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Respiratory manifestations and management in children with Common Variable Immunodeficiency
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Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Review
Respiratory manifestations and management in children with Common Variable Immunodeficiency Chetan Pandit 1,2,*, Peter Hsu 2,3, Peter van Asperen 1,2, Sam Mehr 2,3 1
Department of Respiratory Medicine, The Children’s Hospital at Westmead, Sydney Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney 3 Department of Allergy and Immunology, The Children’s Hospital at Westmead, Sydney 2
EDUCATIONAL AIMS
THE READER WILL COME TO UNDERSTAND:
The broad clinical phenotypes in children with common variable immunodeficiency (CVID) The importance of early diagnosis and management of respiratory morbidity in CVID The role of other treatment options such as prophylactic antibiotics, anti-inflammatory medications and muco-ciliary clearance in delaying respiratory progression in CVID
A R T I C L E I N F O
S U M M A R Y
Keywords: Common variable immunodeficiency Diagnosis Respiratory management
Common variable immunodeficiency is an antibody deficiency that usually presents in childhood with recurrent sino-pulmonary infections. Diagnostic delay is frequent and thus respiratory morbidity is common, ranging from recurrent suppurative bronchitis to bronchiectasis. Immunoglobulin replacement therapy is the mainstay of treatment, whilst prophylactic antibiotic therapy and muco-ciliary clearance are additional treatment options. This review examines the diagnosis and management of respiratory issues in children with CVID. Crown Copyright ß 2016 Published by Elsevier Ltd. All rights reserved.
INTRODUCTION Common variable immunodeficiency is a heterogeneous group of immunodeficiency disorders characterized by dysfunctional antibody production resulting in a spectrum of clinical disease most commonly associated with recurrent sino-pulmonary infections [1]. A small number of patients initially present with autoimmune or auto-inflammatory conditions, but eventually develop recurrent infections. It is the second most frequent primary immunodeficiency (PID) with an estimated prevalence from 1 in 10000 to 1 in 50000. It is characterized by a bimodal presentation of age, usually presenting in early childhood or in young adult years [1–3]. The European Society of Immune Deficiencies (ESID) revised their definition of CVID in 2014 (Table 1) [4]. Essentially, a diagnosis of CVID can be made in a person > 4 years of age with
clinical features of immune dysfunction (i.e at least one of recurrent infections, autoimmunity, granulomatous disease and/or unexplained polyclonal lymphoproliferation) and laboratory evidence of B-cell dysfunction (i.e. marked reduction in IgG and IgA levels 2 standard deviations below normal with/without reduced IgM levels and either poor dynamic antibody responses to vaccines and/or low switched memory B-cells). CVID is a diagnosis of exclusion, such that other causes of hypogammaglobulinaemia and profound T-cell deficiency need to be excluded before a diagnosis can be made. Although hypogammaglobulinemia and therefore sino-pulmonary infections are the defining feature of CVID, the complex and heterogenous pathogenesis of CVID results in many extra-pulmonary manifestations. In this review, we focus on the respiratory manifestations of CVID, and highlight the importance of early diagnosis and treatment. Pathogenesis of CVID
* Corresponding author. Paediatric Respiratory and Sleep Physician, Department of Respiratory Medicine, The Children’s Hospital at Westmead, Locked bag 4001, Westmead, Sydney, New South Wales, Australia 2145. Tel.: +61 2 9845 3397; fax: +61 2 9845 3396. E-mail address: [email protected] (C. Pandit).
CVID is not a monogenic immunodeficiency, but instead a collection of heterogeneous disorders linked by T-B-cell dysregulation resulting in defective antibody production.
http://dx.doi.org/10.1016/j.prrv.2015.12.003 1526-0542/Crown Copyright ß 2016 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Pandit C, et al. Respiratory manifestations and management in children with Common Variable Immunodeficiency. Paediatr. Respir. Rev. (2016), http://dx.doi.org/10.1016/j.prrv.2015.12.003
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2 Table 1 Revised ESID (2014) diagnostic criteria for CVID
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 decrease of IgG and marked decrease of IgA with or without low IgM levels (measured at least twice; <2 SD of the normal levels for their age); AND at least one of the following: Poor antibody response to vaccines (and/or absent isohemagglutinins); i.e. absence of protective levels despite vaccination where defined Low switched memory B cells (<70% of age-related normal value) AND secondary causes of hypogammaglobulinemia have been excluded AND diagnosis is established after the fourth year of life (but symptoms may be present before) AND no evidence of profound T-cell deficiency, defined as two out of the following (y = year of life): CD4 numbers/microliter: 2–6 y < 300, 6–12 y < 250, >12 y < 200 % Naive CD4: 2–6 y < 25%, 6–16 y < 20%, >16 y < 10% T-cell proliferation absent http://esid.org/Working-Parties/Registry/Diagnosis-criteria.
