Lung disease in primary antibody deficiency

Review

Lung disease in primary antibody deficiency Nisha Verma, Bodo Grimbacher, John R Hurst

This Review summarises current knowledge on the pulmonary manifestations of primary antibody deficiency (PAD) syndromes in adults. We describe the major PAD syndromes, with a particular focus on common variable immunodeficiency (CVID). Respiratory infection is a common presenting feature of PAD syndromes. Respiratory complications are frequent and responsible for much of the morbidity and mortality associated with these syndromes. Respiratory complications include acute infections, the sequelae of infection (eg, bronchiectasis), non-infectious immune-mediated manifestations (notably the development of granulomatous-lymphocytic interstitial lung disease in CVID), and an increased risk of lymphoma. Although minor abnormalities are detectable in the lungs of most patients with CVID by CT scanning, not all patients develop lung complications. Mechanisms associated with the maintenance of lung health versus lung disease, and the development of bronchiectasis versus immune-mediated complications, are now being dissected. We review the investigation, treatment, and management strategies for PAD syndromes, and include key research questions relating to both infectious and non-infectious complications of PAD in the lung.

Introduction A knowledge of primary antibody deficiency (PAD) syndromes is important for respiratory clinicians. Respiratory infection is a common presenting feature of PAD and lung complications of established PAD impact patients’ health-status and outcomes. The focus of this Review will be common variable immunodeficiency (CVID), which is the most common and best-described PAD encountered by clinicians. PAD in children, upper airway (sino-nasal) manifestations of adult PAD, or lung disease in acquired antibody deficiency will not be discussed in this Review. This Review provides a state-ofthe-art summary of PAD for the respiratory clinician, and of respiratory manifestations of PAD for the immunologist.

Major PAD syndromes The production of specific antibodies targeted against pathogens is a key task for the mammalian immune system, and insufficient provision of antibodies is the most common immune defect seen in human beings. A selective defect in IgA production is seen in one in 600 healthy blood donors1 and a deficiency in IgG production has a prevalence of about one in 25 000 individuals.2 Various mechanisms can result in PAD (figure 1). Specific antibodies (immunoglobulins) are produced by memory B cells and plasma cells, which derive from B cells. An absence of B cells, as seen in patients with inborn errors of B-cell development (eg, due to mutations in the X chromosomal Bruton’s tyrosine kinase), results in agammaglobulinaemia. Other patients who are able to generate B cells and can produce IgM as a first-line response to antigenic challenge fail to isotype switch to IgG or IgA because of genetic defects in the class switch recombination (CSR) machinery. Such patients are classified as hyper-IgM syndrome or as having a CSR defect. Patients diagnosed with CVID generate B cells but have reduced serum immunoglobulin concentrations. The term “common” in CVID highlights that this

disorder is one of the most frequent immune disorders in human beings and that patients have similar defects in baseline laboratory investigations, while the term “variable” is used because the clinical presentation is heterogeneous. A further group of patients are unable to produce a sufficient amount of one of the IgG subclasses. In human beings, a deficiency of IgG1 (mostly directed against protein antigens) and IgG2 (directed against polysaccharide antigens) is clinically relevant. Finally, patients with specific antibody deficiencies (SPAD) are

Lancet Respir Med 2015 Published Online July 16, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00202-7 Department of Immunology, Royal Free London NHS Foundation Trust, London, UK (N Verma MRCP, Prof B Grimbacher MD); Centre for Chronic Immunodeficiency, Medical Centre, University Hospital Freiburg, Freiburg, Germany (B Grimbacher); and UCL Respiratory, University College London, London, UK (J R Hurst PhD FRCP) Correspondence to: Dr John R Hurst, UCL Respiratory, University College London, London NW3 2PF, UK [email protected]

Key messages • A wide range of primary antibody deficiency (PAD) syndromes exist, illustrating the complexity of antibody production and deficiency. • Respiratory infection is a common presenting feature of PAD, and respiratory clinicians should be alert to this. • Substantial morbidity and mortality results from the respiratory complications that frequently occur in PAD. • Respiratory complications include acute infections, the results of infection (eg, bronchiectasis), and immunemediated diseases (notably granulomatous-lymphocytic interstitial lung disease in common variable immunodeficiency). Other complications such as an increased risk of lymphoma have also been reported. • Pathways determining the development of different lung complications are being defined. • Acute infections need prompt treatment, and the use of antibiotic prophylaxis is recommended in PAD. • The treatment of bronchiectasis in PAD is similar to the management of bronchiectasis due to any other cause, with the exception that immunoglobulin replacement therapy is used in patients with PAD. • The definition, investigation, treatment, and management of granulomatous-lymphocytic interstitial lung disease and other interstitial diseases in PAD remains poorly defined.

