- Email: [email protected]
Immune deficiency and the lung
ARTICLE IN PRESS Current Paediatrics (2004) 14, 115–121
www.elsevierhealth.com/journals/cuoe
Immune deficiency and the lung A.R. Gennerya,*, D.A. Spencerb, A.J. Canta a
Department of Paediatric Immunology, University of Newcastle upon Tyne, Newcastle upon Tyne, UK Department of Respiratory Paediatrics, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Trust, UK
b
KEYWORDS Severe combined immunodeficiency syndrome; Antibody deficiency; Polysaccharide antibody deficiency; Intravenous immunoglobulins
Summary Effective gas exchange means that lungs have large, permeable surfaces. However, this weakens defences against infection. Respiratory infections are common in childhood but are also a common presenting feature of primary immunodeficiency, so it is important to recognise warning signs of an underlying immunodeficiency. It is vital to identify rare infections and unusual patterns of common infection which suggest immunodeficiency in order to enable early diagnosis and appropriate treatment. Combined immunodeficiencies often present with persistent viral infection, whereas antibody deficiencies present with recurrent bacterial infection. Recurrent bacterial infection is a feature of complement deficiency and phagocytic disorders, which may also present with fungal infection. Prompt recognition and early diagnosis with appropriate investigations and aggressive treatment will prevent sequelae which includes bronchiectasis and respiratory failure. & 2003 Elsevier Ltd. All rights reserved.
Practice points *
*
*
*
*
Pulmonary infection is frequently the presenting feature of primary immunodeficiency Infants with severe combined immunodeficiency often present with an unremitting bronchiolitic-like illness of variable severity due to viral respiratory infection as well as pneumocystis carinii pneumonia Children with combined immunodeficiency may have polysaccharide antibody deficiency Hypogammaglobulinaemia is not a diagnosis, and further investigation is required before immunoglobulin treatment is commenced
*Corresponding author. Newcastle General Hospital, Westgate Road, Ward 23, Westgate upon Tyne NE4 6BE, UK. Tel.: þ 44-1912738811; fax: þ 44-191-2730813. E-mail address: [email protected] (A.R. Gennery).
Chest radiographs may be normal, despite the presence of bronchiectasis and regular careful respiratory evaluation is required in children on immunoglobulin treatment
Further research *
*
*
Long-term outcome of children with specific polysaccharide antibody deficiency Evolution of common variable immunodeficiency in childhood Longterm follow-up of children receiving immunoglobulin replacement
Introduction Gas exchange requires a large, moist, warm, permeable surface area. These features preclude
0957-5839/$ - see front matter & 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.cupe.2003.11.004
ARTICLE IN PRESS 116
A.R. Gennery et al.
Table 1 * * * * * * * * *
Warning signs of immunodeficiency.
Greater than one episode of proven pneumonia Invasive infections in more than one system Severe, unusual or persistent infection Requirement of surgery for chronic infection (e.g., tonsillectomy, grommets, boil incision) Investigation of second-line tests for chronic infection (e.g., sweat test, cilial beat frequency) Infection in patients with autoimmune disease Absence of lymphoid tissue Unexplained hepatosplenomegaly or arthropathy Family history of immune deficiency and history of consanguinity
the employment of barrier defences like the skin, thereby exposing the lungs to a vast array of pathogenic organisms, which may cause local or invasive infection. To counter these potentially fatal assaults, different immuno-protective mechanisms have evolved which may fail in immunodeficient individuals. Unsurprisingly, pulmonary infection is frequently the presenting feature of primary immunodeficiency. It is important to recognise rare infections and unusual patterns of common infection which suggest immunodeficiency, as late diagnosis is associated with chronic damage or death (Table 1). Understanding the different immune mechanisms helps to target aspects of immunity for investigation.
Immune defences Immune defences can be broadly divided into barriers, first line non-specific innate responses and second line acquired or specific responses. Barrier defences (including mucous membranes and cilia) are extremely important but will not be dealt with further in this article.
Innate immunity Innate immunity is characterised by cells and proteins which non-specifically recognise invading pathogens. The magnitude of response remains the same on each encounter. Complement proteins bind to micro-organisms, enhancing phagocytosis and directly lysing bacteria. Complement deficiency may present with isolated respiratory symptoms. Innate response cells include neutrophils, monocytes and monocyte-derived cells such as pulmonary macrophages and Kupffer cells. Monocyte and macrophage receptors recognise bacterial wall peptidoglycan, lipopolysaccharide
and fungal glycoprotein. Toll-like receptors are important signalling pattern recognition receptors. Binding antigen to these receptors induces cytokine release which attracts phagocytes, antigen presenting cells and lymphocytes to the area. Macrophages and other phagocytes engulf invading pathogens and fuse the pathogen-containing phagosome with a lysosome containing hydrogen peroxide which destroys the pathogen.
Acquired immunity Macrophages link innate and specific acquired immune responses. The acquired system has memory, allowing greater, and more rapid response each time the same antigen is encountered, and consists of T-helper and T-cytotoxic lymphocytes as well as B lymphocytes which secrete immunoglobulin. Macrophages break down invading pathogens into small antigenic fragments of 8–10 amino acids in length, which are held on the surface of MHC class 1 or 2 molecules, which are on the surface of macrophages. These antigen/MHC combinations are specifically recognised by individual T lymphocyte receptors. Each T lymphocyte bears a receptor of only one specificity. CD4 þ T-helper lymphocytes and cytotoxic CD8 þ T-lymphocytes recognise antigen in association with MHC class 2 molecules and MHC class 1 molecules respectively. Once activated, CD8 þ lymphocytes attack and destroy cells infected with intracellular pathogens such as viruses or mycobacteria. Activated CD4 þ T-helper lymphocytes activate macrophages, cytotoxic T lymphocytes, NK cells and B lymphocytes. Activated B lymphocytes secrete immunoglobulin, firstly IgM but subsequently IgG, IgA or IgE. Immunoglobulin neutralises bacterial and viral toxins, and binds bacteria and viruses to act as an opsonin which greatly aids phagocytosis. The antigen receptor of the immunoglobulin molecule
ARTICLE IN PRESS Immune deficiency and the lung
binds to the pathogen, whilst the other end is bound by immunoglobulin receptors on the surface of macrophages.