This has become increasingly more apparent with the advent of next generation sequencing, which has allowed immunologists to identify previously known mutations in the group of patients presenting with a CVID phenotype. For example, children with monogenic mutations that cause severe combined immune deficiency (SCID) can present atypically with a CVID phenotype, especially if the mutation is hypomorphic and some function of the affected protein is preserved [5]. Genetic defects known to cause familial hemophagocytic lymphohistiocytosis (HLH) can also lead to a clinical phenotype of ‘‘CVID’’, before the catastrophic presentation with hemophagocytic syndrome [6]. Next generation sequencing has also allowed the identification of new genes within the CVID group. Recent examples include CTLA-4 loss of function [7] and PI3K gain of function [8] mutations, along with other previously identified genes such as CD19, TACI and ICOS. However, < 5-10% of all CVID cases currently have a genetic explanation, and multiple centres are currently conducting trials to better delineate genetic mutations leading to a CVID phenotype [9–11]. SPECTRUM OF PULMONARY DISEASE Age of presentation Age of presentation can range from 3 years to 71 years of age with studies identifying 2 peaks, between 6 and 10 years of age and in young adulthood (between 26 and 40 years) [1,14–16]. In both the US and France national studies, nearly 15% of all the patients presented between 4 to 10 years of age [1,15]. A small number of patients (<5%), do not have recurrent infection but rather come to attention initially due to presence of inflammatory or autoimmune complications, but overtime develop recurrent suppurative infections [16]. The primary defect in CVID is usually insufficient production of IgG and IgA antibodies to pathogens. Consequently, patients suffer from frequent or persistent upper respiratory tract infections, especially in the pre-school age [12]. As recurrent infections are common in children, and patients with CVID present with typical symptoms of wet cough and ear infections, diagnostic delay is not infrequent. In one study the average diagnostic delay was 2.5 years for children and 5.5 years for adults [13]. Early diagnosis and optimal management are likely to result in improved clinical and quality-of-life outcomes for patients with CVID. Upper respiratory tract infection Recurrent or chronic otitis media, sinusitis and bronchitis, in isolation or in combination, are the most common presenting features in children and adults with CVID [1,14]. Ear and chest
infections are common in immunocompetent children, particularly in the first 2 years of life. Antibody defects, such as CVID, however must always be considered if a patient is presenting with recurrent or chronic bronchitis, sinusitis and otitis media with ottorrhoea [17]. A patient who presents with recurrent episodes of rhinorrhoea, wheeze, and cough who is well in between episodes is much more likely to be immune competent and have recurrent viral upper respiratory tract infections compared to a patient with recurrent or persistent antibiotic responsive wet cough and/or purulent otitis media. Culture of sputum or ear discharge in such circumstances is useful, since an antibody defect is more likely if encapsulated bacteria are isolated. Recurrent pneumonia Almost three quarters of patients with CVID would have had at least one episode of pneumonia requiring antibiotic therapy before diagnosis, with some children having had multiple episodes of pneumonia [15]. Pneumonia can be severe requiring hospitalization and can also be associated with complications including empyema, pneumatocoeles and lung abscess. Watts et al described 28 (87.5%) out of 32 patients who had an average of 3 or more episodes of pneumonia [18]. Different lobes of the lung are often involved but rarely the same lobe can be affected. This can then progress to bronchiectasis which may require lobectomy in later years. Encapsulated bacteria are the predominant organisms isolated in children with CVID. These include streptococcus pneumoniae and haemophilus influenzae. Staphylococcus aureus has also been frequently isolated [19,20]. Any patient presenting with two or more episodes of pneumonia needs to be investigated for an antibody defect. Asthma Patients with CVID may have recurrent wheezing requiring treatment with bronchodilators for relief. The incidence of asthma has been reported to be between 9% and 15% [21,22]. This may be attributed to intrinsic asthma which is IgE independent and may also be secondary to increased inflammation, producing reversible obstruction and clinical wheezing. Asthma symptoms are likely to delay diagnosis by masking the underlying symptoms of immunodeficiency and therefore any patient presenting with a chronic or recurrent bronchitis with wheeze should be assumed to have an antibody defect until proven otherwise. Such patients must have a full blood count and antibody levels (IgG, IgA and IgM) measured as a minimum, prior to any escalation of asthma medications.
Please cite this article in press as: Pandit C, et al. Respiratory manifestations and management in children with Common Variable Immunodeficiency. Paediatr. Respir. Rev. (2016), http://dx.doi.org/10.1016/j.prrv.2015.12.003
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Bronchiectasis Bronchiectasis is a common complication in children with CVID. The prevalence of bronchiectasis in the large cohort studies ranges considerably from 27% to 90% [1,15]. Bronchiectasis is often progressive and is usually the cause of morbidity and mortality, especially in adulthood. The mechanism of bronchiectasis is due to impaired immune clearance with recurrent, persistent or severe infection. This leads to recurrent episodes of airway inflammation, regeneration, repair and finally structural damage [12,23]. Quinti et al reported the development of bronchiectasis in spite of IVIG therapy and postulated bronchiectasis to be due to ongoing inflammation and mucous plugging [16]. Additional risk factors for bronchiectasis in those with CVID include delay in diagnosis and thus the total duration of damage caused by chronic sinopulmonary infections [14], low memory B-cell numbers, and certain genetic polymorphisms. [24,33]. We would recommend in any patient with CVID presenting with recurrent suppurative chest infections, to have a baseline HRCT chest scan. We would not suggest regular screening with HRCT, as others have suggested, due to the increased radiation exposure with limited clinical benefit in a group that is already at higher risk of lymphoreticular cancers [25]. We would however suggest repeating HRCT if clinically indicated, such that the patient’s respiratory status was worsening despite therapy. Interstitial lung disease Interstitial lung disease in CVID is a potentially devastating outcome, and reported in up to 25% of case series [27]. It is more commonly reported in adolescents and in adulthood. Such patients often present with reduced lung function. Non infectious pulmonary complications are seen in some patients with CVID. Radiographic abnormalities and surgical biopsy have identified patients with lymphoid interstitial pneumonia, granulomatous lung disease, and lymphoid hyperplasia, which have now been grouped under granulocyte-lymphocytic interstitial lung disease (GLILD) [26,27]. These patients are reported to have lower DLCOs and a restrictive pattern on spirometry. They have a more progressive course and are at high risk for early mortality [27]. Recognition of these complications is important as therapeutic options like azathioprine and rituximab has shown promising early results [36,37]. Extra-pulmonary manifestations of CVID Whilst this is not intended to be a comprehensive review of the extra-pulmonary features of CVID, it is important to recognize these features, as they aid in the eventual diagnosis of CVID. Autoimmunity is a common presentation of CVID, and may precede the development of recurrent infection [28]. Autoimmune thrombocytopenia and haemolytic anaemia are the most common presentations. Other more common autoimmune presentations include but are not limited to rheumatoid arthritis, juvenile idiopathic arthritis and inflammatory bowel-like disease. Another consequence of immune dysregulation is lymphoid hyperplasia or lymphoproliferation, which can be granulomatous or non-granulomatous [29]. In addition to peripheral lymph nodes, this can also occur in the lungs, gut, spleen, and parotid glands.
