A Rose is a Rose is a Rose but CVID is Not CVID - Common Variable Immune Deficiency (CVID) What Do...

CHAPTER 2

Advances in Immunology,ISSN 0065-2776, DOI: 10.1

* King’s College Hospital,{ Royal Free Hospital & Un{ Centre for Chronic Immu☆ The sentence ‘‘Rose is a rSacred Emily. In the 1978Not A Rose.’’

‘‘A Rose is a Rose is a Rose,’’but CVID is Not CVID☆:Common Variable ImmuneDeficiency (CVID),What do we Know in 2011?

Patrick F. K. Yong,* James E. D. Thaventhiran,† and

Bodo Grimbacher†,‡

Contents 1. Introduction 48

Volum016/B

Denmiversnode

ose isfilm,

e 111 # 2011 E978-0-12-385991-4.00002-7 All right

ark Hill, London, United Kingdomity College London, Pond Street, London, United Kingdomficiency, University Hospital Freiburg, Hugstetterstraße, Freiburg

a rose is a rose’’ was written by Gertrude Stein as part of the 19The Magic of Lassie, Robert & Richard Sherman penned the song,

lss

, G

13‘‘

2. D
efinition and Diagnostic Criteria 55
3. E
pidemiology 58
4. P
athophysiology/Immunopathology 59
5. E
tiology/Genetics 61
5.1. C
D19-complex mutations (CD19, CD21, CD81) 62
5
.2. C D20 mutation 65
5
.3. T ACI mutations 67
5
.4. B AFF-R mutation 71
5
.5. IC OS mutations 72
5
.6. M sh5 mutations and other DNA repair genes 74
5
.7. G enetic linkage studies 75
5
.8. G enome-wide association studies 76
6. C
VID Classification Schemes 77
6.1. B
cell classification and phenotyping 77
evier Inc.reserved.

ermany

poemA Rose Is

47

48 Patrick F. K. Yong et al.

6
.2. T cell phenotyping 79
6
.3. C linical categorization 80
6
.4. L ate onset combined immune deficiency (LOCID) 80
7. C
linical Presentation and Complications 81
7.1. In
fections 81
7
.2. C hronic respiratory infections and bronchiectasis 82
7
.3. G astrointestinal complications 83
7
.4. A utoimmunity 85
7
.5. G ranulomatous/lymphoproliferative disease/
hyperplasia
86
7
.6. M alignancy 87
8. M
anagement 88
8
.1. IV IG and mortality/infections 89
8
.2. A ntibiotic use 91
8
.3. O rgan and stem cell transplantation 91
8
.4. M onitoring 94
9. P
rognosis and Survival 95
10. S
ummary 95
Refere
nces 96
Abstract Common variable immune deficiency (CVID) is the commonest symp-

tomatic primary immunodeficiency and represents a heterogenous

collection of disorders resulting mostly in antibody deficiency and

recurrent infections. However, autoimmunity, granulomatous inflam-

mation 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 develop-

ments in understanding the underlying etiology and genetics; and

current treatment and monitoring recommendations for patients.

1. INTRODUCTION

Common Variable Immune Deficiency (or Common Variable Immunode-ficiency, abbreviated CVID or CVI) is a heterogeneous collection ofconditions, all characterized by a primary antibody deficiency

‘‘A Rose is a Rose is a Rose,’’ but CVID is Not CVID 49

(hypogammaglobulinemia) of at least two immunoglobulin isotypes. Dueto this, some investigators also use the term CVIDs. It is the commonestprimary immunodeficiency of clinical significance (Gathmann et al., 2009)and is thought to have arisen out of a mostly uncharacterized geneticbasis, although many advances have been made in recent years sinceCVID was first described in 1953 by Janeway et al. and the term coinedin 1973 by Cooper et al.

The main immunological defect is failure of B cell production ofimmunoglobulin, although abnormalities have been described in allother compartments of the immune system as well, with some associationwith clinical phenotype. Clinically, individuals with CVID are prone torecurrent infections, most frequently of the respiratory tract, but otherinfections including those of the gastrointestinal system can also occur.CVID also manifests aspects of immune dysregulation with noninfectiouscomplications including autoimmunity (most typically autoimmune cyto-penias), noninfectious gastrointestinal disease, granulomatous inflamma-tion, lymphoid proliferation, and an increased risk of malignancy.

Due to the heterogeneity and rarity of the disease, progress in under-standing had been relatively slow, although in the last decade, manyadvances (in parallel with the growth and understanding in all aspectsof immunology) have been made in improving knowledge of the basicmechanisms as well as the clinical care of patients with CVID. Some of themain areas where this has occurred andwhich will be discussed further inthis article include:

1. Genetics—in less than the last decade alone seven disease causing orcontributing genes have been identified that give rise to a CVIDphenotype. Attention has now been given to addressing the likeli-hood that many patients with CVID have a polygenic etiology (similarto other immune related diseases like type 1 diabetes and rheumatoidarthritis).

2. Phenotyping/categorization of CVID—both immunological and clin-ical criteria have been developed to categorize patients (furtheracknowledging the heterogeneity of the disease). This sets the groundfor subgrouping patients to both direct future research efforts focus-ing on the likely disease mechanisms in different groups as well asselecting patients for therapy based on likely prognosis.

3. Patient registries—the development and greater use of large diseaseregistries has allowed pooling of a large number of patients, combin-ing experience greater than a single clinician can achieve. This hasgiven a better overall and more accurate picture of both the morecommon and rare immunological and clinical features in CVID. Thedata from this has now begun to generate useful clinical information,with potential implications for patient care.


4. Treatment—although immunoglobulin replacement remains themainstay of treatment for patients with CVID, advances in the wayit is utilized has resulted in improvements both in patient survivaland quality of life.

CVID is defined as a diagnosis of exclusion: The current ESID/PAGIDdiagnostic criteria (Conley et al., 1999; www.esid.org) state that

‘‘CVID is probable in a male or female patient who has a markeddecrease of IgG (at least 2 SD below the mean for age) and a markeddecrease in at least one of the isotypes IgM or IgA, and fulfills all of thefollowing criteria:

1. Onset of immunodeficiency at greater than 2 years of age2. Absent isohemagglutinins and/or poor response to vaccines3. Defined causes of hypogammaglobulinemia have been excluded

according to a list of differential diagnosis of hypogammaglobuline-mia (www.esid.org/clinical-diagnostic-criteria-for-pid-73-0)

Clinical spectrum of disease:Most patients with CVID are recognized tohave immunodeficiency in the second, third, or fourth decade of life, aftertheyhave had several pneumonias; however, children andolder adultsmaybe affected. Viral, fungal, and parasitic infections as well as bacterial infec-tions may be problematic. The serum concentration of IgM is normal inabout half of the patients. Abnormalities in T cell numbers or function arecommon. Themajority of patients havenormal numbers of B cells; however,some have low or absent B cells. Approximately 50% of patients haveautoimmune manifestations. There is an increased risk of malignancy.’’

To illustrate the clinical variability in CVID, we here describe twopatients who have correctly been classified as CVID; however, theirclinical course is so different that the diagnostic label ‘‘CVID’’ was nothelpful, neither for the patients themselves, nor for patient management.

Patient 1, aged 34, was investigated for hypogammaglobulinaemiawhen his immunoglobulins were checked during an episode of gastroen-teritis. At presentation IgG, IgA, and IgM were all undetectable, hislymphocyte subsets were normal, secondary causes of hypogammaglo-bulinaemia were excluded and he failed test vaccinations with Pneumo-vax and Menitorix. Prior to presentation he reported no history ofincreased susceptibility to infections. He declined treatment with IVIGat the time, but remained monitored. Aged 57, that is 23 years later, hewas persuaded to start immunoglobulin replacement following an epi-sode of foot cellulitis. He was initially treated with intravenous immuno-globulin (IVIG) at 400 mg/kg, receiving 20 g every 8 weeks. His troughlevel after 1 year stabilized at 2.9 g/l. Aged 61, he was persuaded toincrease his IVIG treatment to 20 g every 4 weeks because mild cylindricalbronchiectasis had been noted on a high resolution CT scan of his chest.

http://www.esid.org

http://esid.org/clinical-diagnostic-criteria-for-pid-73-0


Following this, his trough level did not change. Throughout his 30 yearhistory of follow up, at no time has he reported an increased frequency ofpulmonary infections. Since being on IVIG replacement, he has had theimpression that his sinusitis is better controlled and that his coryzalsymptoms last for a shorter duration following viral upper respiratorytract infections.

Patient 2 was diagnosed aged 18, following a 2-year history of recur-rent bacterial chest infections. Over 3 years she had required hospitaladmission and in-patient treatment three times, on one occasion warrant-ing intensive care treatment due to a bacterial pneumonia. As with patient1, IgA, IgG, and IgM were undetectable, lymphocyte subsets werenormal, secondary causes of hypogammaglobulinaemia were excludedbut vaccine responses were not assessed. She was initially treated at400 mg/kg, receiving 15 g every 3 weeks. Her trough level at 1 year wasmeasured at 4.8 g/l, and the dose was still being increased. The patientcontinued to suffer from recurrent pulmonary infective episodes and wasdiagnosed 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, shesuffered from severe pneumonia, necessitating ventilation in an intensivetreatment unit. At the age of 29 her bronchiectasis had progressed to theextent that she had to undergo a right lower lobectomy. Currently she ismaintained on IVIG at 30 g every 2 weeks and her most recent troughlevel was 11.0 g/l. She currently has colomycin and cotrimoxazole asantibiotic prophylaxis and she is being considered for home oxygentherapy due to her declining respiratory function. Throughout this timeshe has had multiple infective episodes each year, with on average fourin-patient admission episodes.

These cases highlight the variability within CVID and the problemswith 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, andsuffered no serious bacterial infections. Patient 2 on the other hand, haddeveloped bronchiectasis by the age of 23, and required numerous in-patient admissions with episodes of life-threatening bacterial sepsis bothbefore and after replacement treatment had been commenced. Thesepatients show such differences in presentation, response to treatment,clinical course and in all probability mortality, that only the observedpanhypogammaglobulinaemia link them to the condition we call CVID.

It is easy to understand that clinical studies and research projects con-ducted on such a loosely and ill-defined cohort of patients will yield resultsgreatly dependent on the composition of the cohort studied. Therefore,the overhaul of the diagnostic criteria is timely and a current focus of theESID clinicalworkingpartyheadedbyK.Warnatz fromFreiburg,Germany.


Both patients share the pathological end-point of hypogammaglobu-linaemia but profoundly differ in their need for and response to replace-ment therapy. Hence we propose that any new classification of primary(inborn) hypogammaglobulinaemia categorizes patients into two differ-ent groups, one which links to patients with possible shared etiologiesand another which links patients to possible shared requirements fortreatment, facilitating meaningful clinical outcome trials. The latter maybe structured as suggested in Table 2.2 (the 10-point CVID exclusioncriteria still apply, Table 2.1A):

In addition to this classification of antibody deficiencies, the severity ofeach patient may be assessed with a point score involving features such asnumbers of past pneumonias, presence of bronchiectasis or other paren-chymal 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. Good’s syndrome (rare, but easy to exclude with CT scan)

5. Drugs (see C)

6. Bone-marrow failure (frequent differential in adults, difficult but

important to exclude)7. Lymphoma/leukemia (frequent differential in adults, difficult 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 defined 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

TABLE 2.2 Proposed classification of primary hypogammaglobulinaemia for clinical

outcome trials

1. Selective IgM deficiency (rare, but exists as clinical entity)2. Selective IgA deficiency (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 deficiency (including IgG subclass deficiencies)


Type (b) with recurrent infectionsType (c) without recurrent infections but with other associated

pathology

4. Specific IgG antibody deficiency (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 (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 (b) with recurrent infectionsType (c) without infections but with other clinical symptoms such as

autoimmunity or granuloma formation

7. Other forms of hypogammaglobulinemia



Type (c) without infections but with other associated pathology


lymphoproliferation, coexistence of autoimmune conditions, malignan-cies, etc. (Table 2.3).