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Hyper-IgM syndromes

CVID XLA IgA deficiency

Pluripotent stem cell

Common lymphoid precursor

Pro B cell

Plasma cells

IgA

BTk Pre B cell

Immature B cell

IgM mature B cell

IgG IgG subclass deficiency IgE

Memory cells

Hyper IgM syndrome, other class switch recombination defects

Figure 1: A summary of B-cell development, with reference to primary antibody deficiency disease pathogenesis CVID=common variable immunodeficiency. XLA=X-linked agammaglobulinaemia. BTk=Bruton’s tyrosine kinase. Ig=immunoglobulin.

able to produce immunoglobulins, but these are not specific enough to eliminate the targeted pathogen. This inability to neutralise the pathogen most frequently concerns the polysaccharides present in the capsule of encapsulated bacteria such as Pneumococcus and Haemophilus influenzae, which are major pathogens in respiratory diseases. Antibodies are needed to opsonise capsulated bacteria, which activates the complement system. Consequently, respiratory infections are prevalent in antibody-deficient patients, and pose a clinical challenge. Early recognition and diagnosis of PAD is crucial. We suggest that all patients with underlying structural lung disease should have baseline immunoglobulin concentrations measured at least once, including IgG, IgA, and IgM, to exclude PAD. If clinical suspicion for PAD remains, referral to an immunologist should be sought for more specialist investigations.

X-linked agammaglobulinaemia Agammaglobulinaemia (XLA) is an X-linked disorder and so occurs almost exclusively in males. A defect in the maturation of antibody-producing B cells results in insufficient concentrations of all classes of immunoglobulins. Most patients are diagnosed before the age of 5 years, once protective maternal antibodies have waned. A later diagnosis has been reported in those with a negative family history, with an average age of 5·4 years compared with 2·6 years in those with a positive family history.3 Infection with encapsulated organisms such as Streptococcus pneumoniae and H influenzae are common. Sino-pulmonary infections, most often otitis, are the most frequent presentation. Other infections might occur including conjunctivitis, septic arthritis, osteomyelitis, and enteroviral infection manifesting as diarrhoea and encephalitis. Autosomal recessive forms of agammaglobulinaemia have been reported.4 2

Hyper-IgM syndromes, or CSR syndromes, can be caused either by insufficient B-cell costimulation, such as the absence of CD40:CD40–ligand interaction, or by a defect in the CSR machinery, for example as a result of mutations in AID (activation-induced cytidine deaminase), UNG (uracil DNA glycosylase), or INO80. CSR syndromes are characterised by normal or increased concentrations of IgM but low concentrations of IgG and IgA, and thus patients are susceptible to respiratory infection.5

CVID disorders CVID, the most clinically significant PAD, forms part of a heterogeneous group of antibody disorders. The prevalence of CVID is estimated to be between one in 25 000 and one in 50 000, affecting men and women equally.6 Recurrent bacterial infections, usually of a sinopulmonary origin, are the hallmark feature of this disorder. Known complications include cytopenias, autoimmunity, granuloma formation affecting many organs (generally the lungs and liver), splenomegaly, gastrointestinal tract involvement, and lymphoproliferative disorders. Multiorgan involvement is often seen, with end-organ damage. Although CVID is mainly a B-cell disorder, T-cell abnormalities can occur.7 Symptoms of CVID can occur at any age, although they tend to peak in early childhood, late adolescence, and in the third and fourth decades. The high variability in clinical features seen in CVID can result in delayed diagnosis. The delay from the onset of initial symptoms to formal diagnosis averages around 5 years in developed countries,2 and this is a major obstacle to patients receiving appropriate treatment. A low IgG concentration with low IgA or IgM concentration, or with both, combined with a poor vaccination response to a polysaccharide-based vaccination should always raise suspicion of a diagnosis of CVID. The Registry Working Party of the European Society of Immunodeficiency8 (ESID) have established clinical criteria for a probable diagnosis of CVID (panel).