Antibody production Macrophages and antigen presenting cells which have ingested pathogens migrate to local lymph nodes which is where T and B lymphocyte activation largely takes place. T lymphocytes traffic through blood, lymph and lymph nodes to increase the likelihood of recognising the antigen specific for their particular T lymphocyte receptor. They induce specific B lymphocytes to switch from making low affinity IgM to making high affinity IgG and IgA antibody. Long-lived T and B memory lymphocytes are generated which, upon subsequent exposure with the same antigen, immediately respond without activation by antigen presenting cells. Further information on the innate and adaptive immune response may be found in more detailed texts.
Combined immune deficiencies & lung disease Severe combined immuno deficiency Severe Combined Immuno Deficiency (SCID) involves both T and B lymphocyte failure, usually in the absence of T cells and absence or dysfunction of B cells; this is generally fatal by the age of one year. Whilst different molecular defects give rise to a clinical picture of SCID, the presenting features are common. First hospitalisation is generally between 45–100 days. Affected infants suffer with viral gastro-intestinal and respiratory infection as well as pneumocystis carinii pneumonia. They often present with an unremitting bronchiolitic-like illness of variable severity. Those with pneumocystis carinii pneumonia have a characteristic brassy cough, slowly deteriorating respiratory function and insidiously develop an oxygen requirement, with an evolution taking place over several weeks. Chest radiographs show patchy interstitial shadowing rather than lobar pneumonic changes, often with hyperinflation. Characteristically the thymic shadow is absent and the mid-line pleural borders of the upper lobes may be visible. Importantly the full blood count may be diagnostic with a lymphopenia of o2.8 10 g/L. Common viral pathogens include cytomegalovirus, RSV and parainfluenza viruses.
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Serological tests are unhelpful as these patients cannot make antibody; rapid diagnostic tests such as immunofluorescence and PCR are mandatory. The diagnosis of SCID is a paediatric emergency, in a child with unusual or prolonged viral infection the index of suspicion should be high. Urgent transfer to a specialist centre for further investigation and treatment should not be delayed. Bone marrow transplantation is currently the only curative treatment. Children with established respiratory or liver disease have a poor prognosis and so early diagnosis is critical.
Other combined immune deficiencies Other combined immunodeficiencies with defects in T and B lymphocyte function present after infancy and, whilst not as rapidly fatal, are often associated with a poor outcome. Respiratory symptoms in these patients are common, and often secondary to hypogammaglobulinaemia or poor polysaccharide antibody responses. Children with undetected or under-treated recurrent sinopulmonary infection may develop bronchiectasis.
Di George Syndrome Children with Di George Syndrome normally have a chromosome 22q11 micro-deletion. Classical severe T lymphocyte immunodeficiency is rare, affecting less than 1.5% of patients. More common is immunodysregulation with quantitative or qualitative antibody deficiency.1 Poor pneumococcal polysaccharide antibody production may be associated with IgG2 subclass and IgA deficiency. Recurrent sinopulmonary infection including otorrhoea, sinusitis and chest infections are common. For some patients this is the manifestation of a prolonged maturational antibody defect, but in others the defect is permanent and careful monitoring is required. Regular antibiotic prophylaxis may be indicated. In severe cases intravenous immunoglobulin (IVIG) is required.
Wiskott–Aldrich syndrome Boys with Wiskott–Aldrich syndrome have a triad of eczema, thrombocytopenia with reduced platelet volume, and recurrent infection. In early life, bruising, petechiae and bleeding are characteristic, whilst the eczema may be mild. Opportunistic infection such as pneumocystis carinii pneumonia may occur and herpes viruses are poorly handled.
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Patients have low IgM levels and poor polysaccharide antibody responses; bacterial pneumonia and recurrent sinopulmonary infection are common.
Ataxia telangiectasia Children with ataxia telangiectasia normally present to paediatric neurologists with ataxia before the telangiectasia appear, usually at between 2 and 8 years of age. Ataxia telangiectasia is a DNA repair disorder which leads to impaired T and B cell maturation, a progressive loss of IgA, IgG2 and polysaccharide antibody response. Recurrent sinopulmonary infection with poor polysaccharide pneumococcal antibody responses become increasingly common with age. Antibiotic prophylaxis or in severe cases IVIG may lessen infections and morbidity, but do not retard the inevitable deterioration and early death.
Hyper IgM syndrome Recurrent infection is associated with a number of syndromes where IgM levels are normal or raised whilst IgG or IgA levels are low or absent. X-linked Hyper IgM syndrome (CD40 ligand deficiency) is the best to characterise. Affected boys may present in the first few months of life with pneumocystis carinii pneumonia and are particularly susceptible to cryptosporidial diarrhoea. Recurrent or persistent pneumonia is well recognised whilst neutropenia with oral ulceration occurs in 66% of these patients. Supportive treatments include antibiotic prophylaxis with co-trimoxazole and replacement IVIG. Water should be boiled to prevent infection with cryptosporidium and prophylactic azithromycin also helps protect against this pathogen. Bone marrow transplantation is the only curative procedure.
Phagocyte deficiencies A number of phagocyte defects can lead to recurrent lung disease.
