A Rose Is A Rose Is A Rose But CVID Is Not CVID - Common Variable Immune Deficiency (CVID) What Do We Know in 2011

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A Rose is a Rose is a Rose, but CVID is Not CVID: Common Variable Immune Deficiency (CVID), What do we Know in 2011?
Patrick F. K. Yong,* James E. D. Thaventhiran, and Bodo Grimbacher,
Contents
Introduction Definition and Diagnostic Criteria Epidemiology Pathophysiology/Immunopathology Etiology/Genetics 5.1. CD19-complex mutations (CD19, CD21, CD81) 5.2. CD20 mutation 5.3. TACI mutations 5.4. BAFF-R mutation 5.5. ICOS mutations 5.6. Msh5 mutations and other DNA repair genes 5.7. Genetic linkage studies 5.8. Genome-wide association studies 6. CVID Classification Schemes 6.1. B cell classification and phenotyping
1. 2. 3. 4. 5.
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* Kings College Hospital, Denmark Hill, London, United Kingdom

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Royal Free Hospital & University College London, Pond Street, London, United Kingdom Centre for Chronic Immunodeficiency, University Hospital Freiburg, Hugstetterstrae, Freiburg, Germany The sentence Rose is a rose is a rose is a rose was written by Gertrude Stein as part of the 1913 poem Sacred Emily. In the 1978 film, The Magic of Lassie, Robert & Richard Sherman penned the song, A Rose Is Not A Rose.
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Advances in Immunology, Volume 111 ISSN 0065-2776, DOI: 10.1016/B978-0-12-385991-4.00002-7
2011 Elsevier Inc. All rights reserved.
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Patrick F. K. Yong et al.
6.2. T cell phenotyping 6.3. Clinical categorization 6.4. Late onset combined immune deficiency (LOCID) 7. Clinical Presentation and Complications 7.1. Infections 7.2. Chronic respiratory infections and bronchiectasis 7.3. Gastrointestinal complications 7.4. Autoimmunity 7.5. Granulomatous/lymphoproliferative disease/ hyperplasia 7.6. Malignancy 8. Management 8.1. IVIG and mortality/infections 8.2. Antibiotic use 8.3. Organ and stem cell transplantation 8.4. Monitoring 9. Prognosis and Survival 10. Summary References
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Abstract
Common variable immune deficiency (CVID) is the commonest symptomatic primary immunodeficiency and represents a heterogenous collection of disorders resulting mostly in antibody deficiency and recurrent infections. However, autoimmunity, granulomatous inflammation and malignancy frequently occur as part of the syndrome. The etiology of the condition has been poorly understood although in recent years, significant progress has been made in elucidating genetic mechanisms that can result in a CVID phenotype. In parallel to this, advances in treatment of the condition have also resulted in improved survival and quality of life for patients. There still remains significant work to be done in improving our understanding of the disease. In addition, recognition of the condition remains poor with significant diagnostic delays and avoidable morbidity. In this article, we review CVID with a particular focus on the areas of improving diagnosis and classification, recent developments in understanding the underlying etiology and genetics; and current treatment and monitoring recommendations for patients.
1. INTRODUCTION
Common Variable Immune Deficiency (or Common Variable Immunodeficiency, abbreviated CVID or CVI) is a heterogeneous collection of conditions, all characterized by a primary antibody deficiency
A Rose is a Rose is a Rose, but CVID is Not CVID
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(hypogammaglobulinemia) of at least two immunoglobulin isotypes. Due to this, some investigators also use the term CVIDs. It is the commonest primary immunodeficiency of clinical significance (Gathmann et al., 2009) and is thought to have arisen out of a mostly uncharacterized genetic basis, although many advances have been made in recent years since CVID was first described in 1953 by Janeway et al. and the term coined in 1973 by Cooper et al. The main immunological defect is failure of B cell production of immunoglobulin, although abnormalities have been described in all other compartments of the immune system as well, with some association with clinical phenotype. Clinically, individuals with CVID are prone to recurrent infections, most frequently of the respiratory tract, but other infections including those of the gastrointestinal system can also occur. CVID also manifests aspects of immune dysregulation with noninfectious complications including autoimmunity (most typically autoimmune cytopenias), noninfectious gastrointestinal disease, granulomatous inflammation, lymphoid proliferation, and an increased risk of malignancy. Due to the heterogeneity and rarity of the disease, progress in understanding had been relatively slow, although in the last decade, many advances (in parallel with the growth and understanding in all aspects of immunology) have been made in improving knowledge of the basic mechanisms as well as the clinical care of patients with CVID. Some of the main areas where this has occurred and which will be discussed further in this article include: 1. Geneticsin less than the last decade alone seven disease causing or contributing genes have been identified that give rise to a CVID phenotype. Attention has now been given to addressing the likelihood that many patients with CVID have a polygenic etiology (similar to other immune related diseases like type 1 diabetes and rheumatoid arthritis). 2. Phenotyping/categorization of CVIDboth immunological and clinical criteria have been developed to categorize patients (further acknowledging the heterogeneity of the disease). This sets the ground for subgrouping patients to both direct future research efforts focusing on the likely disease mechanisms in different groups as well as selecting patients for therapy based on likely prognosis. 3. Patient registriesthe development and greater use of large disease registries has allowed pooling of a large number of patients, combining experience greater than a single clinician can achieve. This has given a better overall and more accurate picture of both the more common and rare immunological and clinical features in CVID. The data from this has now begun to generate useful clinical information, with potential implications for patient care.
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4. Treatmentalthough immunoglobulin replacement remains the mainstay of treatment for patients with CVID, advances in the way it is utilized has resulted in improvements both in patient survival and quality of life. CVID is defined as a diagnosis of exclusion: The current ESID/PAGID diagnostic criteria (Conley et al., 1999; www.esid.org) state that CVID is probable in a male or female patient who has a marked decrease of IgG (at least 2 SD below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA, and fulfills all of the following criteria: 1. Onset of immunodeficiency at greater than 2 years of age 2. Absent isohemagglutinins and/or poor response to vaccines 3. Defined causes of hypogammaglobulinemia have been excluded according to a list of differential diagnosis of hypogammaglobulinemia (www.esid.org/clinical-diagnostic-criteria-for-pid-73-0) Clinical spectrum of disease: Most patients with CVID are recognized to have immunodeficiency in the second, third, or fourth decade of life, after they have had several pneumonias; however, children and older adults may be affected. Viral, fungal, and parasitic infections as well as bacterial infections may be problematic. The serum concentration of IgM is normal in about half of the patients. Abnormalities in T cell numbers or function are common. The majority of patients have normal numbers of B cells; however, some have low or absent B cells. Approximately 50% of patients have autoimmune manifestations. There is an increased risk of malignancy. To illustrate the clinical variability in CVID, we here describe two patients who have correctly been classified as CVID; however, their clinical course is so different that the diagnostic label CVID was not helpful, neither for the patients themselves, nor for patient management. Patient 1, aged 34, was investigated for hypogammaglobulinaemia when his immunoglobulins were checked during an episode of gastroenteritis. At presentation IgG, IgA, and IgM were all undetectable, his lymphocyte subsets were normal, secondary causes of hypogammaglobulinaemia were excluded and he failed test vaccinations with Pneumovax and Menitorix. Prior to presentation he reported no history of increased susceptibility to infections. He declined treatment with IVIG at the time, but remained monitored. Aged 57, that is 23 years later, he was persuaded to start immunoglobulin replacement following an episode of foot cellulitis. He was initially treated with intravenous immunoglobulin (IVIG) at 400 mg/kg, receiving 20 g every 8 weeks. His trough level after 1 year stabilized at 2.9 g/l. Aged 61, he was persuaded to increase his IVIG treatment to 20 g every 4 weeks because mild cylindrical bronchiectasis had been noted on a high resolution CT scan of his chest.
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Following this, his trough level did not change. Throughout his 30 year history of follow up, at no time has he reported an increased frequency of pulmonary infections. Since being on IVIG replacement, he has had the impression that his sinusitis is better controlled and that his coryzal symptoms last for a shorter duration following viral upper respiratory tract infections. Patient 2 was diagnosed aged 18, following a 2-year history of recurrent bacterial chest infections. Over 3 years she had required hospital admission and in-patient treatment three times, on one occasion warranting intensive care treatment due to a bacterial pneumonia. As with patient 1, IgA, IgG, and IgM were undetectable, lymphocyte subsets were normal, secondary causes of hypogammaglobulinaemia were excluded but vaccine responses were not assessed. She was initially treated at 400 mg/kg, receiving 15 g every 3 weeks. Her trough level at 1 year was measured at 4.8 g/l, and the dose was still being increased. The patient continued to suffer from recurrent pulmonary infective episodes and was diagnosed at presentation with bronchiectasis. Prophylactic antibiotics (azithromycin) were added into her treatment when she was aged 24. Aged 26, whilst receiving IVIG at a dose of 20 g every 3 weeks, she suffered from severe pneumonia, necessitating ventilation in an intensive treatment unit. At the age of 29 her bronchiectasis had progressed to the extent that she had to undergo a right lower lobectomy. Currently she is maintained on IVIG at 30 g every 2 weeks and her most recent trough level was 11.0 g/l. She currently has colomycin and cotrimoxazole as antibiotic prophylaxis and she is being considered for home oxygen therapy due to her declining respiratory function. Throughout this time she has had multiple infective episodes each year, with on average four in-patient admission episodes. These cases highlight the variability within CVID and the problems with the use of the serum IgG levels as a surrogate marker for health. Patient 1 received no treatment for 23 years with an undetectable IgG. During that time he suffered no deterioration in lung function, and suffered no serious bacterial infections. Patient 2 on the other hand, had developed bronchiectasis by the age of 23, and required numerous inpatient admissions with episodes of life-threatening bacterial sepsis both before and after replacement treatment had been commenced. These patients show such differences in presentation, response to treatment, clinical course and in all probability mortality, that only the observed panhypogammaglobulinaemia link them to the condition we call CVID. It is easy to understand that clinical studies and research projects conducted on such a loosely and ill-defined cohort of patients will yield results greatly dependent on the composition of the cohort studied. Therefore, the overhaul of the diagnostic criteria is timely and a current focus of the ESID clinical working party headed by K. Warnatz from Freiburg, Germany.
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Both patients share the pathological end-point of hypogammaglobulinaemia but profoundly differ in their need for and response to replacement therapy. Hence we propose that any new classification of primary (inborn) hypogammaglobulinaemia categorizes patients into two different groups, one which links to patients with possible shared etiologies and another which links patients to possible shared requirements for treatment, facilitating meaningful clinical outcome trials. The latter may be structured as suggested in Table 2.2 (the 10-point CVID exclusion criteria still apply, Table 2.1A): In addition to this classification of antibody deficiencies, the severity of each patient may be assessed with a point score involving features such as numbers of past pneumonias, presence of bronchiectasis or other parenchymal lung pathology, presence of granulomata, splenomegaly, or
TABLE 2.1 (A) A practical list of alternative diagnoses to exclude prior to making a diagnosis of CVID; (B) Drugs known to induce hypogammaglobulinemia if given repeatedly or over a long period of time
(A) 1. XLA (relatively frequent in young male patients with hypogamma, only males to be considered) 2. XLP (relatively frequent in young male patients with hypogamma, only males to be considered) 3. X-HIGM (relatively frequent in young male patients with hypogamma, only males to be considered) 4. Goods syndrome (rare, but easy to exclude with CT scan) 5. Drugs (see C) 6. Bone-marrow failure (frequent differential in adults, difcult but important to exclude) 7. Lymphoma/leukemia (frequent differential in adults, difcult but important to exclude) 8. Protein loss via the kidney (rare, but easy to exclude) 9. Protein loss via the gastrointestinal tract (rare, but relatively easy screening with alpha-1-antitrypisin in stool) 10. LOCID as dened by CD4 count under 200 or by opportunistic infections (important and easy to rule out) (B) 1. Rituximab 2. Cyclophosphamide 3. Anti-epileptic drugs such as phenytoin and carbamazepine 4. Hydroxychloroquine 5. Gold
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TABLE 2.2 Proposed classication of primary hypogammaglobulinaemia for clinical outcome trials
1. Selective IgM deciency (rare, but exists as clinical entity) 2. Selective IgA deciency (very frequent) Type (a) asymptomatic Type (b) with recurrent infections Type (c) associated with other clinical disorders such as autoimmunity or coeliac disease 3. Selective IgG deciency (including IgG subclass deciencies) Type (a) asymptomatic Type (b) with recurrent infections Type (c) without recurrent infections but with other associated pathology 4. Specic IgG antibody deciency (SPAD) Type (a) failure to respond to vaccination but asymptomatic Type (b) SPAD with recurrent infections Type (c) SPAD without recurrent infections but with other pathology 5. Hypogammaglobulinemia of IgG and IgA with ELEVATED IgM (also called Hyper-IgM syndrome) Type (a) asymptomatic Type (b) with recurrent infections Type (c) without infections but with other clinical symptoms such as autoimmunity or granuloma formation 6. Hypogammaglobulinemia of IgG and IgA and variably IgM (also called CVID) Type (a) asymptomatic Type (b) with recurrent infections Type (c) without infections but with other clinical symptoms such as autoimmunity or granuloma formation 7. Other forms of hypogammaglobulinemia Type (a) asymptomatic Type (b) with recurrent infections Type (c) without infections but with other associated pathology
lymphoproliferation, coexistence of autoimmune conditions, malignancies, etc. (Table 2.3). Furthermore, recent evidence has indicated that patients with CVID differ in their treatment requirements and the variability of individual patient needs overrides standard measures such as trough level (Lucas et al., 2010). Previous guidelines have been based around the adjustment of the dose of IVIG to maintain the serum IgG level above an arbitrarily decided trough level prior to each dose. The newer recommendations
TABLE 2.3 Points
Suggested CVID severity score: The 15 unlucky complications of CVID 0 1 2 3
1. Chronic sinusitis 2. Past meningitis or encephalitis 3. Past pneumonia 4. Bronchiectasis 5. Other parenchymal lung pathology such as brosis, LIP, BOOP, etc. 6. Lung surgery (lobectomy or pneumonectomy) 7. Splenomegly 8. Splenectomy 9. Lymphadenopathy (largest node) 10. CVID enteropathy 11. Autoimmune condition 12. Other rheumatological complaints such as arthralgia 13. Granulomata 14. Lymphoma 15. Cancer (solid tumors) such as bowel, skin or stomach
Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent
Present One bout One bout One lobe Suspected
Two bouts Two bouts Two lobes
> Two bouts > Two bouts > Two lobes Conrmed Performed > 20 cm Performed > 3 cm Severe Conrmed
1114.9 cm < 2 cm Intermittent Suspected Suspected Skin only
1520 cm 23 cm Chronic but mild
Conrmed Lung, liver or spleen CNS (incl. eye) Present Present
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suggest that, rather than concentrating on these absolute trough levels, doctors should adjust the dose of IVIG in each patient individually to render them infection-free. However, data has already been presented that lung disease can progress in patients despite optimal immunoglobulin therapy (Kainulainen et al., 1999; Quinti et al., 2007). Accurate classification of any disease is necessary for the optimum management of a condition. Though both Brutons agammaglobulinaemia and CVID require treatment with IVIG, our differentiation between them facilitates clinicians giving more accurate advice regarding inherited susceptibility and enables accurate monitoring for the differences in complications such as enteroviral encephalitis in Brutons agammaglobulinaemia, or immune thrombocytopenia in CVID. Furthermore, in research, classification is necessary to identify both those patients sharing a common etiology and those patients sharing a common response to treatment to enable improvement in both these factors. The above two patients highlight for CVID that classification for these two aims may not be concordant. Recent genetic studies on familial cases of CVID (see below) have identified mutations in very different genes and pathways, suggesting that a differing pathophysiology can all lead to the common endpoint of hypogammaglobulinemia (Yong et al., 2008a).
2. DEFINITION AND DIAGNOSTIC CRITERIA