Selective IgA deficiency Dimeric IgA2 is the most abundant antibody in mucosal secretions and selective IgA deficiency (sIgAD) is the most common primary immunodeficiency. Although the prevalence of sIgAD is one in 600 in white people,1 less than 10% of patients have clinical symptoms, suggesting the presence of compensatory mechanisms at the mucosal surface. Evidence suggests that patients with sIgAD are at increased risk of both upper and lower respiratory tract, and gastrointestinal infections.9

Immunoglobulin subclass deficiency IgG is the predominant antibody in the circulation and is composed of four subclasses, each with structural differences that confer functional variation. IgG subclass

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Review

deficiency might occur in isolation or in combination with deficiency of other IgG subclass or immunoglobulin isotypes. IgG2 deficiency predominates in childhood. IgG4 is generally present in very low concentrations and is absent in about 8% of white people.10 Hence, IgG4 deficiency alone is not clinically significant. IgG1 and IgG2 subclass deficiencies present in a similar manner to other PADs with recurrent upper and lower respiratory tract infections, sinusitis and otitis media, and an increased susceptibility to invasive infection with encapsulated organisms. Susceptibility to particular pathogens might reveal which subclass is deficient: for instance, patients with reduced concentrations of IgG2 polysaccharide-specific antibodies do not have an important protective mechanism against encapsulated organisms such as S pneumoniae and H influenzae.

Specific antibody deficiency SPAD is diagnosed in patients with normal total immunoglobulin concentrations but an impaired response to, for example, polysaccharide antigens, detected through the use of polysaccharide test vaccinations such as Pneumovax 23. An adequate vaccination response is usually one that is four-times greater than the baseline antibody concentration. To exclude SPAD fully, both the overall pneumococcal titre and serotype-specific pneumococcal antibody concentrations to 13 serotypes (both prevaccination and postvaccination) are measured. Impaired responses to vaccination are seen in children younger than 2 years, who still have an immature immune response to encapsulated bacteria. However, healthy children will grow out of this and SPAD is only diagnosed if the child is older than 2 years of age and still has an impaired response. Other components of the immune system are usually intact and therefore adults present with recurrent upper and lower respiratory tract infections, but often no other organ involvement.

Good’s syndrome Good’s syndrome is characterised by thymoma with associated hypogammaglobulinaemia. Hypogammaglobulinaemia is reported in up to 10% of patients with a thymoma.11 The clinical picture and laboratory investigations are variable; however, patients generally present in a similar way to other PADs with an increased burden of bacterial infections with encapsulated organisms, in addition to opportunistic viral and fungal infections. Urinary tract infections, skin infections, diarrhoea, and autoimmunity have all been described in Good’s syndrome. Associated pathogens include cytomegalovirus and herpes simplex, candida, and P jirovecii.11

Mutations in PAD patients Over the past few years, several specific mutations have been identified in a proportion of patients with PAD,

Panel: European Society of Immunodeficiency registry criteria for a probable diagnosis of common variable immunodeficiency8 At least one of the following: • increased susceptibility to infection • autoimmune manifestations • granulomatous disease • unexplained polyclonal lymphoproliferation • affected family member with antibody deficiency • AND marked reduction of IgG and IgA, with or without low IgM concentrations (measured at least twice; <2 SD of the normal concentrations for their age) • AND at least one of the following: • poor antibody response to vaccines or absent isohaemagglutinins, or both (ie, absence of protective concentrations despite vaccination) • low number of switched memory B cells (<70% of age-related normal value) • AND secondary causes of hypogammaglobulinaemia have been excluded • AND diagnosis is established after the fourth year of life (but symptoms might be present before) • AND no evidence of profound T-cell deficiency

some of which might predispose to specific lung manifestations.