Furthermore, recent evidence has indicated that patients with CVIDdiffer in their treatment requirements and the variability of individualpatient needs overrides standard measures such as trough level (Lucaset al., 2010). Previous guidelines have been based around the adjustmentof the dose of IVIG to maintain the serum IgG level above an arbitrarilydecided ‘‘trough’’ level prior to each dose. The newer recommendations

TABLE 2.3 Suggested CVID severity score: The 15 unlucky complications of CVID

Points 0 1 2 3

1. Chronic sinusitis Absent Present

2. Past meningitis or encephalitis Absent One bout Two bouts >Two bouts

3. Past pneumonia Absent One bout Two bouts >Two bouts

4. Bronchiectasis Absent One lobe Two lobes >Two lobes

5. Other parenchymal lung pathology such as fibrosis, LIP,BOOP, etc.

Absent Suspected Confirmed

6. Lung surgery (lobectomy or pneumonectomy) Absent Performed

7. Splenomegly Absent 11–14.9 cm 15–20 cm >20 cm

8. Splenectomy Absent Performed

9. Lymphadenopathy (largest node) Absent <2 cm 2–3 cm >3 cm

10. CVID enteropathy Absent Intermittent Chronic but mild Severe

11. Autoimmune condition Absent Suspected Confirmed

12. Other rheumatological complaints such as arthralgia Absent Suspected Confirmed13. Granulomata Absent Skin only Lung, liver or spleen CNS (incl. eye)

14. Lymphoma Absent Present

15. Cancer (solid tumors) such as bowel, skin or stomach Absent Present


suggest that, rather than concentrating on these absolute trough levels,doctors should adjust the dose of IVIG in each patient individually torender them ‘‘infection-free.’’ However, data has already been presentedthat lung disease can progress in patients despite optimal immunoglobu-lin therapy (Kainulainen et al., 1999; Quinti et al., 2007).

Accurate classification of any disease is necessary for the optimummanagement of a condition. Though both Bruton’s agammaglobulinae-mia and CVID require treatment with IVIG, our differentiation betweenthem facilitates clinicians giving more accurate advice regarding inher-ited susceptibility and enables accurate monitoring for the differences incomplications such as enteroviral encephalitis in Bruton’s agammaglobu-linaemia, or immune thrombocytopenia in CVID.

Furthermore, in research, classification is necessary to identify boththose patients sharing a common etiology and those patients sharing acommon response to treatment to enable improvement in both these factors.The above two patients highlight for CVID that classification for these twoaims may not be concordant. Recent genetic studies on familial cases ofCVID (see below) have identified mutations in very different genes andpathways, suggesting that a differing pathophysiology can all lead to thecommon endpoint of hypogammaglobulinemia (Yong et al., 2008a).

2. DEFINITION AND DIAGNOSTIC CRITERIA

Diagnostic criteria for CVID were originally defined by the EuropeanSociety for Immunodeficiencies (ESID) and the Pan-American Group forImmunodeficiency (PAGID) in 1999 (Conley et al., 1999). These dividedpatients with hypogammaglobulinaemia into ‘‘probable CVID’’ with areduction in serum IgG and IgA or IgM below 2 SD for age or ‘‘possibleCVID’’ with a reduction in one of IgG, IgA, or IgM below 2 SD for age. Inaddition, to fulfill criteria, the onset of immunodeficiency had to begreater than 2 years of age, there should be a failure to respond to specificantigens (either isohemagglutins or vaccines) and defined causes of hypo-gammaglobulinaemia needed to be excluded (see www.esid.org/clinical-diagnostic-criteria-for-pid-73-0).

Limitations have been noted with these diagnostic criteria, which aresubject to relatively loose boundaries (Chapel and Cunningham-Rundles,2009; Cunningham-Rundles, 2010). Although the criteria have not beenformally revised, it has been suggested that theminimum age of diagnosisbe raised from 2 to 4 years to more adequately exclude children with otherconditions, particularly transient hypogammaglobulinaemia of infancy(Chapel and Cunningham-Rundles, 2009; Cunningham-Rundles, 2010).

It has also been noted that the criteria for immunoglobulin levels allowfor variation between different laboratories and also that the use of 2 SD




allows for 2.5% of normal individuals to fall below the reference range(Cunningham-Rundles, 2010). Several alternative cut-off levels to defineCVID have been proposed. H. Chapel suggested 4.5 g/l (Chapel andCunningham-Rundles, 2009) on the basis that most patients (94.2%) in alarge European study had lower than this level at diagnosis (Chapel et al.,2008) comparable to a large American cohort where 85% of patients hadsimilar values (Cunningham-Rundles and Bodian, 1999). Patients withlevels higher than this could be classified as ‘‘possible’’ CVID. Cunning-ham-Rundles suggested a tiered system for evaluation instead(Cunningham-Rundles, 2010). Hypogammaglobulinaemia was dividedinto several categories depending on the amount of IgG (<1.5, 1.5–2.5, 2.5–4.5, and 4.5–6.0 g/l) with varying degrees of further evaluation required foreach category. It was suggested that following verification of immunoglob-ulin levels, patients with IgG levels <1.5 g/l would not require furtherantibody testing to specific pathogens. For the remaining categories, furtherevaluation for vaccine responses should be considered or undertaken.Those with IgG levels between 4.5 and 6.0 g/l and those with minimallyreduced IgA levels especially should be more extensively evaluated asantibody production is more likely to be preserved at these levels. Patientswith modestly reduced immunoglobulin levels and/or partial antibodyproduction should be reassessed at regular intervals as theremay be furtherdecline and theymaymeet the criteria for immunoglobulin replacement at alater stage (Carvalho Neves et al., 2000; Gutierrez and Kirkpatrick, 1997).

A further criterion in the definition of CVID to be noted is the need fordemonstration of specific IgG responses. Although not specifically statedin the original criteria how this is to be assessed, it has been proposed thatthere should be a demonstrated lack of response (as defined by failure toattain laboratory protective levels or a four-fold increase from baseline) totwo protein vaccines (for example tetanus or diphtheria toxoids andhaemophilus conjugate; Chapel and Cunningham-Rundles, 2009). Vacci-nation responses to pneumococcal polysaccharide are more difficult tointerpret due to the variability of responses in healthy individuals andalso the fact that a proportion of healthy individuals do not makeresponses to several serotypes (Hare et al., 2009; Shelly et al., 1997). Itshould also be noted that there is a suggestion that multiple doses ofpneumococcal polysaccharide vaccination might result in immune hypor-esponsiveness although this is not yet fully worked out (O’Brien et al.,2007). These various findings serve to underline the fact that the immuni-zation issue in CVID is not trivial and difficult to assess as well as to agreeand set universal standards for diagnosis.

Other known causes of hypogammaglobulinemia such as protein lossvia the bowels or kidney (for a complete list see www.esid.org/clinical-diagnostic-criteria-for-pid-73-0) need to be excluded. In general clinicalpractice, it is not practically possible to exclude all the conditions listed;




consequently, we suggest a 10-point list (Table 2.1A) of conditions thatcould be realistically excluded prior to a diagnosis of CVID.

Most importantly, CVID needs to be separated from other primaryimmune deficiencies with problems in antibody production:

1. Agammaglobulinemias such as X-linked agammaglobulinemia (XLA,due to mutations in Btk, MIM#300755) or autosomal recessive agam-maglobulinemias (e.g., due to mutation in the immunoglobulinm heavy chain) need to be excluded. All forms of agammaglobuline-mias are characterized by the complete lack of B cells in the periphery,which leads to a profound lack of all immunoglobulin isotypes. Somehypomorphic mutations in the B cell tyrosine kinase Btk, however,will allow some residual B cell receptor signaling, allowing some Bcells to survive, and hence allow some residual immunoglobulinproduction. Therefore XLA patients may be identified in cohorts ofCVID patients (Kanegane et al., 2000; Sigmon et al., 2008).

2. Class switch recombination (CSR) defects, such as observed inpatients with the hyper-IgM syndromes, will also lead to a decreasein IgG and IgA serum levels (Kracker et al., 2010). Between CSRdefects and CVID a considerable overlap exists, as for example,patients with mutations in ICOS have been historically classified asCVID, but the lack of ICOS on patients’ T cells impairs B cell classswitch and patients, when ill, may produce substantial amounts ofIgM (Warnatz et al., 2006). Hence ICOS deficiency may also be classi-fied as a CSR defect. It should also be noted that only 62.5% of HIGMpatients actually have elevated IgM levels (C. Hennig, Hannover,personnal communication).

3. Patients with X-linked lymphoproliferative syndromes may also dis-play hypogammaglobulinemia and present with a phenotype reminis-cent of CVID, hence mutations in SH2D1A (XLP1, MIM#308240) andXIAP (XLP2, MIM#300635), or the determination of NK T cells insuspected patients may reveal this subset of patients (Eastwood et al.,2004).

In routine clinical practice, it is difficult to screen for all known genesthat can result in a CVID phenotype. One suggestion is to test for geneticmutations in boys with affected male relatives or patients of either genderwith affected family members prior to making a diagnosis of CVID(Chapel and Cunningham-Rundles, 2009). We suggest to screen for muta-tions in Btk in male subjects with peripheral B cell numbers of less than2%; check for mutations in SH2D1A and/or XIAP in males with EBV-associated lymphoproliferative disease or HLH; and to screen for muta-tions in the CD40 ligand in males with an elevated IgM level and/or withopportunistic infections; or AICD in subjects of either gender with anelevated IgM and autoimmunity. All other genetic defects are either too


rare to account for or do not have substantial clinical impact to justify theuse of resources outside the research setting.

In view of the frequency of the occurrence of hypogammaglobulinae-mia in the setting of a lymphoid malignancy, it has also been suggestedthat there is a need to distinguish between this and lymphoid malignancycomplicating longstanding CVID. One possible way of doing this is toallow a 2-year period before making a diagnosis of CVID, to confirmabsence of lymphoid malignancy after identification of the antibodydeficiency (Chapel and Cunningham-Rundles, 2009). Other approachesinclude more aggressive diagnostic work-up with a bone-marrow biopsyand/or lymph node extirpation (n.b., a lymph node core biopsy is rarelydiagnostic in these cases).

Good’s syndrome, the association between thymoma and immunodefi-ciency (Good and Varco, 1955), also needs to be excluded particularly inolder patients with antibody deficiency. Typical features in Good’s syn-drome include an absence of B cells as well as T cell abnormalities includ-ing CD4 lymphopenia, an inverted CD4/CD8 ratio and reduced mitogeninduced proliferation. In a recent systematic review, the average age ofpatients diagnosed with Good’s syndrome was 59.1 years, although therange was 25–90 years with one pediatric case identified (Kelesidis andYang, 2010). One suggested scheme to screen for thymoma is that allpatients with antibody deficiency who are over 49 years of age with absentB cells should undergo CT scanning to exclude thymoma (Chapel andCunningham-Rundles, 2009). However, it should be noted that in thesame systematic review 13% of patients with Good’s syndrome did nothave a reduced or absent peripheral B cell count (Kelesidis and Yang, 2010).

At present, the diagnostic criterion does not include a requirement forsignificant infection although suggestions have beenmade for its inclusion.It should be noted that although the majority of patients with significanthypogammaglobulinaemia will have recurrent infections, a proportion canpresent with autoimmune cytopenias (Michel et al., 2004), granulomatousdisease (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 beenestimated at between 1:10000 and 1:100000 of the population (Chapeland 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 bedue to intrinsic differences in the population surveyed, although there aredifferences in the methods of ascertainment and coverage as well. Thecurrent data in the ESID registry shows a minimal prevalence of CVID of


5/100,000 inhabitants in France, almost 2 in the United Kingdom, andonly 1.3 in Germany. As there is no reason to believe that the trueincidence in these countries differs, it is likely that the prevalence in thelatter countries will increase with time given the increased awareness ofphysicians and better documentation of patients in registries.

In a large American cohort of 248 patients, the age of onset of symptomswas found to be bimodal with peaks in the first and third decades(Cunningham-Rundles and Bodian, 1999). However, in a cohort of 413European 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 andmedian 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 0–61 years) in a European cohort (Chapel et al., 2008) and 8.9years in an Italian cohort (Quinti et al., 2007). Overall there has not beena significant decrease in the diagnostic delay suggesting that awarenessand suspicion of CVID as a differential diagnosis remains poor. Importantawareness 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 ‘The10 warning signs’ (www.jmfworld.com) have been launched around theglobe to improve the diagnostic delay and diagnose and treat CVID andother patients with a primary immune defect as early as possible in orderto prevent secondary complications.