Diagnostic criteria for CVID were originally defined by the European Society for Immunodeficiencies (ESID) and the Pan-American Group for Immunodeficiency (PAGID) in 1999 (Conley et al., 1999). These divided patients with hypogammaglobulinaemia into probable CVID with a reduction in serum IgG and IgA or IgM below 2 SD for age or possible CVID with a reduction in one of IgG, IgA, or IgM below 2 SD for age. In addition, to fulfill criteria, the onset of immunodeficiency had to be greater than 2 years of age, there should be a failure to respond to specific antigens (either isohemagglutins or vaccines) and defined causes of hypogammaglobulinaemia needed to be excluded (see www.esid.org/clinicaldiagnostic-criteria-for-pid-73-0). Limitations have been noted with these diagnostic criteria, which are subject to relatively loose boundaries (Chapel and Cunningham-Rundles, 2009; Cunningham-Rundles, 2010). Although the criteria have not been formally revised, it has been suggested that the minimum age of diagnosis be raised from 2 to 4 years to more adequately exclude children with other conditions, particularly transient hypogammaglobulinaemia of infancy (Chapel and Cunningham-Rundles, 2009; Cunningham-Rundles, 2010). It has also been noted that the criteria for immunoglobulin levels allow for variation between different laboratories and also that the use of 2 SD
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allows for 2.5% of normal individuals to fall below the reference range (Cunningham-Rundles, 2010). Several alternative cut-off levels to define CVID have been proposed. H. Chapel suggested 4.5 g/l (Chapel and Cunningham-Rundles, 2009) on the basis that most patients (94.2%) in a large European study had lower than this level at diagnosis (Chapel et al., 2008) comparable to a large American cohort where 85% of patients had similar values (Cunningham-Rundles and Bodian, 1999). Patients with levels higher than this could be classified as possible CVID. Cunningham-Rundles suggested a tiered system for evaluation instead (Cunningham-Rundles, 2010). Hypogammaglobulinaemia was divided into several categories depending on the amount of IgG (< 1.5, 1.52.5, 2.5 4.5, and 4.56.0 g/l) with varying degrees of further evaluation required for each category. It was suggested that following verification of immunoglobulin levels, patients with IgG levels < 1.5 g/l would not require further antibody testing to specific pathogens. For the remaining categories, further evaluation for vaccine responses should be considered or undertaken. Those with IgG levels between 4.5 and 6.0 g/l and those with minimally reduced IgA levels especially should be more extensively evaluated as antibody production is more likely to be preserved at these levels. Patients with modestly reduced immunoglobulin levels and/or partial antibody production should be reassessed at regular intervals as there may be further decline and they may meet the criteria for immunoglobulin replacement at a later stage (Carvalho Neves et al., 2000; Gutierrez and Kirkpatrick, 1997). A further criterion in the definition of CVID to be noted is the need for demonstration of specific IgG responses. Although not specifically stated in the original criteria how this is to be assessed, it has been proposed that there should be a demonstrated lack of response (as defined by failure to attain laboratory protective levels or a four-fold increase from baseline) to two protein vaccines (for example tetanus or diphtheria toxoids and haemophilus conjugate; Chapel and Cunningham-Rundles, 2009). Vaccination responses to pneumococcal polysaccharide are more difficult to interpret due to the variability of responses in healthy individuals and also the fact that a proportion of healthy individuals do not make responses to several serotypes (Hare et al., 2009; Shelly et al., 1997). It should also be noted that there is a suggestion that multiple doses of pneumococcal polysaccharide vaccination might result in immune hyporesponsiveness although this is not yet fully worked out (OBrien et al., 2007). These various findings serve to underline the fact that the immunization issue in CVID is not trivial and difficult to assess as well as to agree and set universal standards for diagnosis. Other known causes of hypogammaglobulinemia such as protein loss via the bowels or kidney (for a complete list see www.esid.org/clinicaldiagnostic-criteria-for-pid-73-0) need to be excluded. In general clinical practice, it is not practically possible to exclude all the conditions listed;
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consequently, we suggest a 10-point list (Table 2.1A) of conditions that could be realistically excluded prior to a diagnosis of CVID. Most importantly, CVID needs to be separated from other primary immune deficiencies with problems in antibody production: 1. Agammaglobulinemias such as X-linked agammaglobulinemia (XLA, due to mutations in Btk, MIM#300755) or autosomal recessive agammaglobulinemias (e.g., due to mutation in the immunoglobulin m heavy chain) need to be excluded. All forms of agammaglobulinemias are characterized by the complete lack of B cells in the periphery, which leads to a profound lack of all immunoglobulin isotypes. Some hypomorphic mutations in the B cell tyrosine kinase Btk, however, will allow some residual B cell receptor signaling, allowing some B cells to survive, and hence allow some residual immunoglobulin production. Therefore XLA patients may be identified in cohorts of CVID patients (Kanegane et al., 2000; Sigmon et al., 2008). 2. Class switch recombination (CSR) defects, such as observed in patients with the hyper-IgM syndromes, will also lead to a decrease in IgG and IgA serum levels (Kracker et al., 2010). Between CSR defects and CVID a considerable overlap exists, as for example, patients with mutations in ICOS have been historically classified as CVID, but the lack of ICOS on patients T cells impairs B cell class switch and patients, when ill, may produce substantial amounts of IgM (Warnatz et al., 2006). Hence ICOS deficiency may also be classified as a CSR defect. It should also be noted that only 62.5% of HIGM patients actually have elevated IgM levels (C. Hennig, Hannover, personnal communication). 3. Patients with X-linked lymphoproliferative syndromes may also display hypogammaglobulinemia and present with a phenotype reminiscent of CVID, hence mutations in SH2D1A (XLP1, MIM#308240) and XIAP (XLP2, MIM#300635), or the determination of NK T cells in suspected patients may reveal this subset of patients (Eastwood et al., 2004). In routine clinical practice, it is difficult to screen for all known genes that can result in a CVID phenotype. One suggestion is to test for genetic mutations in boys with affected male relatives or patients of either gender with affected family members prior to making a diagnosis of CVID (Chapel and Cunningham-Rundles, 2009). We suggest to screen for mutations in Btk in male subjects with peripheral B cell numbers of less than 2%; check for mutations in SH2D1A and/or XIAP in males with EBVassociated lymphoproliferative disease or HLH; and to screen for mutations in the CD40 ligand in males with an elevated IgM level and/or with opportunistic infections; or AICD in subjects of either gender with an elevated IgM and autoimmunity. All other genetic defects are either too
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rare to account for or do not have substantial clinical impact to justify the use of resources outside the research setting. In view of the frequency of the occurrence of hypogammaglobulinaemia in the setting of a lymphoid malignancy, it has also been suggested that there is a need to distinguish between this and lymphoid malignancy complicating longstanding CVID. One possible way of doing this is to allow a 2-year period before making a diagnosis of CVID, to confirm absence of lymphoid malignancy after identification of the antibody deficiency (Chapel and Cunningham-Rundles, 2009). Other approaches include more aggressive diagnostic work-up with a bone-marrow biopsy and/or lymph node extirpation (n.b., a lymph node core biopsy is rarely diagnostic in these cases). Goods syndrome, the association between thymoma and immunodeficiency (Good and Varco, 1955), also needs to be excluded particularly in older patients with antibody deficiency. Typical features in Goods syndrome include an absence of B cells as well as T cell abnormalities including CD4 lymphopenia, an inverted CD4/CD8 ratio and reduced mitogen induced proliferation. In a recent systematic review, the average age of patients diagnosed with Goods syndrome was 59.1 years, although the range was 2590 years with one pediatric case identified (Kelesidis and Yang, 2010). One suggested scheme to screen for thymoma is that all patients with antibody deficiency who are over 49 years of age with absent B cells should undergo CT scanning to exclude thymoma (Chapel and Cunningham-Rundles, 2009). However, it should be noted that in the same systematic review 13% of patients with Goods syndrome did not have a reduced or absent peripheral B cell count (Kelesidis and Yang, 2010). At present, the diagnostic criterion does not include a requirement for significant infection although suggestions have been made for its inclusion. It should be noted that although the majority of patients with significant hypogammaglobulinaemia will have recurrent infections, a proportion can present with autoimmune cytopenias (Michel et al., 2004), granulomatous disease (Mechanic et al., 1997) or only minor or no infections.
3. EPIDEMIOLOGY
There are no precise data on the prevalence of CVID but it has been estimated at between 1:10000 and 1:100000 of the population (Chapel and Cunningham-Rundles, 2009; Primary immunodeficiency diseases, 1999). There is epidemiologic and registry data from multiple countries (Boyle and Buckley, 2007) showing significant variation which might be due to intrinsic differences in the population surveyed, although there are differences in the methods of ascertainment and coverage as well. The current data in the ESID registry shows a minimal prevalence of CVID of
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5/100,000 inhabitants in France, almost 2 in the United Kingdom, and only 1.3 in Germany. As there is no reason to believe that the true incidence in these countries differs, it is likely that the prevalence in the latter countries will increase with time given the increased awareness of physicians and better documentation of patients in registries. In a large American cohort of 248 patients, the age of onset of symptoms was found to be bimodal with peaks in the first and third decades (Cunningham-Rundles and Bodian, 1999). However, in a cohort of 413 European patients, the age of onset was found to be a continuous curve (although there was decline in the rate of diagnosis in the eighth decade) with the mean age of 35.3 years and median of 33 years (Chapel et al., 2008). The latest registry data from the European Society for Immune Deficiencies (ESID) supports this observation. There was a mean diagnostic delay of 7.46 years (median 5 years, range 061 years) in a European cohort (Chapel et al., 2008) and 8.9 years in an Italian cohort (Quinti et al., 2007). Overall there has not been a significant decrease in the diagnostic delay suggesting that awareness and suspicion of CVID as a differential diagnosis remains poor. Important awareness campaigns such as the J-Project in Central and Eastern Europe (www.ece.dote.hu), the Is it PID? campaign in the United Kingdom (www.isitpid.com), FIND ID in Germany (www.find-id.net), and The 10 warning signs (www.jmfworld.com) have been launched around the globe to improve the diagnostic delay and diagnose and treat CVID and other patients with a primary immune defect as early as possible in order to prevent secondary complications.
4. PATHOPHYSIOLOGY/IMMUNOPATHOLOGY
Multiple immunological abnormalities have been described in almost all compartments of the immune system in CVID. Most of the focus has been on B cell abnormalities (which are discussed later) as the principal defect in CVID is failure of antibody provision. However, a reasonable amount of work has been done looking at the T cell compartment as well and more recently, at innate immunity; Table 2.4 summarizes a list of some of the abnormalities found in these areas. The diverse and widespread distribution of all these abnormalities further serves to highlight the heterogeneity present in CVID and that it is likely that multiple factors play a role in generating the phenotype. Although these findings may be related to the pathogenesis of the disease, it is also possible that they represent epiphenomena as a result of the disease process. Most of the abnormalities described have been identified in peripheral blood cells with limited work done on other tissues. To improve understanding of the process occurring elsewhere, a recent study has analyzed
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TABLE 2.4 Immunological abnormalities seen in CVID
Innate Defective monocyte-derived dendritic cell function immunity (Cunningham-Rundles and Radigan, 2005; Scott-Taylor et al., 2004, 2006) Reduced numbers of blood dendritic cells (Viallard et al., 2005; Yong et al., 2008b) Reduced CD1d restricted invariant NKT cells (Trujillo et al., 2011) Increased TNFa secretion following TLR4 stimulation with lipopolysaccharide (Trujillo et al., 2011) Reduced B cell expression of CD86 and proliferation after stimulation with TLR9 agonists and bacterial extracts (Escobar et al., 2010) TLR7 stimluated PDCs produced little or absent IFNa (Yu et al., 2009) TLR7 and TLR9 stimulated B cells did not upregulate activation-induced cytidine deaminase and failed to produce IgA and IgG (Yu et al., 2007) T cells Reduced thymic output (Giovannetti et al., 2007; Guazzi et al., 2002) Reduced proliferation in reponse to mitogens and antigens (Cunningham-Rundles and Bodian, 1999) Failure of generation of antigen-specic T cells after vaccination (Kondratenko et al., 1997; Stagg et al., 1994) Reduced CD40L expression in activated T cells (Farrington et al., 1994) Reduced attractin levels on T cells (Pozzi et al., 2001) Defects in TCR signaling (Boncristiano et al., 2000; Paccani et al., 2005) Impaired cytokine generation (Aukrust et al., 1994; Sneller and Strober, 1990) Cytokine dysregulation (Holm et al., 2005) Increased T cell apoptosis (Di et al., 2001)
the bone marrow findings in a cohort of 25 patients (Gomes Ochtrop et al., 2011). Abnormalities were found in the lymphoid compartment but not in others (such as the myeloid compartment). As expected, 94% of patients had absent or reduced plasma cells in keeping with reduced IgG levels. In addition, diffuse and nodular CD3 T cell infiltrates were more often seen in CVID patients and these were associated with autoimmune cytopenias. Nodular infiltrates were also associated with an activated T cell compartment indicated by increased CD4CD45RO memory T cells, and
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elevated soluble CD25 and neopterin levels. In 9 out of 25 patients, a partial block in B cell development between the pre-B-I to pre-B-II stage was seen; the authors from Freiburg, Germany, proposed that these CVID patients might represent a new subgroup as the developmental block was associated with lower transitional and mature B cell counts.
5. ETIOLOGY/GENETICS
Although generally sporadic, approximately 10% of cases of CVID demonstrate familial clustering (Hammarstrom et al., 2000) and IgA deficiency has been noted in family members of patients with CVID (Vorechovsky et al., 1999). In addition, patients with IgA deficiency have also been noted to progress to CVID (Espanol et al., 1996). These observations made it likely that CVID had a genetic basis. Initially, several genetic linkage studies in the 1980s and 1990s had focused primarily on the HLA region and demonstrated an association with CVID (and IgA deficiency; Olerup et al., 1992; Volanakis et al., 1992). It was not until 2003 that mutations in ICOS were identified as the first genetic disorder resulting in a CVID phenotype (Grimbacher et al., 2003). The rate of progress in unraveling the genetic basis of CVID has progressed greatly since then. Mutations have been detected in various B cell related TNFRSF member genes (TACI and BAFF-R), in members of the CD19-B cell receptor complex (CD19, CD21 and CD81) and in the B cell differentiation antigen, CD20. In addition, polymorphisms in genes involved in DNA metabolism (MSH5, MSH2, MLH1, RAD50, and NBS1) have also been identified in CVID cohorts (Kuijpers et al., 2010; Offer et al., 2010; Salzer et al., 2005; Sekine et al., 2007; van Zelm et al., 2006, 2010; Warnatz et al., 2009). Deficiencies in signaling pathway molecules including ZAP-70 (Boncristiano et al., 2000) and a guanine nucleotide exchanger, Vav (Paccani et al., 2005) have been observed, although genetic mutations in these molecules have yet to be identified. In a subgroup of patients with CVID, an association between impaired proliferation following TCR engagement and early tyrosine phosphorylation has been shown, subsequently leading to the discovery of defective ZAP-70 recruitment due to a CD3z phosphorylation defect (Boncristiano et al., 2000). Further work identified deficiencies in F-actin reorganization secondary to defective Rac activation as a result of deficient Vav expression (Paccani et al., 2005). Vav mRNA was also reduced in that study, but no promoter region mutations were found in the VAV1 gene to account for this. Some of these genetic mutations are likely to be disease causing (ICOS, CD19, CD20, CD81) whereas the others (TACI, BAFF receptor, Msh5) are likely to require additional genetic contributions as genetic mutation
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alone does not necessarily lead to a CVID phenotype. In addition to the approach of targeting specific genes likely to be related to B cell function, a genome-wide association study has also been undertaken in CVID patients further identifying novel genes for further exploration (Orange et al., 2011). We discuss in further detail below the genetic discoveries to date. It should be noted as well that polymorphisms in certain genes have also been associated with complications in CVID (summarized in Table 2.5).
5.1. CD19-complex mutations (CD19, CD21, CD81)

CD19 is expressed together with CD21, CD81, and CD225 on the surface of mature B cells. CD19 and CD21 are B cell specific antigens unlike CD81 and CD225, which are also present on most other immune cells (Levy et al., 1998). The complex cosignals with the B cells receptor, thus reducing the threshold for signaling following antigen recognition (Carter and Fearon, 1992; Fearon and Carroll, 2000). The complement receptor CD21 also links the innate and adaptive immune systems by binding complement C3d thus linking CD19-complex signaling to the complement pathway (Fearon and Carroll, 2000). CD19 and CD21 bind each other directly and as CD21 lacks an intracellular domain, it is thought that it signals through CD19 which possesses multiple tyrosine residues (Matsumoto et al., 1991; Wang et al., 2002; Figure 2.1). CD81 is a member of the transmembrane pore integral membrane protein family although its function in humans is not fully understood. CD81-knockout mouse models showed reduced CD19 expression on B
TABLE 2.5 Genetic polymorphisms associated with CVID complications Gene Association
TNF (Mullighan et al., 1997, 1999) IL10 (Mullighan et al., 1999) MBL2 (Litzman et al., 2008; Mullighan et al., 2000)
VDR (Mullighan et al., 1999) IL6 (Mullighan et al., 1999)
488A allele associated with granulomatous CVID IL-10 a-t-a haplotype associated with granulomatous CVID Low producing genotpes associated with bronchiectasis, lung brosis, respiratory insufciency but not other complications in CVID Association with B lymphopenia and CD8CD57 lymphocytosis Association with CD8CD57 lymphocytosis
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C3d
Antigen
Dual antigen recognition
CD19 CD21 CD81
B-cell receptor (BCR)

y y y y y y y y y
CD225 (Leu-13)
B cell
CD19-complex
FIGURE 2.1 Recognition of antigen bound to C3d by the B-cell receptor and CD21 respectively. This results in dual signalling through the B-cell receptor and the CD19 complex.
cells, as well as reduced antibody production in response to T-dependent antigens (Maecker and Levy, 1997; Tsitsikov et al., 1997). Molecular defects resulting in CVID have been described in three subunits of the CD19-complex: CD19, CD21, and CD81.
5.1.1. CD19 deficiency

CD19 deficiency (CVID3, MIM#613493) was first described in a Turkish girl and three Colombian siblings (van Zelm et al., 2006). The Turkish girl was born to consanguineous parents and had a homozygous single bp insertion in exon 6 resulting in a frameshift mutation and premature stop codon in the intracellular portion of the molecule. The parents of the Colombian family were said to be unrelated but came from a town in the Andes. Their children had a homozygous 2 bp insertion in exon 11 also resulting in a premature stop codon in the intracellular portion. In a subsequent report, a single Japanese boy was also found to be CD19deficient (Kanegane et al., 2007). He had a compound heterozygote mutation with the maternal allele showing a splice acceptor site mutation site in intron 5 resulting in skipping of exon 6 and coupling of exon 5 and 7; the
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paternal allele showed a large deletion including CD19 and two neighboring genes, although it is uncertain if this was inherited or a de novo event. All patients had similar characteristics, having presented in childhood with mostly recurrent bacterial infections; and found to have hypogammaglobulinaemia and deficient vaccination responses. There were no signs of autoimmunity in the first four patients; the Japanese patient had mild thrombocytopenia, although it is not definite if this is immune-mediated. Immunologically, CD19 deficiency patients had normal numbers of peripheral B cells although the numbers of CD5 and CD27 class-switched memory B cells were reduced. B cells (as measured by CD20 stain) expressed reduced levels of CD21 but normal levels of CD81 and CD225. Germinal center formation was retained as was somatic hypermutation. Van Zelm and colleagues showed that the problem in these patients was in B cell activation, for example Ca2 influx was absent or severely delayed in CD19-deficient cells (van Zelm et al., 2006). Since this initial report, other cases with CD19 deficiency have been presented at scientific meetings, highlighting the usefulness of a CD19 stain in the work-up of patients with hypogammaglobulinemia/CVID.

CD21 (or complement receptor type 2, CR2) deficiency has been described in a single 28-year-old male with mild clinical disease, born of nonconsanguineous parents (First case of human CD21 deficiency, 2004). On one allele, the patient had a point mutation in the 30 splice site of exon 6, resulting in one shortened mRNA lacking exon 6, the second allele carried a mutation in exon 13, changing a TGG triplet to TGA and thus creating a premature stop codon at amino acid position 766. There was absence of CD21 protein expression on B cells and in serum although there were normal levels of CD21 mRNA. Serum IgG and IgA levels were reduced but there were good IgG responses to protein and polysaccharide vaccination. T and B cell counts were within the normal range although there was a reduction in class-switched memory B cells. In vitro, B cells showed reduced binding to C3d-containing immune complexes although BCR and CD40 dependent responses were normal. SHM was present and VH spectratyping only showed a slightly biased IgG and IgA repertoire (Thiel et al., 2009).