Activated PI3K-δ syndrome Activated PI3K-δ syndrome12–16 is a monogenic autosomal dominant defect that leads to overactivation of the PI3K-δ enzyme, resulting in uncontrolled lymphoproliferation. Activated PI3K-δ syndrome is associated with impaired vaccine responses, reduced serum IgG2, and recurrent respiratory infection with airway damage. In the lungs, the expanded lymphoid tissue (including, but not limited to, the lymph nodes) compresses the bronchi, leading to characteristic radiological and bronchoscopical appearances. These lymphoid aggregates can result in post-stenotic pneumonia.

CTLA-4 deficiency CTLA-4 deficiency is an autosomal dominant immune dysregulation syndrome characterised by an activated T-cell compartment.17,18 In this disorder, regulatory T cells fail to exert their immune regulatory effect and autoaggressive immune cell infiltrations attack the lungs, often leading to granulomatous-lymphocytic interstitial lung disease (GLILD).

Lung disease in PAD The respiratory manifestations of PAD follow two basic pathophysiological mechanisms: the sequelae of recurrent acute infections and immune-mediated pathology. Hence, two distinct patterns of chronic lung disease develop—bronchiectasis and interstitial disease.

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Figure 2: Typical lung-window CT findings in bronchiectasis (A) and interstitial lung disease (B), both in patients with underlying antibody deficiency Bronchiectasis is seen as bronchial wall thickening, and dilatation of the bronchus in relation to the accompanying vessel. Peri-bronchial nodules and ground-glass changes are seen in interstitial lung disease. Fibrosis is seen in patients with more advanced interstitial disease.

Lung health Antibody deficiency Possible cofactors Coexistent T-cell dysfunction Altered CD4:CD8 proportionality Increased IgM concentration

GLILD

Possible cofactors Recurrent infection Suboptimum Ig replacement Potential cofactors: MBL deficiency, low IgA, neonatal Fc receptor (FcRn) activity

Absence of cofactors

Bronchiectasis

Lung health

Figure 3: Hypothetical scheme outlining pathways to the development of lung disease in primary antibody deficiency Ig=immunoglobulin. GLILD=granulomatous-lymphocytic interstitial lung disease. MBL=mannose binding lectin.

Bronchiectasis and interstitial disease can be readily distinguished using CT (figure 2) and the two disorders are associated with different immune profiles, at least when examined in retrospective studies. Whether such variables predict the development of future lung complications at the time of diagnosis remains to be assessed, but if confirmed this would be a major clinical development. For example, interstitial disease has been associated with altered CD4:CD8 T-cell proportionality (increased ratio), high IgM concentrations, and a history of autoimmune haemolytic anaemia or immune thrombocytopenic purpura, and tends to occur at a younger age. By contrast, bronchiectasis is more likely to affect older age groups, and is associated with a history of pneumonia and a CD4 T-cell count lower than 700 cells per μL (figure 3).19 The detection of lung involvement in PAD is important because of its effect on quality of life20,21 and mortality.22 In a seminal study,22 mortality in CVID was linked to both structural and functional lung impairment. A diagnosis of structural lung disease included interstitial changes on CT, granulomatous or lymphocytic infiltrates confirmed on lung biopsy, bronchiectasis, or a combination of these features. Functional lung disease included restrictive or 4