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[1,38]. The reasons for the increased frequency of gastric cancers in CVID remains unclear, although in some centers routine screening for H.pylori infection by urea breath testing and monitoring for pernicious anaemia every 12 months (serum B12 and iron levels) is performed in those with CVID, as they are modifiable risk factors. Baseline immune investigations If an antibody defect, such as CVID is suspected, appropriate initial investigations include total immunoglobulin levels (IgG, A, M), a full blood count with a T-B-NK cell subsets and IgG vaccine responses to both protein and polysaccharide conjugated vaccines. The patient’s vaccination status is required to be able to interpret the vaccine responses. At our institution, we perform IgG to tetanus, diphtheria and Haemophilus influenza B for assessment of protein vaccine responses and IgG to pneumococcus for assessment of polysaccharide responses. Performance and interpretation of vaccine responses has been reviewed elsewhere [30]. If immunoglobulin levels are low (particularly IgG and IgA, or IgA alone) and/or poor dynamic responses to vaccines are present, referral to an immunologist must be made. The immunologist should then perform other detailed investigations such as more complex B cell phenotyping to detect reduced switched memory B cells and sequencing of the known CVID genes or genes that can mimic CVID states (e.g. X-linked agammaglobulinaemia; X-linked lymphoproliferative disease) may be appropriate in some patients. Monitoring of respiratory status in CVID Respiratory manifestations in CVID predominantly follow two pathophysiological processes- recurrent pulmonary infections causing bronchiectasis or immune mediated process causing interstitial lung disease. These processes can be identified on a high resolution chest CT which should be done at diagnosis. Identification of these pathologies can help in management and prognostication. Chest CT should be done subsequently if there is a step change in pulmonary symptoms or a continuing drop in lung function. In approximately 15% of patients, there can be an overlap of these two pathologies, which will need to be recognised early (figure 1). Pulmonary function tests should be performed on a 6-12 monthly basis after the diagnosis. Lung function is predominantly obstructive in children with bronchiectasis as a result of mucus plugging and air trapping. If there is a restrictive component, interstitial lung disease should be suspected and may need to be investigated further by performing a DLCO and a lung biopsy. When spirometry is within the normal range, abnormalities might be detectable by changes in mid-expiratory flows. There is limited data which describes rate of decline in lung function in patients with CVID. In their cohort of CVID, Chen at al described an annual decline of 65 ml of lung function as compared to 30 ml in normal healthy controls [31]. The decline in 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 [32]. Furthermore, the notion that immunoglobulin replacement, particularly at higher doses, can be used to reduce the progression of bronchiectasis and thus lung function decline needs confirmation.
Malignancy Immunoglobulin replacement The overall risk of malignancy in CVID is significantly increased to up to 5 fold, with the most common cancer being lymphoma. The incidence of stomach cancer may be increased as well, but recent data appear to show a reduced incidence over prior studies
Immunoglobulin infusions, whether intravenous (IVIG) or subcutaneous (SCIG), are the mainstay of therapy for patients with CVID, given the main issue is inadequate or dysfunctional
Please cite this article in press as: Pandit C, et al. Respiratory manifestations and management in children with Common Variable Immunodeficiency. Paediatr. Respir. Rev. (2016), http://dx.doi.org/10.1016/j.prrv.2015.12.003
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Figure 1. CT scan showing bronchiectasis at diagnosis (a) and recent chest scan showing bilateral nodular changes in addition to worsening of bronchiectasis (b).
antibody production with recurrent infections. The recommended starting dose is usually 0.4-0.6 g/kg per infusion. For the intravenous route, this dose is usually given monthly, whereas for the subcutaneous route the dose is divided into weekly or twice weekly infusions. Measurement of trough IgG levels prior to intravenous infusion is important for assessing adequate immunoglobulin replacement. This is done at our institution at least every 6 months if the patient is stable, or earlier if the child presents with breakthrough suppurative infections. The target trough level is the level required to prevent infections, which varies greatly between patients [33], although patients with bronchiectasis generally require more IVIG compared to those without, due to consumption of IgG from the sump of respiratory pathogens. Both IVIG and SCIG are safe and effective in preventing recurrent infections, antibiotic use, hospitalizations [34] and probably chronic lung disease. There is some evidence that IVIG, especially at high doses, may be protective against development of autoimmunity and aid in the control of lymphoid interstitial disease [35,36]. However, further controlled studies are required to ascertain this. Management of bronchiectasis Due to limited number of studies performed in children with CVID, treatment principles are extrapolated from large studies carried out in children with CF and non-CF bronchiectasis. Treatment of bronchiectasis in CVID, in addition to IVIG, includes antimicrobial management, muco-ciliary clearance therapies and use of anti-inflammatory medications [38,39].