The defect in CD19 suggested that other members of the CD19 coreceptor complex could be involved in the development of CVID and more recently, a defect in CD81 was identified (CVID6, MIM#613496; van Zelm et al., 2010). A 6-year-old Moroccan girl born of consanguineous parents was found to have a homozygous substitution mutation downstream of exon 6. This resulted in disruption of the splice donor site and
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addition of 13 nucleotides to the transcript leading to a frameshift and premature stop codon before the fourth transmembrane domain. Clinically, the patient presented with recurrent respiratory infections at the age of 2 and subsequently developed glomeruonephritis (which eventually progressed to end-stage renal failure despite therapy) and a purpuric rash. This was diagnosed as Henoch Schonlein purpura after a renal biopsy showed mesangial IgA and C3 and a skin biopsy showed leukocytoclastic IgA vasculitis. She also had recurrent thrombocytopenia with antiplatelet antibodies. She was found to have a low IgG but low to normal IgA and normal IgM and commenced on replacement immunoglobulin. The patient had no antibody responses to vaccination as well as a low allohemagglutinin titer. Apart from the lack of CD81 expression on all leukocytes, the gene mutation also resulted in absence of CD19 on B cells due to the dependency of CD19 on CD81 expression. The antibody deficiency was similar to patients with CD19 deficiency with deficient vaccination responses and reduced CD27 memory B cells. Somatic hypermutation was impaired (particularly in IgA) as was Ca2 signaling through the B cell receptor. T cell antigen responses did not seem to be affected.
5.2. CD20 mutation

CD20 is a B cell differentiation antigen widely expressed in B cell development from early pre-B until mature B cell stage, but lost on differentiation in to plasma cells. It is encoded by MS4A1 and belongs to the MS4A family of proteins which have four highly conserved membrane spanning regions (Liang and Tedder, 2001). It was one of the first B cell differentiation antigens described (Stashenko et al., 1980) and is most famous for its use as a target for monoclonal antibodies in the treatment of B cell malignancy and an increasing list of autoimmune diseases. Functionally, CD20 blockade in vitro with monoclonal antibodies has been shown to disrupt B cell proliferation and differentiation (Tedder et al., 1985, 1986). CD20 also belongs to a cell surface complex that regulates Ca2 transport (Bubien et al., 1993). Human and mouse CD20 have similar gene structure and cellular expression and in CD20 knockout mice, B cell IgM expression was slightly reduced and CD19-induced Ca2 mobilization was affected although the B cells had normal development, proliferation, T cell dependent antibody production, and affinity maturation (Uchida et al., 2004). A homozygous mutation in CD20 (CVID5, MIM#613495) has been described in a single Turkish girl of consanguineous descent resulting in a CVID phenotype (Kuijpers et al., 2010). Genetic analysis showed a compound mutation (homozygous 11 bp insertion as well as a partial deletion) in exon 5 of the CD20 gene. This affects a unique donor splice
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site resulting in transcripts with a deletion of exon 5 and insertion of intronic sequences. The individual presented with recurrent bronchopneumonia and respiratory tract infections from the age of 2. She was found to have a reduced IgG level but normal IgA and IgM levels (and therefore stricktly does not classify as CVID) and initially treated with replacement immunoglobulin. However, this was discontinued after 6 months and replaced with antibiotic prophylaxis. The patient had a normal number of circulating B cells but these lacked expression of CD20; her parents showed CD20 expression but only at half that of controls. The patient had reduced class-switched CD27 memory B cells, reduced IgG production in vitro, an altered selection of marginal zone B cells and a reduced response to vaccination with pneumococcal polysaccharide. The authors further confirmed a role of CD20 in T-independent antibody responses in CD20 knockout mice (Kuijpers et al., 2010). Ca2 signaling plays an important role in the activation of B cells (Dolmetsch et al., 1997), raising the possibility that abnormalities may contribute to the development of CVID. B cell receptor cross-linking results in phosphorylation of phospholipase Cg2 (PLCg2) by Syk and Btk. PLCg2 then induces the generation of inositol triphosphate (Kurosaki and Hikida, 2009), which results in transient intracellular calcium release leading to more sustained influx of Ca2 through the Ca2 channels in the plasma membrane (Feske, 2007; Rhee and Bae, 1997). In mouse models, PLCg2 deficiency has been shown to affect B cell development at the transitional B cells stage, antibody response and the maintenance of memory B cells (Hashimoto et al., 2000; Hikida et al., 2003, 2009; Wang et al., 2000). Following on from this data, all the above defects (CD19, CD21, CD81, and CD20) link CVID pathogenesis to B cell activation and Ca2-flux. In keeping with this, Ca2 responses have been shown to be reduced in the mature B cells of CVID patients with reduced switched memory B cells and increased CD21low B cells, although transitional B cells had normal signaling (Foerster et al., 2010). In this study, Ca2 influx across the plasma membrane was reduced (associated with increased expression of CD22, a negative regulator of signaling) although proximal BCR signaling and Ca2 release from the endoplasmic reticulum was normal. These patients had a greater incidence of immune dysregulation and lymphadenopathy. The defect responsible was thought to lie in mechanisms involved in regulating plasma membrane Ca2 channels or homeostasis of intracellular Ca2 levels, although as yet remains unidentified. It was thought that it likely contributes to (although probably not solely responsible for) the B cell dysfunction and an anergic phenotype of CD21low B cells; and possibly the antibody deficiency and failure of immune tolerance (Foerster et al., 2010).
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5.3. TACI mutations

TACI (encoded by TNFRSF13B) belongs to the tumor necrosis factor receptor superfamily and is found on B cells (Schneider, 2005). Other members of this group include the molecules B cell activating factor receptor (BAFF-R) and B cell maturation antigen (BCMA). The ligands for TACI are B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Binding to its ligands induces CSR in both human and mouse cells (Castigli et al., 2004, 2005a; He et al., 2007; Litinskiy et al., 2002). TACI knockout mice also have deficient T-independent type II responses to polysaccharide antigens (von Bulow et al., 2001) and are prone to lymphoproliferation and fatal autoimmunity (Seshasayee et al., 2003). Multiple studies have identified various TACI mutations (CVID2, MIM#240500) in cohorts of patients with CVID (Castigli et al., 2005b; Pan-Hammarstrom et al., 2007; Salzer et al., 2005, 2009). These mutations have been described in the extracellular domain, stalk region, transmembrane region and intracellularly (Castigli et al., 2005b; Salzer et al., 2005, 2009). Table 2.6 lists the mutations and SNPs that have been discovered in TACI so far. Compared to the other mutations described above and found in a limited number of individuals or families, mutations in TACI have been discovered in a more significant proportion of patients with CVID, with 8.9% (50 out of 564) patients possessing at least one abnormal allele in the largest cohort of patients analyzed (Salzer et al., 2009). Eighteen percent of these had biallelic mutations and the remaining 82% had only a single affected allele. However, the relationship between TACI mutations and the development of antibody deficiency is complicated. There is a complex pattern of inheritance with homozygous, heterozygous, and compound heterozygous mutations identified (Castigli et al., 2005b; Salzer et al., 2005). In addition, monoallelic mutations have been described in healthy family members of affected patients suggesting that TACI might represent a disease susceptibility gene in its heterozygous state. In the largest cohort analyzed, all patients with biallelic mutations had antibody deficiency and most showed reduced binding to APRIL (Salzer et al., 2009). The most common TACI mutations (C104R and A181E) were found in a monoallelic state in 2% of 675 controls (compared to 6.9% of affected patients). The relative risk of developing antibody deficiency with a heterozygous TACI mutation was 3.6. Clinically, patients with TACI mutations could present with the complete spectrum of complications seen in CVID; all patients had recurrent infections and antibody deficiency (Salzer et al., 2009). In view of the mouse data, it was hypothesized that patients with TACI deficiency would be more prone to lymphoproliferation and autoimmunity. This is borne out in data from the cohort of 564 patients showing that TACI
TABLE 2.6 Mutations/SNPs identied in TACI

Association with CVID Castigli et al. (2007), 162 Pan-Hammarstrom patients, 100 et al. (2007), 424 Salzer et al. (2005), 162 Castigli et al. (2005b), patients, 100 controls 19 patients, 50 controls patients, 2209 controls controls Similar frequencies in CVID and controls Identied in CVID only Identied in CVID only Identied in CVID only Identied in CVID only Similar frequencies in CVID and controls CVID only, but Identied in CVID only not signicant Similar frequencies in CVID only, but Similar frequencies in CVID and controls not CVID and controls signicant CVID only, but not signicant Identied in CVID only Present in CVID and controls, but change predicted to be deleterious
Exon cDNA 2 81G > A
Protein T27T
Domain affected CRD1, extracellular
Salzer et al. (2009), 533 patients, 675 controls
118T > C 121delG 121G > C 204insA
W40R D41 lfs*43 D41H L69Tfs*12
CRD1, extracellular CRD1, extracellular CRD1, extracellular CRD2, extracellular CRD2, extracellular CRD2, extracellular CRD2, extracellular CRD2, extracellular
215G > A
R72H
277_231del G76fxX3
236A > G 260T > A
Y79C I87N
291T > G
P97P
CRD2, extracellular
Similar frequencies in CVID and controls Identied in CVID only Identied in CVID only Identied in CVID only Signicant increase in Signicant CVID increase in CVID Signicant association with CVID Identied in CVID only Similar frequencies in CVID and controls Identied in CVID only Identied in CVID only Identied in CVID only Identied in CVID only CVID only, but not signicant Association with CVID Signicant increase in Signicant not signicant CVID increase in CVID Identied in CVID only Identied in CVID only
298insT 310T > C
C100Lfs*6 C104R
CRD2, extracellular CRD2, extracellular CRD2, extracellular Stalk region Stalk region Stalk region Stalk region Stalk region Transmembrane
311G > A
C104Y R122W S144X
445G > A 455G > A 492C > A 512T > G
A149T G152E Y164X L171R
542C > A
A181E
Transmembrane Identied in CVID only
Identied in CVID only
571insG 579C > A
D191Gfs*46 Intracellular C193X Intracellular S194X Intracellular R202H Intracellular
602G > A
Identied in CVID only Identied in CVID only
Identied in CVID only
Similar frequencies in CVID only, but CVID and controls not signicant
(continued )
TABLE 2.6
(continued )
Association with CVID Castigli et al. (2007), 162 Pan-Hammarstrom patients, 100 et al. (2007), 424 Salzer et al. (2005), 162 Castigli et al. (2005b), patients, 100 controls 19 patients, 50 controls patients, 2209 controls controls Similar frequencies in CVID and controls
Exon cDNA 5 659T > C
Protein V220A
Domain affected Intracellular
Salzer et al. (2009), 533 patients, 675 controls
736G > T 752C > T
V246F P251L
Intracellular Intracellular
831T > C
S277S
Intracellular
Similar frequencies in Similar frequencies in Similar CVID and controls CVID and controls frequencies in CVID and controls Identied in CVID only Similar frequencies in Similar frequencies in Similar CVID and controls CVID and controls frequencies in CVID and controls Similar frequencies in CVID and controls
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mutations were more strongly associated with autoimmunity (36% vs. 23% of patients with wild-type TACI, most commonly autoimmune thrombocytopenia) and lymphoproliferation (60% vs. 35%, splenomegaly, lymphadenopathy, nodular lymphatic hyperplasia). Of note, heterozygosity for the C104R allele was also associated with lymphoproliferation and autoimmunity. One suggested explanation for this was that the wild-type TACI allele in heterozygotes might promote the survival of auto-reactive B cell clones. Interestingly, patients with a biallelic mutation are clinically less affected, suggesting that no TACI signaling is preferable to a perturbed TACI signal. Immunologically, patients can have normal or reduced percentages of B cells and more rarely, severe B lymphopenia can also be present. The proportion of patients with reduced switched memory B cells is similar to the general CVID population (Salzer et al., 2009). In keeping with the variability in B cell phenotype, immunoglobulin levels at presentation also varied greatly; IgG levels could be between < 1 up to 5 g/l, IgA and IgM were generally low but in a significant number of patients, IgA could be normal and IgM could be normal or elevated. It is likely that TACI mutations contribute to antibody deficiency although given the broad spectrum of clinical and immunological presentation, other disease modifying factors are likely to be important.
5.4. BAFF-R mutation

Mutations in BAFF-R (CVID4, MIM#613494) have been identified in two individualsa brother and sister pair born of a consanguineous marriage (Warnatz et al., 2009). A homozygous 24 bp in-frame deletion (del 8996) was found in exon 2 of the TNFRSF13C gene, causing removal of an 8 hydrophobic amino acid sequence in the BAFF-R transmembrane region and resulting in undetectable BAFF-R protein expression on the B cell surface. The male index case developed symptoms late with his first pneumonia at age 37 and was only diagnosed following a third pneumonia at age 57. The sister, however, was very well apart from severe zoster at the age of 70 and only had two episodes of pneumonia around the age of 80. She did not receive immunoglobulin replacement. There was no history of autoimmunity or lymphoproliferative disorder. The index patient had three children, all obligate heterozygous carriers, who were all healthy. Both patients had reduced IgG (the brother with a marked reduction of 0.6 g/l at presentation but the sister had only slightly reduced levels at 5.51 g/l) and IgM levels, but normal to elevated IgA levels. IgA plasma cells were also found in the gut. They were able to mount T-dependent antibody responses but not T-independent antibody responses. There was a severe persistent B lymphopenia, with increased transitional CD10 B
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cells, suggesting developmental arrest at the transitional B cell stage. Marginal zone IgMCD27 and class-switched memory B cells were also reduced. The marked difference in clinical phenotype despite the similar immunological findings suggested that other factors apart from BAFF-R are necessary for the development of immunodeficiency. Some of these factors such as BTK, CD40L, BAFF, APRIL, TACI, and BCMA were screened for in the index case in the study but no abnormalities were found. In addition, it was noted in the screening exercise that other CVID patients in the cohort had reduced BAFF-R levels which might be due to mutations in the regulatory region (as these were not screened for in that study) that could contribute to the development of CVID (Warnatz et al., 2009).
5.5. ICOS mutations

ICOS deficiency (CVID1, MIM#607594) was the first genetic mutation identified in patients with a CVID phenotype. ICOS belongs to a family of costimulatory molecules on the surface of T cells, which includes CD28, CTLA-4, and PD-1 and possesses a unique ligand, ICOS-L which is expressed on antigen presenting cells including naive B cells (Carreno and Collins, 2002; Hutloff et al., 1999; Sharpe and Freeman, 2002). It is expressed on activated T cells and has a role in T cell differentiation and survival, cytokine secretion and provision of signals for T-dependent antibody responses (Hutloff et al., 1999). Of relevance to B cells, stimulation of ICOS results in potent production of IL-10 (Hutloff et al., 1999) which is important for proliferation of B cells and terminal differentiation into memory and plasma cells (Rousset et al., 1992). ICOS also plays a role in the clonal expansion of established effector Th2 cells (Vieira et al., 2004). In addition, ICOS also provides critical signals (via induction of the transcription factor Bcl6) for differentiation of follicular helper T cells which provide B cell help and are important in germinal center reactions (Akiba et al., 2005; Choi et al., 2011). In total to date, 11 individuals from 5 different families have been identified, 9 of them with the same mutation in ICOS (Grimbacher et al., 2003; Salzer et al., 2004; Takahashi et al., 2009). A homozygous deletion of 1815 bp, spanning a region from intron 1 to intron 3 of the ICOS gene was found in the first nine individuals (from four families) identified (Grimbacher et al., 2003; Salzer et al., 2004). This resulted in an mRNA product with a 443-nucleotide deletion and a putative protein product that encoded a 19-aa signal peptide and 9 nonsense amino acids, introduced by the frameshift; this is consistent with the absence of detectable ICOS protein on T cells. The identical deletion in all these individuals affected was thought to most likely be due to a common founder effect and migration along the Danube River. Further evidence for this was the
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fact that all individuals shared the same homozygous allele at a polymorphic marker (D2S2289) adjacent to the ICOS locus. Subsequently, a Japanese brother and sister pair were found to have a homozygous deletion of T at codon 285 resulting in a coding region frameshift and introducing a premature stop codon at aa 121 (Takahashi et al., 2009). The affected sister had immunodeficiency and significant autoimmunity with rheumatoid arthritis, inflammatory bowel disease, interstitial pneumonitis and psoriasis, although the brother had a much milder phenotype with only a modest reduction in IgG levels and only occasional skin abscesses and psoriasis-like skin lesions. The same mutation was found in heterozygosity in the unaffected mother and another sister. Clinically, ICOS deficiency can present with the full spectrum of disease seen in CVID, with presentation from childhood into adulthood (Takahashi et al., 2009; Warnatz et al., 2006). Recurrent respiratory tract infections were the commonest feature but gastrointestinal infections, lymphoid nodular hyperplasia, splenomegaly, granulomatous skin disease, interstitial pneumonitis, autoimmunity, inflammatory bowel disease and HPV-associated vulval carcinoma were all observed as well. Patients had reduced IgG and IgA levels although some of the patients had low normal IgM values; one patient had an elevated IgM during an episode of bronchopneumonia (Warnatz et al., 2006) and one had a persistenly elevated IgM (Takahashi et al., 2009). There were no class-switched antibody responses detectable to vaccination. B cells numbers were reduced in most adults although the two youngest children had increased numbers of B cells. Numbers of naive B cells were normal in children but classswitched memory B cells were reduced in all individuals. With the exception of the CXCR5 expressing so called follicular helper T cells, and despite the almost exclusive expression of ICOS on activated T cells, the T cell compartment in patients showed little abnormality in the first nine patients identified (Warnatz et al., 2006). Patients had a normal proportion of naive CD3CD45RA cells to antigen-experienced CD3CD45RO cells; normal numbers of HLA-DR T cells and normal in vitro proliferative responses when stimulated with mitogens, antigens, and alloantigens. Stimulation through the CD3:T cell receptor complex resulted in normal levels of TNF-a, IFN-g, IL-2, IL-4, and IL-13 with or without costimulation with anti-CD28 or anti-ICOS (Grimbacher et al., 2003; Warnatz et al., 2006). However, IL10 and IL17 production were reduced. In contrast, testing of the T cell compartment in the Japanese patients showed a decrease in CD4CD45RO memory T cells (both CCR7CD62L central and CCR7CD62L effector memory T cells; Takahashi et al., 2009). Also in contrast, Th1 (IFNg) and Th2 (IL4 and IL5) cytokine production upon stimulation with CD3/CD28 or PMA/ionophore was impaired. Similar to
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previously, IL10 and IL17 secretion was also reduced (Takahashi et al., 2009). Reduced induction of the regulators of Th1, Th2, and Th17 lineage commitmentT-bet, GATA3, MAF, and retinoic acid-related orphan receptor C (RORC) was also noted. There was also a reduction in FoxP3 expression and mRNA levels and reduced CTLA4CD45ROFoxP3 regulatory T cells. Expression of the inhibitory cell surface molecules, CTLA-4 and BTLA (although not PD-1) were reduced after induction. The CD8 T cell compartment was also affected with reduced memory cells and impaired production of IFN-g. There was also increased induction of RANKL and loss of Itch expression in the affected sister. These findings are consistent with the autoimmunity seen in ICOS deficiency, although the discrepancy in detectable T cell abnormalities between the two different mutations is not completely explained at present. Mechanistically, although ICOS deficiency is a form of CSR defect, screening of several cohorts of patients with HIGM syndrome have not identified any further patients with ICOS (or ICOS-L) mutations (Lee et al., 2003, 2005).
5.6. Msh5 mutations and other DNA repair genes