obstructive lung pathology, and reduced diffusion capacity or reduced oxygen saturation, or both. Typically, bronchiectasis, at least when severe, is associated with airflow obstruction (decreased FEV1/FVC ratio). By contrast, interstitial change is usually associated with restrictive abnormalities on pulmonary function, including impairment in gas transfer (reduction in DLCO).23 When spirometry is within the normal range, abnormalities might be detectable by changes in midexpiratory flows. The prevalence of lung disease is lower in XLA than CVID, probably as a result of earlier diagnosis of XLA and the additional immune dysregulation seen in CVID.24 More than 90% of patients with CVID have abnormalities present on CT scan of the lungs.25 These abnormalities are typically mild and present even in patients who are asymptomatic.26 We recommend a baseline chest CT on diagnosis of PAD to identify respiratory complications early in the illness, allowing prompt treatment and providing a baseline from which to assess future change. In patients who are asymptomatic, and in the absence of other biological markers, identifying which patients will go on to develop progressive lung disease is difficult and requires repeat CT assessments (in our practice every 5 years to limit lifetime radiation exposure with repeated scanning, and with annual lung function screening). Although specific cell populations (eg, memory B cells) might be absent or reduced in those with chronic lung disease,26 whether this association is the cause or effect of disease is unknown. Recurrent infections, with a median frequency of 2·5 events per year, and productive cough are the most common difficulties in patients with symptoms.27 At present, assessment of patients with lung involvement includes serial lung function testing every 6–12 months, depending on severity, and repeat CT imaging, since lung involvement can progress despite immunoglobulin replacement.28 Repeated exposure to ionising radiation is a concern, particularly in patients whose genetic defect affects DNA recombination and DNA repair, leading to radio-sensitivity. Protocols should therefore minimise radiation exposure. MRI has been explored as an alternative to CT;29 however, scan resolution remains a challenge (figure 4). Nonetheless, MR sequences can give additional functional information to that provided by CT, for example regarding the cellularity of pulmonary nodules. Little is known about the rates of lung function decline in PAD, or the factors affecting this. Over an average period of 7·6 years, the average decline in FEV1 was 45 mL per year in a small study of 37 patients.30 This decline is greater than would be expected in a healthy population (typically 30 mL per year), and similar to the decline expected in a susceptible smoker. The decline was more rapid in patients diagnosed at a younger age, and was more rapid in patients with XLA than in those with CVID (65 vs 36 mL/year).30 The deterioration in

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Review

FEV1 was reduced in patients on higher doses of immunoglobulin replacement (irrespective of trough concentration). The relation between lung function decline and antibiotic use and infection frequency remains to be defined.31 Furthermore, the notion that immunoglobulin replacement can be used to reduce lung function decline needs further confirmation. A distinction should be drawn between disease severity, which can be assessed using cross-sectional measures such as a single lung function test or CT, and disease activity (or speed of progression of lung disease). In a small study of patients with PAD, the rate of FEV1 decline (but not absolute FEV1 or extent of disease on CT) was directly proportional to the systemic acute phase response (and that systemic inflammation was related to inflammation in the airway).21

Acute infections Acute infections contribute substantially to the costs of care in patients with PAD.32 Immunoglobulin replacement is effective in reducing the risk of infection, including pneumonia, otitis media, and systemic infections, in patients with XLA, hyper-IgM, and CVID.33–35 However, despite immunoglobulin replacement, susceptibility to infection remains variable36 and might be linked to low IgA concentrations. Trough concentrations were associated with infection susceptibility in a metaanalysis of 201 patients.35 Over a 5 year period, 21% of CVID patients and 24% of XLA patients were infection free. Additionally, higher steady-state IgG concentrations in subcutaneous immunoglobulin replacement therapy are associated with fewer acute infections.37 Intravenous and subcutaneous immunoglobulin replacement have been shown to be equally effective routes of administration in reducing infection burden. No specific guidelines exist for an adequate trough concentration, although generally the aim is to be above the lower limit of the normal IgG range. Instead of using a particular trough concentration, it has been proposed that the number of breakthrough infections should define the immunoglobulin dose for each individual patient.34 With regard to the causative pathogens of acute infection, bacterial infections are the most important, particularly Streptococcus, Haemophilus, and Staphylococcus, at least when using culture-based detection. Viral infections, including rhinovirus infection, can be both more frequent and more persistent in PAD.38 Pathogens that are considered opportunistic in diseases such as HIV, for example Pneumocystis and Cytomegalovirus, do not seem to be common in PAD lung disease,39 probably because of the relative preservation of adequate T-cell function in many patients with PAD. Acute infection should be managed as for guidance in patients without underlying PAD, but treatment might need to be prolonged for 10–14 days in patients with established bronchiectasis. Evidence is scarce on appropriate antibiotic prophylaxis and its use in PAD. In

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Figure 4: Comparison of MR (A) and CT images (B) from a patient with common variable immunodeficiency and interstitial lung disease MRI provides less spatial resolution; however, these T2-weighted images show the presence of oedema (high signal) within some nodules. The CT image shows bilateral ground-glass appearance and more dense nodular infiltration, only some of which is visible on MRI.

our clinical experience, similar to other centres nationwide, antibiotic prophylaxis has been associated with a substantially reduced infection burden. Our practice is to offer antibiotic prophylaxis to all patients with PAD and recurrent infections, especially when there are known structural lung changes. Prevention of infections is of key importance in reducing long-term morbidity. We do not routinely use antifungal prophylaxis in the absence of data that fungal pathogens are a common cause of infection in our cohort of CVID patients. In patients with evidence of substantially reduced T-cell counts with or without T-cell dysfunction, we prefer to use co-trimoxazole as the antibiotic prophylaxis to protect against both bacterial and fungal organisms.

