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The immunocompromised patient: primary immunodeficiencies
DEFENCE AGAINST INFECTION
The immunocompromised patient: primary immunodeficiencies
immunodeficiency. Laboratory investigations should start with a broad screen (Figure 1), but then focus on the likely underlying immunodeficiency. It is essential to use age-related normal ranges; for example in infants, a total lymphocyte count of less than 2.5 109/l strongly suggests a diagnosis of severe combined immunodeficiency (SCID). In general, patients suspected of having immunodeficiency should be referred to an immunologist with the necessary resources to make a specific diagnosis and co-ordinate management (Table 3).
A David B Webster
Abstract
Clinical features
The field of primary immunodeficiency diseases (PID) has grown dramatically over the past 10 years, the number of defined genetic causes almost doubling to a current total of about 130 different defects. These often are very rare disorders which have taught us much about the crucial cellular pathways required for protection against infection from a wide variety of microbes. Although most clinicians do not need a detailed knowledge of the different types of PID, they should be aware of the possibility of PID in patients presenting with recurrent or persistent infection, and be able to refer patients to a regional specialized clinic for immunodeficiency. A general understanding of which components of the immune system protect against different infections makes the diagnostic process more interesting and rewarding. Because many of the more severe PIDs present in infancy or childhood, paediatricians should have some special training in the area so that they know which patients require urgent referral to an expert centre. There have been some landmark recent advances in the management of severe PIDs, particularly in the technology of bone marrow transplantation and gene therapy where complete cures have been achieved.
Primary antibody deficiency Antibody defects are the most common primary immunodeficiencies; the prevalence in Caucasians ranges from 1/600 (IgA deficiency) to 1/200,000 (X-linked agammaglobulinaemia), with the most common severe PID (common variable immunodeficiency, CVID) being 1:30,000. Affected patients present with both recurrent upper and lower respiratory infections (sinusitis, otitis media, mastoiditis, chronic bronchitis and bronchiectasis).4 Common pathogens include non-encapsulated Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. Gastrointestinal infections are also common, most often with Giardia lamblia or Campylobacter jejuni. Patients are prone to chronic infection with Mycoplasma spp., including ureaplasmas, in the joints, urogenital tract (urethritis, epididymitis) and occasionally in the lungs; genetically determined low mannose binding lectin (MBL) levels are an additional predisposing factor for mycoplasma infection. Acute viral infections are not a problem but the lack of antibody sometimes leads to persistence of enteroviral infection and associated chronic inflammation in the central nervous system and muscles. Common persistent/latent viruses (e.g. Epsteine Barr virus (EBV) cytomegalovirus) appear to be controlled although in CVID there is evidence of an aggressive compensatory T cell response to CMV with associated chronic inflammatory pathology involving a variety of organs. In general, patients with very low levels of all major immunoglobulin classes (IgA, IgG, IgM) are more prone to infection than those who retain moderate levels of IgG and/or IgM. Selective IgA deficiency does not usually lead to severe infections. However, exceptions are common, suggesting unknown genetic factors influencing the patient’s clinical phenotype. Regular IgG replacement therapy with a commercially available product is the standard treatment, aiming to maintain a serum trough IgG level of about 8 g/l.
Keywords bacterial infection; bone marrow transplantation; complement deficiencies; fungal infection; gene therapy; hypogammaglobulinaemia; immunoglobulin therapy; lymphocyte defects; neutropenia; phagocyte defects; primary immunodeficiency; viral infection
Introduction Primary immunodeficiency diseases (PIDs) result from genetic defects in the development and maturation of cells of the immune system.1,2 They lead to an increased susceptibility to infections, which are usually characteristic of the specific immune defect.3 They are classified into combined cellular and antibody deficiencies, predominant antibody deficiencies, defects in innate immunity (involving phagocytes or complement) and complex miscellaneous disorders/syndromes (Table 1). Patients with many of the lymphocyte disorders are also prone to autoimmune disease and/or lymphomas. Early diagnosis and treatment of PID are essential for the prevention of devastating consequences, because many of the conditions are treatable. It is important to have a high index of suspicion for primary immunodeficiency in all age groups. Table 2 lists features that should alert clinicians to the presence of underlying
Combined cellular and antibody defects Severe combined immunodeficiency (SCID) Severe combined immunodeficiency (SCID) has an incidence of about 1/100,000 live births; currently there are about 18 causative genetic defects identified. Patients usually present in the first six months of life, with failure to thrive, chronic diarrhoea, oral and cutaneous candidiasis and persistent infections despite conventional treatment. Marked deterioration is usually triggered by a broad range of pathogenic and opportunistic bacterial, fungal or viral infections, in particular Pneumocystis jirovecii, herpesviruses and enteric viruses. Infants usually die before one year of age unless treated with bone marrow transplantation
A David B Webster MD FRCP FRCPath is an Honorary Clinical Scientist in the UCL Centre for Primary Immunodeficiency (Royal Free Campus), London, UK. Conflict of interest: none declared.