Msh5 is part of a family of proteins that have roles in DNA mismatch repair and meiotic homologous recombination. It has been shown to play a role in CSR in mice and consequently, a cohort of Swedish and American patients with IgA deficiency and CVID were genotyped for MSH5 mutations (Sekine et al., 2007). This found that an allele with two nonsynonymous single-nucleotide polymorphisms (L85F/P786S) was significantly associated with IgA deficiency and borderline associated with CVID. A SNP in intron 12 (rs3131378) was also frequently associated with IgA deficiency and more modestly associated with CVID. In addition, two rare SNPs were identified in patients that were not found in healthy controls: C580G in two patients with IgA deficiency and Q292H in one patient with CVID. All healthy controls with the L85F/P786S SNP were screened for immunoglobulin deficiency and found to have normal levels. The MSH5 protein encoded by the L85F/P786S allele was also shown to have reduced binding to a partner protein, MSH4 (Sekine et al., 2007). Patients with this allele had increased stretches of Sm-Sa1 microhomology, lower S joint mutation rates and increased in-phase alignment of pentamer motifs. The mutation rate across Sm-Sg3 joints was also lower for patients with that allele. Subsequently, in view of this and the genetic abnormalities seen in the CSR defects, analysis of other DNA metabolism genes was undertaken to determine if there were any more subtle mutations that had an association with IgA deficiency/CVID (Offer et al., 2010). In a cohort of CVID/IgA
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deficiency patients screened for 27 genes involved in DNA metabolism, significant associations were found with nonsynonymous alleles in MSH2, MLH1, RAD50, and NBS1 as well as UTR SNPs in RAD50 and MRE11. The authors also demonstrated that cells with the RAD50-Q372X mutation (resulting in a premature stop codon) had increased sensitivity to ionizing radiation.
5.7. Genetic linkage studies

Several genetic linkage studies have been undertaken in the context of CVID/IgA deficiency. Most of the earlier studies have focused primarily on the MHC region in chromosome 6 and some (but not all) have shown linkage although the exact location in the MHC region of the putative disease-related gene is not certain (Olerup et al., 1992; Volanakis et al., 1992; Vorechovsky et al., 1995). Following the work of Vorechovsky, the MHC susceptibility locus was designated IGAD1 (Vorechovsky et al., 1999, 2000). Subsequent to the studies focusing on the MHC region, several genome-wide linkage studies were published. Kralovicova et al. (2003) analyzed a sample of 210 IgA deficiency/CVID families with 36 markers at the IGAD1 region and identified HLA-DQ/DR as the major IGAD1 locus. They also undertook genome-wide linkage analysis of 101 families with 383 marker loci and this showed the highest linkage scores at 6p, which were not matched anywhere else in the genome. Schaffer et al. subsequently reanalyzed data from the previously genotyped 101 families looking for loci associated specifically with CVID. They analyzed a subset of 40 families with at least one case of CVID and extended the genotype where samples were still available in 32 families (Schaffer et al., 2006). This showed evidence of a CVID locus at chromosome 16q and one possible candidate gene, WW-domain containing oxidoreductase (WWOX) was sequenced but no mutations found. Braig et al. performed a genome-wide linkage study using 205 markers in three families with autosomal dominant CVID, IgA deficiency and dysgammaglobulinaemia. They confirmed linkage in the HLA region (in one family) but also identified a novel linkage to the telomeric region of chromosome 5p (in two families; Braig et al., 2003). A single gene in the region, PDCD6 which has functions related to apoptosis, was identified as the most likely candidate to result in antibody deficiency. However, sequencing of this gene in patients did not reveal any abnormalities. Finck et al. identified genetic linkage of autosomal dominant CVID to chromosome 4q in a genome-wide scan of a five-generation family with six cases of CVID, five cases of IgAD, and three cases of dysgammaglobulinaemia (Finck et al., 2006). The study was further extended to investigate 32 families with one member with CVID and another with CVID or
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IgAD, which supported the linkage to the identified locus. Potential candidate genes in the region (NFkB1, SCYE, CASP6, DAPP1, BANK1) were sequenced in a single individual from the large family but no abnormalities found.
5.8. Genome-wide association studies

Although there are genetic mutations identified in a small percentage of CVID cases, it is likely that a large proportion of CVID is due to more complex polygenic interactions, given the heterogenous nature of the disease, both in terms of clinical presentation and immunological phenotype. To date, most of the research has focused on single gene defects causing or contributing to a CVID phenotype, as well as a limited number of genetic linkage studies. However, advances in technology have allowed high-throughput genome-wide SNP genotyping and to date, a single study examining this and copy number variations (CNV) in CVID has been published (Orange et al., 2011). In this study, a total of 363 CVID patients and 3031 healthy controls were genotyped with the aim of linking SNPs and CNVs to CVID as well as determining if there was a specific genetic signature distinguishing CVID from healthy individuals. Analysis of the data showed a significant association with the MHC region (consistent with previous linkage data) and a suggestive association (although the p value did not reach significance for GWAS significance criteria) with a locus containing ADAM28, ADAM7, ADAMDEC1, and STC1. The genes within these regions have putative immunological functions and associations. The MHC locus has been linked to multiple diseases (Shiina et al., 2004, 2009) including immunological ones and CVID (Kralovicova et al., 2003; Olerup et al., 1992; Volanakis et al., 1992). ADAM family proteins are a group of zinc metalloproteases which have a role in a wide range of biological processes and ADAM28 (also known as lymphocyte metalloprotease MDCL) is expressed on lymphocytes and is the ligand for a4b1 integrin thus enabling cell adhesion (Bridges et al., 2002). STC1 encodes stannioncalcin 1 which has a role in calcium regulation (Sheikh-Hamad, 2010) and may be relevant as a subset of CVID patients have impaired B cell receptor mediated calcium signaling (Foerster et al., 2010). Of note, however, was that the GWAS did not identify any association with the locus containing TACI, nor were any patients with TACI mutations separately identified. SNP association was also performed with respect to individual features of CVID and significant associations were found with all 16 of the parameters that were studied (including nodular regenerative hyperplasia, malabsorption, lymphoma, bronchiectasis, lymphoid interstitial pneumonia, low IgM, organ-specific autoimmunity, low B cells, young
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age, GI enteropathy, low IgA, lymphadenopathy, and cancer), further emphasizing the polygenic contribution towards the CVID phenotype. CNV analysis discovered several novel genes that were hemizygously deleted or duplicated in CVID patients. Eighty-four deletions and 98 duplications were identified in one or more CVID patients but not in controls. Some of these abnormalities were unique, further highlighting the individualistic nature of CVID. The most frequent duplication affected ORC4L which was exclusively seen in 15 cases of CVID. ORC4L is essential for the initiation of DNA replication and has been associated with B cell lymphoproliferative disorders (Radojkovic et al., 2009). Of clinical relevance, two patients with previously undetected 22q11 deletions were also identified in the CNV analysis. Most interestingly, the authors also used a Support Vector Machine (SVM) algorithm to attempt to predict the likelihood of a CVID phenotype. One thousand SNPs were identified from the analysis which allowed identification of CVID patients with 98.7% accuracy (Orange et al., 2011). This was suggested as a useful tool to allow earlier identification and better management of CVID patients particularly in the context of an evolving immunoglobulin profile; where potentially with current diagnostic criteria, a significant amount of time could lapse prior to a diagnosis, resulting in permanent damage due to recurrent infections.
6. CVID CLASSIFICATION SCHEMES

Various attempts have been made to classify patients with CVID into different subgroups, both to help direct research efforts as well as to guide clinical management by identifying patients with less or more severe disease. By and large, most of the work done on classification schemes has focused on B cells, as this is the prime abnormality in CVID. However, T cell phenotyping and categorization by clinical variables has also been undertaken.
6.1. B cell classification and phenotyping

The first classification scheme, developed by Bryant et al., proposed dividing patients with CVID based on immunoglobulin production of peripheral blood lymphocytes after exposure to Staphylococcus aureus Cowan I plus IL-2 or anti-IgM plus IL-2 (Bryant et al., 1990). Patients in Group A were unable to produce any immunoglobulin in vitro, patients in Group B could only produce IgM and patients in Group C were comparable to healthy controls. However, in general functional assays like this were too cumbersome and time-consuming for routine clinical use. Consequently, to utilize the
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ready availability and ease of use of flow cytometers, B cell classification schemes based on memory B cells (as identified by CD27 and IgD/IgM to determine class switch) were proposed by two different groups (Piqueras et al., 2003; Warnatz et al., 2002). Generally, with both schemes, the patients with the most severe disease had the lowest proportion of switched memory B cells. There were differences in the two classification schemes with Piqueras et al. (2003) using memory B cells as a percentage of total B cells and Warnatz et al. (2002) using memory B cells as a percentage of peripheral blood lymphocytes. Additionally, there were differences in which complications occurred more frequently in the group with the lowest proportion of memory B cells; and patients with virtually no B cells (possibly representing an early B cell development or differentiation defect) were not included in either classification. To address these issues and develop consensus, as well as phenotype a larger number of patients, the EUROClass classification scheme was developed (Wehr et al., 2007). This was a multicenter European trial which recruited 303 patients. The scheme divides patients into those with 1% CD19 B cells of total lymphocytes (group B) from those with a higher number of B cells (group B). B patients are further divided into those with a severe deficiency of class-switched CD27IgMIgD B cells ( 2% of CD19 B cells, group smB) or those with > 2% switched memory B cells (group smB). Patients with a severe deficiency of switched memory B cells were further divided into those with an expansion of transitional B cells (group smBTrhi, ! 9% of B cells, staining as CD21intCD38IgM) or those with < 9% transitional B cells (group smBTrnorm). In addition, the classification scheme also distinguished between patients with an expansion of CD21lo B cells (an unusual population not typically seen in healthy controls). Those with ! 10% CD21lo B cells of B cells were designated group CD21lo and those with < 10% were CD21norm. This allowed overlap between patients with expansion of both CD21lo and transitional B cells. Clinically, the severe reduction in switched memory B cells was associated with a higher risk of granulomatous disease and splenomegaly. Splenomegaly was also associated with an increased number of CD21lo B cells. Transitional B cell elevation was associated with a greater risk of lymphadenopathy (Wehr et al., 2007). It was concluded that patients with almost absent B cells had defects of early B cell differentiation and those with severely reduced switched memory B cells most likely had a germinal center defect as seen in ICOS or CD40 ligand deficiency. The defects resulting in expanded transitional or CD21lo B cells remain to be fully worked out. Of note, the EUROClass trial did not have patients below the age of 10 and it has been suggested that as children have higher and less mature B cells, the classification criteria may not be as applicable. A study
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evaluating 45 children between the ages of 219 years (median 6 and 7 years for the two different groups of children) were able to classify them into two groups by just evaluating CD19CD27IgM memory B cells (Yong et al., 2010). Those with < 5 switched memory B cells/ml had lower T cell and total B cell counts, and were the only children to have meningitis, sepsis, bronchiectasis, granulomatous lung disease, autoimmune cytopenias or hematologic malignancy. This is consistent with the findings in adults that reduction in switched memory B cells is associated with more severe disease.
6.2. T cell phenotyping

In view of the multiple abnormalities described in the T cell compartment in CVID as well as the importance of T-B cell interaction for antibody generation, T cell classification schemes have also been proposed (Giovannetti et al., 2008). In a study evaluating multiple functional and phenotypic T cell variables, the authors managed to divide CVID patients into three groups based on the percentage of naive CD45RACD4 T cells (< 15%, 1630% and > 30% of CD4 T cells; Giovannetti et al., 2007). The reduction in naive T cells reflected the degree of abnormality found in the other parameters examined. The group of patients with the lowest numbers of naive T cells had splenomegaly and granulomatous disease. Immunologically, they had reduced thymic output, increased activation, proliferation, and apoptosis and abnormal TCR repertoires. There was also an association with reduced class-switched memory B cells and an expansion of CD21lo B cells, showing a limited degree of concordance with the B cell classification proposed by Warnatz (Warnatz et al., 2002). Further work developing T cell classification schemes has been modest compared to B cell based schemes. More recently, in a study examining T and B cell compartments in 313 French CVID patients, abnormalities were more pronounced in patients with more severe disease (Mouillot et al., 2010). The main abnormalities seen were a reduction in naive CD4 T cells (associated with an increase in CD4CD95 cells) and a reduction in switched memory B cells. Patients were divided into six groups based on levels of naive CD4 T cells, total B cells and switched memory B cells. Approximately half the patients who only had infections had a normal T-B phenotype whereas patients with an abnormal T-B phenotype were significantly more likely to have autoimmune cytopenias and lymphoproliferative disease. Although this study was indicative of the fact that T cell phenotyping could be used to subgroup CVID patients, there was still considerable imprecision when trying to use phenotyping criteria to predict likelihood of complications (for example, approximately half the patients with a normal T-B phenotype had some form of complication).
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Although the phenotypic classification schemes developed so far are able to stratify patients to some extent, further refinement of them would be useful to more accurately subgroup patients and predict complications. The genetic screening tool developed by Orange et al. (2011) may be expensive but the way forward. A prospective analysis has to demonstrate its usefulness.
6.3. Clinical categorization

Based on the European CVID registry data (now superseded by the ESID registry), efforts have also been made to divide patients into separate clinical phenotypes (Chapel et al., 2008). Chapel et al. used a cohort of 334 patients followed-up for an average of 25.6 years to define five distinct clinical phenotypes, which are: no complications, autoimmunity, polyclonal lymphocytic infiltration, enteropathy, and lymphoid malignancy. These phenotyping criteria were selected if they were intrinsic diseaserelated complications. Bronchiectasis and splenomegaly were not used as part of the classification scheme as bronchiectasis was not related to underlying disease and splenomegaly was too common and associated with many complications. Seventeen percent of patients had more than one clinical phenotype. There was no association between diagnostic delay and clinical phenotype although patients with disease complications had significantly lower survival rates. Mortality rates were highest for patients with lymphoid malignancy (RR 5.5), enteropathy (RR 4.0) and polyclonal lymphocytic infiltration (RR 3.0). Predictive markers for the clinical phenotypes were also investigated; elevation in serum IgM (but not IgG) was associated with an increased risk of polyclonal lymphocytic infiltration and lymphoid malignancy. Every additional 1 g/l increase in IgM was associated with a 16% and 31% higher odds ratio for development of polyclonal lymphocytic infiltration and lymphoid malignancy respectively. Higher CD8 T cell levels were associated with a reduced chance of autoimmunity. This study supports the validity of the separate clinical phenotypes and underlines their importance in determining prognosis.
6.4. Late onset combined immune deficiency (LOCID)

Malphettes et al. have defined a subgroup of CVID patients who possess a significant T cell defect and classified them as late-onset combined immune deficiency (LOCID; Malphettes et al., 2009). In a cohort of 313 French patients, 8.9% of patients were found to have features suggestive of a T cell defectas defined by occurrence of an opportunistic infection (using the classification system for HIV) and/or a CD4 count of < 200 106 cells/l. Patients in this subgroup were more likely to come
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from a consanguineous family and have an increased risk of splenomegaly, granulomatous disease, gastrointestinal disease and lymphoma. In addition, they were more likely to require hospitalization and frequent antibiotic use despite being on immunoglobulin replacement. Immunologically, ve CD45RACCR7CD4 T cell counts there was a marked defect in na and B cell counts. Potentially this classification allows discrimination of this group of patients from other patients with CVID to both direct research aimed at discovering the underlying disorder and to guide therapy.
7. CLINICAL PRESENTATION AND COMPLICATIONS

Several large cohorts of CVID patients have been published in the literature and have reported a wide range of complications in CVID although there has been no recent change in the nature of these (CunninghamRundles and Bodian, 1999; Hermaszewski and Webster, 1993; Quinti et al., 2007). Infectious complications are frequently present and in addition, autoimmune, malignant, and inflammatory diseases are not uncommon. Data suggests that better treatment of CVID has resulted in longer survival (Chapel et al., 2008) and consequently, it can be expected that the noninfectious complications are likely to increase as the management of the infectious burden improves. To date, however, the etiology of most of the noninfectious complications remains very poorly understood. It should be noted that there is significant variation in the rate of different complications between different countries in a large European study (Chapel et al., 2008). This study only analyzed Caucasian patients, hence excluding the effect of racial background. With increasing numbers of registries from different countries, this should potentially allow identification of further subgroups/complications occurring due to interactions with the environment/geographical location.
7.1. Infections
Acute and chronic infections represent the major burden of morbidity in patients with CVID and similar numbers of patients are affected both at presentation and during follow-up, approximately 87% in an Italian study of 224 patients over a 11-year follow-up period (Quinti et al., 2007). Recurrent respiratory tract infections are the commonest feature, affecting up to 98% of patients in one cohort (Cunningham-Rundles and Bodian, 1999; Hermaszewski and Webster, 1993; Quinti et al., 2007). The most common organisms isolated are Streptococcus pneumoniae and Haemophilus influenzae (Cunningham-Rundles and Bodian, 1999; Kainulainen et al., 2001; Oksenhendler et al., 2008; Quinti et al., 2007). During follow-up, the incidence of acute pneumonia and acute otitis has
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been noted to decrease although there is an increase in chronic sinusitis and chronic lung disease (Quinti et al., 2007). In the Italian cohort, 49% of patients had pneumonia prior to diagnosis, but 35.7% did not get pneumonia after commencement of immunoglobulin replacement whereas 13.3% of patients continued to get recurrent pneumonia; similarly 39% of patients had acute otitis prior to diagnosis whereas 25.5% had no further otitis after immunoglobulin replacement with 12% continuing to get episodes despite therapy. More unusual infections are also sometimes seen in CVID. Joint infection and destruction with mycoplasma species (Franz et al., 1997), enteroviral meningoencephalitis (Halliday et al., 2003; McKinney et al., 1987; Rudge et al., 1996), and ureaplasma infection of the urinary tract leading to bladder fibrosis (Webster et al., 1982) have been described. The immune mechanisms leading to susceptibility to these organisms remain to be elucidated although adequate replacement immunoglobulin therapy has reduced the incidence of enteroviral infections. The more typical infections associated with T cell deficiency including Pneumocystis jirovecii pneumonia and atypical mycobacterial infections are uncommon in CVID.
7.2. Chronic respiratory infections and bronchiectasis