4. PATHOPHYSIOLOGY/IMMUNOPATHOLOGY

Multiple immunological abnormalities have been described in almost allcompartments of the immune system in CVID. Most of the focus has beenon B cell abnormalities (which are discussed later) as the principal defectin CVID is failure of antibody provision. However, a reasonable amountof work has been done looking at the T cell compartment as well andmorerecently, at innate immunity; Table 2.4 summarizes a list of some of theabnormalities found in these areas. The diverse and widespread distribu-tion of all these abnormalities further serves to highlight the heterogeneitypresent in CVID and that it is likely that multiple factors play a role ingenerating the phenotype. Although these findings may be related to thepathogenesis of the disease, it is also possible that they represent epiphe-nomena as a result of the disease process.

Most of the abnormalities described have been identified in peripheralblood cells with limited work done on other tissues. To improve under-standing of the process occurring elsewhere, a recent study has analyzed

http://www.ece.dote.hu

http://www.isitpid.com

http://www.find-id.net

http://www.jmfworld.com

TABLE 2.4 Immunological abnormalities seen in CVID

Innate

immunity

Defective monocyte-derived dendritic cell function

(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 (Trujilloet 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-specific T cells aftervaccination (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 inothers (such as the myeloid compartment). As expected, 94% of patientshad absent or reduced plasma cells in keeping with reduced IgG levels.In addition, diffuse and nodular CD3þ T cell infiltrates were more oftenseen in CVID patients and these were associated with autoimmune cyto-penias. Nodular infiltrates were also associated with an activated T cellcompartment indicated by increased CD4þCD45ROþmemory T cells, and


elevated soluble CD25 and neopterin levels. In 9 out of 25 patients, apartial block in B cell development between the pre-B-I to pre-B-II stagewas seen; the authors from Freiburg, Germany, proposed that these CVIDpatients might represent a new subgroup as the developmental block wasassociated with lower transitional and mature B cell counts.

5. ETIOLOGY/GENETICS

Although generally sporadic, approximately 10% of cases of CVID dem-onstrate familial clustering (Hammarstrom et al., 2000) and IgA deficiencyhas been noted in family members of patients with CVID (Vorechovskyet al., 1999). In addition, patients with IgA deficiency have also been notedto progress to CVID (Espanol et al., 1996). These observations made itlikely that CVID had a genetic basis.

Initially, several genetic linkage studies in the 1980s and 1990s hadfocused primarily on the HLA region and demonstrated an associationwith 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 firstgenetic disorder resulting in a CVID phenotype (Grimbacher et al., 2003).The rate of progress in unraveling the genetic basis of CVID has pro-gressed greatly since then. Mutations have been detected in various B cellrelated TNFRSF member genes (TACI and BAFF-R), in members of theCD19-B cell receptor complex (CD19, CD21 and CD81) and in the B celldifferentiation antigen, CD20. In addition, polymorphisms in genesinvolved 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 inthese molecules have yet to be identified. In a subgroup of patients withCVID, an association between impaired proliferation following TCRengagement and early tyrosine phosphorylation has been shown, subse-quently leading to the discovery of defective ZAP-70 recruitment due to aCD3z phosphorylation defect (Boncristiano et al., 2000). Further workidentified deficiencies in F-actin reorganization secondary to defectiveRac activation as a result of deficient Vav expression (Paccani et al.,2005). Vav mRNAwas also reduced in that study, but no promoter regionmutations 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) arelikely to require additional genetic contributions as genetic mutation


alone does not necessarily lead to a CVID phenotype. In addition to theapproach of targeting specific genes likely to be related to B cell function,a genome-wide association study has also been undertaken in CVIDpatients further identifying novel genes for further exploration (Orangeet al., 2011). We discuss in further detail below the genetic discoveriesto date. It should be noted as well that polymorphisms in certain geneshave also been associated with complications in CVID (summarized inTable 2.5).

5.1. CD19-complex mutations (CD19, CD21, CD81)

CD19 is expressed together with CD21, CD81, and CD225 on the surfaceof mature B cells. CD19 and CD21 are B cell specific antigens unlike CD81and CD225, which are also present on most other immune cells (Levyet al., 1998). The complex cosignals with the B cells receptor, thus reducingthe threshold for signaling following antigen recognition (Carter andFearon, 1992; Fearon and Carroll, 2000). The complement receptor CD21also links the innate and adaptive immune systems by binding comple-ment C3d thus linking CD19-complex signaling to the complement path-way (Fearon and Carroll, 2000). CD19 and CD21 bind each other directlyand as CD21 lacks an intracellular domain, it is thought that it signalsthrough CD19 which possesses multiple tyrosine residues (Matsumotoet al., 1991; Wang et al., 2002; Figure 2.1).

CD81 is a member of the transmembrane pore integral membraneprotein 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)

þ488A allele associated with

granulomatous CVID

IL10 (Mullighan et al., 1999) IL-10 a-t-a haplotype associated with

granulomatous CVID

MBL2 (Litzman et al., 2008;

Mullighan et al., 2000)

Low producing genotpes associated with

bronchiectasis, lung fibrosis,respiratory insufficiency but not other

complications in CVID

VDR (Mullighan et al., 1999) Association with B lymphopenia and

CD8þCD57þ lymphocytosis

IL6 (Mullighan et al., 1999) Association with CD8þCD57þ

lymphocytosis

B cell

CD21

y

yyyy

yyyy

CD19

CD19-complex

C3d

Antigen

CD225(Leu-13)

Dual antigen recognition

Antigen

CD81

B-cell receptor (BCR)

Antigen

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-dependentantigens (Maecker and Levy, 1997; Tsitsikov et al., 1997).

Molecular defects resulting in CVID have been described in threesubunits of the CD19-complex: CD19, CD21, and CD81.

5.1.1. CD19 deficiencyCD19 deficiency (CVID3, MIM#613493) was first described in a Turkishgirl and three Colombian siblings (van Zelm et al., 2006). The Turkish girlwas born to consanguineous parents and had a homozygous single bpinsertion in exon 6 resulting in a frameshift mutation and premature stopcodon in the intracellular portion of the molecule. The parents of theColombian family were said to be unrelated but came from a town in theAndes. Their children had a homozygous 2 bp insertion in exon 11 alsoresulting in a premature stop codon in the intracellular portion. In asubsequent report, a single Japanese boy was also found to be CD19-deficient (Kanegane et al., 2007). He had a compound heterozygote muta-tion with thematernal allele showing a splice acceptor site mutation site inintron 5 resulting in skipping of exon 6 and coupling of exon 5 and 7; the


paternal allele showed a large deletion including CD19 and two neighbor-ing genes, although it is uncertain if this was inherited or a de novo event.

All patients had similar characteristics, having presented in childhoodwith mostly recurrent bacterial infections; and found to have hypogam-maglobulinaemia and deficient vaccination responses. There were nosigns of autoimmunity in the first four patients; the Japanese patienthad mild thrombocytopenia, although it is not definite if this isimmune-mediated. Immunologically, CD19 deficiency patients had nor-mal numbers of peripheral B cells although the numbers of CD5þ andCD27þ class-switched memory B cells were reduced. B cells (as measuredby CD20 stain) expressed reduced levels of CD21 but normal levels ofCD81 and CD225. Germinal center formation was retained as was somatichypermutation. Van Zelm and colleagues showed that the problem inthese patients was in B cell activation, for example Ca2þ influx was absentor severely delayed in CD19-deficient cells (van Zelm et al., 2006). Sincethis initial report, other cases with CD19 deficiency have been presentedat scientific meetings, highlighting the usefulness of a CD19 stain in thework-up of patients with hypogammaglobulinemia/CVID.

5.1.2. CD21 deficiencyCD21 (or complement receptor type 2, CR2) deficiency has been describedin a single 28-year-old male with mild clinical disease, born of nonconsan-guineous parents (First case of human CD21 deficiency, 2004). On oneallele, the patient had a point mutation in the 30 splice site of exon 6,resulting in one shortenedmRNA lacking exon 6, the second allele carrieda mutation in exon 13, changing a TGG triplet to TGA and thus creating apremature stop codon at amino acid position 766. There was absence ofCD21 protein expression on B cells and in serum although there werenormal levels of CD21 mRNA. Serum IgG and IgA levels were reducedbut there were good IgG responses to protein and polysaccharide vaccina-tion. T and B cell counts were within the normal range although there wasa reduction in class-switched memory B cells. In vitro, B cells showedreduced binding to C3d-containing immune complexes although BCRand CD40 dependent responses were normal. SHM was present and VHspectratyping only showed a slightly biased IgG and IgA repertoire (Thielet al., 2009).

5.1.3. CD81 deficiencyThe defect in CD19 suggested that other members of the CD19 coreceptorcomplex could be involved in the development of CVID and morerecently, a defect in CD81 was identified (CVID6, MIM#613496; vanZelm et al., 2010). A 6-year-old Moroccan girl born of consanguineousparents was found to have a homozygous substitution mutation down-stream of exon 6. This resulted in disruption of the splice donor site and


addition of 13 nucleotides to the transcript leading to a frameshift andpremature stop codon before the fourth transmembrane domain.

Clinically, the patient presented with recurrent respiratory infectionsat the age of 2 and subsequently developed glomeruonephritis (whicheventually progressed to end-stage renal failure despite therapy) and apurpuric rash. This was diagnosed as Henoch Schonlein purpura after arenal biopsy showed mesangial IgA and C3 and a skin biopsy showedleukocytoclastic IgA vasculitis. She also had recurrent thrombocytopeniawith antiplatelet antibodies. She was found to have a low IgG but low tonormal IgA and normal IgM and commenced on replacement immuno-globulin. The patient had no antibody responses to vaccination as well asa low allohemagglutinin titer.

Apart from the lack of CD81 expression on all leukocytes, the genemutation also resulted in absence of CD19 on B cells due to the depen-dency of CD19 on CD81 expression. The antibody deficiency was similarto patients with CD19 deficiency with deficient vaccination responses andreduced CD27þ memory B cells. Somatic hypermutation was impaired(particularly in IgA) as was Ca2þ 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 devel-opment from early pre-B until mature B cell stage, but lost on differentia-tion in to plasma cells. It is encoded by MS4A1 and belongs to the MS4Afamily of proteins which have four highly conserved membrane spanningregions (Liang and Tedder, 2001). It was one of the first B cell differentia-tion antigens described (Stashenko et al., 1980) and is most famous for itsuse as a target for monoclonal antibodies in the treatment of B cellmalignancy and an increasing list of autoimmune diseases.

Functionally, CD20 blockade in vitro with monoclonal antibodies hasbeen shown to disrupt B cell proliferation and differentiation (Tedderet al., 1985, 1986). CD20 also belongs to a cell surface complex that reg-ulates Ca2þ transport (Bubien et al., 1993). Human and mouse CD20 havesimilar gene structure and cellular expression and in CD20 knockoutmice, B cell IgM expression was slightly reduced and CD19-inducedCa2þ mobilization was affected although the B cells had normal develop-ment, proliferation, T cell dependent antibody production, and affinitymaturation (Uchida et al., 2004).

A homozygous mutation in CD20 (CVID5, MIM#613495) has beendescribed in a single Turkish girl of consanguineous descent resulting ina CVID phenotype (Kuijpers et al., 2010). Genetic analysis showed acompound mutation (homozygous 11 bp insertion as well as a partialdeletion) in exon 5 of the CD20 gene. This affects a unique donor splice


site resulting in transcripts with a deletion of exon 5 and insertion ofintronic sequences. The individual presented with recurrent broncho-pneumonia and respiratory tract infections from the age of 2. She wasfound to have a reduced IgG level but normal IgA and IgM levels (andtherefore stricktly does not classify as CVID) and initially treated withreplacement immunoglobulin. However, this was discontinued after 6months and replaced with antibiotic prophylaxis. The patient had anormal number of circulating B cells but these lacked expression ofCD20; her parents showed CD20 expression but only at half thatof controls.

The patient had reduced class-switched CD27þ memory B cells,reduced IgG production in vitro, an altered selection of marginal zone Bcells and a reduced response to vaccination with pneumococcal polysac-charide. The authors further confirmed a role of CD20 in T-independentantibody responses in CD20 knockout mice (Kuijpers et al., 2010).