MEDICINE 37:10
518
Ó 2009 Elsevier Ltd. All rights reserved.
DEFENCE AGAINST INFECTION
Classification of primary immunodeficiencies
Hyper-IgE syndrome-severe eczema, very high IgE, pneumatoceles (most have STAT4 mutations) Mucocutaneous candidiasis (unknown mechanism in most patients)
Primary antibody deficiencies B cell developmental defects: X-linked agammaglobulinaemia Other very rare single gene defects (e.g. BLNK defect)
Defects in the innate immune system involving receptors/signalling: Interferon-g and IL-12 pathway (defects in IFN-gRI or 2, IL12p40, IL12Rb1, STAT1) (causing susceptibility to mycobacterial and salmonella infection) C IRAK-4/MyD88 deficiency e recurrent pneumococcal sepsis in children C NF-kB essential modulator (NEMO) deficiency e with anhidrotic ectodermal dysplasia C WHIM (warts, hypogammaglobulinaemia, neutropenia, myelokathexis) e CXCR4 defect C
B cell maturation defects: Common variable immunodeficiency (mechanism unknown) Rare single gene defects (e.g. ICOS, CD19 deficiency) Class switch/hypermutation defects with high IgM (AID, UNG defects) Specific antibody deficiency (SPAD) (mechanism unknown e often minor symptoms) Selective IgA or IgG deficiency (mechanism unknown e usually asymptomatic) Transient hypogammaglobulinaemia of infancy
Complement component deficiencies Phagocyte defects C Severe congenital neutropenia C Cyclic neutropenia C Chronic granulomatous disease e genetic defects in components of NADPH-oxidase system C Leucocyte adhesion defects C Shwachman syndrome e pancreatic insufficiency, neutropenia, hypogammaglobulinaemia C Lysosome/granule defects e ChediakeHigashi and Griscelli syndromes C Glucose-6-phosphate dehydrogenase deficiency or Myeloperoxidase deficiency (usually minor predisposition to infection)
Severe combined immunodeficiencies: Absent T and B cells (TeB-) Reticular dysgenesis, RAG 1 or 2 or Artemis deficiencies
C
C
Absent T cells (TeBþ) X-linked gc, JAK-3, IL7R, CD45 or FOXN1 defects
C
Non-functional T and B cells Omenn syndrome (eosinophilia, erythrodermia, high IgE) due to partial function of RAG, Artemis or IL7R
C
Purine metabolic defects Adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) deficiencies
C
This classification does not attempt to include all known primary immunodeficiency diseases, but gives an overview of the wide range of defects causing human disease. The genetic causes for most of the conditions above are known.
MHC Class 11 deficiency Various genetic defects in factors regulating MHC11 gene expression
Table 1 Combined or predominantly T cell defects (not usually immediately life threatening) C X-linked hyper-IgM (CD40L defect) C DiGeorge anomaly (thymic aplasia) C Defects in CD3 signalling complex (e.g. ZAP-70, CD8a deficiencies) C MHC class 1 deficiency (genetic defects in TAP1/2 or Tapasin)
(BMT); gene therapy is currently under trial in a few selected SCIDs.5 Early diagnosis and referral to a SCID transplant centre is essential. Although most infants/children with selective T cell deficiency (e.g. DiGeorge syndrome e thymic aplasia) have some residual thymic activity and do not need urgent treatment, a few severe cases have benefited from thymic transplantation.
Other rare well-recognized immunodeficiencies: WiskotteAldrich syndrome (thrombocytopenia, eczema, T cell defect) DNA breakage/repair syndromes (some sensitive to g radiation) Ataxiaetelangiectasia (may have IgA deficiency) Nijmegen breakage syndrome Bloom syndrome, ICF syndrome, ligase1 or 4 defects
Combined immunodeficiency with high mortality There is an increasingly long list of rare conditions associated with lymphocyte functional defects that often lead to early death. Some have additional features outside the immune system that can aid diagnosis (e.g. eczema and thrombocytopenia in WiskotteAldrich syndrome). In some disorders there is a failure to control acute viral infection, particularly the EBV (e.g. X-linked lymphoproliferative disease e XLP), with survivors being prone to EBV-driven Burkitt’s-like lymphoma. Genetic defects in the T cell activation molecule, CD40 ligand, curiously predispose to persistent cryptosporidial infection with malabsorption and cholangitis, although other opportunistic infections may also cause death. BMT is an option for some patients whose defect
Defects/dysregulation in cytotoxic T/NK cells X-linked lymphoproliferative syndrome Perforin or Munc deficiency (hereditary haemophagocytic syndromes) Severe autoimmune/immunodeficiency disorders in children Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) e AIRE gene defect IPEX (immunodeficiency, polyendocrinopathy, enteropathy) due to FOXP3 defect and absent T regulatory cells
MEDICINE 37:10
519
Ó 2009 Elsevier Ltd. All rights reserved.