Bronchiectasis in PAD Clinically significant bronchiectasis is defined as permanent abnormal dilatation of the airways in conjunction with persistent or recurrent bronchial sepsis.40 Chronic productive cough, susceptibility to recurrent exacerbations, and breathlessness are reported in patients with more widespread disease. Despite the importance of detecting primary immunodeficiency as a (treatable) cause of bronchiectasis, a UK national audit reported that only 68% of patients with bronchiectasis had a documented serum immunoglobulin assay.41 The prevalence of bronchiectasis in CVID (23% across a European cohort of 902 patients) varies greatly between centres.42 Difficulties in differentiating minor degrees of bronchiectasis from healthy lung partly explain this difference, and even in the absence of bronchiectasis, airway wall thickening with secondary atelectasis and gas trapping might be visible on CT.43 The health status of patients with PAD and bronchiectasis is largely driven by respiratory involvement, and is related to the degree of airflow obstruction, breathlessness, and the frequency of respiratory infection.21 Thus, preventing infections might be expected to maintain or improve health status, and evidence

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suggests that treatment strategies such as macrolide antibiotics achieve this in patients with bronchiectasis (although some trials excluded PAD populations).44–46 Since only some patients with PAD develop bronchiectasis, cofactors are important. An additional deficiency of mannose-binding lectin, a protein component of the complement pathway, might be one such variable.47 Low IgA concentrations have been associated with the development of bronchiectasis,36 as has low Fc receptor activity.48 In PAD, management of bronchiectasis is the same as management of bronchiectasis resulting from any other cause,44 with correction of the underlying defect (in this case optimum immunoglobulin replacement), sputum clearance training from a respiratory physiotherapist, and prevention of further infection, which usually includes prophylactic antibiotics in patients with PAD. Data regarding antibiotic choice are scarce; however, macrolides are thought to be the most effective.44–46 Notably, evidence for which is the optimum antibiotic for treating bronchiectasis in patients with PAD specifically is particularly scant.49 Whether the beneficial effect of macrolides is due to a classic antibiotic effect remains to be clarified; however, an anti-inflammatory action might be relevant. The general consensus40 is to avoid ciprofloxacin prophylaxis in view of the usefulness of this drug in treating Pseudomonas. The vaccine response of patients with PAD to the influenza and Pneumococcal vaccines that are recommended as part of usual bronchiectasis care might be inadequate. There remains something of a paradox in the notion that IgA is the main effector of mucosal defence, yet IgA deficiency tends to result in less severe lung disease than that associated with IgG deficiency, and replacement of IgG into the systemic circulation is able to reduce the frequency of respiratory infections.22 One explanation is that although IgA is mostly present in the upper airways, IgG is the most prevalent immunoglobulin in the alveolar space. Although immunoglobulin replacement therapy is mainly prescribed to reduce the incidence of acute infection, data from a small study of 13 patients50 suggest it might have beneficial effects on airway inflammation, including a reduction in inflammatory cell count and increased mucus transportability. The presence of potentially pathogenic bacteria and viruses in the lungs of patients with clinically stable PAD has been reported in studies using culture and PCR.51 H influenzae is the most common pathogen identified by culture.27 However, our understanding of the lung microbiome has been transformed, such that we now understand that the differences between health and disease, and stable and exacerbated states, are associated with differences in bacterial populations.52 Although research is underway, no studies to our knowledge have explored how the respiratory microbiome might be altered in patients with underlying PAD or, indeed, 6

whether changes in the microbiome might predispose to, rather than result from, specific types of lung disease.