Ca2þ signaling plays an important role in the activation of B cells(Dolmetsch et al., 1997), raising the possibility that abnormalities maycontribute to the development of CVID. B cell receptor cross-linkingresults in phosphorylation of phospholipase Cg2 (PLCg2) by Syk andBtk. PLCg2 then induces the generation of inositol triphosphate(Kurosaki and Hikida, 2009), which results in transient intracellular cal-cium release leading to more sustained influx of Ca2þ through the Ca2þ

channels in the plasma membrane (Feske, 2007; Rhee and Bae, 1997). Inmouse models, PLCg2 deficiency has been shown to affect B cell develop-ment at the transitional B cells stage, antibody response and the mainte-nance 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 Ca2þ-flux. Inkeeping with this, Ca2þ responses have been shown to be reduced in themature B cells of CVID patients with reduced switched memory B cellsand increased CD21low B cells, although transitional B cells had normalsignaling (Foerster et al., 2010). In this study, Ca2þ influx across theplasma membrane was reduced (associated with increased expressionof CD22, a negative regulator of signaling) although proximal BCR sig-naling and Ca2þ release from the endoplasmic reticulum was normal.These patients had a greater incidence of immune dysregulation andlymphadenopathy. The defect responsible was thought to lie in mechan-isms involved in regulating plasma membrane Ca2þ channels or homeo-stasis of intracellular Ca2þ levels, although as yet remains unidentified.It was thought that it likely contributes to (although probably not solelyresponsible for) the B cell dysfunction and an anergic phenotype ofCD21low B cells; and possibly the antibody deficiency and failure ofimmune tolerance (Foerster et al., 2010).


5.3. TACI mutations

TACI (encoded by TNFRSF13B) belongs to the tumor necrosis factorreceptor superfamily and is found on B cells (Schneider, 2005). Othermembers of this group include the molecules B cell activating factorreceptor (BAFF-R) and B cell maturation antigen (BCMA). The ligandsfor TACI are B cell activating factor (BAFF) and a proliferation-inducingligand (APRIL). Binding to its ligands induces CSR in both human andmouse cells (Castigli et al., 2004, 2005a; He et al., 2007; Litinskiy et al., 2002).TACI knockout mice also have deficient T-independent type II responsesto polysaccharide antigens (von Bulow et al., 2001) and are prone tolymphoproliferation 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 mutationshave been described in the extracellular domain, stalk region, transmem-brane region and intracellularly (Castigli et al., 2005b; Salzer et al., 2005,2009). Table 2.6 lists the mutations and SNPs that have been discovered inTACI so far. Compared to the other mutations described above and foundin a limited number of individuals or families, mutations in TACI havebeen discovered in a more significant proportion of patients with CVID,with 8.9% (50 out of 564) patients possessing at least one abnormal allelein the largest cohort of patients analyzed (Salzer et al., 2009). Eighteenpercent of these had biallelic mutations and the remaining 82% had only asingle affected allele.

However, the relationship between TACI mutations and the develop-ment of antibody deficiency is complicated. There is a complex pattern ofinheritance with homozygous, heterozygous, and compound hetero-zygous mutations identified (Castigli et al., 2005b; Salzer et al., 2005). Inaddition, monoallelic mutations have been described in healthy familymembers of affected patients suggesting that TACI might represent adisease susceptibility gene in its heterozygous state. In the largest cohortanalyzed, all patients with biallelic mutations had antibody deficiencyand most showed reduced binding to APRIL (Salzer et al., 2009). The mostcommon TACImutations (C104R andA181E) were found in amonoallelicstate in 2% of 675 controls (compared to 6.9% of affected patients). Therelative risk of developing antibody deficiency with a heterozygous TACImutation was 3.6.

Clinically, patients with TACI mutations could present with the com-plete spectrum of complications seen in CVID; all patients had recurrentinfections and antibody deficiency (Salzer et al., 2009). In view of themouse data, it was hypothesized that patients with TACI deficiencywould be more prone to lymphoproliferation and autoimmunity. This isborne out in data from the cohort of 564 patients showing that TACI

TABLE 2.6 Mutations/SNPs identified in TACI

Exon cDNA Protein

Domain

affected

Association with CVID

Salzer et al. (2005), 162

patients, 100 controls

Castigli et al. (2005b),

19 patients, 50 controls

Pan-Hammarstrom

et al. (2007), 424


Castigli et al.

(2007), 162

patients, 100

controls



2 81G > A T27T CRD1,

extracellular

Similar

frequencies

in CVID and

controls

118T > C W40R CRD1,

extracellular

Identified in CVID only

121delG D41 lfs*43 CRD1,

extracellular


121G > C D41H CRD1,

extracellular


204insA L69Tfs*12 CRD2,

extracellular

Identified in

CVID only

CVID only, but

not

significant


3 215G > A R72H CRD2,

extracellular

Similar frequencies in

CVID and controls


CVID and controls

CVID only, but

not

significant


CVID and controls

277_231del G76fxX3 CRD2,

extracellular

CVID only, but

not

significant

236A > G Y79C CRD2,

extracellular


260T > A I87N CRD2,

extracellular

Present in CVID and

controls, but change

predicted to be

deleterious

291T > G P97P CRD2,

extracellular

Similar

frequencies

in CVID and

controls

298insT C100Lfs*6 CRD2,

extracellular


310T > C C104R CRD2,

extracellular

Identified in

CVID only

Identified in

CVID only

nificant increase in

VID

Significant

increase in

CVID

Significant association

with CVID

311G > A C104Y CRD2,

extracellular


R122W Stalk region ilar frequencies in

VID and controls

S144X Stalk region Identified in CVID

only

445G > A A149T Stalk region Identified in CVID only

455G > A G152E Stalk region Identified in CVID only

4 492C > A Y164X Stalk region Identified in CVID only

512T > G L171R Transmembrane CVID only, but

not

significant

542C > A A181E Transmembrane Identified in

CVID only

Identified in

CVID only

nificant increase in

VID

Significant

increase in

CVID


not significant

571insG D191Gfs*46 Intracellular Identified in CVID only

579C > A C193X Intracellular Identified in CVID only

S194X Intracellular Identified in

CVID only

602G > A R202H Intracellular Identified in

CVID only

Identified in

CVID only

ilar frequencies in

VID and controls

CVID only, but

not

significant

(continued)

Sig

C

Sim

C

Sig

C

Sim

C

TABLE 2.6 (continued )

Exon cDNA Protein

Domain

affected




Castigli et al. (2005b),

19 patients, 50 controls

Pan-Hammarstrom

et al. (2007), 424


Castigli et al.

(2007), 162

patients, 100

controls



5 659T > C V220A Intracellular Similar frequencies in

CVID and controls


CVID and controls

Similar

frequencies

in CVID and

controls


CVID and controls

736G > T V246F Intracellular Identified in CVID only

752C > T P251L Intracellular Similar frequencies in

CVID and controls

Similar

frequencies

in CVID and

controls


CVID and controls

831T > C S277S Intracellular Similar

frequencies

in CVID and

controls


mutations were more strongly associated with autoimmunity (36% vs.23% of patients with wild-type TACI, most commonly autoimmunethrombocytopenia) and lymphoproliferation (60% vs. 35%, splenomegaly,lymphadenopathy, nodular lymphatic hyperplasia). Of note, heterozygos-ity for the C104R allele was also associated with lymphoproliferation andautoimmunity. One suggested explanation for this was that the wild-typeTACI allele in heterozygotes might promote the survival of auto-reactiveB cell clones. Interestingly, patients with a biallelic mutation areclinically less affected, suggesting that no TACI signaling is preferable toa perturbed TACI signal.

Immunologically, patients can have normal or reduced percentages ofB cells and more rarely, severe B lymphopenia can also be present. Theproportion of patients with reduced switched memory B cells is similar tothe general CVID population (Salzer et al., 2009). In keeping with thevariability in B cell phenotype, immunoglobulin levels at presentationalso varied greatly; IgG levels could be between <1 up to 5 g/l, IgA andIgMwere generally low but in a significant number of patients, IgA couldbe normal and IgM could be normal or elevated.

It is likely thatTACImutations contribute to antibodydeficiencyalthoughgiven the broad spectrum of clinical and immunological presentation, otherdisease modifying factors are likely to be important.

5.4. BAFF-R mutation

Mutations in BAFF-R (CVID4, MIM#613494) have been identified in twoindividuals—a brother and sister pair born of a consanguineous marriage(Warnatz et al., 2009). A homozygous 24 bp in-frame deletion (del 89–96)was found in exon 2 of the TNFRSF13C gene, causing removal of an8 hydrophobic amino acid sequence in the BAFF-R transmembrane regionand resulting in undetectable BAFF-R protein expression on the B cellsurface.

The male index case developed symptoms late with his first pneumo-nia at age 37 and was only diagnosed following a third pneumonia at age57. The sister, however, was very well apart from severe zoster at the ageof 70 and only had two episodes of pneumonia around the age of 80. Shedid not receive immunoglobulin replacement. There was no history ofautoimmunity or lymphoproliferative disorder. The index patient hadthree children, all obligate heterozygous carriers, who were all healthy.

Both patients had reduced IgG (the brother with amarked reduction of0.6 g/l at presentation but the sister had only slightly reduced levels at5.51 g/l) and IgM levels, but normal to elevated IgA levels. IgAþ plasmacells were also found in the gut. They were able to mount T-dependentantibody responses but not T-independent antibody responses. There wasa severe persistent B lymphopenia, with increased transitional CD10þ B


cells, suggesting developmental arrest at the transitional B cell stage.Marginal zone IgMþCD27þ and class-switched memory B cells werealso reduced.

The marked difference in clinical phenotype despite the similar immu-nological findings suggested that other factors apart from BAFF-R arenecessary for the development of immunodeficiency. Some of these fac-tors such as BTK, CD40L, BAFF, APRIL, TACI, and BCMA were screenedfor in the index case in the study but no abnormalities were found.In addition, it was noted in the screening exercise that other CVID patientsin the cohort had reduced BAFF-R levels which might be due to mutationsin the regulatory region (as these were not screened for in that study) thatcould contribute to the development of CVID (Warnatz et al., 2009).

5.5. ICOS mutations

ICOS deficiency (CVID1, MIM#607594) was the first genetic mutationidentified in patients with a CVID phenotype. ICOS belongs to a familyof costimulatory molecules on the surface of T cells, which includes CD28,CTLA-4, and PD-1 and possesses a unique ligand, ICOS-L which isexpressed on antigen presenting cells including naive B cells (Carrenoand Collins, 2002; Hutloff et al., 1999; Sharpe and Freeman, 2002). It isexpressed on activated T cells and has a role in T cell differentiation andsurvival, cytokine secretion and provision of signals for T-dependentantibody responses (Hutloff et al., 1999). Of relevance to B cells, stimulationof ICOS results in potent production of IL-10 (Hutloff et al., 1999) which isimportant for proliferation of B cells and terminal differentiation intomem-ory andplasma cells (Rousset et al., 1992). ICOS also plays a role in the clonalexpansion of established effector Th2 cells (Vieira et al., 2004). In addition,ICOS also provides critical signals (via induction of the transcription factorBcl6) for differentiation of follicular helper T cells which provide B cellhelp 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 beenidentified, 9 of them with the same mutation in ICOS (Grimbacher et al.,2003; Salzer et al., 2004; Takahashi et al., 2009). A homozygous deletion of1815 bp, spanning a region from intron 1 to intron 3 of the ICOS gene wasfound in the first nine individuals (from four families) identified(Grimbacher et al., 2003; Salzer et al., 2004). This resulted in an mRNAproduct with a 443-nucleotide deletion and a putative protein productthat encoded a 19-aa signal peptide and 9 ‘‘nonsense’’ amino acids,introduced by the frameshift; this is consistent with the absence of detect-able ICOS protein on T cells. The identical deletion in all these individualsaffected was thought to most likely be due to a common founder effectand migration along the Danube River. Further evidence for this was the


fact that all individuals shared the same homozygous allele at a polymor-phic marker (D2S2289) adjacent to the ICOS locus.

Subsequently, a Japanese brother and sister pair were found to have ahomozygous deletion of T at codon 285 resulting in a coding regionframeshift and introducing a premature stop codon at aa 121 (Takahashiet al., 2009). The affected sister had immunodeficiency and significantautoimmunity with rheumatoid arthritis, inflammatory bowel disease,interstitial pneumonitis and psoriasis, although the brother had a muchmilder phenotype with only a modest reduction in IgG levels and onlyoccasional skin abscesses and psoriasis-like skin lesions. The same muta-tion was found in heterozygosity in the unaffected mother and anothersister.

Clinically, ICOS deficiency can present with the full spectrum ofdisease seen in CVID, with presentation from childhood into adulthood(Takahashi et al., 2009; Warnatz et al., 2006). Recurrent respiratory tractinfections were the commonest feature but gastrointestinal infections,lymphoid nodular hyperplasia, splenomegaly, granulomatous skin dis-ease, interstitial pneumonitis, autoimmunity, inflammatory bowel dis-ease and HPV-associated vulval carcinoma were all observed as well.