DEFENCE AGAINST INFECTION
Defects in innate immunity Phagocytic defects Primary neutropenia is due to a variety of genetic causes, presenting in early childhood with bacterial and fungal sepsis. Severe neutropenia (e.g. Kostmann syndrome) is usually easy to diagnose on a blood count, but cyclic neutropenia can easily be missed unless repeated blood counts are done weekly over a 4e6-week cycle. Defects in the CXCR4 chemokine receptor on white cells cause an intriguing rare autosomal dominant condition called the WHIM syndrome characterized by neutropenia, widespread papilloma viral Warts, variable Hypogammaglobulinaemia, Immunodeficiency and Myelokathexis (failure of neutrophil release from bone marrow); the severity of the warts is surprising and not understood. Patients with chronic granulomatous disease (CGD) have various genetic defects in the NADPH oxidase system in the wall of the phagocytic vacuole that is crucial for the killing of catalasepositive bacteria and fungi. They suffer from severe recurrent infections, most commonly pneumonia, lymphadenitis, cutaneous and hepatic abscesses, osteomyelitis and septicaemia, the most common organisms being Staphylococcus aureus, Aspergillus spp., and enteric Gram-negative bacteria such as Serratia marcescens and Burkholderia cepacia. The inability to degrade microbial debris is probably the reason why CGD patients are prone to granulomatous infiltration of the gastrointestinal and urinary tracts. Treatment depends on antimicrobial therapy and
When to investigate for immunodeficiency C C
C C C C C C C C C
Family history of immunodeficiency/early death from infection Infants and young children with failure to thrive, opportunistic infections, persisting infections with low-virulence organisms, severe diarrhoea, unusual/extensive skin rashes, hepatosplenomegaly, multiple autoimmunity Recurring/persisting sinopulmonary infection Recurring skin infections, abscesses or periodontitis Recurrent Neisserial infection Extensive warts resistant to standard therapy Atypical mycobacterial or chronic salmonella infection Unexplained chronic enteropathy Candidiasis B cell lymphomas, particularly in young patients Haemophagocytosis, particularly associated with severe EBV infection
EBV: EpsteineBarr virus.
Table 2
predominantly affects the immune system but decisions on timing are difficult as some affected children can have long periods of good quality of life.
Screening investigations Full blood count, including differential WBC and platelet count Quantitative serum immunoglobulins (IgG, IgA, IgM, IgE) Lymphocyte subsets by flow cytometry (absolute T-cell (CD3) and B-cell (CD19/20) counts, CD4, CD8 and NK (CD16/56) counts Baseline antibody titres to tetanus toxoid, pneumococcal and haemophilus polysaccharides in over 5-year-olds – followed by response to booster vaccination if necessary. Total haemolytic complement – both classical and alternative pathways (CH50, AP50)
Refer to Immunodeficiency Centre for special tests Low T-cell count Absence of lymphocyte markers characteristic of specific SCIDs (e.g. MHC Class11) Screen for purine metabolic defects (ADA,PNP) Signs of specific syndromes (e.g. thymic aplasia; IgE ↑ in Omenn’s) Cell radiosensitivity tests if indicated
Bacterial abcesses/sepsis, skin granulomas/ulceration, mycobacterial/BCG infection Neutrophil function tests (e.g. NBT for CGD) FACS analysis for LAD (CD11/18/15s) and HLA Class1 IFN-γ/IL-12 circuit tests Toll/IL-1 activation tests
Hypo-immunoglobulinaemia Absence of lymphocyte markers characteristic of specific PADs
Protein and molecular genetic screening for known inherited PIDs (clinical-laboratory features will indicate priorities)
ADA, adenosine deaminase; CGD, chronic granulotamous disease; FACS, flow cytometry; HLA, human leukocyte antigen; IFN, interferon; LAD, leukocyte adhesion deficiency; MHC, major histocompatibility complex; NBT, nitroblue tetrazolium; PAD, primary antibody deficiency; PNP, purine nucleoside phosphorylase; SCIDs, severe combined immunodeficiencies; WBC, white blood cell. Figure 1 Scheme for investigation of primary immunodeficiency diseases.
MEDICINE 37:10
520
Ó 2009 Elsevier Ltd. All rights reserved.