A.R. Gennery et al.
is toxic to organisms ingested into phagosomes. Acute suppurative lymphadenitis is a common manifestation but severe pneumonia may be the first sign of disease. Infections with catalase positive organisms such as Staphylococcus aureus, Burkholderi cepacia and Aspergillus species are particularly common. In Aspergillus infection the fungal hyphae crosses tissue panes from the lung to the pleurae, the rib and the vertebrae. Noninfectious inflammatory sequelae are increasingly recognised, including restrictive lung defects and inflammatory bowel disease, which may be mistaken for Crohn’s disease. Demonstration of a lack of neutrophil oxidative burst confirms the diagnosis. Prophylactic antibiotic and antifungal treatments reduce morbidity and mortality but currently the only curative treatment is bone marrow transplantation.
Hyper IgE syndrome (Job’s syndrome) This disorder is characterised by extreme elevation of serum IgE (200–4000 units/l), chronic dermatitis and repeated lung and skin infections. Classically this condition presents with pneumonia complicated by pneumatocoele formation due to Staphylococcus aureus infection, although infection with other organisms including Pseudomonas aeruginosa is recognised. Patients may develop chronic lung disease related to pneumatocoeles and are also at risk of developing bronchiectasis. A staphylococcal pneumatocele in infancy is the usual presenting event. Secondary aspergillus infection within old pneumatoceles is well recognised. Severe cases are clearly distinct from severe atopic disease and such patients have high IgE levels, but RASTs to specific allergens are usually negative. In other cases the features of Hyper IgE syndrome and severe atopy may develop. Many patients make poor pneumococcal polysaccharide antibody responses but it is not clear whether it is solely this that accounts for the lung disease. The underlying defect in this condition has not yet been defined. Long term antistaphylococcal antibiotic prophylaxis with flucloxacillin is the mainstay of treatment. In those with a demonstrated antibody defect, IVIG may be useful.
Chronic granulomatous disease
Congenital antibody deficiency
X-linked recessive inheritance is the most common chronic granulomatous disease but autosomal forms are described. The defect lies in the Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, which generates superoxide that
These disorders account for the majority of immunodeficient patients with recurrent sinopulmonary infection. However, recurrent sinopulmonary disease is common in childhood and the challenge is to distinguish ‘unlucky’ patients with
ARTICLE IN PRESS Immune deficiency and the lung
normal immunity from those with an underlying immunological defect. Surprisingly little research has been conducted to determine the number of respiratory infections suffered by normal children. Eight to ten infections per year, particularly in the winter months, are considered normal for those under 5 years of age. Between 5–10 years of age, 4– 5 infections per year are considered normal. Specific warning signs of immunodeficiency include more than one episode of proven pneumonia; invasive infections in more than one system (i.e., pneumonia and meningitis); severe unusual or persistent infections; the requirement of surgery for chronic infection such as tonsillectomy, grommets or boil incision; the instigation of second-line tests for chronic infections (e.g., sweat tests or cilial beat frequency); and infections in patients with pre-existing autoimmune disease. Other warning signs include an absence of lymphoid tissue or unexplained signs such as hepatosplenomegaly or arthropathy. A family history of primary immunodeficiency or history of consanguinity is also extremely important.2
Transient hypogammaglobulinaemia of infancy During the final 3 months of pregnancy maternal IgG is actively transferred from the mother to the foetus giving high immunoglobulin levels at birth, which decay over the next 4–6 months. As the infant encounters antigenic stimuli it begins to make antibody, initially IgM then switching to IgG. Sometimes IgG production is delayed and as the transferred maternal IgG levels fall through natural decay, a transient IgG nadir occurs at around the age of 4–6 months which may be associated with recurrent sinopulmonary infection. IgG levels usually reach the normal range by 12 months of age but occasionally this physiological nadir is prolonged for up to 2 years. Antibiotic prophylaxis may be required or IVIG replacement in unusually severe cases. By definition ‘transient hypogammaglobulinaemia of infancy’ is a retrospective diagnosis.
Primary agammaglobulinaemia A number of genetic defects can lead to absence of one or more of the major classes of antibody. Xlinked agammaglobulinaemia (Bruton’s disease) is the best to characterise. Autosomal recessive forms have been described and therefore girls may also be affected. The cardinal features of primary antibody deficiency are the same regardless of
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the underlying genetic defect. The onset of symptoms generally occur between the age of 6– 12 months as maternally acquired IgG decays. Chronic respiratory infection is the first manifestation in over 70% of patients. Although symptoms begin within the second 6 months of life the diagnosis is often not made until the age of 2.5– 3.5 years or later. Invasive bacterial infections also occur in the gastrointestinal tract or skin. Diagnostic delay often leads to bronchiectasis and chronic respiratory infection, the most common cause of death in these patients. Patients presenting with recurrent invasive sinopulmonary bacterial infection in the first year of life should be suspected of having an antibody deficiency until this has been excluded.
Polysaccharide antibody deficiency Pneumococcal polysaccharide antibody deficiency is one of the most common presentations at paediatric immunology clinics. Below 2 years of age most children cannot make antibody to pneumococcal polysaccharide. Children below the age of 5 years may have a delay in making pneumococcal polysaccharide antibody. This, together with the fact that they are often in close contact with other children in nurseries, and their relatively na.ıve immune system means that they present with recurrent sinopulmonary infections. In those with maturational delay of the polysaccharide antibody system the prognosis is good, by 5–6 years of age they can make pneumococcal polysaccharide antibody and infections become less frequent. In a minority of patients this defect may be a manifestation of other underlying combined immunodeficiencies such as Di George Syndrome or Wiskott–Aldrich syndrome and other features characteristic of these diseases should be sought.
Common variable immune deficiency Common Variable Immune Deficiency (CVID), classically a disease of late adolescence and early to middle adulthood, is increasingly diagnosed in young children. It is poorly characterised with recognised features including low levels of 2 or more major antibody isotypes, impaired specific antibody responses and occassionally T lymphocyte impairment. The key clinical presentation is recurrent sinopulmonary infection with organisms such as Haemophilus influenzae and Streptococcus pneumoniae. Bronchiectasis is inevitable if diagnosis or treatment is delayed. Other features of the disease include gastrointestinal infection with
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Giardia lamblia and autoimmune disease or lympho-reticular malignancy. There are no specific diagnostic tests.