The occurrence of recurrent upper respiratory tract infections can result in chronic sinusitis and hearing loss. Unchecked recurrent lower respiratory tract infections have been thought to result in eventual development of bronchiectasis, which is present in 476% of patients depending on the cohort (Chapel et al., 2008; Cunningham-Rundles and Bodian, 1999; Hermaszewski and Webster, 1993; Kainulainen et al., 1999; Martinez Garcia et al., 2001; Oksenhendler et al., 2008; Quinti et al., 2007; Thickett et al., 2002; Watts et al., 1986). In addition, bronchiectasis can already be present at diagnosis, up to 34% and increasing to 46% during follow-up in the Italian cohort (Quinti et al., 2007) although this was only found in 14% of patients initially in a French cohort (Oksenhendler et al., 2008). However, data from a recent large European study showed that moderate respiratory tract infections were not associated with the development of bronchiectasis; rather only previous severe infections (pneumonia and septicemia) were (Chapel et al., 2008). In the same study, it was also shown that serious infections were not related to IgG levels < 1.5 g/l at presentation nor was bronchiectasis related to diagnostic delay (as surrogate measure for duration of nontreatment), time since onset of symptoms, or smoking. As would be expected, bronchiectasis was associated with earlier mortality. Although treatment with replacement immunoglobulin has been shown to reduce the incidence of pneumonia (Busse et al., 2002; Orange et al., 2010), chronic lung disease
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including bronchiectasis can still develop despite adequate therapy (Quinti et al., 2007). These findings indicate that immunoglobulin deficiency alone is not the only reason for progressive lung disease and that other factors are likely to play an important role as well. In support of this, there is data to indicate that IgM memory B cells and antipneumococcal polysaccharide IgM antibodies are protective against recurrent bacterial pneumonia and bronchiectasis; and can be used to stratify patients into high- and low-risk for lung complications (Carsetti et al., 2005).
7.3. Gastrointestinal complications

It is not surprising that patients with CVID have a high incidence of gastrointestinal disease (2060%; Cunningham-Rundles and Bodian, 1999; Hermans et al., 1976; Hermaszewski and Webster, 1993; Quinti et al., 2007; Washington et al., 1996) given that IgA plays a major role in mucosal defense. In addition, gastrointestinal disease can sometimes be the sole presenting feature in CVID (3% in the one cohort; Quinti et al., 2007). There is some data indicating that CVID patients with absent IgA have a higher incidence of GI infections compared to those with residual IgA (Oksenhendler et al., 2008). However, CVID patients are more prone to GI complications compared to patients with XLA and IgAD suggesting that other factors apart from immunoglobulin deficiency also play a role in the development of gut disease. There is some data to indicate T cell cytokine production abnormalities in CVID and increased T cell numbers in the colon of patients with CVID and inflammatory bowel disease suggesting that T cell defects are likely to play a role as well (Agarwal et al., 2011). However, the same investigators were unable to demonstrate increased inflammatory cytokines from lamina propria lymphocytes in the CVID subgroup with IBD. Transient or persistent diarrhea is the commonest gastrointestinal manifestation in CVID, found in between 20% and 60% of patients depending on study (Cunningham-Rundles and Bodian, 1999; Hermans et al., 1976; Hermaszewski and Webster, 1993; Quinti et al., 2007; Washington et al., 1996). Common pathogens identified include giardia, campylobacter, and salmonella species (Oksenhendler et al., 2008). In addition, CMV has also been found in gut biopsies of CVID patients (Daniels et al., 2007). Helicobacter pylori infection is associated with gastritis in CVID (Zullo et al., 1999). Multiple noninfectious gastrointestinal pathologies have also been described in CVIDthese include nodular lymphoid hyperplasia, granulomas, atrophic gastritis, pernicious anemia, inflammatory bowel disease, lymphocytic colitis, collagenous enterocolitis and flattened villi (Cunningham-Rundles and Bodian, 1999; Daniels et al., 2007; Hermaszewski and Webster, 1993).
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Chronic gastritis is a frequent finding affecting 10% of patients at diagnosis and 28% during follow-up in the Italian cohort where patients underwent endoscopy every 2 years (Quinti et al., 2007). Intestinal metaplasia of the gastric mucosa was common and despite Helicobacter pylori eradication therapy, recolonization would often occur (Quinti et al., 2007). The small bowel enteropathy in CVID resembles that seen in celiac disease with short villi, crypt hyperplasia and intraepithelial lymphocytosis. However, the enteropathy does not respond to gluten avoidance. One notable feature in CVID is the absence of plasma cells although this was only the case in 68% of patients in one study (Daniels et al., 2007). The small bowel enteropathy can result in diarrhea, weight loss and malabsorption; and in the most severe cases loss of essential nutrients has resulted in difficult-to-treat osteomalacia and neurological disease (Aslam et al., 2004). Large bowel enteropathy resembling Crohns disease and ulcerative colitis has also been described in CVID (Daniels et al., 2007; Hermaszewski and Webster, 1993). It is not clear if these have the same pathogenesis as classical inflammatory bowel disease although one study has shown that compared to Crohns disease, lamina propria mucosal cells from CVID patients with large bowel enteropathy produced significantly more Th1 cytokines, IL12, and IFNg without an excess of IL17, IL23, or TNFa; implying that an alternative inflammatory pathway is responsible for pathology (Mannon et al., 2006). Treatment of inflammatory bowel disease in CVID is similar to that of classical IBD with anti-inflammatory agents like 5-aminosalicylic acid compounds or steroids (either topical or nonabosorbed like budesonide; Agarwal and Mayer, 2010; Cunningham-Rundles, 2010). Following failure to respond to probiotics, we recommend to trial a high dose course of prednisolone (0.5 mg/kg BW) mostly for diagnostic purposes. If patients respond, we select better tolerated steroid preparations such as budesonide (up to 9 mg in adults) which has a high first-pass effect in the liver and hence produces less systemic side effects, or other immunosuppresive agents such as azathioprine and 6-mercaptopurine which can also be used as doses are too low to affect systemic T cell function (Agarwal and Mayer, 2010). The TNF antagonist infliximab has also been used in CVID patients with severe enteropathy with a modest benefit in one study (Chua et al., 2007) and an impressive response in unpublished cases (personal observation). Nodular lymphoid hyperplasia is relatively common in CVID, present in 8% in one cohort (Quinti et al., 2007). The cause of this is unknown at present although it has been suggested as a compensatory mechanism for the hypogammaglobulinaemia (Agarwal and Mayer, 2010). The likelihood of this predisposing towards the development of mucosa associated lymphoma is uncertain.
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Abnormalities in liver function tests are not uncommon and in two different cohorts, 43% of patients had abnormalities, most often affecting alkaline phosphatase levels (Malamut et al., 2008; Ward et al., 2008). Autoimmune hepatitis and primary biliary cirrhosis have both been described in CVID (Cunningham-Rundles and Bodian, 1999). Excluding a viral hepatitis infection (primarily hepatitis C contracted through contaminated immunoglobulin preparations) is always a medico-legal duty. Nodular regenerative hyperplasia has more recently been recognized as a significant cause of liver disease with 84% of CVID patients with liver function test abnormalities in one cohort showing this on biopsy (Malamut et al., 2008). Cholestasis (mostly anicteric) and portal hypertension were the main clinical findings; histologically intrasinusoidal lymphocytic infiltration, portal vessel abnormalities and epitheloid granulomas were seen in 90%, 43%, and 44% of that cohort (Malamut et al., 2008). In another study, 13 out of 16 patients (81%) with unexplained liver abnormalities were found to have nodular regenerative hyperplasia (Ward et al., 2008). In both cohorts, patients with NRH were more likely to have other autoimmune disease and nonceliac lymphocytic enteropathy; raising the possibility of an underlying autoimmune mechanism.
7.4. Autoimmunity
Autoimmune disease frequently complicates CVID and can be present in 2548% of patients depending on the country (Chapel et al., 2008; Cunningham-Rundles and Bodian, 1999; Quinti et al., 2007). The most common manifestations are autoimmune cytopeniasautoimmune thrombocytopenia and autoimmune hemolytic anemia, and less commonly immune neutropenia. A multitude of other immune diseases including vitiligo, psoriasis, pernicious anemia, rheumatoid arthritis, systemic lupus, Sjogrens syndrome, primary biliary cirrhosis, hepatitis, and thyroiditis have all been described (Chapel et al., 2008; CunninghamRundles and Bodian, 1999). One series has shown that in up to 62% of patients, the autoimmune thrombocytopenia preceded the diagnosis of antibody deficiency (Michel et al., 2004). Consequently, this highlights the importance of screening for hypogammaglobulinaemia in these hematological conditions. Wang et al. have noted that the frequency of recurrent episodes of autoimmune cytopenias decreased following institution of immunoglobulin replacement (Wang and Cunningham-Rundles, 2005) although this was not noted in a different study (Michel et al., 2004). Therapy for standard ITP/AIHA including steroids, high-dose IVIG and antirhesus D immunoglobulin have been effective (Wang and CunninghamRundles, 2005). Rituximab has also been used in refractory cases of ITP/ AIHA with success (Cunningham-Rundles, 2010). It has also been
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recommended that splenectomy be avoided due to the risk of severe infections (Cunningham-Rundles and Bodian, 1999) although this is not universal (Michel et al., 2004). A current survey of 53 splenectomised CVID patients is underway and will address this specific question (Huisson and Warnatz, privileged communication). The treatment for other autoimmune diseases follows standard protocols. Immune suppression is often tolerated well in patients with CVID, possibly due to the protection IgG replacement and antibiotics are providing.
7.5. Granulomatous/lymphoproliferative disease/hyperplasia

Polyclonal lymphoid infiltration is not uncommonly seen in CVID and is associated with the development of lymphoid malignancy and a worse prognosis (Bates et al., 2004; Chapel et al., 2008; Morimoto and Routes, 2005). Splenomegaly, cervical, mediastinal, and abdominal lymphoid hyperplasia can be found in up to 20% of patients; biopsies can show atypical lymphoid hyperplasia, reactive lymphoid hyperplasia or granulomatous inflammation (Cunningham-Rundles, 2010). Granulomatous inflammation affects between 8% and 22% of patients with CVID (Ardeniz and Cunningham-Rundles, 2009; Bates et al., 2004; Cunningham-Rundles and Bodian, 1999; Morimoto and Routes, 2005) and can be mistaken for straightforward sarcoidosis resulting in diagnostic delay. It commonly affects the lungs, lymph nodes and spleen but can be found in most other organs including liver, parotid glands, meninges, and bone marrow (Ardeniz and Cunningham-Rundles, 2009; Mechanic et al., 1997). In a subset of patients, lung granuloma can also be accompanied by an intense lymphocytic infiltration; a condition described as granulomatous lymphocytic interstitial lung disease (GLILD) which carries a poorer outcome (Morimoto and Routes, 2005). Granulomatous disease is also associated with lymphoid interstitial pneumonia and lymphadenopathy (Chapel et al., 2008). A comprehensive review on lung pathology observed in CVID is underway and preliminary results can be viewed at www.chest-ct-goup.eu. Patients with granulomatous disease are also more prone to autoimmune phenomenon; for example 54% of patients with granulomas had autoimmunity (Ardeniz and Cunningham-Rundles, 2009). Survival is also reduced with one study showing a median survival of 13.7 years in CVID patients with granulomatous/lymphoid interstitial infiltrates compared to 28.8 years in patients without these complications (Morimoto and Routes, 2005). The etiology of granulomatous disease remains uncertain as HHV-8 in the lung (Wheat et al., 2005) and cytomegalovirus in the gut have been implicated, but never confirmed (Raeiszadeh et al., 2006). In addition, polymorphisms in TNF and IL10 genes have also been associated with granulomatous disease suggesting a role for altered
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inflammatory regulation contributing to the pathogenesis (Mullighan et al., 1997, 1999). The treatment of granulomatous disease and lymphocytic infiltration remains uncertain without any controlled studies. One suggested scheme involves the long-term use of hydroxycholoroquine on the basis of its effect on TLR responses and antigen presentation and for its use in sarcoidosis and autoimmunity (Cunningham-Rundles, 2010). However, although its effect on the skin may be sufficient, but in general hydroxychloroquine is of limited potency in more severe forms of granulomatosis. Therefore, oral steroids are frequently used with great benefit and a high response rate, but long-term usage needs to be balanced against the risk of side effects and infections. Inhaled steroids are also used for lung granulomas (Cunningham-Rundles, 2010). TNF inhibitors have also been tried and some success reported although none of these were used in controlled trials (Hatab and Ballas, 2005; Lin et al., 2006; Thatayatikom et al., 2005). The authors own experience is that anti-TNF may help in CVID enteropathy but not in granulomatous disease. In this context, it should be noted that although trials of TNF inhibitors have shown possible benefit in sarcoid (Doty et al., 2005), concerns regarding the development of sarcoid while on TNF inhibitors have been raised (Daien et al., 2009). Lymphoid interstitial pneumonia and other pulmonary lymphoid infiltrative diseases also represent therapeutic challenges as they can result in end-stage lung damage requiring oxygen therapy. In view of the T cell predominance in the lung infiltrate, ciclosporin has been used in a limited number of patients with some success although some of them eventually died due to respiratory disease (Ardeniz and CunninghamRundles, 2009; Davies et al., 2000). One suggested approach to managing lymphoid hyperplasia is taking biopsies of lymph nodes, infiltrates, or nodules if there is any doubt about their nature (Cunningham-Rundles, 2010). Tissue is also saved for EpsteinBarr-encoded RNAs analysis, cytogenetics and T and B cell clonality studies by molecular methods. The authors, however, make the point that clonal lymphocytes are not necessarily indicative of lymphoma as these results can be found in biopsies that show reactive hyperplasia (Gompels et al., 2003). It is also suggested that splenectomy should not be undertaken except for marked hypersplenism, uncontrollable autoimmunity or where lymphoma is a genuine concern (Cunningham-Rundles, 2010).
7.6. Malignancy
The overall incidence of malignancy is increased in CVID, although certain cancers are significantly more common, particularly gastric carcinoma and non-Hodgkin lymphomas which have an increased risk of 716 and 1218 times higher respectively, depending on the study
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(Cunningham-Rundles and Bodian, 1999; Quinti et al., 2007; Vajdic et al., 2010). Other cancers including colorectal cancer, breast cancer, ovarian cancer, prostate cancer, multiple myeloma and melanoma have been described although small numbers make it difficult to ascertain if these are genuinely increased in CVID (Cunningham-Rundles and Bodian, 1999; Quinti et al., 2007). However, data from the Australian registry does seem to suggest that malignancies occurring in CVID might be restricted to a fairly narrow spectrum compared to T cell immunodeficiencies (Vajdic et al., 2010). The reasons for the increased risk of malignancy in CVID are likely to be multifactorial (Chua et al., 2008). These would potentially include a complex interplay between chronic antigen stimulation from infection, the acquisition of genetic abnormalities and immune dysregulation. For example, the B cell related molecule BAFF has been shown to be increased with infection as well as when NHL tumors become more aggressive, potentially linking the factors mentioned above together (He et al., 2003; Novak et al., 2004). Atrophic gastritis is common in CVID and frequently associated with Helicobacter pylori infection (Zullo et al., 1999); as is pernicious anemia (Dhalla et al., 2011). In the general population, both H. pylori infection and pernicious anemia are known to increase the risk of gastric cancer (Forman et al., 1994; Hsing et al., 1993). Given the known increased risk of gastric cancer in CVID patients, surveillance protocols have been proposed and will be trialed in the near future (Dhalla et al., 2011). The suggested protocol involves testing all CVID patients for H. pylori and eradication as necessary, treatment of pernicious anemia with vitamin B12; and initial upper GI endoscopy if there are risk factors with repeat endoscopy depending on degree of risk. Lymphomas when present in CVID are frequently extranodal, B cell in origin and normally EBV negative (Cunningham-Rundles and Bodian, 1999; Gompels et al., 2003). Dissimilar to other primary immunodeficiencies, lymphoma in CVID is more common in the fourth to seventh decade of life. Mucosa associated lymphoid tissue lymphomas have also been reported in CVID (Cunningham-Rundles et al., 2002).
8. MANAGEMENT
The main therapeutic modalities available to treat CVID remain broadly the same with replacement immunoglobulin for the antibody deficiency and antibiotics for treatment and prevention of infections, as well as appropriate therapy for the noninfectious complications.
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8.1. IVIG and mortality/infections

Replacement immunoglobulin therapy for antibody deficiency represents the mainstay of treatment in CVID and although no randomized placebo trials have ever been done, it has been shown to reduce the rate of infections and their long-term complications (Busse et al., 2002; Cunningham-Rundles et al., 1984; de Gracia et al., 2004; Nolte et al., 1979; Roifman et al., 1985). Delivery of immunoglobulin through both the intravenous and subcutaneous routes appears to be equally effective in preventing infections (Chapel et al., 2000) and to be safe (Gardulf et al., 1995a). The use of subcutaneous immunoglobulins has also increased the ease and availability of home therapy for patients as well as improving quality of life compared to hospital administered IVIG (Gardulf et al., 1995b, 2007). Intravenous home therapy is licensed in the United Kingdom. Current practice for immunoglobulin replacement involves commencing an individual on therapy (usually in at a dose of 400 mg/kg total monthly dose) and then increasing the dose to achieve a target trough level. However, the optimum trough level to be achieved with immunoglobulin has been unclear with varying amounts suggested in different guidelines; levels > 800 mg/dl (Orange et al., 2006), > 700 mg/dl (Shehata et al., 2010) and between 650 and 1000 mg/dl (Roifman et al., 2008) have all been recommended. More recently, data from larger numbers of patients is now available to help guide the decision: Orange et al. (2010) performed a meta-analysis to evaluate trough IgG levels and incidence of pneumonia. In total, 17 studies with 676 patients (2127 patient-years of follow-up) were combined in the analysis. This showed that pneumonia incidence decreased as trough IgG levels were increased from 500 up to at least 1000 mg/dl. Pneumonia incidence at the higher dose was five times less than at the lowest dose. Lucas et al. (2010) analyzed data from 90 patients accumulated over 22 years from a single center. The centers policy had been to adjust immunoglobulin doses in relation to infective episodes rather than to aim for a specific trough level. Retrospective analysis of patient data following this policy showed a wide range of IgG trough levels (500 1700 mg/dl) and immunoglobulin doses (0.21.2 g/kg/month) required to control infections. Based on this, the authors concluded that the correct therapy for a given patient needed to be individualized. Their data also showed that in patients with bronchiectasis and splenomegaly, larger amounts of immunoglobulin therapy were required to maintain equivalent trough levels. Data was analyzed by clinical phenotype of patients (Lucas et al., 2010) and patients without disease complications were found to need lower doses of immunoglobulin replacement compared to those with enteropathy, cytopenias, or lymphoid interstitial pneumonia.
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Consistent with the findings of Lucas et al. (2010), there is also retrospective UK data in 107 patients showing no relationship between body mass index, trough IgG levels, infusion frequency and total annual dose (Khan et al., 2011). The patients had had their immunoglobulin dose titrated for optimum effect, suggesting that adjusting immunoglobulin dose by clinical outcome rather than using a fixed amount by body weight is appropriate. Quinti et al. analyzed data from 201 Italian patients with CVID and 101 patients with XLA in a 5-year multicenter prospective study with 1365 patient-years of follow-up (778 for CVID patients; Quinti et al., 2011). CVID patients had a reduction in pneumonia prevalence after commencement of immunoglobulin therapy (from 39.4% to 22.3%). Patients who experienced infections during treatment had a lower IgA and IgM. In some patients (particularly those with enteropathy) increasing the dose of replacement immunoglobulin did not result in adequate IgG levels and in other patients, raising the level of IgG did not prevent pneumonias. They also found that patients with pneumonia did not have significantly lower levels of IgG compared to those without in contrast to the previous two studies discussed; however, on grouping patients into intervals, they found that those with trough levels < 4 g/l were more likely to get pneumonia. Based on this, Quinti et al. advocated the approach of commencing replacement immunoglobulin therapy with low IgG levels even before the occurrence of serious infection. There was also no difference in trough levels between patients who developed bronchiectasis and those who did not; although IgA levels and age (but not pneumonia) were independently associated with development of bronchiectasis. One other approach that has been explored to help guide immunoglobulin replacement therapy was measuring specific antibody levels to individual pathogens. Chua et al. looked for discordance of antipneumococcal, antihaemophilus, and antitetanus toxoid antibody levels with total IgG levels to see if this could explain why different patients required different trough IgG levels to remain infection-free (Chua et al., 2011). They found, however, that the use of specific pathogen antibody levels did not contribute further to identifying patients who were more susceptible to chest infections when total trough IgG levels were adequate (defined in their study as > 7.0 g/l). Taken together, these data suggest that there might not be an IgG trough level that is universally appropriate (CVID is not CVID), and that there is merit in increasing the dose of immunoglobulin to reduce infection rates, although further data is required for trough doses > 1000 mg/dl. In addition, replacement of IgA/IgM (in addition to IgG) is worth considering as novel treatment strategies, because low levels are associated with greater infection burden. Risk factors for individual patients might also need to be taken into consideration for tailoring therapy.
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8.2. Antibiotic use