DEFENCE AGAINST INFECTION
residues on many microbes and subsequently activates complement, is controversial but a low MBL seems to increase susceptibility to infection in otherwise immunocompromised patients, particularly in young children.
Principles of management C C C
C
C
C
C C
C
Early diagnosis and referral to immunodeficiency clinical centre Protective isolation for severe T cell defects or neutropenia Co-trimoxazole prophylaxis for pneumocystis in severe T cell deficiencies Blood transfusions should be irradiated and cytomegalovirusnegative in T cell deficiency to avoid graft-vs-host disease and infection Consider early bone marrow transplantation/gene therapy for syndromes with poor prognosis (e.g. most SCIDs, X-HIM, XLP, CGD, WiskotteAldrich) Avoid live attenuated vaccines in all severe antibody and cellular immune deficiencies Regular immunoglobulin replacement in hypogammaglobulinaemia Antifungal prophylaxis in chronic granulomatous disease and chronic mucocutaneous candidiasis Aggressive treatment of infections with antibiotics
Defects in macrophage activation These involve rare genetic defects in the interleukin 12/23-gamma-Interferon axis whereby signals from lymphocytes activate macrophages to kill intracellular microbes. This leads to a susceptibility to chronic mycobacterial infection, usually atypical mycobacteria or Mycobacterium tuberculosis (BCGosis) following routine BCG vaccination, and sometimes to chronic salmonella infection. Long term anti-mycobacterial therapy is usually required and some patients respond to IFN-g therapy. Toll and IL-1 receptor signaling pathway defects (IRAK-4, MyD88) Inherited defects in molecules involved in the activation cascade within phagocytes following ligation of surface Toll and IL-1 receptors lead to susceptibility to severe pyogenic infection with limited types of organisms (mainly pneumococcus and staphylococcus) in children, with clinical recovery in surviving adults after acquiring other defence mechanisms (mainly specific antibodies). The discovery of these rare patients shows that Toll and IL-1 receptor signaling is redundant for control of many microbial infections. Defects in the activation of NF-kB, a critical downstream component of this pathway, cause both a more severe immunodeficiency with additional susceptibility to atypical mycobacterial infection, and anhidrotic ectodermal dysplasia (e.g. NEMO defect).
CGD, chronic granulotamous disease; SCIDs, severe combined immunodeficiencies; X-HIM, X-linked hyper-IgM syndrome; XLP, X-linked lymphoproliferative syndrome.
Table 3
bone marrow transplantation (BMT) in severe cases; gene therapy is under trial. There are some very rare defects in leucocyte adhesion molecules (b-integrins or fucosylated ligands) that prevent neutrophils from leaving capillaries, leading to severe infection, persistent neutrophilia and sometimes a rapidly spreading skin necrosis, probably due to capillary plugging, following trivial local infection. Survival usually depends on a successful BMT.
Management The principles of diagnosis and management are shown in Figure 1 and Table 3. A
Complement deficiencies The prevalence ranges from 1:10,000 (C2 deficiency) to 1: million; clinical expression is variable and onset of symptoms can be at any age. C3-deficient patients have increased susceptibility to bacterial infection in which opsonization is important in host defence (e.g. Streptococcus pneumoniae, Streptococcus pyogenes, capsulated Haemophilus influenzae). Those with C1, C2 or C4 deficiency have a similar but less marked susceptibility because they can activate C3 via the alternative pathway, but they are susceptible to immune complex diseases, particularly systemic lupus erythematosus. Deficiencies in the terminal C5e9 components result in failure of formation of the membrane attack complex and susceptibility to Neisseria meningitidis. Deficiencies in factor H, factor I and properdin are also associated with increased susceptibility to N. meningitidis. Patients with complement component deficiencies should be vaccinated with pneumococcal, meningococcal and H. influenzae vaccines, and may require antibiotic prophylaxis. The clinical significance of a commonly inherited deficiency of mannose binding lectin (MBL), which binds to mannose
MEDICINE 37:10
REFERENCES 1 Geha RS, Notarangelo LP, 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: 776e94. 2 Ochs HD, Smith CIE, Puck JM, eds. Primary immunodeficiency diseases: a molecular and genetic approach. 2nd edn. Oxford University Press, 2007. 3 Bustamonte J, Zhang SY, von Bermuth Abel L, Casanova JL. From infectious diseases to primary immunodeficiency. Immunol Allergy Clin North Am 2008; 28: 235e58. 4 Wood P, Stanworth S, Burton J, et al. for the UK Primary immunodeficiency network. Recognition, clinical diagnosis and management of patients with primary antibody deficiency: a systematic review. Clin Exp Immunol 2007; 149: 410e23. 5 Thrasher AJ. Gene therapy for primary immunodeficiency. Immunol Allergy Clin North Am 2008; 28: 257e71.
