Primary immunodeficiency diseases (PIDs) are genetically determined disorders of the immune system resulting in greatly enhanced susceptibility to infectious disease, autoimmunity and malignancy. While individual PIDs are rare, as a group, it is estimated that between 1:2000 and 1:10 000 live births are affected by a PID. Moreover, PIDs can present at any age from birth to adulthood, posing a considerable challenge for the practising physician to know when and how to work-up a patient for a possible immune defect. In this review, we outline the basic organisation of the human immune system and the types of infections that occur when elements of the immune system are dysfunctional. Importantly, we provide practical guidelines for identifying patients who should be referred for assessment of possible immunodeficiency and an overview of screening investigations and effective therapeutic options available for these patients.
- primary immunodeficiency
- clinical immunology
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Primary immunodeficiency diseases (PIDs) are a group of genetic disorders in which parts of the human immune system are missing or dysfunctional. PIDs interfere with the essential protective functions of the immune system, resulting in greatly enhanced susceptibility to infectious disease, autoimmunity and malignancy. Many clinicians have a limited appreciation of PIDs as knowledge obtained during medical school and clinical training is often outdated and many PIDs have only been fully characterised in recent years. Lack of understanding of PIDs translates directly into significant delays in diagnosis and treatment, often with tragic results for the affected patient.1 2
PIDs are not rare. Prevalence rate estimates for PIDs range from 1:2000 to 1:10 000.3 PIDs are sufficiently common that primary care and specialist physicians are likely to see PID patients in their practice and should test for these disorders in patients with recurring, unusual or serious infections. Indeed PIDs may present in such a subtle fashion that the diagnosis will be made only if the physician is aware of this group of diseases.
The objective of this review is to improve physician recognition and diagnosis of PIDs. As a starting point we provide an overview of the basic structure of the human immune system and then we expand this framework to provide clinical based guidance to facilitate the diagnosis of PIDs. While PIDs can impact all aspects of human immune function, we deliberately focus on four major types of PID which as a group represent the clinical phenotype of up to 90% of patients diagnosed with PIDs.4 Although we appreciate that most PID patients will be managed in specialist centres, we end by highlighting the variety of effective treatments that are currently available for people living with PIDs.
PubMed (available via the NCBI www.ncbi.nlm.nih.gov/sites/entrez) was searched to identify relevant articles published from 1995 to May 2009. MeSH major topic search term was “Immunologic deficiency syndromes” modified with the terms NOT “HIV” and NOT “AIDS”. Individual diseases were searched independently. Citations were screened for relevance, timeliness and scope. The quality of the evidence supporting any therapeutic recommendation in table 1 was categorised using the scheme of Shekell et al.5
Organisation of the human immune system: three levels of host defence
The human microbial defence system can be viewed as consisting of three levels: (1) anatomical and physiological barriers; (2) innate immunity; and (3) adaptive immunity (fig 1). The integrity of each of these defence systems should be considered in patients with recurrent, severe or opportunistic infections (table 2).
Anatomical and physiological barriers provide the crucial first line of defence against pathogens. These barriers include intact skin, mucociliary clearance, low stomach pH and bacteriolytic lysozyme in secretions. The extreme susceptibility to infections caused by burns or cystic fibrosis demonstrates that intact innate and adaptive immune systems are not able to compensate for failure of essential anatomical and physiological barriers.
Innate immunity, an evolutionarily ancient form of host defence, is activated if the anatomical and physiological barriers are breached.6 The innate immune system relies upon a limited repertoire of receptors to detect invading pathogens, but compensates for this limited number of invariant receptors by rapidly targeting conserved microbial components shared by large groups of pathogens. PIDs due to genetic defects in neutrophil development, toll-like receptor signalling and complement, reveal the protective role played by the innate immune system.7
T and B lymphocytes are the main self-defence weapons of the adaptive immune system. In contrast to the limited number of pathogen receptors utilised by the innate immune system, the adaptive immune system boasts an extremely diverse, randomly generated repertoire of receptors. Some of the most common and severe PIDs interfere with adaptive immune function, including severe combined immunodeficiency (SCID; absent or dysfunctional T cells) and common variable immunodeficiency (CVID; inability of B cells to produce protective antibody).