malaise. Sputum cultures can guide the choice of antibiotic therapy which should target common encapsulated organisms. In the absence of formal evidence, the duration of antibiotic treatment has been suggested to be for 10-14 days to delay subsequent exacerbations [3]. Prophylactic antibiotics Due to the repeated cycle of infection resulting in structural lung damage, patients with CVID will develop bronchiectasis at some stage in their lives. It has been demonstrated that, the presence of bronchiectasis at diagnosis predicts poor outcome and early diagnosis with aggressive management of bronchiectasis predicts a good outcome [42]. Despite the lack of evidence, it has been suggested that prophylactic antibiotics should be used if there are more than three sinopulmonary infections despite adequate IVIG replacement [40,43]. Some clinicians commence antibiotics if there are severe infections or if there is a severe antibody deficiency. In a survey performed on practitioners managing children and adults with CVID, 90% of immunologists had their CVID patients on prophylactic antibiotics with nearly 90% reporting a perceived benefit for CVID patients [3]. The most commonly used prophylactic antibiotic was amoxicillin in both pediatric and adult patients. Cotrimoxazole [trimethoprim-sulfamethoxazole] is also used as a prophylactic antibiotic and is well tolerated with minimal side effects [39]. There is no good evidence that antibiotic rotation is helpful. Macrolide antibiotics
Antimicrobial treatment Along with IVIG replacement therapy, antimicrobial therapy constitutes an important arm in the management of children with CVID. The use of antibiotics can vary widely. Some physicians use antibiotics to treat only acute sinopulmonary exacerbations while some use them prophylactically. Aggressive management of pseudomonas in CF units has contributed to improved outcomes [19,20]. Although this has not been formally studied in patients with CVID, an approach similar to those with cystic fibrosis may translate into better outcomes. For patients who are chronically colonized with pseudomonas, nebulized colomycin and tobramycin may have a role in reducing frequency of exacerbation and improving lung function [40,41].
Macrolides, especially azithromycin, have been used in children with Cystic Fibrosis [CF] due to their anti-inflammatory and immunomodulatory properties in addition to antibiotic properties [43,44]. When administered on alternate days in CF patients, these patients were shown to have significantly fewer exacerbations and had a reduced antibiotic requirement and compared with nonazithromycin treated group [44]. There was no change in lung function at the end of the trial. Recently published trials involving adult non-CF bronchiectasis patients, treated azithromycin for 6 to 12 months, suggest a reduction in exacerbation frequency and improved lung function. Therefore, in patients with breakthrough infections and/or declining lung function despite IVIG therapy, macrolide antibiotics should be considered in those with CVID [46,47].
Acute sino-pulmonary exacerbation Muco-ciliary clearance An infective exacerbation is suggested by an increase in cough, sputum production, dyspnoea and haemoptysis which may or may not be associated with systemic symptoms such as fever, and
Children who develop bronchiectasis often have a chronic moist cough. Similar to CF patients, bronchopulmonary hygiene is an
Please cite this article in press as: Pandit C, et al. Respiratory manifestations and management in children with Common Variable Immunodeficiency. Paediatr. Respir. Rev. (2016), http://dx.doi.org/10.1016/j.prrv.2015.12.003
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important part of daily therapy. This includes regular chest physiotherapy especially during times of acute exacerbations and in the presence of a background moist cough [45]. Chest physiotherapy manoeuvres are akin to CF and include Positive Expiratory Pressure (PEP) mask in the school age group [48– 50]. PEP therapy, in combination with hypertonic saline, has been shown to be more effective for sputum clearance than standard treatment. Limited trials have been conducted specifically in CVID patients, but data extrapolated from non-CF bronchiectasis patients shows the importance of regular bronchopulmonary hygiene in reducing exacerbations and therefore reducing respiratory morbidity [50–52]. Granulocytic-lymphocytic interstitial lung disease The optimal management of patients with GLILD is unclear. Corticosteroids are used most commonly with a general improvement in symptoms, although most of these are anecdotal reports. Immunosuppressant agents such as azathioprine, rituximab, cyclosporine and methotrexate have been used as steroid sparing agents with variable effects and should be used in consultation with immunologists [37,53,54]. Prognosis Survival of patients with CVID has increased over the last two decades with better understanding of disease and clinical phenotypes. Data registries from the 1990s indicate that, mortality in the US and UK was reported to be 23% to 30% during a follow-up of 1-25 years [55,56]. Recent data from the European Society for Immunodeficiencies registry reported a 15% mortality (51/334) over a longer mean follow-up period of 22.5 years. Overall survival continues to be less than age matched controls [57] CONCLUSION Common variable immunodeficiency is a primary antibody deficiency causing recurrent sino-pulmonary infections in childhood. Recent longitudinal cohorts have improved our understanding of clinical presentation and management. Respiratory morbidity is the commonest presentation and a high degree of suspicion is needed to a prevent delay in diagnosis. IVIG constitutes the mainstay of treatment and other treatment options include appropriate prophylactic antibiotics, anti-inflammatory therapy and mucociliary clearance therapy will supplement immunoglobulin replacement therapy. Non-infective manifestations of pulmonary disease are less common but are associated with decreased survival. FUTURE DIRECTIONS FOR RESEARCH Identification of genetic mutations which can improve understanding of various pathophysiological processes and help in predicting clinical course Randomized controlled multicentre studies to explore the effectiveness of treatment strategies like prophylactic oral antibiotics and anti-inflammatory medications to prevent deterioration in lung function
Acknowledgement We would like to acknowledge the late Professor Peter van Asperen whose contribution to writing this manuscript was invaluable.