Investigation of the child with recurrent sinopulmonary infection Children presenting with recurrent sinopulmonary or endobronchial infection, or who have one or more of the other warning signs of antibody deficiency require investigation. Previously, it has been, suggested that children who have persistent cough in the absence of wheeze may have so called ‘cough variant asthma’. It is now recognised that the vast majority of children with genuine asthma will also wheeze, and so further investigation should be considered in children with chronic isolated cough. Investigations should include full blood count; lymphocyte subsets specifically looking for absence of B cells (characteristic of some forms of agammaglobulinaemia); measurement of IgG, IgA and IgM level; IgG subclasses levels with an assessment of specific antibody responses to tetanus and haemophilus, as well as to pneumococcus if the child is over 2 years of age. Age-related reference ranges should be used, as the normal levels change with age and an erroneous diagnosis may be made if adult reference ranges are used. Antibody deficiency to specific antigens, most commonly to pneumococcal polysaccharide antigens, can occur in the presence of normal levels of IgG and normal IgG subclasses. Low levels of
A.R. Gennery et al.
specific antibody should be rechecked 4 weeks after a vaccination challenge, with a less than fourfold rise in antibody level to within the normal range considered as abnormal. Other abnormalities require further investigation or looking for specific genetic defects. IgA and IgG2 subclass deficiency are common and may be inconsequential. Isolated low IgA levels in an asymptomatic child require no further investigation or treatment. All children with antibody deficiency should have a detailed respiratory assessment. A plain chest radiograph (Fig. 1) is an important first-line investigation, but this may appear normal in children with extensive endobronchial infection, and high resolution computerised tomography (HRCT) of the chest is usually necessary.3 Spirometry should be performed on children from 5 years of age onwards; although this is not useful as a diagnostic investigation, serial measurements may give an early warning of respiratory deterioration. A bronchoscopy should be carefully considered in the investigation of the child with persistent cough in order to exclude an obstructive cause. Endobronchial and alveolar specimens should be obtained for culture, which includes looking for opportunistic infection (Table 2).
Treatment of antibody deficiency Persistent and progressive lung damage due to recurrent lung infection is the most common cause of morbidity and mortality in antibody deficiency.
Figure 1 Normal plain chest radiograph with contemporaneous high resolution CT scan of chest showing bronchiectasis (arrowed).
ARTICLE IN PRESS Immune deficiency and the lung
Table 2 Investigations in children with respiratory infection and suspected primary immunodeficiency. * * * *
* * * *
FBC and WCC differential Lymphocyte subsets IgG & IgG subclasses Specific tetanus, HiB and (if 4 2 years) pneumococcal antibodies Simple spirometry (if 45 years) Plain chest radiograph HRCT of chest Bronchoscopy
Early diagnosis and aggressive treatment is vital to reduce this otherwise inevitable downward progression and early death. Often, it is not appreciated that even mild infection, when recurrent, can significantly contribute to this progression. In severe antibody deficiency, antibody replacement with IVIG is required. Importantly, IVIG is a blood product with the potential to transmit infectious agents such as hepatitis C. Before instituting immunoglobulin therapy it is important to ensure that there is no prior infection with hepatitis C (using PCR as serological tests will be useless). Serum should be saved and stored in case the patient subsequently develops viral infection. Full blood count and liver function tests should be monitored before each second infusion. It is critical to note the batch number of each immunoglobulin infusion given. A dose of 0.4–0.5 gm/kg given once every 3 weeks is indicated as antibody replacement therapy, with the dose being altered according to trough IgG levels, aiming for trough IgG levels of 8– 10 g/l. Annual spirometry should be performed, and HRCT performed biannually.4,5 In patients with poor antibody function but who make antibody, trough levels should be run significantly higher than 8– 10 g/l because some of the antibody being mea-
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sured will be the patient’s intrinsic poorly functioning antibody.
References 1. Gennery AR, Barge D, O’Sullivan JJ, Flood TJ, Abinun M, Cant AJ. Antibody deficiency and autoimmunity in 22q11.2 Deletion Syndrome. Arch Dis Child 2002;86:422–5. 2. Chapel H. Consensus document for the diagnosis, management of patients with primary antibody deficiencies. Royal College of Pathologists, 1995. 3. Eastham KM, Kall AJ, Mitchel L, Spencer DA. The need to redefine non-cystic fibrosis bronchiectasis in childhood. Thorax (submitted for publication). 4. Quartier P, Debre M, De Blic J, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinaemia: a retrospective survey of 31 patients. J Pediatr 1999;134:589–96. 5. Plebani A, Soresina A, Rondelli R, et al. Clinical, immunological, and molecular analysis in a large cohort of patients with x-linked agammaglobulinemia: an italian multicenter study. Clin Immunol 2002;104:221–30.
Further reading 1. Janeway CA, Travers P, Walport M, Shlomchick M. Immunobiology: the immune system in health and disease, 5th ed. Edinburgh: Churchill Livingstone; 2001. 2. Ochs HD, Smith CIE, Puck JM (eds). Primary immunodeficiency diseases: a molecular and genetic approach. Oxford: Oxford University Press; 1999. 3. Cant AJ, Gibb DM, Davies EG, Cale C, Gennery AR. Immunodeficiency. In: McIntosh N, Helms P, Smyth R, editors. Forfar and Arneil’s textbook of paediatrics, 6th ed. Edinburgh: Churchill Livingstone; 2003 [chapter 25]. In press.