Generally, an aggressive approach is adopted for the treatment of acute respiratory infections to prevent long-term complications. If possible, appropriate microbiological specimens should be sent but this should not delay commencing empirical therapy while waiting for results. In addition, an extended treatment course (1014 days) of antibiotics is normally given to prevent relapse although the evidence base for this is limited. Antibiotic prophylaxis should also be considered for frequent infections (> 3 per year) or severe infections although again, the evidence for this is poor. In the context of management of bronchiectasis, there is also limited data in CVID, and most treatment strategies have been adapted from the experience with cystic fibrosis (CF) patients. Some physicians recommend increased doses of immunoglobulin in bronchiectasis. Antimicrobial prophylaxis with macrolides have been shown to have a possible benefit in CF-related and non-CF bronchiectasis (Clement et al., 2006; Cymbala et al., 2005; Davies and Wilson, 2004; Koh et al., 1997; Tsang et al., 1999; Yalcin et al., 2006). In the CF setting, colonization with pseudomonas usually marks the start of declining lung function and attempts at eradication on first growth (Taccetti et al., 2005) as well as aerosolized antibiotics may be beneficial (Chuchalin et al., 2007; Jensen et al., 1987; Moss, 2002). Although pseudomonas is less common in CVID, it would be reasonable to undertake these measures as well. We have summarized the local antibiotic protocols used in one of the London units as an example of the management issues discussed above (Tables 2.7, and 2.8); obviously this needs to be adapted to local needs, policies, and antibiotic resistances.
8.3. Organ and stem cell transplantation

There are a limited number of reports of lung and liver transplantation in CVID (Burton et al., 2007; Cunningham-Rundles and Bodian, 1999). These have had some (short-term) benefit although the limited numbers of cases make it difficult to draw any firm conclusions. Stem cell transplantation represents a potential cure for the immunodeficiency but at present, there is no clarity about when (and if) this should be undertaken in patients with CVID. It is most likely to be of benefit when there is severe immune deficit with T cell compromise (i.e., patients likely to fall into the LOCID subgroup). However, these patients are more likely to resemble a combined immune defect and should be screened for hypomorphic mutations that can cause SCID. There is virtually nothing in the literature regarding the role of stem cell transplantation in classical CVID; however, the Freiburg group has prepared a report on the first four cases with us (Rizzi et al., submitted).
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TABLE 2.7 An example of an antibiotic protocol for treatment of respiratory infections in CVID patients
Antibiotic protocol for respiratory infections All patients with productive cough require sputum monitoring. Patients should hold a stock of sputum pots at home to bring to the GP surgery or hospital prior to starting antibiotics. Patients should be encouraged to bring a sputum sample to clinic if possible. Generally treatment should commence immediately using the protocol below, and not be delayed pending sensitivities First line treatmentpatients not taking prophylaxis Preferred: Amoxicillin 500 mg tds Alternative for those with penicillin allergy: Macrolide Other possibilities (e.g., due to allergy to both agents): Levooxacin 500 mg od/moxioxacin 400 mg od First line treatmentpatients taking prophylaxis Preferred agent is Co-amoxiclav 625 mg tds For those with b-lactam allergy: If taking ciprooxacin prophylaxis, use a macrolide If taking a non-ciprooxacin based regime, use ciprooxacin Treatment failure If treatment fails, review clinical features considering the following: Antibiotics unsuitable/insufcient/non-compliance Resistant common organism, for example, drug resistant HIB Unusual organism, for example, Pseudomonas, MTB, opportunistic infection Complication has developed, for example, empyema, abscess Dealing with rst growth of Pseudomonas Upon the rst growth of pseudomonas, an attempt should be made to eradicate the organism with the following regime: Ciprooxacin 750 mg bd for 3 weeks Colomycin nebuliser 1 megaunit bd for 3 weeks (premed with salbutamol, rst dose with Respiratory Physio on Daycare) Repeat sputum culture following treatment if still productive If pseudomonas persistent or ciprooxacin-resistant, the patient should be admitted for a 2-week course of intravenous treatment nebulised colomycin. Patients usually receive two antibiotics, for example, ceftazidime gentamicin. Resist attempts to discharge the patient on early oral treatment, as this may be the last chance to eradicate the organism and oral therapy has already failed. Home therapy via a PICC line may be possible Repeat treatment if pseudomonas recurs later
TABLE 2.8 Example of a management protocol for antibody-decient patients requiring long-term prophylactic antibiotic treatment
Antimicrobial prophylaxis in the setting of humoral immunodeciency may be particularly indicated in the following situations: 1. Patients with partial antibody deciencies who are not currently candidates for immunoglobulin replacement. The spectrum of partial antibody deciencies includes IgA deciency, IgG subclass deciency and specic antibody deciency 2. Patients with deciencies of factors such as early complement that are non amenable to replacement 3. Patients with signicant antibody deciencies who are not yet established on immunoglobulin replacement 4. Antibody-decient patients with recurrent infections despite adequate immunoglobulin replacement 5. Bronchiectatic antibody-decient patients with progressive disease, evidenced by declining lung function and/or radiological deterioration 6. Patients with congenital or acquired asplenia, who have risk of invasive bacterial infection 7. Prophylaxis of respiratory infection in patients without bronchiectasis Consider treatment when infections are FREQUENT (four or more signicant infections per year) and/or SEVERE/DISRUPTIVE (e.g., hospital admission, prolonged period off work, secondary complications such as empyema) Infections should be microbiologically conrmed wherever possible. Consideration should be given to noninfective causes for symptoms such as chronic cough and sore throat, for example, reux, steroid inhalers, asthma, postnasal drip, postinfective bronchial hyperreactivity. Equally, patients with chronic cough may have developed bronchiectasis. Adequate trough IgG levels should be documented for immunoglobulin-treated individuals with recurrent infections For those not receiving replacement therapy, a constant review of symptoms, exacerbation frequency, microbiology, lung function and vaccine responses is required, as immunoglobulin replacement may be necessary The use of antimicrobial prophylaxis in the nonbronchiectasis setting is not supported by any published evidence. The commonest organisms are Streptococcus pneumoniae, Haemophilus inuenzae and Moraxella catarrhalis. Possible regimes for adults are: Azithromycin 250 mg three times per WEEK, if ineffective up to 1500 mg per WEEK Cotrimoxazole 960 mg three times per WEEK, dose can be increased Amoxicillin 500 mg, two times per DAY Ciprooxacin 250 mg, two times per DAY The choice will depend on previous microbiology and patient preference There is no published evidence that antibiotic rotation is benecial; although theoretically it might be, in practice it has fallen out of favor
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8.4. Monitoring
At present, there remains little evidence to guide appropriate monitoring in CVID and most protocols are derived from expert opinion. Respiratory monitoring generally consists of pulmonary function testing (PFT) and radiological imaging. Although PFT is not as sensitive as HRCT scans for detection and monitoring of lung disease (Bates et al., 2004; Watts et al., 1986), they carry no long-term risks and can be performed more frequently. We perform PFT at baseline and then annually. Plain chest radiographs do not provide as much information as HRCT and are of limited value. HRCT is the best method for detection of bronchiectasis and interstitial lung disease but does carry a significant exposure to ionizing radiation, which might be especially significant in CVID patients who are radiosensitive (Palanduz et al., 1998; Vorechovsky et al., 1993). A 3- to 5-year screening interval has been used by several investigators (Cunningham-Rundles, 2010; Quinti et al., 2007). we perform a HRCT scan of the chest at baseline, at 5-yearly intervals, and when clinically indicated. Screening for gastrointestinal and lymphoproliferative complications is more unclear. Some investigators do not advocate screening for gastrointestinal disease unless there are symptoms (Cunningham-Rundles, 2010); although in view of the increased risk of gastric cancer, proposals have been made for H. pylori screening and endoscopy if there are any risk factors (Dhalla et al., 2011). In the 1990s, yearly upper endoscopies were carried out in the Freiburg center. This was stopped in the 2000s. Since then, one patient has died due to gastric cancer. In the London cohort a patient has been saved by early diagnosis and total gastrectomy. As the lymph node architecture in CVID patients is often difficult to interpret even for the experienced pathologist, mere lymph node core needle biopsies may not be sufficient for the difficult differential diagnosis of benign versus malignant lymphoproliferation in CVID, and the excision of the whole lymph node is recommended by the authors. This should be undertaken for persistently enlarged nodes although it has been noted that lymphomas in CVID are frequently extranodal (Cunningham-Rundles, 2010). One group also undertook annual ultrasound measurements of splenic size (Quinti et al., 2007). This showed in 26% of patients a constant increase in splenic size during follow-up, whereas in 5% splenomegaly was only detectable at diagnosis but returned to normal thereafter. With the discovery of data predicting the increased risk of complications in certain subgroups (Chapel et al., 2008), development of patienttailored protocols depending on the clinical phenotype and risk factors might well be more appropriate.
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9. PROGNOSIS AND SURVIVAL