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Please cite this article in press as: Pandit C, et al. Respiratory manifestations and management in children with Common Variable Immunodeficiency. Paediatr. Respir. Rev. (2016), http://dx.doi.org/10.1016/j.prrv.2015.12.003
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Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Review
Respiratory manifestations and management in children with Common Variable Immunodeficiency Chetan Pandit 1,2,*, Peter Hsu 2,3, Peter van Asperen 1,2, Sam Mehr 2,3 1
Department of Respiratory Medicine, The Children’s Hospital at Westmead, Sydney Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney 3 Department of Allergy and Immunology, The Children’s Hospital at Westmead, Sydney 2
EDUCATIONAL AIMS
THE READER WILL COME TO UNDERSTAND:
The broad clinical phenotypes in children with common variable immunodeficiency (CVID) The importance of early diagnosis and management of respiratory morbidity in CVID The role of other treatment options such as prophylactic antibiotics, anti-inflammatory medications and muco-ciliary clearance in delaying respiratory progression in CVID
A R T I C L E I N F O
S U M M A R Y
Keywords: Common variable immunodeficiency Diagnosis Respiratory management
Common variable immunodeficiency is an antibody deficiency that usually presents in childhood with recurrent sino-pulmonary infections. Diagnostic delay is frequent and thus respiratory morbidity is common, ranging from recurrent suppurative bronchitis to bronchiectasis. Immunoglobulin replacement therapy is the mainstay of treatment, whilst prophylactic antibiotic therapy and muco-ciliary clearance are additional treatment options. This review examines the diagnosis and management of respiratory issues in children with CVID. Crown Copyright ß 2016 Published by Elsevier Ltd. All rights reserved.
INTRODUCTION Common variable immunodeficiency is a heterogeneous group of immunodeficiency disorders characterized by dysfunctional antibody production resulting in a spectrum of clinical disease most commonly associated with recurrent sino-pulmonary infections [1]. A small number of patients initially present with autoimmune or auto-inflammatory conditions, but eventually develop recurrent infections. It is the second most frequent primary immunodeficiency (PID) with an estimated prevalence from 1 in 10000 to 1 in 50000. It is characterized by a bimodal presentation of age, usually presenting in early childhood or in young adult years [1–3]. The European Society of Immune Deficiencies (ESID) revised their definition of CVID in 2014 (Table 1) [4]. Essentially, a diagnosis of CVID can be made in a person > 4 years of age with
clinical features of immune dysfunction (i.e at least one of recurrent infections, autoimmunity, granulomatous disease and/or unexplained polyclonal lymphoproliferation) and laboratory evidence of B-cell dysfunction (i.e. marked reduction in IgG and IgA levels 2 standard deviations below normal with/without reduced IgM levels and either poor dynamic antibody responses to vaccines and/or low switched memory B-cells). CVID is a diagnosis of exclusion, such that other causes of hypogammaglobulinaemia and profound T-cell deficiency need to be excluded before a diagnosis can be made. Although hypogammaglobulinemia and therefore sino-pulmonary infections are the defining feature of CVID, the complex and heterogenous pathogenesis of CVID results in many extra-pulmonary manifestations. In this review, we focus on the respiratory manifestations of CVID, and highlight the importance of early diagnosis and treatment. Pathogenesis of CVID
* Corresponding author. Paediatric Respiratory and Sleep Physician, Department of Respiratory Medicine, The Children’s Hospital at Westmead, Locked bag 4001, Westmead, Sydney, New South Wales, Australia 2145. Tel.: +61 2 9845 3397; fax: +61 2 9845 3396. E-mail address: [email protected] (C. Pandit).
CVID is not a monogenic immunodeficiency, but instead a collection of heterogeneous disorders linked by T-B-cell dysregulation resulting in defective antibody production.
http://dx.doi.org/10.1016/j.prrv.2015.12.003 1526-0542/Crown Copyright ß 2016 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Pandit C, et al. Respiratory manifestations and management in children with Common Variable Immunodeficiency. Paediatr. Respir. Rev. (2016), http://dx.doi.org/10.1016/j.prrv.2015.12.003
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2 Table 1 Revised ESID (2014) diagnostic criteria for CVID
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 decrease of IgG and marked decrease of IgA with or without low IgM levels (measured at least twice; <2 SD of the normal levels for their age); AND at least one of the following: Poor antibody response to vaccines (and/or absent isohemagglutinins); i.e. absence of protective levels despite vaccination where defined Low switched memory B cells (<70% of age-related normal value) AND secondary causes of hypogammaglobulinemia have been excluded AND diagnosis is established after the fourth year of life (but symptoms may be present before) AND no evidence of profound T-cell deficiency, defined as two out of the following (y = year of life): CD4 numbers/microliter: 2–6 y < 300, 6–12 y < 250, >12 y < 200 % Naive CD4: 2–6 y < 25%, 6–16 y < 20%, >16 y < 10% T-cell proliferation absent http://esid.org/Working-Parties/Registry/Diagnosis-criteria.