521
Ó 2009 Elsevier Ltd. All rights reserved.
The immunocompromised patient: primary immunodeficiencies
immunodeficiency. Laboratory investigations should start with a broad screen (Figure 1), but then focus on the likely underlying immunodeficiency. It is essential to use age-related normal ranges; for example in infants, a total lymphocyte count of less than 2.5 109/l strongly suggests a diagnosis of severe combined immunodeficiency (SCID). In general, patients suspected of having immunodeficiency should be referred to an immunologist with the necessary resources to make a specific diagnosis and co-ordinate management (Table 3).
A David B Webster
Abstract
Clinical features
The field of primary immunodeficiency diseases (PID) has grown dramatically over the past 10 years, the number of defined genetic causes almost doubling to a current total of about 130 different defects. These often are very rare disorders which have taught us much about the crucial cellular pathways required for protection against infection from a wide variety of microbes. Although most clinicians do not need a detailed knowledge of the different types of PID, they should be aware of the possibility of PID in patients presenting with recurrent or persistent infection, and be able to refer patients to a regional specialized clinic for immunodeficiency. A general understanding of which components of the immune system protect against different infections makes the diagnostic process more interesting and rewarding. Because many of the more severe PIDs present in infancy or childhood, paediatricians should have some special training in the area so that they know which patients require urgent referral to an expert centre. There have been some landmark recent advances in the management of severe PIDs, particularly in the technology of bone marrow transplantation and gene therapy where complete cures have been achieved.
Primary antibody deficiency Antibody defects are the most common primary immunodeficiencies; the prevalence in Caucasians ranges from 1/600 (IgA deficiency) to 1/200,000 (X-linked agammaglobulinaemia), with the most common severe PID (common variable immunodeficiency, CVID) being 1:30,000. Affected patients present with both recurrent upper and lower respiratory infections (sinusitis, otitis media, mastoiditis, chronic bronchitis and bronchiectasis).4 Common pathogens include non-encapsulated Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. Gastrointestinal infections are also common, most often with Giardia lamblia or Campylobacter jejuni. Patients are prone to chronic infection with Mycoplasma spp., including ureaplasmas, in the joints, urogenital tract (urethritis, epididymitis) and occasionally in the lungs; genetically determined low mannose binding lectin (MBL) levels are an additional predisposing factor for mycoplasma infection. Acute viral infections are not a problem but the lack of antibody sometimes leads to persistence of enteroviral infection and associated chronic inflammation in the central nervous system and muscles. Common persistent/latent viruses (e.g. Epsteine Barr virus (EBV) cytomegalovirus) appear to be controlled although in CVID there is evidence of an aggressive compensatory T cell response to CMV with associated chronic inflammatory pathology involving a variety of organs. In general, patients with very low levels of all major immunoglobulin classes (IgA, IgG, IgM) are more prone to infection than those who retain moderate levels of IgG and/or IgM. Selective IgA deficiency does not usually lead to severe infections. However, exceptions are common, suggesting unknown genetic factors influencing the patient’s clinical phenotype. Regular IgG replacement therapy with a commercially available product is the standard treatment, aiming to maintain a serum trough IgG level of about 8 g/l.
Keywords bacterial infection; bone marrow transplantation; complement deficiencies; fungal infection; gene therapy; hypogammaglobulinaemia; immunoglobulin therapy; lymphocyte defects; neutropenia; phagocyte defects; primary immunodeficiency; viral infection
Introduction Primary immunodeficiency diseases (PIDs) result from genetic defects in the development and maturation of cells of the immune system.1,2 They lead to an increased susceptibility to infections, which are usually characteristic of the specific immune defect.3 They are classified into combined cellular and antibody deficiencies, predominant antibody deficiencies, defects in innate immunity (involving phagocytes or complement) and complex miscellaneous disorders/syndromes (Table 1). Patients with many of the lymphocyte disorders are also prone to autoimmune disease and/or lymphomas. Early diagnosis and treatment of PID are essential for the prevention of devastating consequences, because many of the conditions are treatable. It is important to have a high index of suspicion for primary immunodeficiency in all age groups. Table 2 lists features that should alert clinicians to the presence of underlying
Combined cellular and antibody defects Severe combined immunodeficiency (SCID) Severe combined immunodeficiency (SCID) has an incidence of about 1/100,000 live births; currently there are about 18 causative genetic defects identified. Patients usually present in the first six months of life, with failure to thrive, chronic diarrhoea, oral and cutaneous candidiasis and persistent infections despite conventional treatment. Marked deterioration is usually triggered by a broad range of pathogenic and opportunistic bacterial, fungal or viral infections, in particular Pneumocystis jirovecii, herpesviruses and enteric viruses. Infants usually die before one year of age unless treated with bone marrow transplantation
A David B Webster MD FRCP FRCPath is an Honorary Clinical Scientist in the UCL Centre for Primary Immunodeficiency (Royal Free Campus), London, UK. Conflict of interest: none declared.