Further Information Primary Immunodeficiency Association (PIA), Alliance House, 12 Caxton Street, London, SW1H 0QS. Tel.: 020 7976 7640; Fax: 020 7976 7641; E-mail: [email protected]. Website: www.pia.org.uk
www.elsevierhealth.com/journals/cuoe
Immune deficiency and the lung A.R. Gennerya,*, D.A. Spencerb, A.J. Canta a
Department of Paediatric Immunology, University of Newcastle upon Tyne, Newcastle upon Tyne, UK Department of Respiratory Paediatrics, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Trust, UK
b
KEYWORDS Severe combined immunodeficiency syndrome; Antibody deficiency; Polysaccharide antibody deficiency; Intravenous immunoglobulins
Summary Effective gas exchange means that lungs have large, permeable surfaces. However, this weakens defences against infection. Respiratory infections are common in childhood but are also a common presenting feature of primary immunodeficiency, so it is important to recognise warning signs of an underlying immunodeficiency. It is vital to identify rare infections and unusual patterns of common infection which suggest immunodeficiency in order to enable early diagnosis and appropriate treatment. Combined immunodeficiencies often present with persistent viral infection, whereas antibody deficiencies present with recurrent bacterial infection. Recurrent bacterial infection is a feature of complement deficiency and phagocytic disorders, which may also present with fungal infection. Prompt recognition and early diagnosis with appropriate investigations and aggressive treatment will prevent sequelae which includes bronchiectasis and respiratory failure. & 2003 Elsevier Ltd. All rights reserved.
Practice points *
*
*
*
*
Pulmonary infection is frequently the presenting feature of primary immunodeficiency Infants with severe combined immunodeficiency often present with an unremitting bronchiolitic-like illness of variable severity due to viral respiratory infection as well as pneumocystis carinii pneumonia Children with combined immunodeficiency may have polysaccharide antibody deficiency Hypogammaglobulinaemia is not a diagnosis, and further investigation is required before immunoglobulin treatment is commenced
*Corresponding author. Newcastle General Hospital, Westgate Road, Ward 23, Westgate upon Tyne NE4 6BE, UK. Tel.: þ 44-1912738811; fax: þ 44-191-2730813. E-mail address: [email protected] (A.R. Gennery).
Chest radiographs may be normal, despite the presence of bronchiectasis and regular careful respiratory evaluation is required in children on immunoglobulin treatment
Further research *
*
*
Long-term outcome of children with specific polysaccharide antibody deficiency Evolution of common variable immunodeficiency in childhood Longterm follow-up of children receiving immunoglobulin replacement
Introduction Gas exchange requires a large, moist, warm, permeable surface area. These features preclude
0957-5839/$ - see front matter & 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.cupe.2003.11.004
ARTICLE IN PRESS 116
A.R. Gennery et al.
Table 1 * * * * * * * * *
Warning signs of immunodeficiency.
Greater than one episode of proven pneumonia Invasive infections in more than one system Severe, unusual or persistent infection Requirement of surgery for chronic infection (e.g., tonsillectomy, grommets, boil incision) Investigation of second-line tests for chronic infection (e.g., sweat test, cilial beat frequency) Infection in patients with autoimmune disease Absence of lymphoid tissue Unexplained hepatosplenomegaly or arthropathy Family history of immune deficiency and history of consanguinity
the employment of barrier defences like the skin, thereby exposing the lungs to a vast array of pathogenic organisms, which may cause local or invasive infection. To counter these potentially fatal assaults, different immuno-protective mechanisms have evolved which may fail in immunodeficient individuals. Unsurprisingly, pulmonary infection is frequently the presenting feature of primary immunodeficiency. It is important to recognise rare infections and unusual patterns of common infection which suggest immunodeficiency, as late diagnosis is associated with chronic damage or death (Table 1). Understanding the different immune mechanisms helps to target aspects of immunity for investigation.
Immune defences Immune defences can be broadly divided into barriers, first line non-specific innate responses and second line acquired or specific responses. Barrier defences (including mucous membranes and cilia) are extremely important but will not be dealt with further in this article.
Innate immunity Innate immunity is characterised by cells and proteins which non-specifically recognise invading pathogens. The magnitude of response remains the same on each encounter. Complement proteins bind to micro-organisms, enhancing phagocytosis and directly lysing bacteria. Complement deficiency may present with isolated respiratory symptoms. Innate response cells include neutrophils, monocytes and monocyte-derived cells such as pulmonary macrophages and Kupffer cells. Monocyte and macrophage receptors recognise bacterial wall peptidoglycan, lipopolysaccharide
and fungal glycoprotein. Toll-like receptors are important signalling pattern recognition receptors. Binding antigen to these receptors induces cytokine release which attracts phagocytes, antigen presenting cells and lymphocytes to the area. Macrophages and other phagocytes engulf invading pathogens and fuse the pathogen-containing phagosome with a lysosome containing hydrogen peroxide which destroys the pathogen.
Acquired immunity Macrophages link innate and specific acquired immune responses. The acquired system has memory, allowing greater, and more rapid response each time the same antigen is encountered, and consists of T-helper and T-cytotoxic lymphocytes as well as B lymphocytes which secrete immunoglobulin. Macrophages break down invading pathogens into small antigenic fragments of 8–10 amino acids in length, which are held on the surface of MHC class 1 or 2 molecules, which are on the surface of macrophages. These antigen/MHC combinations are specifically recognised by individual T lymphocyte receptors. Each T lymphocyte bears a receptor of only one specificity. CD4 þ T-helper lymphocytes and cytotoxic CD8 þ T-lymphocytes recognise antigen in association with MHC class 2 molecules and MHC class 1 molecules respectively. Once activated, CD8 þ lymphocytes attack and destroy cells infected with intracellular pathogens such as viruses or mycobacteria. Activated CD4 þ T-helper lymphocytes activate macrophages, cytotoxic T lymphocytes, NK cells and B lymphocytes. Activated B lymphocytes secrete immunoglobulin, firstly IgM but subsequently IgG, IgA or IgE. Immunoglobulin neutralises bacterial and viral toxins, and binds bacteria and viruses to act as an opsonin which greatly aids phagocytosis. The antigen receptor of the immunoglobulin molecule
ARTICLE IN PRESS Immune deficiency and the lung
binds to the pathogen, whilst the other end is bound by immunoglobulin receptors on the surface of macrophages.