Patients had reduced IgG and IgA levels although some of the patientshad low normal IgM values; one patient had an elevated IgM during anepisode of bronchopneumonia (Warnatz et al., 2006) and one had a persis-tenly elevated IgM (Takahashi et al., 2009). There were no class-switchedantibody responses detectable to vaccination. B cells numberswere reducedin most adults although the two youngest children had increased numbersof B cells. Numbers of naive B cells were normal in children but class-switched memory B cells were reduced in all individuals.

With the exception of the CXCR5 expressing so called follicular helperT cells, and despite the almost exclusive expression of ICOS on activatedT cells, the T cell compartment in patients showed little abnormality in thefirst nine patients identified (Warnatz et al., 2006). Patients had a normalproportion of ‘‘naive’’ CD3þCD45RAþ cells to ‘‘antigen-experienced’’CD3þCD45ROþ cells; normal numbers of HLA-DRþ T cells and normalin vitro proliferative responses when stimulated with mitogens, antigens,and alloantigens. Stimulation through the CD3:T cell receptor complexresulted in normal levels of TNF-a, IFN-g, IL-2, IL-4, and IL-13 with orwithout costimulation with anti-CD28 or anti-ICOS (Grimbacher et al.,2003; Warnatz et al., 2006). However, IL10 and IL17 production werereduced.

In contrast, testing of the T cell compartment in the Japanese patientsshowed adecrease inCD4þCD45ROþmemoryT cells (bothCCR7þCD62Lþ

central and CCR7�CD62L� effector memory T cells; Takahashi et al., 2009).Also in contrast, Th1 (IFNg) andTh2 (IL4 and IL5) cytokineproductionuponstimulation with CD3/CD28 or PMA/ionophore was impaired. Similar to


previously, IL10 and IL17 secretionwas also reduced (Takahashi et al., 2009).Reduced induction of the regulators of Th1, Th2, and Th17 lineage commit-ment—T-bet, GATA3, MAF, and retinoic acid-related orphan receptor C(RORC)was also noted. Therewas also a reduction in FoxP3 expression andmRNA levels and reduced CTLA4þCD45ROþFoxP3þ 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 compart-mentwas also affectedwith reducedmemorycells and impairedproductionof IFN-g. There was also increased induction of RANKL and loss of Itchexpression in the affected sister. These findings are consistent with theautoimmunity seen in ICOS deficiency, although the discrepancy in detect-able T cell abnormalities between the two different mutations is notcompletely explained at present.

Mechanistically, although ICOS deficiency is a form of CSR defect,screening of several cohorts of patients with HIGM syndrome have notidentified any further patients with ICOS (or ICOS-L) mutations (Leeet 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 mismatchrepair and meiotic homologous recombination. It has been shown to playa role in CSR in mice and consequently, a cohort of Swedish and Ameri-can patients with IgA deficiency and CVID were genotyped for MSH5mutations (Sekine et al., 2007). This found that an allele with two non-synonymous single-nucleotide polymorphisms (L85F/P786S) was signif-icantly associated with IgA deficiency and borderline associated withCVID. A SNP in intron 12 (rs3131378) was also frequently associatedwith IgA deficiency and more modestly associated with CVID. In addi-tion, two rare SNPs were identified in patients that were not found inhealthy controls: C580G in two patients with IgA deficiency and Q292H inone patient with CVID. All healthy controls with the L85F/P786S SNPwere screened for immunoglobulin deficiency and found to have normallevels.

The MSH5 protein encoded by the L85F/P786S allele was also shownto have reduced binding to a partner protein, MSH4 (Sekine et al., 2007).Patients with this allele had increased stretches of Sm-Sa1microhomology,lower S joint mutation rates and increased ‘‘in-phase’’ alignment of pen-tamer motifs. The mutation rate across Sm-Sg3 joints was also lower forpatients with that allele.

Subsequently, in view of this and the genetic abnormalities seen in theCSR defects, analysis of other DNA metabolism genes was undertaken todetermine if there were anymore subtle mutations that had an associationwith IgA deficiency/CVID (Offer et al., 2010). In a cohort of CVID/IgA


deficiency patients screened for 27 genes involved in DNA metabolism,significant associations were found with nonsynonymous alleles inMSH2, MLH1, RAD50, and NBS1 as well as UTR SNPs in RAD50 andMRE11. The authors also demonstrated that cells with the RAD50-Q372Xmutation (resulting in a premature stop codon) had increased sensitivityto ionizing radiation.

5.7. Genetic linkage studies

Several genetic linkage studies have been undertaken in the context ofCVID/IgA deficiency. Most of the earlier studies have focused primarilyon the MHC region in chromosome 6 and some (but not all) have shownlinkage although the exact location in the MHC region of the putativedisease-related gene is not certain (Olerup et al., 1992; Volanakis et al.,1992; Vorechovsky et al., 1995). Following the work of Vorechovsky, theMHC susceptibility locus was designated IGAD1 (Vorechovsky et al.,1999, 2000).

Subsequent to the studies focusing on the MHC region, severalgenome-wide linkage studies were published. Kralovicova et al. (2003)analyzed a sample of 210 IgA deficiency/CVID families with 36 markersat the IGAD1 region and identified HLA-DQ/DR as the major IGAD1locus. They also undertook genome-wide linkage analysis of 101 familieswith 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 gen-otyped 101 families looking for loci associated specifically with CVID.They analyzed a subset of 40 families with at least one case of CVID andextended the genotype where samples were still available in 32 families(Schaffer et al., 2006). This showed evidence of a CVID locus at chromo-some 16q and one possible candidate gene, WW-domain containing oxi-doreductase (WWOX) was sequenced but no mutations found.

Braig et al. performed a genome-wide linkage study using 205 markersin three families with autosomal dominant CVID, IgA deficiency anddysgammaglobulinaemia. They confirmed linkage in the HLA region(in one family) but also identified a novel linkage to the telomeric regionof chromosome 5p (in two families; Braig et al., 2003). A single gene in theregion, PDCD6which has functions related to apoptosis, was identified asthe 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 tochromosome 4q in a genome-wide scan of a five-generation family withsix cases of CVID, five cases of IgAD, and three cases of dysgammaglo-bulinaemia (Finck et al., 2006). The study was further extended to investi-gate 32 families with one member with CVID and another with CVID or


IgAD, which supported the linkage to the identified locus. Potentialcandidate genes in the region (NFkB1, SCYE, CASP6, DAPP1, BANK1)were sequenced in a single individual from the large family but noabnormalities found.

5.8. Genome-wide association studies

Although there are genetic mutations identified in a small percentage ofCVID cases, it is likely that a large proportion of CVID is due to morecomplex polygenic interactions, given the heterogenous nature of thedisease, both in terms of clinical presentation and immunological pheno-type. To date, most of the research has focused on single gene defectscausing or contributing to a CVID phenotype, as well as a limited numberof genetic linkage studies. However, advances in technology haveallowed high-throughput genome-wide SNP genotyping and to date, asingle study examining this and copy number variations (CNV) in CVIDhas been published (Orange et al., 2011).

In this study, a total of 363 CVID patients and 3031 healthy controlswere genotyped with the aim of linking SNPs and CNVs to CVID as wellas determining if there was a specific genetic ‘‘signature’’ distinguishingCVID from healthy individuals. Analysis of the data showed a significantassociation with the MHC region (consistent with previous linkage data)and a suggestive association (although the p value did not reach signifi-cance for GWAS significance criteria) with a locus containing ADAM28,ADAM7, ADAMDEC1, and STC1. The genes within these regions haveputative immunological functions and associations. The MHC locus hasbeen linked to multiple diseases (Shiina et al., 2004, 2009) includingimmunological ones and CVID (Kralovicova et al., 2003; Olerup et al.,1992; Volanakis et al., 1992). ADAM family proteins are a group of zincmetalloproteases which have a role in a wide range of biological processesand ADAM28 (also known as lymphocyte metalloprotease MDCL) isexpressed on lymphocytes and is the ligand for a4b1 integrin thusenabling cell adhesion (Bridges et al., 2002). STC1 encodes stannioncalcin1 which has a role in calcium regulation (Sheikh-Hamad, 2010) and maybe relevant as a subset of CVID patients have impaired B cell receptormediated calcium signaling (Foerster et al., 2010).

Of note, however, was that the GWAS did not identify any associationwith the locus containing TACI, nor were any patients with TACI muta-tions separately identified.

SNP association was also performed with respect to individual fea-tures of CVID and significant associations were found with all 16 of theparameters that were studied (including nodular regenerative hyperpla-sia, malabsorption, lymphoma, bronchiectasis, lymphoid interstitialpneumonia, low IgM, organ-specific autoimmunity, low B cells, young


age, GI enteropathy, low IgA, lymphadenopathy, and cancer), furtheremphasizing the polygenic contribution towards the CVID phenotype.

CNV analysis discovered several novel genes that were hemizygouslydeleted or duplicated in CVID patients. Eighty-four deletions and 98duplications were identified in one or more CVID patients but not incontrols. Some of these abnormalities were unique, further highlightingthe individualistic nature of CVID. The most frequent duplicationaffected ORC4L which was exclusively seen in 15 cases of CVID.ORC4L is essential for the initiation of DNA replication and has beenassociated with B cell lymphoproliferative disorders (Radojkovic et al.,2009). Of clinical relevance, two patients with previously undetected22q11 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 pheno-type. One thousand SNPs were identified from the analysis whichallowed identification of CVID patients with 98.7% accuracy (Orangeet al., 2011). This was suggested as a useful tool to allow earlier identifica-tion and better management of CVID patients particularly in the contextof an evolving immunoglobulin profile; where potentially with currentdiagnostic criteria, a significant amount of time could lapse prior to adiagnosis, resulting in permanent damage due to recurrent infections.

6. CVID CLASSIFICATION SCHEMES

Various attempts have been made to classify patients with CVID intodifferent subgroups, both to help direct research efforts as well as toguide clinical management by identifying patients with less or moresevere disease. By and large, most of the work done on classificationschemes has focused on B cells, as this is the prime abnormality inCVID. However, T cell phenotyping and categorization by clinical vari-ables has also been undertaken.

6.1. B cell classification and phenotyping

The first classification scheme, developed by Bryant et al., proposeddividing patients with CVID based on immunoglobulin production ofperipheral blood lymphocytes after exposure to Staphylococcus aureusCowan I plus IL-2 or anti-IgM plus IL-2 (Bryant et al., 1990). Patients inGroup Awere unable to produce any immunoglobulin in vitro, patients inGroup B could only produce IgM and patients in Group C were compa-rable to healthy controls.

However, in general functional assays like this were too cumbersomeand time-consuming for routine clinical use. Consequently, to utilize the


ready availability and ease of use of flow cytometers, B cell classificationschemes based on memory B cells (as identified by CD27 and IgD/IgM todetermine class switch) were proposed by two different groups (Piqueraset al., 2003; Warnatz et al., 2002). Generally, with both schemes, thepatients with the most severe disease had the lowest proportion ofswitched memory B cells. There were differences in the two classificationschemes with Piqueras et al. (2003) using memory B cells as a percentageof total B cells and Warnatz et al. (2002) using memory B cells as apercentage of peripheral blood lymphocytes. Additionally, there weredifferences in which complications occurred more frequently in thegroup with the lowest proportion of memory B cells; and patients withvirtually no B cells (possibly representing an early B cell development ordifferentiation defect) were not included in either classification.

To address these issues and develop consensus, as well as phenotype alarger number of patients, the EUROClass classification scheme wasdeveloped (Wehr et al., 2007). This was a multicenter European trialwhich recruited 303 patients. The scheme divides patients into thosewith �1% CD19þ B cells of total lymphocytes (group B�) from thosewith a higher number of B cells (group Bþ). Bþ patients are furtherdivided into those with a severe deficiency of class-switchedCD27þIgM�IgD� B cells (�2% of CD19þ B cells, group smB�) or thosewith >2% switched memory B cells (group smBþ). Patients with a severedeficiency of switched memory B cells were further divided into thosewith an expansion of transitional B cells (group smB�Trhi, �9% of B cells,staining as CD21intCD38þþIgMþþ) or those with <9% transitional B cells(group smB�Trnorm). In addition, the classification scheme also distin-guished between patients with an expansion of CD21lo B cells (an unusualpopulation 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 withexpansion of both CD21lo and transitional B cells.