MEDICINE 37:10
518
Ó 2009 Elsevier Ltd. All rights reserved.
DEFENCE AGAINST INFECTION
Classification of primary immunodeficiencies
Hyper-IgE syndrome-severe eczema, very high IgE, pneumatoceles (most have STAT4 mutations) Mucocutaneous candidiasis (unknown mechanism in most patients)
Primary antibody deficiencies B cell developmental defects: X-linked agammaglobulinaemia Other very rare single gene defects (e.g. BLNK defect)
Defects in the innate immune system involving receptors/signalling: Interferon-g and IL-12 pathway (defects in IFN-gRI or 2, IL12p40, IL12Rb1, STAT1) (causing susceptibility to mycobacterial and salmonella infection) C IRAK-4/MyD88 deficiency e recurrent pneumococcal sepsis in children C NF-kB essential modulator (NEMO) deficiency e with anhidrotic ectodermal dysplasia C WHIM (warts, hypogammaglobulinaemia, neutropenia, myelokathexis) e CXCR4 defect C
B cell maturation defects: Common variable immunodeficiency (mechanism unknown) Rare single gene defects (e.g. ICOS, CD19 deficiency) Class switch/hypermutation defects with high IgM (AID, UNG defects) Specific antibody deficiency (SPAD) (mechanism unknown e often minor symptoms) Selective IgA or IgG deficiency (mechanism unknown e usually asymptomatic) Transient hypogammaglobulinaemia of infancy
Complement component deficiencies Phagocyte defects C Severe congenital neutropenia C Cyclic neutropenia C Chronic granulomatous disease e genetic defects in components of NADPH-oxidase system C Leucocyte adhesion defects C Shwachman syndrome e pancreatic insufficiency, neutropenia, hypogammaglobulinaemia C Lysosome/granule defects e ChediakeHigashi and Griscelli syndromes C Glucose-6-phosphate dehydrogenase deficiency or Myeloperoxidase deficiency (usually minor predisposition to infection)
Severe combined immunodeficiencies: Absent T and B cells (TeB-) Reticular dysgenesis, RAG 1 or 2 or Artemis deficiencies
C
C
Absent T cells (TeBþ) X-linked gc, JAK-3, IL7R, CD45 or FOXN1 defects
C
Non-functional T and B cells Omenn syndrome (eosinophilia, erythrodermia, high IgE) due to partial function of RAG, Artemis or IL7R
C
Purine metabolic defects Adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) deficiencies
C
This classification does not attempt to include all known primary immunodeficiency diseases, but gives an overview of the wide range of defects causing human disease. The genetic causes for most of the conditions above are known.
MHC Class 11 deficiency Various genetic defects in factors regulating MHC11 gene expression
Table 1 Combined or predominantly T cell defects (not usually immediately life threatening) C X-linked hyper-IgM (CD40L defect) C DiGeorge anomaly (thymic aplasia) C Defects in CD3 signalling complex (e.g. ZAP-70, CD8a deficiencies) C MHC class 1 deficiency (genetic defects in TAP1/2 or Tapasin)
(BMT); gene therapy is currently under trial in a few selected SCIDs.5 Early diagnosis and referral to a SCID transplant centre is essential. Although most infants/children with selective T cell deficiency (e.g. DiGeorge syndrome e thymic aplasia) have some residual thymic activity and do not need urgent treatment, a few severe cases have benefited from thymic transplantation.
Other rare well-recognized immunodeficiencies: WiskotteAldrich syndrome (thrombocytopenia, eczema, T cell defect) DNA breakage/repair syndromes (some sensitive to g radiation) Ataxiaetelangiectasia (may have IgA deficiency) Nijmegen breakage syndrome Bloom syndrome, ICF syndrome, ligase1 or 4 defects
Combined immunodeficiency with high mortality There is an increasingly long list of rare conditions associated with lymphocyte functional defects that often lead to early death. Some have additional features outside the immune system that can aid diagnosis (e.g. eczema and thrombocytopenia in WiskotteAldrich syndrome). In some disorders there is a failure to control acute viral infection, particularly the EBV (e.g. X-linked lymphoproliferative disease e XLP), with survivors being prone to EBV-driven Burkitt’s-like lymphoma. Genetic defects in the T cell activation molecule, CD40 ligand, curiously predispose to persistent cryptosporidial infection with malabsorption and cholangitis, although other opportunistic infections may also cause death. BMT is an option for some patients whose defect
Defects/dysregulation in cytotoxic T/NK cells X-linked lymphoproliferative syndrome Perforin or Munc deficiency (hereditary haemophagocytic syndromes) Severe autoimmune/immunodeficiency disorders in children Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) e AIRE gene defect IPEX (immunodeficiency, polyendocrinopathy, enteropathy) due to FOXP3 defect and absent T regulatory cells
MEDICINE 37:10
519
Ó 2009 Elsevier Ltd. All rights reserved.