Interstitial lung disease in PAD Any of the interstitial lung diseases might be seen in association with PAD; however, GLILD is the most common, the most investigated, and the most closely associated with poor clinical outcomes. The term GLILD, although helpful for clinicians, is less widely accepted by pathologists and a precise clinico-pathologico-radiological definition similar to other interstitial lung diseases is needed. Radiologically, the typical pattern of interstitial lung disease in PAD is a generalised diffuse reticular change, often with ground-glass appearance, and a lower lobe predominance (figure 2B). In one report,53 large, illdefined bronchocentric nodules or small randomly distributed nodules were noted in 50% of patients, invariably in association with reticular change, and 38% of patients had thoracic lymphadenopathy. Histologically, GLILD is characterised by both granulomatous and lymphoproliferative features including non-necrotising granuloma, lymphocytic interstitial pneumonitis, and follicular bronchiolitis (figure 5). In lymphoid hyperplasia, a variable preponderance of B cells and T cells is noted (usually T cell predominant). The cells are organised into distinct zones, with evidence of active cellular proliferation.54 GLILD is best described as the pulmonary manifestation of a systemic syndrome associated with autoimmune cytopenia, splenomegaly, enteritis, and adenopathy. GLILD is not seen in XLA, suggesting that T-cell dysfunction is central to the pathogenesis, although the detailed mechanisms remain poorly understood. Various studies have examined the role of viruses, such as herpes viruses, in driving lymphocyte proliferation; however, results have been inconsistent.55,56 Clinically, patients with interstitial lung disease and PAD experience cough and breathlessness. Impairment in gas transfer seems to be the most frequent abnormality on lung function testing.57 Since the natural course of GLILD is poorly documented in patients with PAD, observational studies such as STILPAD58 are continuing. Our approach is to substantiate the diagnosis of GLILD at surgical (video-assisted thoracic surgery) lung biopsy (figure 6). A lung biopsy is not a trivial procedure, but the relative preponderance of different cell populations could be used to guide second-line therapy. However, direct evidence in support of this approach remains scarce.54 The differential diagnosis of GLILD includes infection, other interstitial lung diseases, and lymphoma. We perform bronchoalveolar lavage (BAL) before the biopsy to exclude infection. GLILD has been associated with BAL lymphocytosis (>20%) in most patients,59,60 but whether further analysis of cells retrieved at BAL enables surgical biopsy to be avoided has yet to be properly examined. The CD4:CD8 preponderence in patients with GLILD varies between studies. A higher CD4:CD8 ratio

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was associated with a more favourable outcome in terms of lung function decline in one study;60 however, this association was not seen in another study.61 Abnormalities present in blood lymphocyte populations in CVID might be present in BAL too;62 however, data for lung lymphocyte populations in CVID are scarce. One study63 used transbronchial biopsy to assess patients. However, a firm diagnosis could not be made in over two-thirds of patients. Disease progression can be seen in patients receiving immunoglobulin replacement therapy.28 To our knowledge, no appropriate studies have examined whether immunoglobulin optimisation alone can improve lung function in GLILD. High-dose corticosteroids are often used as first-line therapy, although evidence of their effectiveness is weak.57,63 Combination therapies are probably needed for a complete response, since around half of patients do not respond to steroids.57 Based on our clinical experience, a dose of 1 mg/kg per day of prednisone is needed until a maximum improvement in lung function and radiology is seen. The dose is then tapered (figure 6). Abnormalities visible on plain radiography can be used to monitor therapy in preference to CT. Patients are monitored for CD4 lymphopenia secondary to corticosteroid immunosuppression and prophylaxis for Pneumocystis is considered if the CD4 count falls to less than 200 × 10⁹ cells per L. No specific evidence showing the beneficial effects of prophylaxis in patients with CVID has been reported; however, increasing evidence suggests prophylaxis has a protective effect in non-HIV immunocompromised patients.64 Case reports suggest rituximab can improve pulmonary function.54 Rituximab was used in conjunction with azathioprine (targeting T cells) in a small series, resulting in improved spirometry values and fewer imaging abnormalities.65 Other T-cell agents that have been trialled include ciclosporin66 and abatacept (unpublished), and case reports exist for infliximab.67 We have clinical experience using mycophenolate as a second-line therapy (unpublished), and bone marrow transplants have been done in selected patients with GLILD.68 Although larger datasets are needed, GLILD is undoubtedly associated with reduced life expectancy in CVID.69 Data for the outcomes of lung transplantation are scarce. Lung transplantations have been successfully performed; however, the outcomes are variable,70 and granulomas have been reported to recur.27 Patients with underlying PAD and histologically confirmed GLILD rarely display no symptoms. When this is the case, treatment should still be considered to prevent further end-organ damage.

