with noninfectious features, is IPEX syndrome Any PID 163 (38%) 267 (62%) 1.8 (1.2–2.7) ∗ due to mutations in the FOXP3 gene. IPEX is due Neutrophil 10 (14%) 63 (86%) 7.0 (3.3–14) to a deficiency of T regulatory cells, and children PID present with severe, often unremitting autoimmune Complement 9 (41%) 13 (59%) 1.6 (0.6–4.0) enteropathy, endocrinopathies, such as thyroid dis- PID ease and diabetes mellitus, autoimmune cytopenias, B cell PID 42 (40%) 63 (60%) 1.7 (1.0–2.8) and eczema. Recurrent infections may or may not T cell PID 102 (44%) 128 (56%) 1.4 (0.9–2.1) occur as part of the clinical course.24 Even some ∗Significant at P < 0.01 by Chi-square, compared with of the earliest PIDs to be described, for example the group that did not have a PID.