Ann. N.Y. Acad. Sci.

ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S
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
1
Department of Paediatric Allergy and Immunology, Royal Manchester Children’s Hospital, University of Manchester,
Manchester, United Kingdom. 2 Department 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. peter.arkwright@nhs.net

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 The development of the 10 warning signs
was recognized.3 The earliest PID to be described of primary immunodeficiency
included disorders of neutrophils (chronic gran-
ulomatous disease),4 T lymphocytes (severe com- 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),
1 ≥4 ear infections in one year
northern Africa (African Society for Immunode-
2 ≥2 serious sinus infections in one year
ficiency), South America (Latin American Group
3 ≥2 pneumonias in one year
for Primary Immunodeficiencies), and other parts
4 Recurrent, deep skin or organ abscesses
of the world. Better training of physicians has led to
5 Persistent thrush in mouth or fungal
diagnosis of more patients with PID.13 The preva-
infection on skin
lence of PID is currently estimated to be 1/10,000
6 ≥2 deep-seated infections including
people in the Western world.
septicemia
A number of nonprofit organizations (Jeffery
7 ≥2 months on antibiotics with little
Modell Foundation, International Patient Organ-
effect
isation for Primary Immunodeficiencies, Primary
8 Need for intravenous antibiotics to clear
Immunodeficiency Association) provide valuable
infections
support for families with PID as well as health
9 Failure of an infant to gain weight or
care professionals looking after these patients. Re-
grow normally
cently, these organizations have become increas-
10 Family history of primary
ingly vocal in promoting public awareness of PID
immunodeficiency
at a government level as well as among the gen-
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. We therefore 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. chronic granulomatous disease25 and Omenn syn-
drome, may present with prominent autoinflamma-
infections as suggested by the 10 warning signs may tory features involving the gut, skin, and other or-
be courting disaster, for instance, in patients with gans. Periodic fever syndromes are now recognized
toll-like receptor (TLR) pathway PID. Defects in within the wider PID classification. Autoinflamma-
the IRAK4 and MyD88 genes are associated with tion in this group of conditions can affect bones and
life-threatening/fatal infections with Staphylococcus joints, brain, eyes and ears, skin, and serous mem-
aureus and Streptococcus pneumoniae.16 Fifty per- branes.26 Malignancy is also a presenting feature of
cent of children with IRAK4/MyD88 were dead by some PIDs. Patients with X-linked lymphoprolifer-
the age of eight years, most before the age of two ative disease27 and IL-2-inducible T cell kinase defi-
years. Mutations in TLR3 and downstream signaling ciency28 may present with lymphoproliferative dis-
molecules have been associated with herpes simplex ease/lymphomas. Patients with DNA repair enzyme
encephalitis, which is often either fatal or leads to se- defects, such as Nijmegen breakage syndrome, may
vere neurological disability.17,18 Although naivety of also present with cancer, particularly non-Hodgkin
young children’s immune system explains why some lymphoma.29,30 These PIDs are examples of which
develop infectious diseases, there is now a growing delayed diagnosis is common and the 10 warning
recognition that an underlying PID should be con- signs of yesteryear are least useful. Curative treat-
sidered when children present with infections with ment is available for a number of these disorders and
certain common pathogens.19,20 In these children, outcome is better where the diagnosis is made before
the 10 warning signs fail to provide appropriate the development of extensive disease and end-organ
warning. damage.
PID presenting with noninfectious A new dimension to PID: epithelial
diseases barrier-centered immunodeficiencies
The 10 warning signs make no mention of au- Atopic dermatitis (eczema) affects up to one in
toimmune or malignant manifestations of PID, five people in Western countries. It is character-
which may be the presenting clinical feature ized by a propensity to chronic or recurrent viral
(Table 3).13,21–23 Our recent study assessing the (eczema herpeticum, eczema vaccinatum, warts and
usefulness of the 10 warning signs of PID15 molluscum contagiosum) and bacterial—especially
excluded 20% of patients with PID in whom S. aureus—infections localized to the skin.31 Im-
their clinical presentation did not involve infec- petigo is a common cause of eczema flares, partic-
tious diseases (autoimmune lymphoproliferative ularly in children.32 Thus, atopic dermatitis can be
disease [ALPS], familial hemophagocytic histio- defined as a PID, although until now it has been