Differentiating between primary and secondary immunodeficiency
While the focus of this article is on primary or genetic immunodeficiency, clinicians must be alert for the much more common possibility of secondary or acquired immunodeficiency in patients presenting with an unusual pattern of infections. In contrast to patients with PIDs, those with secondary immunodeficiencies are born with a normal immune system but an acquired insult causes immunocompromise. Careful history and physical examination should detect most secondary immunodeficiencies, including malnutrition, splenectomy, haematological malignancy, immunosuppressive or immunomodulatory therapy, human immunodeficiency virus (HIV) infection, and protein losing enteropathy.
A clinical approach to the diagnosis of PIDs
As most patients with PIDs present with infections, the differential diagnosis and initial investigations for an underlying immune defect should be guided by the clinical presentation. In patients with PIDs, individual infections are not necessarily more severe than those that occur in a normal host. Rather, the clinical features suggestive of an immune defect may be the recurring and/or chronic nature of infections with common pathogens which may result in end organ damage, such as bronchiectasis. In addition, patients with PIDs will often respond poorly to standard antimicrobial therapy or they may have repeated infections with the same pathogen. The virulence of the infecting organism should also be considered, and a patient’s immunocompetence should be questioned when invasive infections are caused by poorly virulent or opportunistic pathogens. For example, infection with the opportunistic pathogens Pneumocystis jiroveci (previously Pneumocystis carinii) or atypical mycobacteria should prompt an investigation for underlying immunodeficiency.
Typical clinical presentations for patients with PIDs are:
antibody deficiency and recurrent bacterial infections
T lymphocyte deficiency and opportunistic infections
other lymphocyte defects causing opportunistic infections
neutrophil defects causing immunodeficiency.
Antibody deficiency and recurrent bacterial infections
Antibody deficiency is the most common form of PID. It is estimated that up to 80% of PID patients have antibody production defects.4 The clinical consequence of antibody deficiency is recurrent sinopulmonary infection—otitis media, sinusitis, and pneumonia. While sinopulmonary infections are common in the general population, investigation for a PID is indicated in patients with recurrent, refractory or very severe infections.8
A number of clinical entities mimicking antibody deficiencies must be considered in patients presenting with recurrent sinopulmonary infections, including: allergic rhinosinusitis, cystic fibrosis, primary ciliary dyskinesia, and anatomic lesions interfering with the drainage functions of the Eustachian tube and ostiomeatal complex. Environmental circumstances leading to increased exposure to infection (for example, crowded households, daycare, older siblings) or irritated airways (for example, environmental tobacco smoke) must also be considered.
Initial laboratory interrogation of humoral immune function should include quantification of serum immunoglobulins (that is, IgG, IgA, IgM, and IgE), as well as examination of the patient’s ability to produce functional or specific antibody. Serum immunoglobin levels must be interpreted using age appropriate reference ranges. The most convenient way to determine the patient’s capacity to generate specific antibodies is to measure antibody titres following immunisation with protein (for example, tetanus or diphtheria toxoids) and polysaccharide antigens (for example, pneumococcal capsular polysaccharides). If initial titres are low, the response 4–6 weeks after booster vaccination should be assessed.
Patients with recurrent sinopulmonary infections and normal humoral immunity should be studied for complement deficiency. Congenital absence of critical components of the complement cascade (for example, C2, C3, and C4) cause clinical features indistinguishable from antibody deficiency syndromes. Functional assays of classical (CH50) and alternative (AH50) pathways of complement activity are routinely available and will detect clinically relevant defects of complement function.
Two antibody production disorders causing controversy and confusion are selective IgA deficiency and IgG subclass deficiency.9 Selective IgA deficiency (defined as an undetectable serum IgA level) is extremely common, with prevalence of approximately 1 in 500, and at least 80% of the IgA deficient individuals are asymptomatic.10 Hence, the clinical relevance of selective IgA deficiency must be determined in light of the history of recurrent sinopulmonary infections or other disorders reported to be associated with IgA deficiency, including atopy, gastrointestinal disease (especially coeliac disease), and autoimmunity. The clinical relevance of IgG subclass deficiency is uncertain as IgG subclass deficiency can also be asymptomatic.11 A patient’s ability to produce specific antibodies against protein and polysaccharide antigens should determine the need for therapeutic intervention. Consequently, we do not recommend measuring IgG subclasses as an initial screen for humoral immune function.
T lymphocyte deficiency and opportunistic infections
Severe combined immune deficiency (SCID) is a heterogeneous group of disorders caused by genetic defects impairing T lymphocyte development and function.12 The “combined” nature of these immune deficiencies results from the inability of T cells to provide immunological “help” to the antibody producing B cells or a direct impact on B cell development, resulting in the combined clinical features of both T cell and B cell dysfunction.