This has become increasingly more apparent with the advent of next generation sequencing, which has allowed immunologists to identify previously known mutations in the group of patients presenting with a CVID phenotype. For example, children with monogenic mutations that cause severe combined immune deficiency (SCID) can present atypically with a CVID phenotype, especially if the mutation is hypomorphic and some function of the affected protein is preserved [5]. Genetic defects known to cause familial hemophagocytic lymphohistiocytosis (HLH) can also lead to a clinical phenotype of ‘‘CVID’’, before the catastrophic presentation with hemophagocytic syndrome [6]. Next generation sequencing has also allowed the identification of new genes within the CVID group. Recent examples include CTLA-4 loss of function [7] and PI3K gain of function [8] mutations, along with other previously identified genes such as CD19, TACI and ICOS. However, < 5-10% of all CVID cases currently have a genetic explanation, and multiple centres are currently conducting trials to better delineate genetic mutations leading to a CVID phenotype [9–11]. SPECTRUM OF PULMONARY DISEASE Age of presentation Age of presentation can range from 3 years to 71 years of age with studies identifying 2 peaks, between 6 and 10 years of age and in young adulthood (between 26 and 40 years) [1,14–16]. In both the US and France national studies, nearly 15% of all the patients presented between 4 to 10 years of age [1,15]. A small number of patients (<5%), do not have recurrent infection but rather come to attention initially due to presence of inflammatory or autoimmune complications, but overtime develop recurrent suppurative infections [16]. The primary defect in CVID is usually insufficient production of IgG and IgA antibodies to pathogens. Consequently, patients suffer from frequent or persistent upper respiratory tract infections, especially in the pre-school age [12]. As recurrent infections are common in children, and patients with CVID present with typical symptoms of wet cough and ear infections, diagnostic delay is not infrequent. In one study the average diagnostic delay was 2.5 years for children and 5.5 years for adults [13]. Early diagnosis and optimal management are likely to result in improved clinical and quality-of-life outcomes for patients with CVID. Upper respiratory tract infection Recurrent or chronic otitis media, sinusitis and bronchitis, in isolation or in combination, are the most common presenting features in children and adults with CVID [1,14]. Ear and chest
infections are common in immunocompetent children, particularly in the first 2 years of life. Antibody defects, such as CVID, however must always be considered if a patient is presenting with recurrent or chronic bronchitis, sinusitis and otitis media with ottorrhoea [17]. A patient who presents with recurrent episodes of rhinorrhoea, wheeze, and cough who is well in between episodes is much more likely to be immune competent and have recurrent viral upper respiratory tract infections compared to a patient with recurrent or persistent antibiotic responsive wet cough and/or purulent otitis media. Culture of sputum or ear discharge in such circumstances is useful, since an antibody defect is more likely if encapsulated bacteria are isolated. Recurrent pneumonia Almost three quarters of patients with CVID would have had at least one episode of pneumonia requiring antibiotic therapy before diagnosis, with some children having had multiple episodes of pneumonia [15]. Pneumonia can be severe requiring hospitalization and can also be associated with complications including empyema, pneumatocoeles and lung abscess. Watts et al described 28 (87.5%) out of 32 patients who had an average of 3 or more episodes of pneumonia [18]. Different lobes of the lung are often involved but rarely the same lobe can be affected. This can then progress to bronchiectasis which may require lobectomy in later years. Encapsulated bacteria are the predominant organisms isolated in children with CVID. These include streptococcus pneumoniae and haemophilus influenzae. Staphylococcus aureus has also been frequently isolated [19,20]. Any patient presenting with two or more episodes of pneumonia needs to be investigated for an antibody defect. Asthma Patients with CVID may have recurrent wheezing requiring treatment with bronchodilators for relief. The incidence of asthma has been reported to be between 9% and 15% [21,22]. This may be attributed to intrinsic asthma which is IgE independent and may also be secondary to increased inflammation, producing reversible obstruction and clinical wheezing. Asthma symptoms are likely to delay diagnosis by masking the underlying symptoms of immunodeficiency and therefore any patient presenting with a chronic or recurrent bronchitis with wheeze should be assumed to have an antibody defect until proven otherwise. Such patients must have a full blood count and antibody levels (IgG, IgA and IgM) measured as a minimum, prior to any escalation of asthma medications.
Please cite this article in press as: Pandit C, et al. Respiratory manifestations and management in children with Common Variable Immunodeficiency. Paediatr. Respir. Rev. (2016), http://dx.doi.org/10.1016/j.prrv.2015.12.003
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Bronchiectasis Bronchiectasis is a common complication in children with CVID. The prevalence of bronchiectasis in the large cohort studies ranges considerably from 27% to 90% [1,15]. Bronchiectasis is often progressive and is usually the cause of morbidity and mortality, especially in adulthood. The mechanism of bronchiectasis is due to impaired immune clearance with recurrent, persistent or severe infection. This leads to recurrent episodes of airway inflammation, regeneration, repair and finally structural damage [12,23]. Quinti et al reported the development of bronchiectasis in spite of IVIG therapy and postulated bronchiectasis to be due to ongoing inflammation and mucous plugging [16]. Additional risk factors for bronchiectasis in those with CVID include delay in diagnosis and thus the total duration of damage caused by chronic sinopulmonary infections [14], low memory B-cell numbers, and certain genetic polymorphisms. [24,33]. We would recommend in any patient with CVID presenting with recurrent suppurative chest infections, to have a baseline HRCT chest scan. We would not suggest regular screening with HRCT, as others have suggested, due to the increased radiation exposure with limited clinical benefit in a group that is already at higher risk of lymphoreticular cancers [25]. We would however suggest repeating HRCT if clinically indicated, such that the patient’s respiratory status was worsening despite therapy. Interstitial lung disease Interstitial lung disease in CVID is a potentially devastating outcome, and reported in up to 25% of case series [27]. It is more commonly reported in adolescents and in adulthood. Such patients often present with reduced lung function. Non infectious pulmonary complications are seen in some patients with CVID. Radiographic abnormalities and surgical biopsy have identified patients with lymphoid interstitial pneumonia, granulomatous lung disease, and lymphoid hyperplasia, which have now been grouped under granulocyte-lymphocytic interstitial lung disease (GLILD) [26,27]. These patients are reported to have lower DLCOs and a restrictive pattern on spirometry. They have a more progressive course and are at high risk for early mortality [27]. Recognition of these complications is important as therapeutic options like azathioprine and rituximab has shown promising early results [36,37]. Extra-pulmonary manifestations of CVID Whilst this is not intended to be a comprehensive review of the extra-pulmonary features of CVID, it is important to recognize these features, as they aid in the eventual diagnosis of CVID. Autoimmunity is a common presentation of CVID, and may precede the development of recurrent infection [28]. Autoimmune thrombocytopenia and haemolytic anaemia are the most common presentations. Other more common autoimmune presentations include but are not limited to rheumatoid arthritis, juvenile idiopathic arthritis and inflammatory bowel-like disease. Another consequence of immune dysregulation is lymphoid hyperplasia or lymphoproliferation, which can be granulomatous or non-granulomatous [29]. In addition to peripheral lymph nodes, this can also occur in the lungs, gut, spleen, and parotid glands.