DEFENCE AGAINST INFECTION
Defects in innate immunity Phagocytic defects Primary neutropenia is due to a variety of genetic causes, presenting in early childhood with bacterial and fungal sepsis. Severe neutropenia (e.g. Kostmann syndrome) is usually easy to diagnose on a blood count, but cyclic neutropenia can easily be missed unless repeated blood counts are done weekly over a 4e6-week cycle. Defects in the CXCR4 chemokine receptor on white cells cause an intriguing rare autosomal dominant condition called the WHIM syndrome characterized by neutropenia, widespread papilloma viral Warts, variable Hypogammaglobulinaemia, Immunodeficiency and Myelokathexis (failure of neutrophil release from bone marrow); the severity of the warts is surprising and not understood. Patients with chronic granulomatous disease (CGD) have various genetic defects in the NADPH oxidase system in the wall of the phagocytic vacuole that is crucial for the killing of catalasepositive bacteria and fungi. They suffer from severe recurrent infections, most commonly pneumonia, lymphadenitis, cutaneous and hepatic abscesses, osteomyelitis and septicaemia, the most common organisms being Staphylococcus aureus, Aspergillus spp., and enteric Gram-negative bacteria such as Serratia marcescens and Burkholderia cepacia. The inability to degrade microbial debris is probably the reason why CGD patients are prone to granulomatous infiltration of the gastrointestinal and urinary tracts. Treatment depends on antimicrobial therapy and
When to investigate for immunodeficiency C C
C C C C C C C C C
Family history of immunodeficiency/early death from infection Infants and young children with failure to thrive, opportunistic infections, persisting infections with low-virulence organisms, severe diarrhoea, unusual/extensive skin rashes, hepatosplenomegaly, multiple autoimmunity Recurring/persisting sinopulmonary infection Recurring skin infections, abscesses or periodontitis Recurrent Neisserial infection Extensive warts resistant to standard therapy Atypical mycobacterial or chronic salmonella infection Unexplained chronic enteropathy Candidiasis B cell lymphomas, particularly in young patients Haemophagocytosis, particularly associated with severe EBV infection
EBV: EpsteineBarr virus.
Table 2
predominantly affects the immune system but decisions on timing are difficult as some affected children can have long periods of good quality of life.
Screening investigations Full blood count, including differential WBC and platelet count Quantitative serum immunoglobulins (IgG, IgA, IgM, IgE) Lymphocyte subsets by flow cytometry (absolute T-cell (CD3) and B-cell (CD19/20) counts, CD4, CD8 and NK (CD16/56) counts Baseline antibody titres to tetanus toxoid, pneumococcal and haemophilus polysaccharides in over 5-year-olds – followed by response to booster vaccination if necessary. Total haemolytic complement – both classical and alternative pathways (CH50, AP50)
Refer to Immunodeficiency Centre for special tests Low T-cell count Absence of lymphocyte markers characteristic of specific SCIDs (e.g. MHC Class11) Screen for purine metabolic defects (ADA,PNP) Signs of specific syndromes (e.g. thymic aplasia; IgE ↑ in Omenn’s) Cell radiosensitivity tests if indicated
Bacterial abcesses/sepsis, skin granulomas/ulceration, mycobacterial/BCG infection Neutrophil function tests (e.g. NBT for CGD) FACS analysis for LAD (CD11/18/15s) and HLA Class1 IFN-γ/IL-12 circuit tests Toll/IL-1 activation tests
Hypo-immunoglobulinaemia Absence of lymphocyte markers characteristic of specific PADs
Protein and molecular genetic screening for known inherited PIDs (clinical-laboratory features will indicate priorities)
ADA, adenosine deaminase; CGD, chronic granulotamous disease; FACS, flow cytometry; HLA, human leukocyte antigen; IFN, interferon; LAD, leukocyte adhesion deficiency; MHC, major histocompatibility complex; NBT, nitroblue tetrazolium; PAD, primary antibody deficiency; PNP, purine nucleoside phosphorylase; SCIDs, severe combined immunodeficiencies; WBC, white blood cell. Figure 1 Scheme for investigation of primary immunodeficiency diseases.
MEDICINE 37:10
520
Ó 2009 Elsevier Ltd. All rights reserved.