Since combined immune deficiencies severely impair the protective functions of the adaptive immune system, affected individuals often present within the first few months of life with multiple severe infections. Clinical features that should alert clinicians to the possibility of SCID include interstitial pneumonia, chronic diarrhoea and persistent candidiasis associated with growth failure. Severe, life threatening infections are caused by common viruses (for example, respiratory syncytial virus, adenovirus, parainfluenza, cytomegalovirus) and opportunistic pathogens, including Pneumocystis jiroveci and Aspergillus species. Uncontrolled replication of bacille Calmette–Guérin (BCG) following vaccination is another classic presentation of SCID.
SCID is a true medical emergency. Due to the very high risk of overwhelming infection, infants with suspected SCID must be rapidly assessed by a physician expert in clinical immunology as outcomes are greatly improved with early intervention. The clinical diagnosis of SCID can usually be confirmed with relatively simple laboratory investigations. The first investigations should include a complete blood count with differential and quantification of serum immunoglobulins (IgG, IgA, IgM, IgE).
All forms of SCID affect T cell development. Since ∼70% of circulating lymphocytes are T cells, lymphopenia is a key feature of most SCID and is present at birth. An absolute lymphocyte count below 2000 cells/μl (2×109/l) in an infant should raise the suspicion of SCID.13 In some forms of SCID, increased B cell numbers normalise the lymphocyte count, so a normal or even elevated absolute lymphocyte count does not rule out the diagnosis of SCID: if clinical suspicion is high, further testing must be pursued.
Other lymphocyte defects causing opportunistic infections
There are several forms of immunodeficiency in which the functions of T and B cells are affected but are not categorised as “severe” immunodeficiency since at least partial T cell function usually remains. As a group these disorders represent approximately 5–10% of PIDs and we review four of the more common and well characterised defects of this group: Wiskott–Aldrich syndrome, DiGeorge syndrome, ataxia–telangiectasia, and hyper IgE syndrome.
Wiskott–Aldrich syndrome is characterised by the clinical triad of thrombocytopenia with small platelets, eczema, and recurrent bacterial respiratory infections.14 15 This disorder has X-linked recessive inheritance, and the earliest manifestations demanding clinical attention are often petechiae and abnormal bleeding. Thrombocytopenia is the most consistent feature, and the diagnosis should be carefully ruled out in any males with this presentation.
DiGeorge syndrome presents with a classic triad of congenital cardiac anomaly, thymic and parathyroid hypoplasia, and recurrent infections.16 Approximately 80% of patients have a hemizygous deletion of chromosome 22q11 that is readily detected using fluorescence in situ hybridisation (FISH) analysis. Interrupted aortic arch type B is the most common cardiac defect found in chromosome 22q11 deletion syndromes, but any cardiac anomaly is possible. Thymic hypoplasia leads to T cell lymphopenia, while parathyroid hypoplasia leads to hypocalcaemia. If the hypoparathyroidism is severe, neonatal tetany may be the initial clinical presentation; otherwise the cardiac defect is usually the most prominent manifestation. Most patients have so-called “partial” DiGeorge syndrome, where some thymus tissue is present and the T cell number is sufficient for essentially normal immune function. In patients with “complete” DiGeorge syndrome, there is no thymus and hence the infant has no T cells. This is an immunological emergency similar to SCID and emerging data suggest that many of these patients may be cured by thymus transplantation.17
Ataxia–telangiectasia, as the name suggests, is a syndrome whose principal manifestations include progressive cerebellar ataxia with onset in infancy, together with ocular and cutaneous telangiectases that usually begin to appear around age 3–5 years.18 It is important to recognise this disease early, as there is significant sensitivity to ionising radiation, and extreme predisposition to cancer (mainly lymphoma). Many patients also have recurrent respiratory bacterial infections and variable hypogammaglobulinaemia, impaired antibody production, and lymphopenia. For unknown reasons, the serum alpha fetoprotein value is markedly elevated in at least 95% of patients, and this is a very useful screening test.