Ann. N.Y. Acad. Sci. 1238 (2011) 7–14 

c 2011 New York Academy of Sciences. 9
Ten warning signs of PID in the 21st century Arkwright & Gennery

Table 3. Groups of PID and example diseases that may be associated with autoimmune/autoinflammatory or
malignancy as a presenting feature

Autoinflammatory Autoimmune Malignancy

Familial hemophagocytic HLH – lymphoma

lymphohistocytosis,
e.g., XLP, XIAP, Griselli,
Chediak-Higashi, perforin
Munc13–4, Munc 18, and
Syntaxin 11
Familial periodic fever polyserositis
syndromes,
e.g., TRAPS, HIDS, FMF, – – –
CINCA, and Muckel-Wells
DNA repair/cell cycle disorders, – skin, thyroid lymphoma, other
e.g., ataxia-telangiectasis, – – –
Nijmegen-breakage syndrome,
ligase IV, and Cernunnos
Omenn syndrome, hepatitis, encephalopathy, – –
e.g., RAG deficiency pneumonitis, enteropathy
Complement deficiencies hemolytic-uremic syndrome, SLE –
—especially C1q, also HAE, angioedema
factor H, MCP and factor I,
the activator factor B, or the
C3 factor
defects in apoptosis, – autoimmune cytopenias lymphoma
e.g., ALPS
APECED – organ-specific –
autoimmunity
Defects in nucleic acid disposal – SLE-like –
—immuno-osteodysplasias,
SAMHD1 deficiency,
Aicardi–Goutières syndrome
Reduced T regulatory function, IBD cytopenia –
e.g., IPEX, IL-10R deficiency
Other – – –
—pulmonary alveolar
proteinolysis, haemolytic
uremic syndrome

routinely classified as a dermatological or allergic to one that limits exposure/expels them (Th2 re-
disorder. sponse).33,34 In this regard, surface epithelial cells,
There is increasing recognition over the last although not bone marrow-derived, are an integral
decade that skin epithelial cells do not just form an part of the immune system. Thymic stromal lym-
inert barrier between the host and its environment phopoietin (TSLP), an epithelium-derived IL-7–like
but actively respond to surface immunogens and cytokine is now considered an important master
redirect the immune response from one that engulfs switch and key regulator of epithelium-orchestrated
and internally digests pathogens (Th1 response), Th2 immunity.35,36