DEFENCE AGAINST INFECTION
residues on many microbes and subsequently activates complement, is controversial but a low MBL seems to increase susceptibility to infection in otherwise immunocompromised patients, particularly in young children.
Principles of management C C C
C
C
C
C C
C
Early diagnosis and referral to immunodeficiency clinical centre Protective isolation for severe T cell defects or neutropenia Co-trimoxazole prophylaxis for pneumocystis in severe T cell deficiencies Blood transfusions should be irradiated and cytomegalovirusnegative in T cell deficiency to avoid graft-vs-host disease and infection Consider early bone marrow transplantation/gene therapy for syndromes with poor prognosis (e.g. most SCIDs, X-HIM, XLP, CGD, WiskotteAldrich) Avoid live attenuated vaccines in all severe antibody and cellular immune deficiencies Regular immunoglobulin replacement in hypogammaglobulinaemia Antifungal prophylaxis in chronic granulomatous disease and chronic mucocutaneous candidiasis Aggressive treatment of infections with antibiotics
Defects in macrophage activation These involve rare genetic defects in the interleukin 12/23-gamma-Interferon axis whereby signals from lymphocytes activate macrophages to kill intracellular microbes. This leads to a susceptibility to chronic mycobacterial infection, usually atypical mycobacteria or Mycobacterium tuberculosis (BCGosis) following routine BCG vaccination, and sometimes to chronic salmonella infection. Long term anti-mycobacterial therapy is usually required and some patients respond to IFN-g therapy. Toll and IL-1 receptor signaling pathway defects (IRAK-4, MyD88) Inherited defects in molecules involved in the activation cascade within phagocytes following ligation of surface Toll and IL-1 receptors lead to susceptibility to severe pyogenic infection with limited types of organisms (mainly pneumococcus and staphylococcus) in children, with clinical recovery in surviving adults after acquiring other defence mechanisms (mainly specific antibodies). The discovery of these rare patients shows that Toll and IL-1 receptor signaling is redundant for control of many microbial infections. Defects in the activation of NF-kB, a critical downstream component of this pathway, cause both a more severe immunodeficiency with additional susceptibility to atypical mycobacterial infection, and anhidrotic ectodermal dysplasia (e.g. NEMO defect).
CGD, chronic granulotamous disease; SCIDs, severe combined immunodeficiencies; X-HIM, X-linked hyper-IgM syndrome; XLP, X-linked lymphoproliferative syndrome.
Table 3
bone marrow transplantation (BMT) in severe cases; gene therapy is under trial. There are some very rare defects in leucocyte adhesion molecules (b-integrins or fucosylated ligands) that prevent neutrophils from leaving capillaries, leading to severe infection, persistent neutrophilia and sometimes a rapidly spreading skin necrosis, probably due to capillary plugging, following trivial local infection. Survival usually depends on a successful BMT.
Management The principles of diagnosis and management are shown in Figure 1 and Table 3. A
Complement deficiencies The prevalence ranges from 1:10,000 (C2 deficiency) to 1: million; clinical expression is variable and onset of symptoms can be at any age. C3-deficient patients have increased susceptibility to bacterial infection in which opsonization is important in host defence (e.g. Streptococcus pneumoniae, Streptococcus pyogenes, capsulated Haemophilus influenzae). Those with C1, C2 or C4 deficiency have a similar but less marked susceptibility because they can activate C3 via the alternative pathway, but they are susceptible to immune complex diseases, particularly systemic lupus erythematosus. Deficiencies in the terminal C5e9 components result in failure of formation of the membrane attack complex and susceptibility to Neisseria meningitidis. Deficiencies in factor H, factor I and properdin are also associated with increased susceptibility to N. meningitidis. Patients with complement component deficiencies should be vaccinated with pneumococcal, meningococcal and H. influenzae vaccines, and may require antibiotic prophylaxis. The clinical significance of a commonly inherited deficiency of mannose binding lectin (MBL), which binds to mannose
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REFERENCES 1 Geha RS, Notarangelo LP, 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: 776e94. 2 Ochs HD, Smith CIE, Puck JM, eds. Primary immunodeficiency diseases: a molecular and genetic approach. 2nd edn. Oxford University Press, 2007. 3 Bustamonte J, Zhang SY, von Bermuth Abel L, Casanova JL. From infectious diseases to primary immunodeficiency. Immunol Allergy Clin North Am 2008; 28: 235e58. 4 Wood P, Stanworth S, Burton J, et al. for the UK Primary immunodeficiency network. Recognition, clinical diagnosis and management of patients with primary antibody deficiency: a systematic review. Clin Exp Immunol 2007; 149: 410e23. 5 Thrasher AJ. Gene therapy for primary immunodeficiency. Immunol Allergy Clin North Am 2008; 28: 257e71.
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