Antibody production Macrophages and antigen presenting cells which have ingested pathogens migrate to local lymph nodes which is where T and B lymphocyte activation largely takes place. T lymphocytes traffic through blood, lymph and lymph nodes to increase the likelihood of recognising the antigen specific for their particular T lymphocyte receptor. They induce specific B lymphocytes to switch from making low affinity IgM to making high affinity IgG and IgA antibody. Long-lived T and B memory lymphocytes are generated which, upon subsequent exposure with the same antigen, immediately respond without activation by antigen presenting cells. Further information on the innate and adaptive immune response may be found in more detailed texts.
Combined immune deficiencies & lung disease Severe combined immuno deficiency Severe Combined Immuno Deficiency (SCID) involves both T and B lymphocyte failure, usually in the absence of T cells and absence or dysfunction of B cells; this is generally fatal by the age of one year. Whilst different molecular defects give rise to a clinical picture of SCID, the presenting features are common. First hospitalisation is generally between 45–100 days. Affected infants suffer with viral gastro-intestinal and respiratory infection as well as pneumocystis carinii pneumonia. They often present with an unremitting bronchiolitic-like illness of variable severity. Those with pneumocystis carinii pneumonia have a characteristic brassy cough, slowly deteriorating respiratory function and insidiously develop an oxygen requirement, with an evolution taking place over several weeks. Chest radiographs show patchy interstitial shadowing rather than lobar pneumonic changes, often with hyperinflation. Characteristically the thymic shadow is absent and the mid-line pleural borders of the upper lobes may be visible. Importantly the full blood count may be diagnostic with a lymphopenia of o2.8 10 g/L. Common viral pathogens include cytomegalovirus, RSV and parainfluenza viruses.
117
Serological tests are unhelpful as these patients cannot make antibody; rapid diagnostic tests such as immunofluorescence and PCR are mandatory. The diagnosis of SCID is a paediatric emergency, in a child with unusual or prolonged viral infection the index of suspicion should be high. Urgent transfer to a specialist centre for further investigation and treatment should not be delayed. Bone marrow transplantation is currently the only curative treatment. Children with established respiratory or liver disease have a poor prognosis and so early diagnosis is critical.
Other combined immune deficiencies Other combined immunodeficiencies with defects in T and B lymphocyte function present after infancy and, whilst not as rapidly fatal, are often associated with a poor outcome. Respiratory symptoms in these patients are common, and often secondary to hypogammaglobulinaemia or poor polysaccharide antibody responses. Children with undetected or under-treated recurrent sinopulmonary infection may develop bronchiectasis.
Di George Syndrome Children with Di George Syndrome normally have a chromosome 22q11 micro-deletion. Classical severe T lymphocyte immunodeficiency is rare, affecting less than 1.5% of patients. More common is immunodysregulation with quantitative or qualitative antibody deficiency.1 Poor pneumococcal polysaccharide antibody production may be associated with IgG2 subclass and IgA deficiency. Recurrent sinopulmonary infection including otorrhoea, sinusitis and chest infections are common. For some patients this is the manifestation of a prolonged maturational antibody defect, but in others the defect is permanent and careful monitoring is required. Regular antibiotic prophylaxis may be indicated. In severe cases intravenous immunoglobulin (IVIG) is required.
Wiskott–Aldrich syndrome Boys with Wiskott–Aldrich syndrome have a triad of eczema, thrombocytopenia with reduced platelet volume, and recurrent infection. In early life, bruising, petechiae and bleeding are characteristic, whilst the eczema may be mild. Opportunistic infection such as pneumocystis carinii pneumonia may occur and herpes viruses are poorly handled.
ARTICLE IN PRESS 118
Patients have low IgM levels and poor polysaccharide antibody responses; bacterial pneumonia and recurrent sinopulmonary infection are common.
Ataxia telangiectasia Children with ataxia telangiectasia normally present to paediatric neurologists with ataxia before the telangiectasia appear, usually at between 2 and 8 years of age. Ataxia telangiectasia is a DNA repair disorder which leads to impaired T and B cell maturation, a progressive loss of IgA, IgG2 and polysaccharide antibody response. Recurrent sinopulmonary infection with poor polysaccharide pneumococcal antibody responses become increasingly common with age. Antibiotic prophylaxis or in severe cases IVIG may lessen infections and morbidity, but do not retard the inevitable deterioration and early death.
Hyper IgM syndrome Recurrent infection is associated with a number of syndromes where IgM levels are normal or raised whilst IgG or IgA levels are low or absent. X-linked Hyper IgM syndrome (CD40 ligand deficiency) is the best to characterise. Affected boys may present in the first few months of life with pneumocystis carinii pneumonia and are particularly susceptible to cryptosporidial diarrhoea. Recurrent or persistent pneumonia is well recognised whilst neutropenia with oral ulceration occurs in 66% of these patients. Supportive treatments include antibiotic prophylaxis with co-trimoxazole and replacement IVIG. Water should be boiled to prevent infection with cryptosporidium and prophylactic azithromycin also helps protect against this pathogen. Bone marrow transplantation is the only curative procedure.
Phagocyte deficiencies A number of phagocyte defects can lead to recurrent lung disease.