Clinically, the severe reduction in switched memory B cells was asso-ciated with a higher risk of granulomatous disease and splenomegaly.Splenomegaly was also associated with an increased number of CD21lo Bcells. Transitional B cell elevation was associated with a greater risk oflymphadenopathy (Wehr et al., 2007). It was concluded that patients withalmost absent B cells had defects of early B cell differentiation and thosewith severely reduced switched memory B cells most likely had a germi-nal center defect as seen in ICOS or CD40 ligand deficiency. The defectsresulting in expanded transitional or CD21lo B cells remain to be fullyworked out.

Of note, the EUROClass trial did not have patients below the age of 10and it has been suggested that as children have higher and less mature Bcells, the classification criteria may not be as applicable. A study


evaluating 45 children between the ages of 2–19 years (median 6 and 7years for the two different groups of children) were able to classify theminto two groups by just evaluating CD19þCD27þIgM� memory B cells(Yong et al., 2010). Those with <5 switched memory B cells/ml had lowerT cell and total B cell counts, and were the only children to have meningi-tis, sepsis, bronchiectasis, granulomatous lung disease, autoimmune cyto-penias or hematologic malignancy. This is consistent with the findings inadults that reduction in switched memory B cells is associated with moresevere disease.

6.2. T cell phenotyping

In view of the multiple abnormalities described in the T cell compartmentin CVID as well as the importance of T-B cell interaction for antibodygeneration, T cell classification schemes have also been proposed(Giovannetti et al., 2008). In a study evaluating multiple functional andphenotypic T cell variables, the authors managed to divide CVID patientsinto three groups based on the percentage of naive CD45RAþCD4 T cells(<15%, 16–30% and >30% of CD4 T cells; Giovannetti et al., 2007). Thereduction in naive T cells reflected the degree of abnormality found in theother parameters examined. The group of patients with the lowest num-bers 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 wasalso an association with reduced class-switched memory B cells and anexpansion of CD21lo B cells, showing a limited degree of concordancewith the B cell classification proposed by Warnatz (Warnatz et al., 2002).

Further work developing T cell classification schemes has beenmodestcompared to B cell based schemes. More recently, in a study examining Tand B cell compartments in 313 French CVID patients, abnormalities weremore 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 CD4þCD95þ cells) and a reduction inswitched memory B cells. Patients were divided into six groups basedon levels of naive CD4 T cells, total B cells and switched memory B cells.Approximately half the patients who only had infections had a normalT-B phenotype whereas patients with an abnormal T-B phenotype weresignificantly more likely to have autoimmune cytopenias and lympho-proliferative disease. Although this study was indicative of the fact thatT cell phenotyping could be used to subgroup CVID patients, there wasstill considerable imprecision when trying to use phenotyping criteria topredict likelihood of complications (for example, approximately half thepatients with a normal T-B phenotype had some form of complication).


Although the phenotypic classification schemes developed so far areable to stratify patients to some extent, further refinement of them wouldbe useful to more accurately subgroup patients and predict complica-tions. The genetic screening tool developed by Orange et al. (2011) may beexpensive but the way forward. A prospective analysis has to demon-strate its usefulness.

6.3. Clinical categorization

Based on the European CVID registry data (now superseded by the ESIDregistry), efforts have also been made to divide patients into separateclinical phenotypes (Chapel et al., 2008). Chapel et al. used a cohort of334 patients followed-up for an average of 25.6 years to define five distinctclinical phenotypes, which are: no complications, autoimmunity, poly-clonal lymphocytic infiltration, enteropathy, and lymphoid malignancy.These phenotyping criteria were selected if they were intrinsic disease-related complications. Bronchiectasis and splenomegaly were not used aspart of the classification scheme as bronchiectasis was not related tounderlying disease and splenomegaly was too common and associatedwith many complications. Seventeen percent of patients had more thanone clinical phenotype.

There was no association between diagnostic delay and clinical phe-notype although patients with disease complications had significantlylower survival rates. Mortality rates were highest for patients with lym-phoid malignancy (RR 5.5), enteropathy (RR 4.0) and polyclonal lympho-cytic infiltration (RR 3.0). Predictive markers for the clinical phenotypeswere also investigated; elevation in serum IgM (but not IgG) was asso-ciated with an increased risk of polyclonal lymphocytic infiltration andlymphoid malignancy. Every additional 1 g/l increase in IgM was asso-ciated with a 16% and 31% higher odds ratio for development of poly-clonal lymphocytic infiltration and lymphoid malignancy respectively.Higher CD8 T cell levels were associated with a reduced chance ofautoimmunity. This study supports the validity of the separate clinicalphenotypes 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 asignificant T cell defect and classified them as late-onset combined immunedeficiency (LOCID; Malphettes et al., 2009). In a cohort of 313 Frenchpatients, 8.9% of patients were found to have features suggestive of a Tcell defect—as defined by occurrence of an opportunistic infection (usingthe classification system for HIV) and/or a CD4þ count of<200 � 106 cells/l. Patients in this subgroup were more likely to come


from a consanguineous family and have an increased risk of splenomegaly,granulomatous disease, gastrointestinal disease and lymphoma. In addi-tion, they were more likely to require hospitalization and frequent antibi-otic use despite being on immunoglobulin replacement. Immunologically,there was a marked defect in naıve CD45RAþCCR7þCD4þ T cell countsand B cell counts. Potentially this classification allows discrimination of thisgroup of patients from other patients with CVID to both direct researchaimed 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 litera-ture and have reported a wide range of complications in CVID althoughthere has been no recent change in the nature of these (Cunningham-Rundles and Bodian, 1999; Hermaszewski andWebster, 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 sur-vival (Chapel et al., 2008) and consequently, it can be expected that thenoninfectious complications are likely to increase as the management ofthe infectious burden improves. To date, however, the etiology of most ofthe noninfectious complications remains very poorly understood.

It should be noted that there is significant variation in the rate ofdifferent complications between different countries in a large Europeanstudy (Chapel et al., 2008). This study only analyzed Caucasian patients,hence excluding the effect of racial background. With increasing numbersof registries from different countries, this should potentially allow identi-fication of further subgroups/complications occurring due to interactionswith the environment/geographical location.

7.1. Infections

Acute and chronic infections represent the major burden of morbidity inpatients with CVID and similar numbers of patients are affected both atpresentation and during follow-up, approximately 87% in an Italian studyof 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 andBodian, 1999; Hermaszewski and Webster, 1993; Quinti et al., 2007).The most common organisms isolated are Streptococcus pneumoniae andHaemophilus 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


been noted to decrease although there is an increase in chronic sinusitisand chronic lung disease (Quinti et al., 2007). In the Italian cohort, 49% ofpatients had pneumonia prior to diagnosis, but 35.7% did not get pneu-monia after commencement of immunoglobulin replacement whereas13.3% of patients continued to get recurrent pneumonia; similarly 39%of patients had acute otitis prior to diagnosis whereas 25.5% had nofurther otitis after immunoglobulin replacement with 12% continuing toget episodes despite therapy.

More unusual infections are also sometimes seen in CVID. Joint infec-tion and destruction with mycoplasma species (Franz et al., 1997), entero-viral meningoencephalitis (Halliday et al., 2003; McKinney et al., 1987;Rudge et al., 1996), and ureaplasma infection of the urinary tract leadingto bladder fibrosis (Webster et al., 1982) have been described. The immunemechanisms leading to susceptibility to these organisms remain to beelucidated although adequate replacement immunoglobulin therapy hasreduced the incidence of enteroviral infections. The more typical infec-tions associated with T cell deficiency including Pneumocystis jiroveciipneumonia and atypical mycobacterial infections are uncommonin CVID.

7.2. Chronic respiratory infections and bronchiectasis

The occurrence of recurrent upper respiratory tract infections can result inchronic sinusitis and hearing loss. Unchecked recurrent lower respiratorytract infections have been thought to result in eventual development ofbronchiectasis, which is present in 4–76% of patients depending on thecohort (Chapel et al., 2008; Cunningham-Rundles and Bodian, 1999;Hermaszewski and Webster, 1993; Kainulainen et al., 1999; MartinezGarcia et al., 2001; Oksenhendler et al., 2008; Quinti et al., 2007; Thickettet al., 2002; Watts et al., 1986). In addition, bronchiectasis can already bepresent at diagnosis, up to 34% and increasing to 46% during follow-up inthe 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 mod-erate respiratory tract infections were not associated with the develop-ment of bronchiectasis; rather only previous severe infections(pneumonia and septicemia) were (Chapel et al., 2008). In the samestudy, it was also shown that serious infections were not related to IgGlevels <1.5 g/l at presentation nor was bronchiectasis related to diagnos-tic delay (as surrogate measure for duration of nontreatment), time sinceonset of symptoms, or smoking. As would be expected, bronchiectasiswas associated with earlier mortality. Although treatment with replace-ment immunoglobulin has been shown to reduce the incidence ofpneumonia (Busse et al., 2002; Orange et al., 2010), chronic lung disease


including bronchiectasis can still develop despite adequate therapy(Quinti et al., 2007). These findings indicate that immunoglobulin defi-ciency alone is not the only reason for progressive lung disease and thatother 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 antipneumococcalpolysaccharide IgM antibodies are protective against recurrent bacterialpneumonia and bronchiectasis; and can be used to stratify patients intohigh- 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 ofgastrointestinal disease (20–60%; Cunningham-Rundles and Bodian,1999; Hermans et al., 1976; Hermaszewski and Webster, 1993; Quintiet al., 2007; Washington et al., 1996) given that IgA plays a major role inmucosal defense. In addition, gastrointestinal disease can sometimes bethe sole presenting feature in CVID (3% in the one cohort; Quinti et al.,2007). There is some data indicating that CVID patients with absent IgAhave a higher incidence of GI infections compared to those with residualIgA (Oksenhendler et al., 2008). However, CVID patients are more proneto GI complications compared to patients with XLA and IgAD suggestingthat other factors apart from immunoglobulin deficiency also play a rolein the development of gut disease. There is some data to indicate T cellcytokine production abnormalities in CVID and increased T cell numbersin the colon of patients with CVID and inflammatory bowel diseasesuggesting that T cell defects are likely to play a role as well (Agarwalet al., 2011). However, the same investigators were unable to demonstrateincreased inflammatory cytokines from lamina propria lymphocytes inthe CVID subgroup with IBD.

Transient or persistent diarrhea is the commonest gastrointestinalmanifestation in CVID, found in between 20% and 60% of patientsdepending on study (Cunningham-Rundles and Bodian, 1999; Hermanset 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). Inaddition, CMV has also been found in gut biopsies of CVID patients(Daniels et al., 2007). Helicobacter pylori infection is associated withgastritis in CVID (Zullo et al., 1999).

Multiple noninfectious gastrointestinal pathologies have also beendescribed in CVID—these include nodular lymphoid hyperplasia, gran-ulomas, atrophic gastritis, pernicious anemia, inflammatory boweldisease, lymphocytic colitis, collagenous enterocolitis and flattened villi(Cunningham-Rundles and Bodian, 1999; Daniels et al., 2007;Hermaszewski and Webster, 1993).


Chronic gastritis is a frequent finding affecting 10% of patients atdiagnosis and 28% during follow-up in the Italian cohort where patientsunderwent endoscopy every 2 years (Quinti et al., 2007). Intestinal meta-plasia of the gastric mucosa was common and despite Helicobacter pylorieradication therapy, recolonization would often occur (Quinti et al., 2007).

The small bowel enteropathy in CVID resembles that seen in celiacdisease with short villi, crypt hyperplasia and intraepithelial lymphocy-tosis. However, the enteropathy does not respond to gluten avoidance.One notable feature in CVID is the absence of plasma cells although thiswas only the case in 68% of patients in one study (Daniels et al., 2007). Thesmall bowel enteropathy can result in diarrhea, weight loss and malab-sorption; and in the most severe cases loss of essential nutrients hasresulted in difficult-to-treat osteomalacia and neurological disease(Aslam et al., 2004).

Large bowel enteropathy resembling Crohn’s disease and ulcerativecolitis has also been described in CVID (Daniels et al., 2007;Hermaszewski and Webster, 1993). It is not clear if these have the samepathogenesis as classical inflammatory bowel disease although one studyhas shown that compared to Crohn’s disease, lamina propria mucosalcells from CVID patients with large bowel enteropathy produced signifi-cantly more Th1 cytokines, IL12, and IFNgwithout an excess of IL17, IL23,or TNFa; implying that an alternative inflammatory pathway is responsi-ble for pathology (Mannon et al., 2006).