Mortality in CVID is increased compared to the general population although data now suggests that there has been an improvement in mortality over time. Data published in 1999 on an American cohort had a 23% mortality rate at 7 years of follow-up (Cunningham-Rundles and Bodian, 1999). The probability of survival for 20 years after a diagnosis of CVID was 64% for males and 67% for females compared to 92% and 94% respectively for the background population (Cunningham-Rundles and Bodian, 1999). Data from a UK cohort of 240 patients published in 1993 showed a 30% mortality over a 25-year period (Hermaszewski and Webster, 1993). A more recent Italian cohort published in 2007 showed 6% mortality after 11 years of follow-up (Quinti et al., 2007). The most recent published data from the ESID registry showed a 15% mortality rate over a 22.5-year follow-up period, a significant improvement when compared to the previous United Kingdom and American cohorts (Chapel et al., 2008). Analysis of that data also revealed other information; certain clinical phenotypes (which were autoimmunity, lymphoid proliferation, enteropathy, lymphoid malignancy) were associated with greater risk of death compared to patients who only had recurrent infections (Chapel et al., 2008). Brochiectasis was also associated with a worse outcome. However, there were some unusual findings; a very low serum IgG of < 1.5 g/l was not significantly associated with diagnostic delay, serious infections before diagnosis, a greater incidence of lung disease or mortality (Chapel et al., 2008). Also, unexpectedly, mortality was also not related to the age at onset of symptoms, age at diagnosis or duration of diagnostic delay.
10. SUMMARY
Recent years have seen many exciting developments in the field of CVID (and primary immunodeficiencies in general). The rate of genetic discoveries that cause or contribute to a CVID phenotype is increasing, and genome-wide studies are now starting to be performed. Subsequently, these gene mutations have shown us what happens in humans when specific parts of the immune system are nonfunctional. Several attempts have also been made at tackling the heterogeneity of the disease by developing various classification schemes. Hopefully these distinct subgroups of patients will enable more focused research both aimed at understanding the pathology as well as improving their clinical care. There is now data showing that patients with CVID are surviving longer, possibly due to better treatment of the disease, even though overall the diagnostic delay of CVID is not greatly different.
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However, we still have very limited understanding of the heterogeneity of the condition and how the genetic discoveries fit into causing illness. In addition, we have very little understanding of how many of the complications in CVID arise, much less the best way of treating them. The classification of patients into different subgroups is a promising start to addressing these issues although much work still needs to be done. In conclusion, there is much we have learnt about the immune system from patients with CVID. In turn, it is hoped that as we better understand the complexity of illness, care of patients will continue to improve.
REFERENCES
Agarwal, S., and Mayer, L. (2010). Gastrointestinal manifestations in primary immune disorders. Inflamm. Bowel Dis. 16(4), 703711. Agarwal, S., Smereka, P., Harpaz, N., Cunningham-Rundles, C., and Mayer, L. (2011). Characterization of immunologic defects in patients with common variable immunodeficiency (CVID) with intestinal disease. Inflamm. Bowel Dis. 17(1), 251259. Akiba, H., Takeda, K., Kojima, Y., et al. (2005). The role of ICOS in the CXCR5 follicular B helper T cell maintenance in vivo. J. Immunol. 175(4), 23402348. Ardeniz, O., and Cunningham-Rundles, C. (2009). Granulomatous disease in common variable immunodeficiency. Clin. Immunol. 133(2), 198207. Aslam, A., Misbah, S. A., Talbot, K., and Chapel, H. (2004). Vitamin E deficiency induced neurological disease in common variable immunodeficiency: Two cases and a review of the literature of vitamin E deficiency. Clin. Immunol. 112(1), 2429. Aukrust, P., Muller, F., and Froland, S. S. (1994). Elevated serum levels of interleukin-4 and interleukin-6 in patients with common variable immunodeficiency (CVI) are associated with chronic immune activation and low numbers of CD4 lymphocytes. Clin. Immunol. Immunopathol. 70(3), 217224. Bates, C. A., Ellison, M. C., Lynch, D. A., Cool, C. D., Brown, K. K., and Routes, J. M. (2004). Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J. Allergy Clin. Immunol. 114(2), 415421. Boncristiano, M., Majolini, M. B., DElios, M. M., et al. (2000). Defective recruitment and activation of ZAP-70 in common variable immunodeficiency patients with T cell defects. Eur. J. Immunol. 30(9), 26322638. Boyle, J. M., and Buckley, R. H. (2007). Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J. Clin. Immunol. 27(5), 497502. Braig, D. U., Schaffer, A. A., Glocker, E., et al. (2003). Linkage of autosomal dominant common variable immunodeficiency to chromosome 5p and evidence for locus heterogeneity. Hum. Genet. 112(4), 369378. Bridges, L. C., Tani, P. H., Hanson, K. R., Roberts, C. M., Judkins, M. B., and Bowditch, R. D. (2002). The lymphocyte metalloprotease MDC-L (ADAM 28) is a ligand for the integrin alpha4beta1. J. Biol. Chem. 277(5), 37843792. Bryant, A., Calver, N. C., Toubi, E., Webster, A. D., and Farrant, J. (1990). Classification of patients with common variable immunodeficiency by B cell secretion of IgM and IgG in response to anti-IgM and interleukin-2. Clin. Immunol. Immunopathol. 56(2), 239248. Bubien, J. K., Zhou, L. J., Bell, P. D., Frizzell, R. A., and Tedder, T. F. (1993). Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2 conductance found constitutively in B lymphocytes. J. Cell Biol. 121(5), 11211132.
97
Burton, C. M., Milman, N., Andersen, C. B., Marquart, H., and Iversen, M. (2007). Common variable immune deficiency and lung transplantation. Scand. J. Infect. Dis. 39(4), 362367. Busse, P. J., Razvi, S. F., and Cunningham-Rundles, C. (2002). Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J. Allergy Clin. Immunol. 109(6), 10011004. Carreno, B. M., and Collins, M. (2002). The B7 family of ligands and its receptors: New pathways for costimulation and inhibition of immune responses. Annu. Rev. Immunol. 20, 2953. Carsetti, R., Rosado, M. M., Donnanno, S., et al. (2005). The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency. J. Allergy Clin. Immunol. 115(2), 412417. Carter, R. H., and Fearon, D. T. (1992). CD19: Lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256(5053), 105107. Carvalho Neves, F. W., Ferreira De Carvalho, J. F., Damaceno, N., Vidal, P. F., Gonzales, L. C., and Mastroti, R. A. (2000). Evolution of IgA deficiency to IgG subclass deficiency and common variable immunodeficiency. Allergol. Immunopathol. (Madr.) 28(1), 1820. Castigli, E., Scott, S., Dedeoglu, F., et al. (2004). Impaired IgA class switching in APRILdeficient mice. Proc. Natl. Acad. Sci. USA. 101(11), 39033908. Castigli, E., Wilson, S. A., Scott, S., et al. (2005a). TACI and BAFF-R mediate isotype switching in B cells. J. Exp. Med. 201(1), 3539. Castigli, E., Wilson, S. A., Garibyan, L., et al. (2005b). TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat. Genet. 37(8), 829834. Castigli, E., Wilson, S., Garibyan, L., et al. (2007). Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat. Genet. 39(4), 430431. Chapel, H., and Cunningham-Rundles, C. (2009). Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions. Br. J. Haematol. 145(6), 709727. Chapel, H. M., Spickett, G. P., Ericson, D., Engl, W., Eibl, M. M., and Bjorkander, J. (2000). The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J. Clin. Immunol. 20(2), 94100. Chapel, H., Lucas, M., Lee, M., et al. (2008). Common variable immunodeficiency disorders: Division into distinct clinical phenotypes. Blood 112(2), 277286. Choi, Y. S., Kageyama, R., Eto, D., et al. (2011). ICOS Receptor Instructs T Follicular Helper Cell versus Effector Cell Differentiation via Induction of the Transcriptional Repressor Bcl6. Immunity 34, 932946. Chua, I., Standish, R., Lear, S., et al. (2007). Anti-tumour necrosis factor-alpha therapy for severe enteropathy in patients with common variable immunodeficiency (CVID). Clin. Exp. Immunol. 150(2), 306311. Chua, I., Quinti, I., and Grimbacher, B. (2008). Lymphoma in common variable immunodeficiency: Interplay between immune dysregulation, infection and genetics. Curr. Opin. Hematol. 15(4), 368374. Chua, I., Lagos, M., Charalambous, B. M., Workman, S., Chee, R., and Grimbacher, B. (2011). Pathogen-specific IgG antibody levels in immunodeficient patients receiving immunoglobulin replacement do not provide additional benefit to therapeutic management over total serum IgG. J. Allergy Clin. Immunol. 127(6), 14101411. Chuchalin, A., Csiszer, E., Gyurkovics, K., et al. (2007). A formulation of aerosolized tobramycin (Bramitob) in the treatment of patients with cystic fibrosis and Pseudomonas aeruginosa infection: A double-blind, placebo-controlled, multicenter study. Paediatr. Drugs 9(Suppl 1), 2131.
98
Clement, A., Tamalet, A., Leroux, E., Ravilly, S., Fauroux, B., and Jais, J. P. (2006). Long term effects of azithromycin in patients with cystic fibrosis: A double blind, placebo controlled trial. Thorax 61(10), 895902. Conley, M. E., Notarangelo, L. D., and Etzioni, A. (1999). Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin. Immunol. 93(3), 190197. Cooper, M. D., Faulk, W. P., Fudenberg, H. H., et al. (1973). Classification of primary immunodeficiencies. N. Engl. J. Med. 288(18), 966967. Cunningham-Rundles, C. (2010). How I treat common variable immune deficiency. Blood 116(1), 715. Cunningham-Rundles, C., and Bodian, C. (1999). Common variable immunodeficiency: Clinical and immunological features of 248 patients. Clin. Immunol. 92(1), 3448. Cunningham-Rundles, C., and Radigan, L. (2005). Deficient IL-12 and dendritic cell function in common variable immune deficiency. Clin. Immunol. 115(2), 147153. Cunningham-Rundles, C., Siegal, F. P., Smithwick, E. M., et al. (1984). Efficacy of intravenous immunoglobulin in primary humoral immunodeficiency disease. Ann. Intern. Med. 101 (4), 435439. Cunningham-Rundles, C., Cooper, D. L., Duffy, T. P., and Strauchen, J. (2002). Lymphomas of mucosal-associated lymphoid tissue in common variable immunodeficiency. Am. J. Hematol. 69(3), 171178. Cymbala, A. A., Edmonds, L. C., Bauer, M. A., et al. (2005). The disease-modifying effects of twice-weekly oral azithromycin in patients with bronchiectasis. Treat. Respir. Med. 4(2), 117122. Daien, C. I., Monnier, A., Claudepierre, P., et al. (2009). Sarcoid-like granulomatosis in patients treated with tumor necrosis factor blockers: 10 cases. Rheumatology (Oxford) 48(8), 883886. Daniels, J. A., Lederman, H. M., Maitra, A., and Montgomery, E. A. (2007). Gastrointestinal tract pathology in patients with common variable immunodeficiency (CVID): A clinicopathologic study and review. Am. J. Surg. Pathol. 31(12), 18001812. Davies, G., and Wilson, R. (2004). Prophylactic antibiotic treatment of bronchiectasis with azithromycin. Thorax 59(6), 540541. Davies, C. W., Juniper, M. C., Gray, W., Gleeson, F. V., Chapel, H. M., and Davies, R. J. (2000). Lymphoid interstitial pneumonitis associated with common variable hypogammaglobulinaemia treated with cyclosporin A. Thorax 55(1), 8890. de Gracia, J., Vendrell, M., Alvarez, A., et al. (2004). Immunoglobulin therapy to control lung damage in patients with common variable immunodeficiency. Int. Immunopharmacol. 4(6), 745753. Dhalla, F., da Silva, S. P., Lucas, M., Travis, S., and Chapel, H. (2011). Review of gastric cancer risk factors in patients with common variable immunodeficiency disorders, resulting in a proposal for a surveillance programme. Clin. Exp. Immunol. 165, 17. Di, R. M., Serrano, D., Zhou, Z., George, I., Becker, K., and Cunningham-Rundles, C. (2001). Enhanced T cell apoptosis in common variable immunodeficiency: Negative role of the fas/fasligand system and of the Bcl-2 family proteins and possible role of TNF-RS. Clin. Exp. Immunol. 125(1), 117122. Dolmetsch, R. E., Lewis, R. S., Goodnow, C. C., and Healy, J. I. (1997). Differential activation of transcription factors induced by Ca2 response amplitude and duration. Nature 386 (6627), 855858. Doty, J. D., Mazur, J. E., and Judson, M. A. (2005). Treatment of sarcoidosis with infliximab. Chest 127(3), 10641071. Eastwood, D., Gilmour, K. C., Nistala, K., et al. (2004). Prevalence of SAP gene defects in male patients diagnosed with common variable immunodeficiency. Clin. Exp. Immunol. 137(3), 584588.
99
Escobar, D., Pons, J., Clemente, A., et al. (2010). Defective B cell response to TLR9 ligand (CpG-ODN), Streptococcus pneumoniae and Haemophilus influenzae extracts in common variable immunodeficiency patients. Cell. Immunol. 262(2), 105111. Espanol, T., Catala, M., Hernandez, M., Caragol, I., and Bertran, J. M. (1996). Development of a common variable immunodeficiency in IgA-deficient patients. Clin. Immunol. Immunopathol. 80(3 Pt 1), 333335. Farrington, M., Grosmaire, L. S., Nonoyama, S., et al. (1994). CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency. Proc. Natl. Acad. Sci. USA 91(3), 10991103. Fearon, D. T., and Carroll, M. C. (2000). Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annu. Rev. Immunol. 18, 393422. Feske, S. (2007). Calcium signalling in lymphocyte activation and disease. Nat. Rev. Immunol. 7(9), 690702. Finck, A., van Der Meer, J. W., Schaffer, A. A., et al. (2006). Linkage of autosomal-dominant common variable immunodeficiency to chromosome 4q. Eur. J. Hum. Genet. 14(7), 867875. First case of human CD21 deficiency (2004). First case of human CD21 deficiency presenting with hypogammaglobulinaemia but virtually normal specific antibody production upon vaccination. XIth Meeting of the European society for Immunodeficiencies; 04 Oct, p. 21. Foerster, C., Voelxen, N., Rakhmanov, M., et al. (2010). B cell receptor-mediated calcium signaling is impaired in B lymphocytes of type Ia patients with common variable immunodeficiency. J. Immunol. 184(12), 73057313. Forman, D., Webb, P., and Parsonnet, J. (1994). H pylori and gastric cancer. Lancet 343(8891), 243244. Franz, A., Webster, A. D., Furr, P. M., and Taylor-Robinson, D. (1997). Mycoplasmal arthritis in patients with primary immunoglobulin deficiency: Clinical features and outcome in 18 patients. Br. J. Rheumatol. 36(6), 661668. Gardulf, A., Andersen, V., Bjorkander, J., et al. (1995a). Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: Safety and costs. Lancet 345 (8946), 365369. Gardulf, A., Bjorvell, H., Andersen, V., et al. (1995b). Lifelong treatment with gammaglobulin for primary antibody deficiencies: The patients experiences of subcutaneous self-infusions and home therapy. J. Adv. Nurs. 21(5), 917927. Gardulf, A., Borte, M., Ochs, H. D., and Nicolay, U. (2007). Prognostic factors for healthrelated quality of life in adults and children with primary antibody deficiencies receiving SCIG home therapy. Clin. Immunol. 126(1):8188. Epub 2007 Oct 26. Gathmann, B., Grimbacher, B., Beaute, J., et al. (2009). The European internet-based patient and research database for primary immunodeficiencies: Results 20062008. Clin. Exp. Immunol. 157(Suppl 1), 311. Giovannetti, A., Pierdominici, M., Mazzetta, F., et al. (2007). Unravelling the complexity of T cell abnormalities in common variable immunodeficiency. J. Immunol. 178(6), 39323943. Giovannetti, A., Pierdominici, M., and Aiuti, F. (2008). T-cell homeostasis: The dark(ened) side of common variable immunodeficiency. Blood 112(2), 446447. Gomes Ochtrop, M. L., Goldacker, S., May, A. M., et al. (2011). T- and B-lymphocyte abnormalities in bone marrow biopsies of common variable immunodeficiency. Blood 118, 309318. Gompels, M. M., Hodges, E., Lock, R. J., et al. (2003). Lymphoproliferative disease in antibody deficiency: A multi-centre study. Clin. Exp. Immunol. 134(2), 314320. Good, R. A., and Varco, R. L. (1955). A clinical and experimental study of agammaglobulinemia. J. Lancet 75(6), 245271. Grimbacher, B., Hutloff, A., Schlesier, M., et al. (2003). Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat. Immunol. 4(3), 261268.
100
Guazzi, V., Aiuti, F., Mezzaroma, I., et al. (2002). Assessment of thymic output in common variable immunodeficiency patients by evaluation of T cell receptor excision circles. Clin. Exp. Immunol. 129(2), 346353. Gutierrez, M. G., and Kirkpatrick, C. H. (1997). Progressive immunodeficiency in a patient with IgA deficiency. Ann. Allergy Asthma Immunol. 79(4), 297301. Halliday, E., Winkelstein, J., and Webster, A. D. (2003). Enteroviral infections in primary immunodeficiency (PID): A survey of morbidity and mortality. J. Infect. 46(1), 18. Hammarstrom, L., Vorechovsky, I., and Webster, D. (2000). Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin. Exp. Immunol. 120(2), 225231. Hare, N. D., Smith, B. J., and Ballas, Z. K. (2009). Antibody response to pneumococcal vaccination as a function of preimmunization titer. J. Allergy Clin. Immunol. 123(1), 195200. Hashimoto, A., Takeda, K., Inaba, M., et al. (2000). Cutting edge: Essential role of phospholipase C-gamma 2 in B cell development and function. J. Immunol. 165(4), 17381742. Hatab, A. Z., and Ballas, Z. K. (2005). Caseating granulomatous disease in common variable immunodeficiency treated with infliximab. J. Allergy Clin. Immunol. 116(5), 11611162. He, B., Raab-Traub, N., Casali, P., and Cerutti, A. (2003). EBV-encoded latent membrane protein 1 cooperates with BAFF/BLyS and APRIL to induce T cell-independent Ig heavy chain class switching. J. Immunol. 171(10), 52155224. He, B., Xu, W., Santini, P. A., et al. (2007). Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26(6), 812826. Hermans, P. E., az-Buxo, J. A., and Stobo, J. D. (1976). Idiopathic late-onset immunoglobulin deficiency. Clinical observations in 50 patients. Am. J. Med. 61(2), 221237. Hermaszewski, R. A., and Webster, A. D. (1993). Primary hypogammaglobulinaemia: A survey of clinical manifestations and complications. Q. J. Med. 86(1), 3142. Hikida, M., Johmura, S., Hashimoto, A., Takezaki, M., and Kurosaki, T. (2003). Coupling between B cell receptor and phospholipase C-gamma2 is essential for mature B cell development. J. Exp. Med. 198(4), 581589. Hikida, M., Casola, S., Takahashi, N., et al. (2009). PLC-gamma2 is essential for formation and maintenance of memory B cells. J. Exp. Med. 206(3), 681689. Holm, A. M., Aukrust, P., Damas, J. K., Muller, F., Halvorsen, B., and Froland, S. S. (2005). Abnormal interleukin-7 function in common variable immunodeficiency. Blood 105(7), 28872890. Hsing, A. W., Hansson, L. E., McLaughlin, J. K., et al. (1993). Pernicious anemia and subsequent cancer. A population-based cohort study. Cancer 71(3), 745750. Hutloff, A., Dittrich, A. M., Beier, K. C., et al. (1999). ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397(6716), 263266. Janeway, C., Apt, L., and Gitlin, D. (1953). Agammaglobulinemia. Trans. Assoc. Am. Physicians 66, 200202. Jensen, T., Pedersen, S. S., Garne, S., Heilmann, C., Hoiby, N., and Koch, C. (1987). Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection. J. Antimicrob. Chemother. 19(6), 831838. Kainulainen, L., Varpula, M., Liippo, K., Svedstrom, E., Nikoskelainen, J., and Ruuskanen, O. (1999). Pulmonary abnormalities in patients with primary hypogammaglobulinemia. J. Allergy Clin. Immunol. 104(5), 10311036. Kainulainen, L., Nikoskelainen, J., and Ruuskanen, O. (2001). Diagnostic findings in 95 Finnish patients with common variable immunodeficiency. J. Clin. Immunol. 21(2), 145149. Kanegane, H., Tsukada, S., Iwata, T., et al. (2000). Detection of Brutons tyrosine kinase mutations in hypogammaglobulinaemic males registered as common variable
101