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[1,38]. The reasons for the increased frequency of gastric cancers in CVID remains unclear, although in some centers routine screening for H.pylori infection by urea breath testing and monitoring for pernicious anaemia every 12 months (serum B12 and iron levels) is performed in those with CVID, as they are modifiable risk factors. Baseline immune investigations If an antibody defect, such as CVID is suspected, appropriate initial investigations include total immunoglobulin levels (IgG, A, M), a full blood count with a T-B-NK cell subsets and IgG vaccine responses to both protein and polysaccharide conjugated vaccines. The patient’s vaccination status is required to be able to interpret the vaccine responses. At our institution, we perform IgG to tetanus, diphtheria and Haemophilus influenza B for assessment of protein vaccine responses and IgG to pneumococcus for assessment of polysaccharide responses. Performance and interpretation of vaccine responses has been reviewed elsewhere [30]. If immunoglobulin levels are low (particularly IgG and IgA, or IgA alone) and/or poor dynamic responses to vaccines are present, referral to an immunologist must be made. The immunologist should then perform other detailed investigations such as more complex B cell phenotyping to detect reduced switched memory B cells and sequencing of the known CVID genes or genes that can mimic CVID states (e.g. X-linked agammaglobulinaemia; X-linked lymphoproliferative disease) may be appropriate in some patients. Monitoring of respiratory status in CVID Respiratory manifestations in CVID predominantly follow two pathophysiological processes- recurrent pulmonary infections causing bronchiectasis or immune mediated process causing interstitial lung disease. These processes can be identified on a high resolution chest CT which should be done at diagnosis. Identification of these pathologies can help in management and prognostication. Chest CT should be done subsequently if there is a step change in pulmonary symptoms or a continuing drop in lung function. In approximately 15% of patients, there can be an overlap of these two pathologies, which will need to be recognised early (figure 1). Pulmonary function tests should be performed on a 6-12 monthly basis after the diagnosis. Lung function is predominantly obstructive in children with bronchiectasis as a result of mucus plugging and air trapping. If there is a restrictive component, interstitial lung disease should be suspected and may need to be investigated further by performing a DLCO and a lung biopsy. When spirometry is within the normal range, abnormalities might be detectable by changes in mid-expiratory flows. There is limited data which describes rate of decline in lung function in patients with CVID. In their cohort of CVID, Chen at al described an annual decline of 65 ml of lung function as compared to 30 ml in normal healthy controls [31]. The decline in 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 [32]. Furthermore, the notion that immunoglobulin replacement, particularly at higher doses, can be used to reduce the progression of bronchiectasis and thus lung function decline needs confirmation.
Malignancy Immunoglobulin replacement The overall risk of malignancy in CVID is significantly increased to up to 5 fold, with the most common cancer being lymphoma. The incidence of stomach cancer may be increased as well, but recent data appear to show a reduced incidence over prior studies
Immunoglobulin infusions, whether intravenous (IVIG) or subcutaneous (SCIG), are the mainstay of therapy for patients with CVID, given the main issue is inadequate or dysfunctional
Please cite this article in press as: Pandit C, et al. Respiratory manifestations and management in children with Common Variable Immunodeficiency. Paediatr. Respir. Rev. (2016), http://dx.doi.org/10.1016/j.prrv.2015.12.003
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Figure 1. CT scan showing bronchiectasis at diagnosis (a) and recent chest scan showing bilateral nodular changes in addition to worsening of bronchiectasis (b).
antibody production with recurrent infections. The recommended starting dose is usually 0.4-0.6 g/kg per infusion. For the intravenous route, this dose is usually given monthly, whereas for the subcutaneous route the dose is divided into weekly or twice weekly infusions. Measurement of trough IgG levels prior to intravenous infusion is important for assessing adequate immunoglobulin replacement. This is done at our institution at least every 6 months if the patient is stable, or earlier if the child presents with breakthrough suppurative infections. The target trough level is the level required to prevent infections, which varies greatly between patients [33], although patients with bronchiectasis generally require more IVIG compared to those without, due to consumption of IgG from the sump of respiratory pathogens. Both IVIG and SCIG are safe and effective in preventing recurrent infections, antibiotic use, hospitalizations [34] and probably chronic lung disease. There is some evidence that IVIG, especially at high doses, may be protective against development of autoimmunity and aid in the control of lymphoid interstitial disease [35,36]. However, further controlled studies are required to ascertain this. Management of bronchiectasis Due to limited number of studies performed in children with CVID, treatment principles are extrapolated from large studies carried out in children with CF and non-CF bronchiectasis. Treatment of bronchiectasis in CVID, in addition to IVIG, includes antimicrobial management, muco-ciliary clearance therapies and use of anti-inflammatory medications [38,39].