Treatment of inflammatory bowel disease in CVID is similar to that ofclassical IBD with anti-inflammatory agents like 5-aminosalicylic acidcompounds or steroids (either topical or nonabosorbed like budesonide;Agarwal and Mayer, 2010; Cunningham-Rundles, 2010). Following fail-ure to respond to probiotics, we recommend to trial a high dose course ofprednisolone (0.5 mg/kg BW) mostly for diagnostic purposes. If patientsrespond, we select better tolerated steroid preparations such as budeso-nide (up to 9 mg in adults) which has a high first-pass effect in the liverand hence produces less systemic side effects, or other immunosuppre-sive agents such as azathioprine and 6-mercaptopurine which can also beused as doses are too low to affect systemic T cell function (Agarwal andMayer, 2010). The TNF antagonist infliximab has also been used in CVIDpatients 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, presentin 8% in one cohort (Quinti et al., 2007). The cause of this is unknown atpresent although it has been suggested as a compensatory mechanism forthe hypogammaglobulinaemia (Agarwal and Mayer, 2010). The likeli-hood of this predisposing towards the development of mucosa associatedlymphoma is uncertain.


Abnormalities in liver function tests are not uncommon and in twodifferent cohorts, 43% of patients had abnormalities, most often affectingalkaline phosphatase levels (Malamut et al., 2008; Ward et al., 2008).Autoimmune hepatitis and primary biliary cirrhosis have both beendescribed in CVID (Cunningham-Rundles and Bodian, 1999). Excludinga viral hepatitis infection (primarily hepatitis C contracted through con-taminated immunoglobulin preparations) is always a medico-legal duty.Nodular regenerative hyperplasia has more recently been recognized as asignificant cause of liver disease with 84% of CVID patients with liverfunction test abnormalities in one cohort showing this on biopsy(Malamut et al., 2008). Cholestasis (mostly anicteric) and portal hyperten-sion were the main clinical findings; histologically intrasinusoidal lym-phocytic infiltration, portal vessel abnormalities and epitheloidgranulomas were seen in 90%, 43%, and 44% of that cohort (Malamutet al., 2008). In another study, 13 out of 16 patients (81%) with unexplainedliver abnormalities were found to have nodular regenerative hyperplasia(Ward et al., 2008). In both cohorts, patients with NRHwere more likely tohave 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 in25–48% of patients depending on the country (Chapel et al., 2008;Cunningham-Rundles and Bodian, 1999; Quinti et al., 2007). The mostcommon manifestations are autoimmune cytopenias—autoimmunethrombocytopenia and autoimmune hemolytic anemia, and less com-monly immune neutropenia. A multitude of other immune diseasesincluding vitiligo, psoriasis, pernicious anemia, rheumatoid arthritis, sys-temic lupus, Sjogren’s syndrome, primary biliary cirrhosis, hepatitis, andthyroiditis have all been described (Chapel et al., 2008; Cunningham-Rundles and Bodian, 1999). One series has shown that in up to 62% ofpatients, the autoimmune thrombocytopenia preceded the diagnosis ofantibody deficiency (Michel et al., 2004). Consequently, this highlights theimportance of screening for hypogammaglobulinaemia in these hemato-logical conditions.

Wang et al. have noted that the frequency of recurrent episodes ofautoimmune cytopenias decreased following institution of immunoglob-ulin replacement (Wang and Cunningham-Rundles, 2005) although thiswas not noted in a different study (Michel et al., 2004). Therapy forstandard ITP/AIHA including steroids, high-dose IVIG and antirhesusD immunoglobulin have been effective (Wang and Cunningham-Rundles, 2005). Rituximab has also been used in refractory cases of ITP/AIHA with success (Cunningham-Rundles, 2010). It has also been


recommended that splenectomy be avoided due to the risk of severeinfections (Cunningham-Rundles and Bodian, 1999) although this is notuniversal (Michel et al., 2004). A current survey of 53 splenectomisedCVID patients is underway and will address this specific question(Huisson and Warnatz, privileged communication). The treatment forother autoimmune diseases follows standard protocols. Immune suppres-sion is often tolerated well in patients with CVID, possibly due to theprotection IgG replacement and antibiotics are providing.

7.5. Granulomatous/lymphoproliferative disease/hyperplasia

Polyclonal lymphoid infiltration is not uncommonly seen in CVID and isassociated with the development of lymphoid malignancy and a worseprognosis (Bates et al., 2004; Chapel et al., 2008; Morimoto and Routes,2005). Splenomegaly, cervical, mediastinal, and abdominal lymphoidhyperplasia can be found in up to 20% of patients; biopsies canshow atypical lymphoid hyperplasia, reactive lymphoid hyperplasia orgranulomatous inflammation (Cunningham-Rundles, 2010). Granuloma-tous inflammation affects between 8% and 22% of patients withCVID (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 diagnos-tic delay. It commonly affects the lungs, lymph nodes and spleen but canbe found in most other organs including liver, parotid glands, meninges,and bone marrow (Ardeniz and Cunningham-Rundles, 2009; Mechanicet al., 1997). In a subset of patients, lung granuloma can also be accom-panied by an intense lymphocytic infiltration; a condition described asgranulomatous lymphocytic interstitial lung disease (GLILD) which car-ries a poorer outcome (Morimoto and Routes, 2005). Granulomatousdisease is also associated with lymphoid interstitial pneumonia andlymphadenopathy (Chapel et al., 2008). A comprehensive review onlung pathology observed in CVID is underway and preliminary resultscan be viewed at www.chest-ct-goup.eu.

Patients with granulomatous disease are also more prone to autoim-mune phenomenon; for example 54% of patients with granulomas hadautoimmunity (Ardeniz and Cunningham-Rundles, 2009). Survival isalso reduced with one study showing a median survival of 13.7 years inCVID patients with granulomatous/lymphoid interstitial infiltrates com-pared to 28.8 years in patients without these complications (Morimotoand Routes, 2005). The etiology of granulomatous disease remains uncer-tain as HHV-8 in the lung (Wheat et al., 2005) and cytomegalovirus in thegut have been implicated, but never confirmed (Raeiszadeh et al., 2006).In addition, polymorphisms in TNF and IL10 genes have also been asso-ciated with granulomatous disease suggesting a role for altered

http://www.chest-ct-goup.eu


inflammatory regulation contributing to the pathogenesis (Mullighanet al., 1997, 1999).

The treatment of granulomatous disease and lymphocytic infiltrationremains uncertain without any controlled studies. One suggested schemeinvolves the long-term use of hydroxycholoroquine on the basis of itseffect on TLR responses and antigen presentation and for its use insarcoidosis and autoimmunity (Cunningham-Rundles, 2010). However,although its effect on the skin may be sufficient, but in general hydroxy-chloroquine is of limited potency in more severe forms of granulomatosis.Therefore, oral steroids are frequently used with great benefit and a highresponse rate, but long-term usage needs to be balanced against the risk ofside effects and infections. Inhaled steroids are also used for lung granu-lomas (Cunningham-Rundles, 2010). TNF inhibitors have also been triedand some success reported although none of these were used in con-trolled trials (Hatab and Ballas, 2005; Lin et al., 2006; Thatayatikom et al.,2005). The authors own experience is that anti-TNF may help in CVIDenteropathy but not in granulomatous disease. In this context, it should benoted that although trials of TNF inhibitors have shown possible benefitin sarcoid (Doty et al., 2005), concerns regarding the development ofsarcoid while on TNF inhibitors have been raised (Daien et al., 2009).

Lymphoid interstitial pneumonia and other pulmonary lymphoidinfiltrative diseases also represent therapeutic challenges as they canresult in end-stage lung damage requiring oxygen therapy. In view ofthe T cell predominance in the lung infiltrate, ciclosporin has been used ina limited number of patients with some success although some of themeventually died due to respiratory disease (Ardeniz and Cunningham-Rundles, 2009; Davies et al., 2000).

One suggested approach to managing lymphoid hyperplasia is takingbiopsies of lymph nodes, infiltrates, or nodules if there is any doubt abouttheir nature (Cunningham-Rundles, 2010). Tissue is also saved for Epstein-Barr-encodedRNAs analysis, cytogenetics andT andB cell clonality studiesby molecular methods. The authors, however, make the point that clonallymphocytes are not necessarily indicative of lymphomaas these results canbe found in biopsies that show reactive hyperplasia (Gompels et al., 2003). Itis also suggested that splenectomy should not be undertaken except formarked hypersplenism, uncontrollable autoimmunity or where lymphomais a genuine concern (Cunningham-Rundles, 2010).

7.6. Malignancy

The overall incidence of malignancy is increased in CVID, althoughcertain cancers are significantly more common, particularly gastric carci-noma and non-Hodgkin lymphomas which have an increased risk of 7–16and 12–18 times higher respectively, depending on the study


(Cunningham-Rundles and Bodian, 1999; Quinti et al., 2007; Vajdic et al.,2010). Other cancers including colorectal cancer, breast cancer, ovariancancer, prostate cancer, multiple myeloma and melanoma have beendescribed although small numbers make it difficult to ascertain if theseare genuinely increased in CVID (Cunningham-Rundles and Bodian,1999; Quinti et al., 2007). However, data from the Australian registrydoes seem to suggest that malignancies occurring in CVID might berestricted to a fairly narrow spectrum compared to T cell immunodefi-ciencies (Vajdic et al., 2010).

The reasons for the increased risk of malignancy in CVID are likely tobe multifactorial (Chua et al., 2008). These would potentially include acomplex interplay between chronic antigen stimulation from infection,the acquisition of genetic abnormalities and immune dysregulation. Forexample, the B cell related molecule BAFF has been shown to be increasedwith 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 withHelicobacter pylori infection (Zullo et al., 1999); as is pernicious anemia(Dhalla et al., 2011). In the general population, both H. pylori infection andpernicious anemia are known to increase the risk of gastric cancer(Forman et al., 1994; Hsing et al., 1993). Given the known increased riskof gastric cancer in CVID patients, surveillance protocols have beenproposed and will be trialed in the near future (Dhalla et al., 2011). Thesuggested protocol involves testing all CVID patients for H. pylori anderadication as necessary, treatment of pernicious anemia with vitaminB12; and initial upper GI endoscopy if there are risk factors with repeatendoscopy depending on degree of risk.

Lymphomas when present in CVID are frequently extranodal, B cell inorigin and normally EBV negative (Cunningham-Rundles and Bodian,1999; Gompels et al., 2003). Dissimilar to other primary immunodeficien-cies, lymphoma in CVID is more common in the fourth to seventh decadeof life. Mucosa associated lymphoid tissue lymphomas have also beenreported in CVID (Cunningham-Rundles et al., 2002).

8. MANAGEMENT

The main therapeutic modalities available to treat CVID remain broadlythe same with replacement immunoglobulin for the antibody deficiencyand antibiotics for treatment and prevention of infections, as well asappropriate therapy for the noninfectious complications.


8.1. IVIG and mortality/infections

Replacement immunoglobulin therapy for antibody deficiency representsthe mainstay of treatment in CVID and although no randomized placebotrials have ever been done, it has been shown to reduce the rate ofinfections 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 intra-venous and subcutaneous routes appears to be equally effective in pre-venting infections (Chapel et al., 2000) and to be safe (Gardulf et al., 1995a).The use of subcutaneous immunoglobulins has also increased the easeand availability of home therapy for patients as well as improving qualityof 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 commenc-ing an individual on therapy (usually in at a dose of 400 mg/kg totalmonthly dose) and then increasing the dose to achieve a ‘‘target’’ troughlevel. However, the optimum trough level to be achieved with immuno-globulin has been unclear with varying amounts suggested in differentguidelines; 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 availableto help guide the decision: Orange et al. (2010) performed a meta-analysisto evaluate trough IgG levels and incidence of pneumonia. In total, 17studies with 676 patients (2127 patient-years of follow-up) were combinedin the analysis. This showed that pneumonia incidence decreased astrough 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 thelowest dose.