A.R. Gennery et al.
is toxic to organisms ingested into phagosomes. Acute suppurative lymphadenitis is a common manifestation but severe pneumonia may be the first sign of disease. Infections with catalase positive organisms such as Staphylococcus aureus, Burkholderi cepacia and Aspergillus species are particularly common. In Aspergillus infection the fungal hyphae crosses tissue panes from the lung to the pleurae, the rib and the vertebrae. Noninfectious inflammatory sequelae are increasingly recognised, including restrictive lung defects and inflammatory bowel disease, which may be mistaken for Crohn’s disease. Demonstration of a lack of neutrophil oxidative burst confirms the diagnosis. Prophylactic antibiotic and antifungal treatments reduce morbidity and mortality but currently the only curative treatment is bone marrow transplantation.
Hyper IgE syndrome (Job’s syndrome) This disorder is characterised by extreme elevation of serum IgE (200–4000 units/l), chronic dermatitis and repeated lung and skin infections. Classically this condition presents with pneumonia complicated by pneumatocoele formation due to Staphylococcus aureus infection, although infection with other organisms including Pseudomonas aeruginosa is recognised. Patients may develop chronic lung disease related to pneumatocoeles and are also at risk of developing bronchiectasis. A staphylococcal pneumatocele in infancy is the usual presenting event. Secondary aspergillus infection within old pneumatoceles is well recognised. Severe cases are clearly distinct from severe atopic disease and such patients have high IgE levels, but RASTs to specific allergens are usually negative. In other cases the features of Hyper IgE syndrome and severe atopy may develop. Many patients make poor pneumococcal polysaccharide antibody responses but it is not clear whether it is solely this that accounts for the lung disease. The underlying defect in this condition has not yet been defined. Long term antistaphylococcal antibiotic prophylaxis with flucloxacillin is the mainstay of treatment. In those with a demonstrated antibody defect, IVIG may be useful.
Chronic granulomatous disease
Congenital antibody deficiency
X-linked recessive inheritance is the most common chronic granulomatous disease but autosomal forms are described. The defect lies in the Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, which generates superoxide that
These disorders account for the majority of immunodeficient patients with recurrent sinopulmonary infection. However, recurrent sinopulmonary disease is common in childhood and the challenge is to distinguish ‘unlucky’ patients with
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normal immunity from those with an underlying immunological defect. Surprisingly little research has been conducted to determine the number of respiratory infections suffered by normal children. Eight to ten infections per year, particularly in the winter months, are considered normal for those under 5 years of age. Between 5–10 years of age, 4– 5 infections per year are considered normal. Specific warning signs of immunodeficiency include more than one episode of proven pneumonia; invasive infections in more than one system (i.e., pneumonia and meningitis); severe unusual or persistent infections; the requirement of surgery for chronic infection such as tonsillectomy, grommets or boil incision; the instigation of second-line tests for chronic infections (e.g., sweat tests or cilial beat frequency); and infections in patients with pre-existing autoimmune disease. Other warning signs include an absence of lymphoid tissue or unexplained signs such as hepatosplenomegaly or arthropathy. A family history of primary immunodeficiency or history of consanguinity is also extremely important.2
Transient hypogammaglobulinaemia of infancy During the final 3 months of pregnancy maternal IgG is actively transferred from the mother to the foetus giving high immunoglobulin levels at birth, which decay over the next 4–6 months. As the infant encounters antigenic stimuli it begins to make antibody, initially IgM then switching to IgG. Sometimes IgG production is delayed and as the transferred maternal IgG levels fall through natural decay, a transient IgG nadir occurs at around the age of 4–6 months which may be associated with recurrent sinopulmonary infection. IgG levels usually reach the normal range by 12 months of age but occasionally this physiological nadir is prolonged for up to 2 years. Antibiotic prophylaxis may be required or IVIG replacement in unusually severe cases. By definition ‘transient hypogammaglobulinaemia of infancy’ is a retrospective diagnosis.
Primary agammaglobulinaemia A number of genetic defects can lead to absence of one or more of the major classes of antibody. Xlinked agammaglobulinaemia (Bruton’s disease) is the best to characterise. Autosomal recessive forms have been described and therefore girls may also be affected. The cardinal features of primary antibody deficiency are the same regardless of
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the underlying genetic defect. The onset of symptoms generally occur between the age of 6– 12 months as maternally acquired IgG decays. Chronic respiratory infection is the first manifestation in over 70% of patients. Although symptoms begin within the second 6 months of life the diagnosis is often not made until the age of 2.5– 3.5 years or later. Invasive bacterial infections also occur in the gastrointestinal tract or skin. Diagnostic delay often leads to bronchiectasis and chronic respiratory infection, the most common cause of death in these patients. Patients presenting with recurrent invasive sinopulmonary bacterial infection in the first year of life should be suspected of having an antibody deficiency until this has been excluded.
Polysaccharide antibody deficiency Pneumococcal polysaccharide antibody deficiency is one of the most common presentations at paediatric immunology clinics. Below 2 years of age most children cannot make antibody to pneumococcal polysaccharide. Children below the age of 5 years may have a delay in making pneumococcal polysaccharide antibody. This, together with the fact that they are often in close contact with other children in nurseries, and their relatively na.ıve immune system means that they present with recurrent sinopulmonary infections. In those with maturational delay of the polysaccharide antibody system the prognosis is good, by 5–6 years of age they can make pneumococcal polysaccharide antibody and infections become less frequent. In a minority of patients this defect may be a manifestation of other underlying combined immunodeficiencies such as Di George Syndrome or Wiskott–Aldrich syndrome and other features characteristic of these diseases should be sought.
Common variable immune deficiency Common Variable Immune Deficiency (CVID), classically a disease of late adolescence and early to middle adulthood, is increasingly diagnosed in young children. It is poorly characterised with recognised features including low levels of 2 or more major antibody isotypes, impaired specific antibody responses and occassionally T lymphocyte impairment. The key clinical presentation is recurrent sinopulmonary infection with organisms such as Haemophilus influenzae and Streptococcus pneumoniae. Bronchiectasis is inevitable if diagnosis or treatment is delayed. Other features of the disease include gastrointestinal infection with
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Giardia lamblia and autoimmune disease or lympho-reticular malignancy. There are no specific diagnostic tests.