Other Lung Complications in PAD Organising pneumonia (previously referred to as bronchiolitis obliterans organising pneumonia) has been reported in association with CVID.71 The diagnosis is established from a biopsy sample and organising

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Figure 5: Histology of granulomatous-lymphocytic interstitial lung disease showing a polymorphous infiltrate of lymphocytes, plasma cells, and macrophages High (A) and low (B) power photomicrographs of a video-assisted thoracoscopic surgery lung biopsy from a patient with common variable immune deficiency and granulomatous-lymphocytic interstitial lung disease.

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Clinical suspicion • Symptoms • Radiology • Impaired gas transfer • Granulomatous disease in other organs Baseline investigation • CT • Spirometry, lung volumes, and gas transfer • Bronchoscopy to exclude infection • Lung biopsy to confirm diagnosis and guide therapy Management • Optimise immunoglobulin replacement • Consider antibiotic prophylaxis • Induce remission with high-dose corticosteroids and wean; consider second-line therapy • Monitor symptoms, radiology, and lung function • Manage relapse with intensified immunosuppression

Figure 6: An approach to the diagnosis and management of granulomatouslymphocytic interstitial lung disease in common variable immunodeficiency

pneumonia is treated using systemic corticosteroids as first-line therapy. Patients with CVID are at increased risk of lymphoma, typically B-cell non-Hodgkin lymphoma. Mucosaassociated lymphoid tissue lymphoma might occur in the lung72 and should be considered in the differential diagnosis of GLILD.

Processes of care We advocate a shared-care approach, ideally with joint respiratory and immunology clinics for patients with respiratory complications of PAD. This will help with access to a multiprofessional team including radiologists, pathologists, respiratory clinicians, and respiratory physiotherapists in addition to the immunodeficiency team. Historically, there has been a delay both in patients with immunodeficiency seeing chest specialists and chest specialists making the diagnosis of PAD in patients first presenting with respiratory pathology.27

Key research questions Key research questions remain regarding the optimum monitoring regimen for lung disease in patients with

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Search strategy and selection criteria

See Online for appendix

A comprehensive literature review was performed with support from the Clinical Effectiveness Enquiry Service at the Royal Free London NHS Foundation Trust. Medline and Embase were searched on Nov 19, 2014, using text words and subject headings relating to primary immune (antibody) deficiency syndromes and lung diseases. The search strategy is provided in the supplementary appendix. The search was restricted to English language publications, and after removal of duplicates, 2360 articles remained. Titles and abstracts were screened for suitability for inclusion (original reports and reviews relating to lung disease in peripheral artery disease). Additional citations were generated by examining the reference lists from the selected reports.

PAD, and appropriate strategies for diagnosis and management. We propose the following key research priorities: How can we best identify which PAD patients will retain healthy lungs, and which will develop bronchiectasis or GLILD? What is the best prophylactic antibiotic management for patients with PAD and bronchiectasis? What is the optimum management for patients with GLILD? Is immunosuppression the only treatment for GLILD, and if so, which is the optimum immunosuppressive regimen? How frequently should lung involvement be monitored by CT and lung function, and in which patients is follow-up with MRI acceptable?

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Conclusion Respiratory manifestations of PAD are important because of the effect on morbidity and mortality. Bronchiectasis is the most common manifestation, with GLILD occurring in about 15% of patients with CVID. Bronchiectasis should be managed according to standard guidelines; however, evidence for the effective diagnosis, monitoring, and treatment of GLILD is scarce and remains a research priority.

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Declaration of interests We declare no competing interests.

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Contributors The first draft was written by NV and JRH. All Authors then revised the manuscript for important intellectual content.

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Acknowledgments We are grateful for the assistance of Sophie Pattison, Clinical Support Librarian, Medical Library, and the Royal Free Hospital for performing the original literature search.

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