Lucas et al. (2010) analyzed data from 90 patients accumulated over22 years from a single center. The center’s policy had been to adjustimmunoglobulin doses in relation to infective episodes rather than toaim for a specific trough level. Retrospective analysis of patient datafollowing this policy showed a wide range of IgG trough levels (500–1700 mg/dl) and immunoglobulin doses (0.2–1.2 g/kg/month) requiredto control infections. Based on this, the authors concluded that the correcttherapy for a given patient needed to be individualized. Their data alsoshowed that in patients with bronchiectasis and splenomegaly, largeramounts of immunoglobulin therapy were required to maintain equiva-lent trough levels. Data was analyzed by clinical phenotype of patients(Lucas et al., 2010) and patients without disease complications were foundto need lower doses of immunoglobulin replacement compared to thosewith enteropathy, cytopenias, or lymphoid interstitial pneumonia.


Consistent with the findings of Lucas et al. (2010), there is also retro-spective UK data in 107 patients showing no relationship between bodymass index, trough IgG levels, infusion frequency and total annual dose(Khan et al., 2011). The patients had had their immunoglobulin dosetitrated for optimum effect, suggesting that adjusting immunoglobulindose by clinical outcome rather than using a fixed amount by body weightis appropriate.

Quinti et al. analyzed data from 201 Italian patients with CVID and 101patients with XLA in a 5-year multicenter prospective study with 1365patient-years of follow-up (778 for CVID patients; Quinti et al., 2011).CVID patients had a reduction in pneumonia prevalence after commence-ment of immunoglobulin therapy (from 39.4% to 22.3%). Patients whoexperienced infections during treatment had a lower IgA and IgM. Insome patients (particularly those with enteropathy) increasing the dose ofreplacement immunoglobulin did not result in adequate IgG levels and inother patients, raising the level of IgG did not prevent pneumonias. Theyalso found that patients with pneumonia did not have significantly lowerlevels of IgG compared to those without in contrast to the previous twostudies discussed; however, on grouping patients into intervals, theyfound that those with trough levels <4 g/l were more likely to getpneumonia. Based on this, Quinti et al. advocated the approach of com-mencing replacement immunoglobulin therapy with low IgG levels evenbefore the occurrence of serious infection. There was also no difference intrough levels between patients who developed bronchiectasis and thosewho did not; although IgA levels and age (but not pneumonia) wereindependently associated with development of bronchiectasis.

One other approach that has been explored to help guide immuno-globulin replacement therapy was measuring specific antibody levels toindividual pathogens. Chua et al. looked for discordance of antipneumo-coccal, antihaemophilus, and antitetanus toxoid antibody levels with totalIgG levels to see if this could explain why different patients requireddifferent trough IgG levels to remain infection-free (Chua et al., 2011).They found, however, that the use of specific pathogen antibody levelsdid not contribute further to identifying patients who were more suscep-tible 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 IgGtrough level that is universally appropriate (CVID is not CVID), andthat there is merit in increasing the dose of immunoglobulin to reduceinfection rates, although further data is required for trough doses >1000mg/dl. In addition, replacement of IgA/IgM (in addition to IgG) is worthconsidering as novel treatment strategies, because low levels are asso-ciated with greater infection burden. Risk factors for individual patientsmight also need to be taken into consideration for tailoring therapy.


8.2. Antibiotic use

Generally, an aggressive approach is adopted for the treatment of acuterespiratory infections to prevent long-term complications. If possible,appropriate microbiological specimens should be sent but this shouldnot delay commencing empirical therapy while waiting for results. Inaddition, an extended treatment course (10–14 days) of antibiotics isnormally given to prevent relapse although the evidence base for this islimited.

Antibiotic prophylaxis should also be considered for frequent infec-tions (>3 per year) or severe infections although again, the evidence forthis is poor. In the context of management of bronchiectasis, there is alsolimited data in CVID, and most treatment strategies have been adaptedfrom the experience with cystic fibrosis (CF) patients. Some physiciansrecommend increased doses of immunoglobulin in bronchiectasis. Anti-microbial prophylaxis with macrolides have been shown to have a possi-ble benefit in CF-related and non-CF bronchiectasis (Clement et al., 2006;Cymbala et al., 2005; Davies andWilson, 2004; Koh et al., 1997; Tsang et al.,1999; Yalcin et al., 2006). In the CF setting, colonization with pseudomonasusually marks the start of declining lung function and attempts at eradi-cation on first growth (Taccetti et al., 2005) as well as aerosolized anti-biotics may be beneficial (Chuchalin et al., 2007; Jensen et al., 1987; Moss,2002). Although pseudomonas is less common in CVID, it would bereasonable to undertake these measures as well.

We have summarized the local antibiotic protocols used in one of theLondon 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 inCVID (Burton et al., 2007; Cunningham-Rundles and Bodian, 1999). Thesehave had some (short-term) benefit although the limited numbers of casesmake it difficult to draw any firm conclusions. Stem cell transplantationrepresents a potential cure for the immunodeficiency but at present, there isno clarity about when (and if) this should be undertaken in patients withCVID. It is most likely to be of benefit when there is severe immune deficitwith T cell compromise (i.e., patients likely to fall into the LOCID sub-group). However, these patients are more likely to resemble a combinedimmunedefect and should be screened for hypomorphicmutations that cancause SCID. There is virtually nothing in the literature regarding the role ofstem cell transplantation in ‘‘classical’’ CVID; however, the Freiburg grouphas prepared a report on the first four cases with us (Rizzi et al., submitted).

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 treatment—patients not taking prophylaxis

Preferred: Amoxicillin 500 mg tdsAlternative for those with penicillin allergy: Macrolide

Other possibilities (e.g., due to allergy to both agents):

Levofloxacin 500 mg od/moxifloxacin 400 mg od

First line treatment—patients taking prophylaxis

Preferred agent is Co-amoxiclav 625 mg tds

For those with b-lactam allergy:� If taking ciprofloxacin prophylaxis, use a macrolide� If taking a non-ciprofloxacin based regime, use ciprofloxacin

Treatment failure

If treatment fails, review clinical features considering the following:

– Antibiotics unsuitable/insufficient/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 first growth of Pseudomonas

Upon the first growth of pseudomonas, an attempt should bemade to

eradicate the organism with the following regime:

Ciprofloxacin 750 mg bd for 3 weeks

Colomycin nebuliser 1 megaunit bd for 3 weeks (premed with

salbutamol, first dose with Respiratory Physio on Daycare)

Repeat sputum culture following treatment if still productive

If pseudomonas persistent or ciprofloxacin-resistant, the patient

should be admitted for a 2-week course of intravenoustreatment þ nebulised colomycin. Patients usually receive two

antibiotics, for example, ceftazidime þ 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-deficient patients

requiring long-term prophylactic antibiotic treatment

Antimicrobial prophylaxis in the setting of humoral immunodeficiency

may be particularly indicated in the following situations:

1. Patients with ‘‘partial’’ antibody deficiencies who are not currently

candidates for immunoglobulin replacement. The spectrum of partial

antibody deficiencies includes IgA deficiency, IgG subclass

deficiency and specific antibody deficiency

2. Patients with deficiencies of factors such as early complement that are

non amenable to replacement3. Patients with significant antibody deficiencies who are not yet

established on immunoglobulin replacement

4. Antibody-deficient patients with recurrent infections despite

adequate immunoglobulin replacement

5. Bronchiectatic antibody-deficient 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 infection7. Prophylaxis of respiratory infection in patients without bronchiectasis

� Consider treatment when infections are FREQUENT (four or more

significant infections per year) and/or SEVERE/DISRUPTIVE (e.g.,

hospital admission, prolonged period off work, secondary

complications such as empyema)� Infections should be microbiologically confirmed wherever possible.� Consideration should be given to noninfective causes for symptoms

such as chronic cough and sore throat, for example, reflux, steroidinhalers, asthma, postnasal drip, postinfective bronchial hyper-

reactivity. 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 replacementmay benecessary

� The use of antimicrobial prophylaxis in the nonbronchiectasis setting is

not supported by any published evidence. The commonest organisms

are Streptococcus pneumoniae, Haemophilus influenzae and

Moraxella catarrhalis. Possible regimes for adults are:

– Azithromycin 250 mg three times perWEEK, 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

– Ciprofloxacin 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 beneficial;

although theoretically it might be, in practice it has fallen out of favor


8.4. Monitoring

At present, there remains little evidence to guide appropriate monitoringin CVID and most protocols are derived from expert opinion. Respiratorymonitoring generally consists of pulmonary function testing (PFT) andradiological imaging. Although PFT is not as sensitive as HRCT scans fordetection and monitoring of lung disease (Bates et al., 2004; Watts et al.,1986), they carry no long-term risks and can be performed more fre-quently. We perform PFT at baseline and then annually.

Plain chest radiographs do not provide as much information as HRCTand are of limited value. HRCT is the best method for detection ofbronchiectasis and interstitial lung disease but does carry a significantexposure to ionizing radiation, which might be especially significant inCVID patients who are radiosensitive (Palanduz et al., 1998; Vorechovskyet al., 1993). A 3- to 5-year screening interval has been used by severalinvestigators (Cunningham-Rundles, 2010; Quinti et al., 2007). we per-form a HRCT scan of the chest at baseline, at 5-yearly intervals, and whenclinically indicated.

Screening for gastrointestinal and lymphoproliferative complicationsis more unclear. Some investigators do not advocate screening for gastro-intestinal disease unless there are symptoms (Cunningham-Rundles,2010); although in view of the increased risk of gastric cancer, proposalshave beenmade forH. pylori screening and endoscopy if there are any riskfactors (Dhalla et al., 2011). In the 1990s, yearly upper endoscopies werecarried out in the Freiburg center. This was stopped in the 2000s. Sincethen, one patient has died due to gastric cancer. In the London cohort apatient has been saved by early diagnosis and total gastrectomy.

As the lymph node architecture in CVID patients is often difficult tointerpret even for the experienced pathologist, mere lymph node coreneedle biopsies may not be sufficient for the difficult differential diagno-sis of benign versus malignant lymphoproliferation in CVID, and theexcision of the whole lymph node is recommended by the authors. Thisshould be undertaken for persistently enlarged nodes although it hasbeen noted that lymphomas in CVID are frequently extranodal(Cunningham-Rundles, 2010). One group also undertook annual ultra-sound measurements of splenic size (Quinti et al., 2007). This showed in26% of patients a constant increase in splenic size during follow-up,whereas in 5% splenomegaly was only detectable at diagnosis butreturned to normal thereafter.

With the discovery of data predicting the increased risk of complica-tions in certain subgroups (Chapel et al., 2008), development of patient-tailored protocols depending on the clinical phenotype and risk factorsmight well be more appropriate.


9. PROGNOSIS AND SURVIVAL

Mortality in CVID is increased compared to the general populationalthough data now suggests that there has been an improvement inmortal-ity 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 CVIDwas64% for males and 67% for females compared to 92% and 94% respectivelyfor 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 andWebster, 1993). Amorerecent Italian cohort published in 2007 showed 6%mortality after 11 years offollow-up (Quinti et al., 2007). Themost recent publisheddata from the ESIDregistry showed a 15% mortality rate over a 22.5-year follow-up period, asignificant improvement when compared to the previous United Kingdomand American cohorts (Chapel et al., 2008).

Analysis of that data also revealed other information; certain clinicalphenotypes (which were autoimmunity, lymphoid proliferation, enterop-athy, lymphoid malignancy) were associated with greater risk of deathcompared 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 wasnot significantly associated with diagnostic delay, serious infectionsbefore diagnosis, a greater incidence of lung disease or mortality (Chapelet al., 2008). Also, unexpectedly, mortality was also not related to the age atonset 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 discov-eries that cause or contribute to a CVID phenotype is increasing, andgenome-wide studies are now starting to be performed. Subsequently,these gene mutations have shown us what happens in humans whenspecific parts of the immune system are nonfunctional.

Several attempts have also been made at tackling the heterogeneity ofthe disease by developing various classification schemes. Hopefully thesedistinct subgroups of patients will enable more focused research bothaimed at understanding the pathology as well as improving their clinicalcare. There is now data showing that patients with CVID are survivinglonger, possibly due to better treatment of the disease, even thoughoverall the diagnostic delay of CVID is not greatly different.


However, we still have very limited understanding of the heterogene-ity of the condition and how the genetic discoveries fit into causing illness.In addition, we have very little understanding of how many of thecomplications in CVID arise, much less the best way of treating them.The classification of patients into different subgroups is a promising startto addressing these issues although much work still needs to be done.

In conclusion, there is much we have learnt about the immune systemfrom patients with CVID. In turn, it is hoped that as we better understandthe complexity of illness, care of patients will continue to improve.

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A Rose is a Rose is a Rose but CVID is Not CVID - Common Variable Immune Deficiency (CVID) What Do...

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