Hyper IgE syndrome (HIES) is a multisystem PID classically characterised by eczema, skin abscesses, recurrent staphylococcal infections of the skin and lungs, pneumatocele formation, candidiasis, eosinophilia, and elevated serum levels of IgE. Non-immunologic features of HIES include characteristic facial appearance, scoliosis, retained primary teeth, joint hyperextensibility, bone fractures following minimal trauma, and craniosynostosis.19 In 2007, mutations in the signal transducer and activator of transcription 3 (STAT3) were shown to be a cause of the autosomal dominant form of HIES.20 21
Neutrophil defects causing immunodeficiency
Neutropenia is often discovered in the course of an evaluation for acute infection. The clinical challenge is to differentiate between infection occurring secondary to neutropenia, and neutropenia occurring secondary to infection. Severe neutropenia, defined as an absolute neutrophil count below 500 cells/μl (0.5×109/l), suppresses inflammation and increases susceptibility to bacterial and fungal infections. Neutropenia often presents with bacterial infections of mucous membranes, gingiva and skin. To identify the cause of a patient’s neutropenia it is helpful to consider whether there are defects intrinsic or extrinsic to the neutrophils or their progenitors. Extrinsic neutrophil defects resulting in acquired neutropenia are the most common in clinical practice and include infections and drugs suppressing marrow function, autoimmune neutrophil destruction, bone marrow infiltration, and nutritional deficiencies. Intrinsic neutrophil defects resulting in inherited or congenital neutropenia are caused by rare genetic defects that severely impact neutrophil development and function (for example, Kostmann syndrome, Shwachman–Diamond syndrome). Regardless of the aetiology, fever in conjunction with neutropenia is a medical emergency that must be addressed with appropriate evaluation and prompt administration of antibiotics.
In patients with normal neutrophil numbers, the most common phagocytic cell defect is chronic granulomatous disease (CGD). The diagnosis of CGD should be considered in any patient with deep seated abscesses caused by a limited repertoire of catalase producing organisms—specifically, Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia species and Aspergillus species.22 Patients with CGD harbour genetic mutations that reduce the ability of their neutrophils to generate superoxide ions and hydrogen peroxide, resulting in a profound impairment of their ability to kill intracellular microorganisms. Measurement of phagocyte oxidase activity confirms the diagnosis of CGD.23
Overview of therapeutic options for patients with PIDs
The general approach to managing patients with PIDs involves three related elements: managing and preventing infections, improving immune competence, and curing the underlying immune defect.
Managing and preventing infections
Infections are by far the most common complications of PIDs. Clinicians should strive to achieve the dual objectives of preventing infections and thoroughly eradicating any infections that may develop.
Infections in PID patients may be caused by both common community acquired pathogens, as well as opportunistic organisms that are rarely pathogenic for immunocompetent individuals. If infection is suspected in an individual with an underlying PID, it is critical to define the pathogen and extent of infection using traditional culture and molecular microbiology techniques combined with imaging and biopsy. Accurate characterisation of every infection will facilitate optimal therapy but it is important to appreciate that standard dose and duration of antimicrobial regimens may not be adequate to cure infections in immunocompromised hosts.
Key learning points
Primary immunodeficiency diseases (PIDs) are not rare. As a group, PIDs affect between 1:2000 and 1:10 000 live births.
Infections are the most common presentation of PIDs.
PIDs can present at any age from birth to adulthood.
PIDs should be considered when infections are (any of the following):
recurring or chronic
result in organ damage (for example, bronchiectasis)
respond poorly to standard antimicrobial treatment
caused by poorly virulent or opportunistic organisms
recurrent and caused by the same pathogen.
Most PIDs can be readily diagnosed using standard laboratory tests.
Effective treatment options are available to control or cure PIDs.
Early diagnosis of PIDs results in improved clinical outcomes.
Current research questions
Generation of population based data related to incidence and prevalence of PIDs.
Development of newborn screening for severe combined immunodeficiency (SCID). Babies born with SCID are asymptomatic at birth but without an effective intervention, the majority die of opportunistic infections in the first year of life.
Determination of how best to educate primary care providers, specialist physicians, parents and other caregivers to encourage early recognition of PIDs, ensuring patients benefit from appropriate referral and treatment.
Use of multicentre collaborative trials to optimise treatments for PIDs, including haematopoietic stem cell transplantation and gene therapy.
Establishing diagnostic algorithms for PIDs to ensure patients receive an accurate diagnosis in a timely and cost effective fashion.