10 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

Activation of this innate, nonhemopoietic com- Recognizing PID in the 21st century
ponent of the immune system in atopic dermatitis
Rather than promoting the 10 warning signs of PID
is now known to be a defect in the superficial stra-
to the general public, consolidating and refining a
tum corneum of the skin, which normally protects
specialist-led approach to the timely identification
the underlying live keratinocytes from exposure to
of PID would help to focus limited resources avail-
pathogens and allergens. The surface of the stratum
able from both health care professionals and support
corneum consists of a relatively impermeable bar-
organizations. Optimal detection of PID requires
rier formed by aggregation of keratin filaments by
a multipronged approach: (1) ongoing training of
a filament-aggregating factor, filaggrin. Up to 50%
clinicians, particularly those involved in secondary
of patients with moderate to severe disease have
and tertiary practice regarding the diverse clinical
inherited defects in skin barrier function due to mu-
presentations of PID, as with the J Project in east-
tations in the filaggrin gene.37–39 The poor skin bar-
ern Europe; (2) ensuring that parents who have had
rier results not only in dry ichthyotic skin, dermati-
a child with PID are provided with genetic coun-
tis, and propensity to other allergic diseases40,41 but
seling and that their family practitioners as well as
also the predisposition to cutaneous infections.42,43
obstetricians realize the importance of consulting
Thus, eczema occurs not only secondary to rare
with PID specialists in all future pregnancies; and
PIDs such as Wiskott-Aldrich syndrome, Hyper
(3) use of evolving laboratory screening tests as they
IgE syndrome, and IPEX, but as a primary con-
become available. Success of this model requires the
dition and may well constitute the most common
combined and collaborative input of specialists in
PID.
PID and other disciplines, as well as PID advocacy
Recognizing PID: 60 years on groups. Early diagnosis ensures a 95% chance of
cure and/or long-term survival for many patients
There is no doubt that our understanding of PID has
with PID.
undergone a revolution over the last 60 years. The
diagnosis of PID includes not only patients present- Training of clinicians managing patients
ing with recurrent severe and unusual infections but with PID
also those with sporadic infections, such as herpes Ongoing training of clinicians working not only in
simplex encephalitis, as well as autoinflammation infectious diseases and immunology, but also gen-
and autoimmunity (Table 3). The human adaptive eral pediatricians and physicians and specialists in
immune system has evolved from the ability to alter intensive care, rheumatology, hematology, oncol-
the structure of genomic DNA and cancers may also ogy, gastroenterology, and neurology is important if
be presenting feature of PID.44 “A typical PID” may the diverse phenotypes that PID patients can present
cause just as much morbidity and mortality as PID with are to be recognized. Rather than a simple list
with a more classical presentation. of warning signs, these specialists require detailed
The challenge for physicians is to recognize the knowledge of clinical presentations as it relates to
diverse ways PID may present if unnecessary deaths their speciality and where to seek help and advice
are to be avoided in our patients and other affected regarding the investigation of these diseases. As the
family members. Nonprofit organizations are right majority of patients will initially present to hospital
to work with physicians to help promote knowledge doctors, a focus on hospital specialists rather than
of these conditions to those that need it most. There the general public and family doctors is likely to
is no doubt that they have contributed to the de- be more effective in reducing disease burden, while
velopment and promotion of professional services at the same time avoiding inappropriate referrals
for patients with PID worldwide. The 10 warning and public anxiety. Further prospective studies are,
signs are however a relic of yesteryear. They fail to however, needed to confirm this supposition.
recognize the complexity and diversity of PID as
we understand them today and if promoted as the Counseling and education of families who
screening test for PID, risk patients with less classical have a child with a PID and their personal
presentations being missed, or their diagnosis being health care physicians
delayed. A new diagnostic paradigm is required for Family history is the key warning feature of PID.15
the 21st century. A focus on parents who have a child with a PID

Ann. N.Y. Acad. Sci. 1238 (2011) 7–14 

c 2011 New York Academy of Sciences. 11
Ten warning signs of PID in the 21st century Arkwright & Gennery

is important if unnecessary morbidity and mor- toimmunity, autoinflammation, and neoplasia. Use
tality of affected siblings is to be avoided. Parents of the 10 warning signs in public and physician-
should be provided with genetic counseling and be based awareness campaigns is not supported by cur-
encouraged to discuss future pregnancies with their rent evidence or advances in our understanding of
family doctor and geneticist before, or at least in diverse presentations of PID. Most PIDs present to
the early stages of subsequent pregnancies. Using hospital physicians. The key useful warning sign is a
this approach, birth of children with severe PID family history. A more focused approach of educat-
would potentially be avoided and affected infants ing, training, and counseling hospital doctors and
treated before they succumb to clinical complica- families with patients would target limited resources
tions. Parental acceptance of genetic counseling is on those where impact is likely to be greatest. It
variable and often depends on their ethnic and so- is also likely to avoid unnecessary concern within
cial background. Specialists as well as society must the general public and unnecessary referrals to
meet the challenge of educating and influencing so- specialists.
cial attitudes in groups where this approach may Acknowledgments
have greatest impact on disease morbidity and mor-
tality.45 In regions where specific diseases are high, We are grateful to Professor A.J. Cant and Dr. S.
for example, ␤-thalassemia in some regions of the Hambleton, Department of Paediatric Immunol-
Mediterranean region, Government regulations re- ogy, Newcastle upon Tyne; and Dr. S.M. Hughes, De-
quiring genetic screening and counseling before partment of Paediatric Immunology, Royal Manch-
marriage has been successfully implemented leading ester Children’s Hospital for their critical reading of
to a decline in disease incidence.46 Support organi- this manuscript and their comments.
zations may well be able to provide valuable support Conflicts of interest
and influence.
Worldwide, one billion people live in countries The authors declare no conflicts of interest.
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