malaise. Sputum cultures can guide the choice of antibiotic therapy which should target common encapsulated organisms. In the absence of formal evidence, the duration of antibiotic treatment has been suggested to be for 10-14 days to delay subsequent exacerbations [3]. Prophylactic antibiotics Due to the repeated cycle of infection resulting in structural lung damage, patients with CVID will develop bronchiectasis at some stage in their lives. It has been demonstrated that, the presence of bronchiectasis at diagnosis predicts poor outcome and early diagnosis with aggressive management of bronchiectasis predicts a good outcome [42]. Despite the lack of evidence, it has been suggested that prophylactic antibiotics should be used if there are more than three sinopulmonary infections despite adequate IVIG replacement [40,43]. Some clinicians commence antibiotics if there are severe infections or if there is a severe antibody deficiency. In a survey performed on practitioners managing children and adults with CVID, 90% of immunologists had their CVID patients on prophylactic antibiotics with nearly 90% reporting a perceived benefit for CVID patients [3]. The most commonly used prophylactic antibiotic was amoxicillin in both pediatric and adult patients. Cotrimoxazole [trimethoprim-sulfamethoxazole] is also used as a prophylactic antibiotic and is well tolerated with minimal side effects [39]. There is no good evidence that antibiotic rotation is helpful. Macrolide antibiotics
Antimicrobial treatment Along with IVIG replacement therapy, antimicrobial therapy constitutes an important arm in the management of children with CVID. The use of antibiotics can vary widely. Some physicians use antibiotics to treat only acute sinopulmonary exacerbations while some use them prophylactically. Aggressive management of pseudomonas in CF units has contributed to improved outcomes [19,20]. Although this has not been formally studied in patients with CVID, an approach similar to those with cystic fibrosis may translate into better outcomes. For patients who are chronically colonized with pseudomonas, nebulized colomycin and tobramycin may have a role in reducing frequency of exacerbation and improving lung function [40,41].
Macrolides, especially azithromycin, have been used in children with Cystic Fibrosis [CF] due to their anti-inflammatory and immunomodulatory properties in addition to antibiotic properties [43,44]. When administered on alternate days in CF patients, these patients were shown to have significantly fewer exacerbations and had a reduced antibiotic requirement and compared with nonazithromycin treated group [44]. There was no change in lung function at the end of the trial. Recently published trials involving adult non-CF bronchiectasis patients, treated azithromycin for 6 to 12 months, suggest a reduction in exacerbation frequency and improved lung function. Therefore, in patients with breakthrough infections and/or declining lung function despite IVIG therapy, macrolide antibiotics should be considered in those with CVID [46,47].
Acute sino-pulmonary exacerbation Muco-ciliary clearance An infective exacerbation is suggested by an increase in cough, sputum production, dyspnoea and haemoptysis which may or may not be associated with systemic symptoms such as fever, and
Children who develop bronchiectasis often have a chronic moist cough. Similar to CF patients, bronchopulmonary hygiene is an
Please cite this article in press as: Pandit C, et al. Respiratory manifestations and management in children with Common Variable Immunodeficiency. Paediatr. Respir. Rev. (2016), http://dx.doi.org/10.1016/j.prrv.2015.12.003
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important part of daily therapy. This includes regular chest physiotherapy especially during times of acute exacerbations and in the presence of a background moist cough [45]. Chest physiotherapy manoeuvres are akin to CF and include Positive Expiratory Pressure (PEP) mask in the school age group [48– 50]. PEP therapy, in combination with hypertonic saline, has been shown to be more effective for sputum clearance than standard treatment. Limited trials have been conducted specifically in CVID patients, but data extrapolated from non-CF bronchiectasis patients shows the importance of regular bronchopulmonary hygiene in reducing exacerbations and therefore reducing respiratory morbidity [50–52]. Granulocytic-lymphocytic interstitial lung disease The optimal management of patients with GLILD is unclear. Corticosteroids are used most commonly with a general improvement in symptoms, although most of these are anecdotal reports. Immunosuppressant agents such as azathioprine, rituximab, cyclosporine and methotrexate have been used as steroid sparing agents with variable effects and should be used in consultation with immunologists [37,53,54]. Prognosis Survival of patients with CVID has increased over the last two decades with better understanding of disease and clinical phenotypes. Data registries from the 1990s indicate that, mortality in the US and UK was reported to be 23% to 30% during a follow-up of 1-25 years [55,56]. Recent data from the European Society for Immunodeficiencies registry reported a 15% mortality (51/334) over a longer mean follow-up period of 22.5 years. Overall survival continues to be less than age matched controls [57] CONCLUSION Common variable immunodeficiency is a primary antibody deficiency causing recurrent sino-pulmonary infections in childhood. Recent longitudinal cohorts have improved our understanding of clinical presentation and management. Respiratory morbidity is the commonest presentation and a high degree of suspicion is needed to a prevent delay in diagnosis. IVIG constitutes the mainstay of treatment and other treatment options include appropriate prophylactic antibiotics, anti-inflammatory therapy and mucociliary clearance therapy will supplement immunoglobulin replacement therapy. Non-infective manifestations of pulmonary disease are less common but are associated with decreased survival. FUTURE DIRECTIONS FOR RESEARCH Identification of genetic mutations which can improve understanding of various pathophysiological processes and help in predicting clinical course Randomized controlled multicentre studies to explore the effectiveness of treatment strategies like prophylactic oral antibiotics and anti-inflammatory medications to prevent deterioration in lung function
Acknowledgement We would like to acknowledge the late Professor Peter van Asperen whose contribution to writing this manuscript was invaluable.
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Please cite this article in press as: Pandit C, et al. Respiratory manifestations and management in children with Common Variable Immunodeficiency. Paediatr. Respir. Rev. (2016), http://dx.doi.org/10.1016/j.prrv.2015.12.003