It is preferable to prevent or minimise infections experienced by patients with PIDs. Simple interventions such as regular hand washing and avoiding large crowds may offer some benefits, but advocating complete social isolation is unlikely to be in the patient’s best interest. Prophylactic antimicrobials are often used in patients with PIDs and antimicrobial choice is tailored to the disease specific pattern of infectious susceptibility. For example, patients with significant T cell dysfunction receive prophylactic trimethoprim–sulfamethoxazole to minimise the risk of Pneumocystis jiroveci pneumonia, while combined antibacterial and antifungal therapy is necessary for patients with CGD.
Vaccination plays an important role in protecting immunocompromised patients, although vaccines must be administered in a strategic and thoughtful fashion. Live bacterial and live virus vaccines are contraindicated in patients with PIDs associated with significant antibody or cellular defects. Specifically, patients with PIDs should not receive oral polio vaccine, BCG, measles–mumps–rubella (MMR) vaccine, yellow fever, live typhoid, varicella vaccine, live influenza vaccine, or the recently released live oral rotavirus vaccine. Inactivated or subunit vaccines may be administered safely to immunocompromised patients; however, since the immunologic response following active immunisation may be inadequate, it is often beneficial to document vaccine effectiveness with serum antibody titres. Passive immunisation should also be considered, such as the use of varicella zoster immunoglobulin (VZIG) for post-exposure prophylaxis.
Improving immune competence
Regular administration of intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) is the treatment of choice for patients with the inability to produce functional, protective antibodies. IVIG and SCIG are prepared from the pooled plasma of several thousand donors, providing the PID patient with protection against numerous common bacterial and viral pathogens.24 Many of studies have demonstrated both the clinical benefits of immunoglobulin replacement and the therapeutic equivalence between the intravenous (IVIG) and subcutaneous (SCIG) routes of immunoglobulin administration.25
Curing the underlying immune defect
The ultimate goal of managing patients with PIDs is to cure the fundamental immune defect. Haematopoietic stem cell transplantation (HSCT), by providing fully functional, genetically normal progenitor cells, has the capacity to cure a number of severe forms of PID, including SCID, Wiskott–Aldrich syndrome, CGD, and others.26 Since the first transplants were attempted 40 years ago there has been a dramatic improvement in outcomes. Indeed, an infant born today with SCID who is healthy at the time of transplant and who receives an HLA matched donor transplant very early in life can expect a better than 90% chance of long term disease-free survival.13 27
As the molecular causes of many human PIDs were discovered, optimism arose that gene therapy would eventually replace HSCT as a more specific and safer form of therapy. Despite encouraging preliminary results in patients with X-linked SCID, unexpected lymphoproliferative complications occurred in one of the gene therapy trials for this disease.28 Despite the recent success of gene therapy as a treatment for SCID caused by adenosine deaminase deficiency,29 HSCT is currently the most widely available treatment option for patients with severe PIDs that are otherwise fatal early in life.
Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol 2005;94:S1–63.
Orange JS, Hossny EM, Weiler CR, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 2006;117:S525–53.
Aiuti A, Cattaneo F, Galimberti S, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 2009;360:447–58.
Geha RS, Notarangelo LD, Casanova JL, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol 2007;120:776–94.
PIDs are sufficiently common that practising clinicians will encounter these immunocompromised patients during their careers. Many PIDs can be diagnosed easily, and effective treatment options are available. The sobering reality is that the early warning signs of PIDs are easily overlooked, often with tragic consequences for the affected patient. It is our hope that increased physician awareness of PIDs combined with knowledge of common clinical presentations will ensure these vulnerable patients receive a timely diagnosis and potentially life saving therapy.
Multiple choice questions (true (T)/false (F); answers after the references)
It is estimated that between 1:2000 and 1:10 000 live births are affected by a PID.
PIDs are caused by infections that specifically interfere with the function of the immune system.
Diagnosis of most PIDs requires sophisticated tests that are generally only available in highly specialised centres.
Recurrent sinopulmonary infections (that is, otitis media, sinusitis, and pneumonia) are a common presentation of antibody deficiency disorders.
The majority of patients with selective IgA deficiency are symptomatic, presenting with atopy, gastrointestinal disease (especially coeliac disease) and autoimmunity.
1 (T); 2 (F); 3 (F); 4 (T); 5 (F)
Funding SET was supported by the Chaim Roifman Scholar Award from the Canadian Immunodeficiency Society and a Career Development Award from the Canadian Child Health Clinician Scientist Program (CCHCSP)-a CIHR Strategic Training Program.
Competing interests None.
Provenance and Peer review Not commissioned; externally peer reviewed.
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