immunodeficiency (CVID) in the Japanese Immunodeficiency Registry. Clin. Exp. Immunol. 120(3), 512517. Kanegane, H., Agematsu, K., Futatani, T., et al. (2007). Novel mutations in a Japanese patient with CD19 deficiency. Genes Immun. 8(8), 663670. Kelesidis, T., and Yang, O. (2010). Goods syndrome remains a mystery after 55 years: A systematic review of the scientific evidence. Clin. Immunol. 135(3), 347363. Khan, S., Grimbacher, B., Boecking, C., et al. (2011). Serum trough IgG level and annual intravenous immunoglobulin dose are not related to body size in patients on regular replacement therapy. Drug Metab. Lett. 5(2), 132136. Koh, Y. Y., Lee, M. H., Sun, Y. H., Sung, K. W., and Chae, J. H. (1997). Effect of roxithromycin on airway responsiveness in children with bronchiectasis: A double-blind, placebocontrolled study. Eur. Respir. J. 10(5), 994999. Kondratenko, I., Amlot, P. L., Webster, A. D., and Farrant, J. (1997). Lack of specific antibody response in common variable immunodeficiency (CVID) associated with failure in production of antigen-specific memory T cells. MRC Immunodeficiency Group. Clin. Exp. Immunol. 108(1), 913. Kracker, S., Gardes, P., Mazerolles, F., and Durandy, A. (2010). Immunoglobulin class switch recombination deficiencies. Clin. Immunol. 135(2), 193203. Kralovicova, J., Hammarstrom, L., Plebani, A., Webster, A. D., and Vorechovsky, I. (2003). Fine-scale mapping at IGAD1 and genome-wide genetic linkage analysis implicate HLADQ/DR as a major susceptibility locus in selective IgA deficiency and common variable immunodeficiency. J. Immunol. 170(5), 27652775. Kuijpers, T. W., Bende, R. J., Baars, P. A., et al. (2010). CD20 deficiency in humans results in impaired T cell-independent antibody responses. J. Clin. Invest. 120(1), 214222. Kurosaki, T., and Hikida, M. (2009). Tyrosine kinases and their substrates in B lymphocytes. Immunol. Rev. 228(1), 132148. Lee, W. I., Zhu, Q., Gambineri, E., Jin, Y., Welcher, A. A., and Ochs, H. D. (2003). Inducible CO-stimulator molecule, a candidate gene for defective isotype switching, is normal in patients with hyper-IgM syndrome of unknown molecular diagnosis. J. Allergy Clin. Immunol. 112(5), 958964. Lee, W. I., Torgerson, T. R., Schumacher, M. J., Yel, L., Zhu, Q., and Ochs, H. D. (2005). Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome. Blood 105(5), 18811890. Levy, S., Todd, S. C., and Maecker, H. T. (1998). CD81 (TAPA-1): A molecule involved in signal transduction and cell adhesion in the immune system. Annu. Rev. Immunol. 16, 89109. Liang, Y., and Tedder, T. F. (2001). Identification of a CD20-, FcepsilonRIbeta-, and HTm4related gene family: Sixteen new MS4A family members expressed in human and mouse. Genomics 72(2), 119127. Lin, J. H., Liebhaber, M., Roberts, R. L., Dyer, Z., and Stiehm, E. R. (2006). Etanercept treatment of cutaneous granulomas in common variable immunodeficiency. J. Allergy Clin. Immunol. 117(4), 878882. Litinskiy, M. B., Nardelli, B., Hilbert, D. M., et al. (2002). DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat. Immunol. 3(9), 822829. Litzman, J., Freiberger, T., Grimbacher, B., et al. (2008). Mannose-binding lectin gene polymorphic variants predispose to the development of bronchopulmonary complications but have no influence on other clinical and laboratory symptoms or signs of common variable immunodeficiency. Clin. Exp. Immunol. 153(3), 324330. Lucas, M., Lee, M., Lortan, J., Lopez-Granados, E., Misbah, S., and Chapel, H. (2010). Infection outcomes in patients with common variable immunodeficiency disorders: Relationship to immunoglobulin therapy over 22 years. J. Allergy Clin. Immunol. 125(6), 13541360.
102
Maecker, H. T., and Levy, S. (1997). Normal lymphocyte development but delayed humoral immune response in CD81-null mice. J. Exp. Med. 185(8), 15051510. Malamut, G., Ziol, M., Suarez, F., et al. (2008). Nodular regenerative hyperplasia: The main liver disease in patients with primary hypogammaglobulinemia and hepatic abnormalities. J. Hepatol. 48(1), 7482. Malphettes, M., Gerard, L., Carmagnat, M., et al. (2009). Late-onset combined immune deficiency: A subset of common variable immunodeficiency with severe T cell defect. Clin. Infect. Dis. 49(9), 13291338. Mannon, P. J., Fuss, I. J., Dill, S., et al. (2006). Excess IL-12 but not IL-23 accompanies the inflammatory bowel disease associated with common variable immunodeficiency. Gastroenterology 131(3), 748756. Martinez Garcia, M. A., de Rojas, M. D., Nauffal Manzur, M. D., et al. (2001). Respiratory disorders in common variable immunodeficiency. Respir. Med. 95(3), 191195. Matsumoto, A. K., Kopicky-Burd, J., Carter, R. H., Tuveson, D. A., Tedder, T. F., and Fearon, D. T. (1991). Intersection of the complement and immune systems: A signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19. J. Exp. Med. 173(1), 5564. McKinney, R. E., Jr., Katz, S. L., and Wilfert, C. M. (1987). Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev. Infect. Dis. 9(2), 334356. Mechanic, L. J., Dikman, S., and Cunningham-Rundles, C. (1997). Granulomatous disease in common variable immunodeficiency. Ann. Intern. Med. 127(8 Pt 1), 613617. Michel, M., Chanet, V., Galicier, L., et al. (2004). Autoimmune thrombocytopenic purpura and common variable immunodeficiency: Analysis of 21 cases and review of the literature. Medicine (Baltimore) 83(4), 254263. Morimoto, Y., and Routes, J. M. (2005). Granulomatous disease in common variable immunodeficiency. Curr. Allergy Asthma Rep. 5(5), 370375. Moss, R. B. (2002). Long-term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis. Chest 121(1), 5563. Mouillot, G., Carmagnat, M., Gerard, L., et al. (2010). B-cell and T-cell phenotypes in CVID patients correlate with the clinical phenotype of the disease. J. Clin. Immunol. 30(5), 746755. Mullighan, C. G., Fanning, G. C., Chapel, H. M., and Welsh, K. I. (1997). TNF and lymphotoxin-alpha polymorphisms associated with common variable immunodeficiency: Role in the pathogenesis of granulomatous disease. J. Immunol. 159(12), 62366241. Mullighan, C. G., Marshall, S. E., Bunce, M., and Welsh, K. I. (1999). Variation in immunoregulatory genes determines the clinical phenotype of common variable immunodeficiency. Genes Immun. 1(2), 137148. Mullighan, C. G., Marshall, S. E., and Welsh, K. I. (2000). Mannose binding lectin polymorphisms are associated with early age of disease onset and autoimmunity in common variable immunodeficiency. Scand. J. Immunol. 51(2), 111122. Nolte, M. T., Pirofsky, B., Gerritz, G. A., and Golding, B. (1979). Intravenous immunoglobulin therapy for antibody deficiency. Clin. Exp. Immunol. 36(2), 237243. Novak, A. J., Grote, D. M., Stenson, M., et al. (2004). Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: Correlation with disease activity and patient outcome. Blood 104(8), 22472253. OBrien, K. L., Hochman, M., and Goldblatt, D. (2007). Combined schedules of pneumococcal conjugate and polysaccharide vaccines: Is hyporesponsiveness an issue? Lancet Infect. Dis. 7(9), 597606. Offer, S. M., Pan-Hammarstrom, Q., Hammarstrom, L., and Harris, R. S. (2010). Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID. PLoS One 5(8), e12260. Oksenhendler, E., Gerard, L., Fieschi, C., et al. (2008). Infections in 252 patients with common variable immunodeficiency. Clin. Infect. Dis. 46(10), 15471554.
103
Olerup, O., Smith, C. I., Bjorkander, J., and Hammarstrom, L. (1992). Shared HLA class IIassociated genetic susceptibility and resistance, related to the HLA-DQB1 gene, in IgA deficiency and common variable immunodeficiency. Proc. Natl. Acad. Sci. USA 89(22), 1065310657. Orange, J. S., Hossny, E. M., Weiler, C. R., et al. (2006). Use of intravenous immunoglobulin in human disease: A review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J. Allergy Clin. Immunol. 117(4 Suppl), S525S553. Orange, J. S., Grossman, W. J., Navickis, R. J., and Wilkes, M. M. (2010). Impact of trough IgG on pneumonia incidence in primary immunodeficiency: A meta-analysis of clinical studies. Clin. Immunol. 137(1), 2130. Orange, J. S., Glessner, J. T., Resnick, E., et al. (2011). Genome-wide association identifies diverse causes of common variable immunodeficiency. J. Allergy Clin. Immunol. 127, 1360. Paccani, S. R., Boncristiano, M., Patrussi, L., et al. (2005). Defective Vav expression and impaired F-actin reorganization in a subset of patients with common variable immunodeficiency characterized by T-cell defects. Blood 106(2), 626634. Palanduz, S., Palanduz, A., Yalcin, I., et al. (1998). In vitro chromosomal radiosensitivity in common variable immune deficiency. Clin. Immunol. Immunopathol. 86(2), 180182. Pan-Hammarstrom, Q., Salzer, U., Du, L., et al. (2007). Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat. Genet. 39(4), 429430. Piqueras, B., Lavenu-Bombled, C., Galicier, L., et al. (2003). Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. J. Clin. Immunol. 23(5), 385400. Pozzi, N., Gaetaniello, L., Martire, B., et al. (2001). Defective surface expression of attractin on T cells in patients with common variable immunodeficiency (CVID). Clin. Exp. Immunol. 123(1), 99104. Primary immunodeficiency diseases (1999). Report of an IUIS Scientific Committee. International Union of Immunological Societies. Clin. Exp. Immunol. 118(Suppl 1), 128. Quinti, I., Soresina, A., Spadaro, G., et al. (2007). Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J. Clin. Immunol. 27(3), 308316. Quinti, I., Soresina, A., Guerra, A., et al. (2011). Effectiveness of immunoglobulin replacement therapy on clinical outcome in patients with primary antibody deficiencies: Results from a multicenter prospective cohort study. J. Clin. Immunol. 31(3), 315322. Radojkovic, M., Ristic, S., Divac, A., Tomic, B., Nestorovic, A., and Radojkovic, D. (2009). Novel ORC4L gene mutation in B-cell lymphoproliferative disorders. Am. J. Med. Sci. 338 (6), 527529. Raeiszadeh, M., Kopycinski, J., Paston, S. J., et al. (2006). The T cell response to persistent herpes virus infections in common variable immunodeficiency. Clin. Exp. Immunol. 146 (2), 234242. Rhee, S. G., and Bae, Y. S. (1997). Regulation of phosphoinositide-specific phospholipase C isozymes. J. Biol. Chem. 272(24), 1504515048. Rizzi, M., Neumann, C., Goldacker, S., (Freiburg i.Brs.), Grimbacher, B., (London/GB), Rolink, A., (Basel/CH), Warnatz, K., Peter, H.-H., (Freiburg i.Br.), Allogeneic stem cell transplantation in CVID: 3 case reports (2010). Proceedings of the 40th Annual Meeting r Immunologie. 2225 DGfI German Society for Immunology Deutsche Gesellschaft fu September 2010. LEIPZIG. Roifman, C. M., Lederman, H. M., Lavi, S., Stein, L. D., Levison, H., and Gelfand, E. W. (1985). Benefit of intravenous IgG replacement in hypogammaglobulinemic patients with chronic sinopulmonary disease. Am. J. Med. 79(2), 171174.
104
Roifman, C. M., Berger, M., and Notarangelo, L. D. (2008). Management of primary antibody deficiency with replacement therapy: Summary of guidelines. Immunol. Allergy Clin. North Am. 28(4), (8756, x). Rousset, F., Garcia, E., Defrance, T., et al. (1992). Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc. Natl. Acad. Sci. USA 89 (5), 18901893. Rudge, P., Webster, A. D., Revesz, T., et al. (1996). Encephalomyelitis in primary hypogammaglobulinaemia. Brain 119(Pt 1), 115. Salzer, U., Maul-Pavicic, A., Cunningham-Rundles, C., et al. (2004). ICOS deficiency in patients with common variable immunodeficiency. Clin. Immunol. 113(3), 234240. Salzer, U., Chapel, H. M., Webster, A. D., et al. (2005). Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat. Genet. 37(8), 820828. Salzer, U., Bacchelli, C., Buckridge, S., et al. (2009). Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood 113(9), 19671976. Schaffer, A. A., Pfannstiel, J., Webster, A. D., Plebani, A., Hammarstrom, L., and Grimbacher, B. (2006). Analysis of families with common variable immunodeficiency (CVID) and IgA deficiency suggests linkage of CVID to chromosome 16q. Hum. Genet. 118 (6), 725729. Schneider, P. (2005). The role of APRIL and BAFF in lymphocyte activation. Curr. Opin. Immunol. 17(3), 282289. Scott-Taylor, T. H., Green, M. R., Eren, E., and Webster, A. D. (2004). Monocyte derived dendritic cell responses in common variable immunodeficiency. Clin. Exp. Immunol. 138 (3), 484490. Scott-Taylor, T. H., Green, M. R., Raeiszadeh, M., Workman, S., and Webster, A. D. (2006). Defective maturation of dendritic cells in common variable immunodeficiency. Clin. Exp. Immunol. 145(3), 420427. Sekine, H., Ferreira, R. C., Pan-Hammarstrom, Q., et al. (2007). Role for Msh5 in the regulation of Ig class switch recombination. Proc. Natl. Acad. Sci. USA 104(17), 71937198. Seshasayee, D., Valdez, P., Yan, M., Dixit, V. M., Tumas, D., and Grewal, I. S. (2003). Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI as an inhibitory BLyS receptor. Immunity 18(2), 279288. Sharpe, A. H., and Freeman, G. J. (2002). The B7-CD28 superfamily. Nat. Rev. Immunol. 2(2), 116126. Shehata, N., Palda, V., Bowen, T., et al. (2010). The use of immunoglobulin therapy for patients with primary immune deficiency: An evidence-based practice guideline. Transfus. Med. Rev. 24(Suppl 1), S28S50. Sheikh-Hamad, D. (2010). Mammalian stanniocalcin-1 activates mitochondrial antioxidant pathways: New paradigms for regulation of macrophages and endothelium. Am. J. Physiol. Renal Physiol. 298(2), F248F254. Shelly, M. A., Jacoby, H., Riley, G. J., Graves, B. T., Pichichero, M., and Treanor, J. J. (1997). Comparison of pneumococcal polysaccharide and CRM197-conjugated pneumococcal oligosaccharide vaccines in young and elderly adults. Infect. Immun. 65(1), 242247. Shiina, T., Inoko, H., and Kulski, J. K. (2004). An update of the HLA genomic region, locus information and disease associations: 2004. Tissue Antigens 64(6), 631649. Shiina, T., Hosomichi, K., Inoko, H., and Kulski, J. K. (2009). The HLA genomic loci map: Expression, interaction, diversity and disease. J. Hum. Genet. 54(1), 1539. Sigmon, J. R., Kasasbeh, E., and Krishnaswamy, G. (2008). X-linked agammaglobulinemia diagnosed late in life: Case report and review of the literature. Clin. Mol. Allergy 6, 5. Sneller, M. C., and Strober, W. (1990). Abnormalities of lymphokine gene expression in patients with common variable immunodeficiency. J. Immunol. 144(10), 37623769.
105
Stagg, A. J., Funauchi, M., Knight, S. C., Webster, A. D., and Farrant, J. (1994). Failure in antigen responses by T cells from patients with common variable immunodeficiency (CVID). Clin. Exp. Immunol. 96(1), 4853. Stashenko, P., Nadler, L. M., Hardy, R., and Schlossman, S. F. (1980). Characterization of a human B lymphocyte-specific antigen. J. Immunol. 125(4), 16781685. Taccetti, G., Campana, S., Festini, F., Mascherini, M., and Doring, G. (2005). Early eradication therapy against Pseudomonas aeruginosa in cystic fibrosis patients. Eur. Respir. J. 26(3), 458461. Takahashi, N., Matsumoto, K., Saito, H., et al. (2009). Impaired CD4 and CD8 effector function and decreased memory T cell populations in ICOS-deficient patients. J. Immunol. 182(9), 55155527. Tedder, T. F., Boyd, A. W., Freedman, A. S., Nadler, L. M., and Schlossman, S. F. (1985). The B cell surface molecule B1 is functionally linked with B cell activation and differentiation. J. Immunol. 135(2), 973979. Tedder, T. F., Forsgren, A., Boyd, A. W., Nadler, L. M., and Schlossman, S. F. (1986). Antibodies reactive with the B1 molecule inhibit cell cycle progression but not activation of human B lymphocytes. Eur. J. Immunol. 16(8), 881887. Thatayatikom, A., Thatayatikom, S., and White, A. J. (2005). Infliximab treatment for severe granulomatous disease in common variable immunodeficiency: A case report and review of the literature. Ann. Allergy Asthma Immunol. 95(3), 293300. Thiel, J., Kimmig, L., Salzer, U., et al. (2009). The clinical and immunological phenotype of human CD21 deficiency. In: Clinical Immunology (pp. S57S58). Academic Press inc Elsevier Science. DOI-10.1016/j.clim.2009.03.164. Thickett, K. M., Kumararatne, D. S., Banerjee, A. K., Dudley, R., and Stableforth, D. E. (2002). Common variable immune deficiency: Respiratory manifestations, pulmonary function and high-resolution CT scan findings. QJM 95(10), 655662. Trujillo, C. M., Muskus, C., Arango, J., Patino, P. J., and Montoya, C. J. (2011). Quantitative and functional evaluation of innate immune responses in patients with common variable immunodeficiency. J. Investig. Allergol. Clin. Immunol. 21(3), 207215. Tsang, K. W., Ho, P. I., Chan, K. N., et al. (1999). A pilot study of low-dose erythromycin in bronchiectasis. Eur. Respir. J. 13(2), 361364. Tsitsikov, E. N., Gutierrez-Ramos, J. C., and Geha, R. S. (1997). Impaired CD19 expression and signaling, enhanced antibody response to type II T independent antigen and reduction of B-1 cells in CD81-deficient mice. Proc. Natl. Acad. Sci. USA 94(20), 1084410849. Uchida, J., Lee, Y., Hasegawa, M., et al. (2004). Mouse CD20 expression and function. Int. Immunol. 16(1), 119129. Vajdic, C. M., Mao, L., van Leeuwen, M. T., Kirkpatrick, P., Grulich, A. E., and Riminton, S. (2010). Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency? Blood 116(8), 12281234. van Zelm, M. C., Reisli, I., van der, B. M., et al. (2006). An antibody-deficiency syndrome due to mutations in the CD19 gene. N. Engl. J. Med. 354(18), 19011912. van Zelm, M. C., Smet, J., Adams, B., et al. (2010). CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J. Clin. Invest. 120(4), 12651274. Viallard, J. F., Camou, F., Andre, M., et al. (2005). Altered dendritic cell distribution in patients with common variable immunodeficiency. Arthritis Res. Ther. 7(5), R1052R1055. Vieira, P. L., Wassink, L., Smith, L. M., et al. (2004). ICOS-mediated signaling regulates cytokine production by human T cells and provides a unique signal to selectively control the clonal expansion of Th2 helper cells. Eur. J. Immunol. 34(5), 12821290. Volanakis, J. E., Zhu, Z. B., Schaffer, F. M., et al. (1992). Major histocompatibility complex class III genes and susceptibility to immunoglobulin A deficiency and common variable immunodeficiency. J. Clin. Invest. 89(6), 19141922.
106
von Bulow, G. U., van Deursen, J. M., and Bram, R. J. (2001). Regulation of the T-independent humoral response by TACI. Immunity 14(5), 573582. Vorechovsky, I., Scott, D., Haeney, M. R., and Webster, D. A. (1993). Chromosomal radiosensitivity in common variable immune deficiency. Mutat. Res. 290(2), 255264. Vorechovsky, I., Zetterquist, H., Paganelli, R., et al. (1995). Family and linkage study of selective IgA deficiency and common variable immunodeficiency. Clin. Immunol. Immunopathol. 77(2), 185192. Vorechovsky, I., Webster, A. D., Plebani, A., and Hammarstrom, L. (1999). Genetic linkage of IgA deficiency to the major histocompatibility complex: Evidence for allele segregation distortion, parent-of-origin penetrance differences, and the role of anti-IgA antibodies in disease predisposition. Am. J. Hum. Genet. 64(4), 10961109. Vorechovsky, I., Cullen, M., Carrington, M., Hammarstrom, L., and Webster, A. D. (2000). Fine mapping of IGAD1 in IgA deficiency and common variable immunodeficiency: Identification and characterization of haplotypes shared by affected members of 101 multiple-case families. J. Immunol. 164(8), 44084416. Wang, J., and Cunningham-Rundles, C. (2005). Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID). J. Autoimmun. 25(1), 5762. Wang, D., Feng, J., Wen, R., et al. (2000). Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors. Immunity 13(1), 2535. Wang, Y., Brooks, S. R., Li, X., Anzelon, A. N., Rickert, R. C., and Carter, R. H. (2002). The physiologic role of CD19 cytoplasmic tyrosines. Immunity 17(4), 501514. Ward, C., Lucas, M., Piris, J., Collier, J., and Chapel, H. (2008). Abnormal liver function in common variable immunodeficiency disorders due to nodular regenerative hyperplasia. Clin. Exp. Immunol. 153(3), 331337. Warnatz, K., Denz, A., Drager, R., et al. (2002). Severe deficiency of switched memory B cells (CD27()IgM()IgD()) in subgroups of patients with common variable immunodeficiency: A new approach to classify a heterogeneous disease. Blood 99(5), 15441551. Warnatz, K., Bossaller, L., Salzer, U., et al. (2006). Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood 107(8), 30453052. Warnatz, K., Salzer, U., Rizzi, M., et al. (2009). B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Proc. Natl. Acad. Sci. USA 106(33), 1394513950. Washington, K., Stenzel, T. T., Buckley, R. H., and Gottfried, M. R. (1996). Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia. Am. J. Surg. Pathol. 20(10), 12401252. Watts, W. J., Watts, M. B., Dai, W., Cassidy, J. T., Grum, C. M., and Weg, J. G. (1986). Respiratory dysfunction in patients with common variable hypogammaglobulinemia. Am. Rev. Respir. Dis. 134(4), 699703. Webster, A. D., Taylor-Robinson, D., Furr, P. M., and Asherson, G. L. (1982). Chronic cystitis and urethritis associated with ureaplasmal and mycoplasmal infection in primary hypogammaglobulinaemia. Br. J. Urol. 54(3), 287291. Wehr, C., Kivioja, T., Schmitt, C., et al. (2007). The EUROclass trial: Defining subgroups in common variable immunodeficiency. Blood. 111(1), 7785. Epub 2007 Sep 26. Wheat, W. H., Cool, C. D., Morimoto, Y., et al. (2005). Possible role of human herpesvirus 8 in the lymphoproliferative disorders in common variable immunodeficiency. J. Exp. Med. 202(4), 479484. Yalcin, E., Kiper, N., Ozcelik, U., et al. (2006). Effects of claritromycin on inflammatory parameters and clinical conditions in children with bronchiectasis. J. Clin. Pharm. Ther. 31(1), 4955.
107
Yong, P. F., Tarzi, M., Chua, I., Grimbacher, B., and Chee, R. (2008a). Common variable immunodeficiency: An update on etiology and management. Immunol. Allergy Clin. North. Am. 28(2), 367386, ixx. Yong, P. F., Workman, S., Wahid, F., Exley, A., Webster, A. D., and Ibrahim, M. A. (2008b). Selective deficits in blood dendritic cell subsets in common variable immunodeficiency and X-linked agammaglobulinaemia but not specific polysaccharide antibody deficiency. Clin. Immunol. 127(1), 3442. Yong, P. L., Orange, J. S., and Sullivan, K. E. (2010). Pediatric common variable immunodeficiency: Immunologic and phenotypic associations with switched memory B cells. Pediatr. Allergy Immunol. 21(5), 852858. Yu, D., Tan, A. H., Hu, X., et al. (2007). Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450(7167), 299303. Yu, J. E., Knight, A. K., Radigan, L., et al. (2009). Toll-like receptor 7 and 9 defects in common variable immunodeficiency. J. Allergy Clin. Immunol. 124(2), 349356, (356). Zullo, A., Romiti, A., Rinaldi, V., et al. (1999). Gastric pathology in patients with common variable immunodeficiency. Gut 45(1), 7781.

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Advances in Immunology, Volume 111 ISSN 0065-2776, DOI: 10.1016/B978-0-12-385991-4.00002-7

2011 Elsevier Inc. All rights reserved.

Patrick F. K. Yong et al.