Investigation of the child with recurrent sinopulmonary infection Children presenting with recurrent sinopulmonary or endobronchial infection, or who have one or more of the other warning signs of antibody deficiency require investigation. Previously, it has been, suggested that children who have persistent cough in the absence of wheeze may have so called ‘cough variant asthma’. It is now recognised that the vast majority of children with genuine asthma will also wheeze, and so further investigation should be considered in children with chronic isolated cough. Investigations should include full blood count; lymphocyte subsets specifically looking for absence of B cells (characteristic of some forms of agammaglobulinaemia); measurement of IgG, IgA and IgM level; IgG subclasses levels with an assessment of specific antibody responses to tetanus and haemophilus, as well as to pneumococcus if the child is over 2 years of age. Age-related reference ranges should be used, as the normal levels change with age and an erroneous diagnosis may be made if adult reference ranges are used. Antibody deficiency to specific antigens, most commonly to pneumococcal polysaccharide antigens, can occur in the presence of normal levels of IgG and normal IgG subclasses. Low levels of
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specific antibody should be rechecked 4 weeks after a vaccination challenge, with a less than fourfold rise in antibody level to within the normal range considered as abnormal. Other abnormalities require further investigation or looking for specific genetic defects. IgA and IgG2 subclass deficiency are common and may be inconsequential. Isolated low IgA levels in an asymptomatic child require no further investigation or treatment. All children with antibody deficiency should have a detailed respiratory assessment. A plain chest radiograph (Fig. 1) is an important first-line investigation, but this may appear normal in children with extensive endobronchial infection, and high resolution computerised tomography (HRCT) of the chest is usually necessary.3 Spirometry should be performed on children from 5 years of age onwards; although this is not useful as a diagnostic investigation, serial measurements may give an early warning of respiratory deterioration. A bronchoscopy should be carefully considered in the investigation of the child with persistent cough in order to exclude an obstructive cause. Endobronchial and alveolar specimens should be obtained for culture, which includes looking for opportunistic infection (Table 2).
Treatment of antibody deficiency Persistent and progressive lung damage due to recurrent lung infection is the most common cause of morbidity and mortality in antibody deficiency.
Figure 1 Normal plain chest radiograph with contemporaneous high resolution CT scan of chest showing bronchiectasis (arrowed).
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Table 2 Investigations in children with respiratory infection and suspected primary immunodeficiency. * * * *
* * * *
FBC and WCC differential Lymphocyte subsets IgG & IgG subclasses Specific tetanus, HiB and (if 4 2 years) pneumococcal antibodies Simple spirometry (if 45 years) Plain chest radiograph HRCT of chest Bronchoscopy
Early diagnosis and aggressive treatment is vital to reduce this otherwise inevitable downward progression and early death. Often, it is not appreciated that even mild infection, when recurrent, can significantly contribute to this progression. In severe antibody deficiency, antibody replacement with IVIG is required. Importantly, IVIG is a blood product with the potential to transmit infectious agents such as hepatitis C. Before instituting immunoglobulin therapy it is important to ensure that there is no prior infection with hepatitis C (using PCR as serological tests will be useless). Serum should be saved and stored in case the patient subsequently develops viral infection. Full blood count and liver function tests should be monitored before each second infusion. It is critical to note the batch number of each immunoglobulin infusion given. A dose of 0.4–0.5 gm/kg given once every 3 weeks is indicated as antibody replacement therapy, with the dose being altered according to trough IgG levels, aiming for trough IgG levels of 8– 10 g/l. Annual spirometry should be performed, and HRCT performed biannually.4,5 In patients with poor antibody function but who make antibody, trough levels should be run significantly higher than 8– 10 g/l because some of the antibody being mea-
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sured will be the patient’s intrinsic poorly functioning antibody.
References 1. Gennery AR, Barge D, O’Sullivan JJ, Flood TJ, Abinun M, Cant AJ. Antibody deficiency and autoimmunity in 22q11.2 Deletion Syndrome. Arch Dis Child 2002;86:422–5. 2. Chapel H. Consensus document for the diagnosis, management of patients with primary antibody deficiencies. Royal College of Pathologists, 1995. 3. Eastham KM, Kall AJ, Mitchel L, Spencer DA. The need to redefine non-cystic fibrosis bronchiectasis in childhood. Thorax (submitted for publication). 4. Quartier P, Debre M, De Blic J, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinaemia: a retrospective survey of 31 patients. J Pediatr 1999;134:589–96. 5. Plebani A, Soresina A, Rondelli R, et al. Clinical, immunological, and molecular analysis in a large cohort of patients with x-linked agammaglobulinemia: an italian multicenter study. Clin Immunol 2002;104:221–30.
Further reading 1. Janeway CA, Travers P, Walport M, Shlomchick M. Immunobiology: the immune system in health and disease, 5th ed. Edinburgh: Churchill Livingstone; 2001. 2. Ochs HD, Smith CIE, Puck JM (eds). Primary immunodeficiency diseases: a molecular and genetic approach. Oxford: Oxford University Press; 1999. 3. Cant AJ, Gibb DM, Davies EG, Cale C, Gennery AR. Immunodeficiency. In: McIntosh N, Helms P, Smyth R, editors. Forfar and Arneil’s textbook of paediatrics, 6th ed. Edinburgh: Churchill Livingstone; 2003 [chapter 25]. In press.
Further Information Primary Immunodeficiency Association (PIA), Alliance House, 12 Caxton Street, London, SW1H 0QS. Tel.: 020 7976 7640; Fax: 020 7976 7641; E-mail: [email protected]. Website: www.pia.org.uk