New diagnostic criteria for CVID

Abstract

Response to: Kumar R, Bhatia A. Common variable immunodeficiency in adults: current diagnostic protocol and laboratory measures. Expert Rev. Clin. Immunol. 10(2), 000–000 (2014).

We read with interest the article published by Drs Kumar and Bhatia on common variable immune deficiency (CVID) [1]. Our recent paper [2] on proposed new criteria for CVID was cited in the review by Kumar and Bhatia. A table (Box 2 in the article [1]) similar to our diagnostic criteria appears to have been attributed to us, along with diagnostic Categories A–D.

CVID is probably a heterogeneous group of polygenic disorders culminating in late-onset antibody failure. It is unlikely that a single diagnostic genetic test will become available in the foreseeable future. This is a difficult area as we have many patients with profound laboratory abnormalities who are relatively well [3]. Other patients are very ill with extensive suppurative lung disease but have minimal laboratory abnormalities. As the cause(s) of this/these complex disorder(s) is/are not known, our criteria were designed to ensure that patients with immune system failure (ISF) would be identified and treated with immunoglobulin. The main difference between our proposed criteria and the European Society of Immune Deficiency and Pan-American Group for Immune Deficiency is the emphasis on clinical symptoms of ISF. Given the difficulties assessing vaccine responses [2], this aspect of the diagnosis has been de-emphasized in our criteria.

Our criteria comprise four parts (Table 1). Patients must meet the major criteria in Category A. Adult patients must have an IgG < 5 g/l (not 4.5 g/l), which is the cutoff used in the French DEFI study [4]. This is well below the two standard deviations for IgG as stated in the Pan-American Group for Immune Deficiency/European Society of Immune Deficiency criteria [5]. Patients must be over 4 years of age [6] and must not have a secondary cause for their hypogammaglobulinemia [7].

Table 1. Proposed diagnostic criteria for common variable immune deficiency.

A	Must meet all major criteria
	Hypogammaglobulinemia IgG <5 g/l [4] No other cause identified for immune defect [7] Age >4 years [6]
B	Sequelae directly attributable to immune system failure (one or more)
	Recurrent, severe or unusual infections Poor response to antibiotics Breakthrough infections in spite of prophylactic antibiotics Infections in spite of appropriate vaccination, for example, HPV disease Bronchiectasis and/or chronic sinus disease Inflammatory disorders or autoimmunity [9]
C	Supportive laboratory evidence (three or more criteria)
	Concomitant reduction or deficiency of IgA (<0.8 g/l) and/or IgM (<0.4 g/l) [10,11] Presence of B cells but reduced memory B cell subsets and/or increased CD21 low subsets by flow cytometry [12] IgG3 deficiency (<0.2 g/l) [13,14] Impaired vaccine responses compared with age-matched controls [15] Transient vaccine responses compared with age-matched controls [3] Absent isohemagglutinins (if not blood group AB) [16] Serological evidence of significant autoimmunity, for example, Coombes test Sequence variations of genes predisposing to CVID, for example, TACI, BAFFR, MSH5, etc. [17,18]
D	Presence of relatively specific histological markers of CVID (not required for diagnosis but presence increases diagnostic certainty)
	Lymphoid interstitial pneumonitis [19] Granulomatous disorder [20,21] Nodular regenerative hyperplasia of the liver [22,23] Nodular lymphoid hyperplasia of the gut [24] Absence of plasma cells on gut biopsy [25,26]

Meeting criteria in Categories ABC or ABD indicate probable CVID. Patients meeting criteria ABC and ABD should be treated with intravenous immunoglobulin/subcutaneous immunoglobulin (Figure 1). Patients meeting criteria A alone, AB or AC or AD but not B, are termed possible CVID. Some of these patients may need to be treated with intravenous immunoglobulin/subcutaneous immunoglobulin. Patients with levels of IgG >5 g/l, not meeting any other criteria, are termed hypogammaglobulinemia of uncertain significance (HGUS).

CVID: Common variable immune deficiency.

If patients satisfy Category A criteria, then they must have clinical evidence of ISF, usually susceptibility to infections or autoimmunity (Category B criteria). They must then meet Category C or D criteria. Category C criteria consist of a series of laboratory findings, which are not specific on their own but in combination will support the diagnosis of CVID. Category D consists of characteristic histological findings in CVID, which are consistent with the diagnosis. Patients meeting Categories A, B and C or D have probable CVID and will qualify for long-term immunoglobulin treatment (Figure 1). Those patients meeting only Category A have possible CVID and some with profound hypogammaglobulinemia will qualify for immunoglobulin treatment [2]. Those with mild reductions in IgG have been termed hypogammaglobulinemia of uncertain significance. These patients will need long-term follow-up as some will evolve into CVID. The diagnostic and treatment algorithm is shown in Figure 1.

Figure 1. Diagnostic and treatment algorithm for common variable immune deficiency. Patients must meet all major criteria in Category A for consideration of CVID. Category B confirms the presence of symptoms indicating immune system failure. To have probable CVID, patients must also have supportive laboratory evidence of immune system dysfunction (Category C) or characteristic histological lesions of CVID (Category D). Patients with mild hypogammaglobulinemia (IgG >5 g/l) are termed hypogammaglobulinemia of uncertain significance (HGUS). Patients meeting Category A criteria but not other criteria are deemed to have possible CVID. Most patients with probable CVID are likely to require IVIG/SCIG. Some patients with possible CVID will require IVIG/SCIG, but most patients with hypogammaglobulinemia of uncertain significance are unlikely to need IVIG/SCIG replacement.

We are in the process of validating these criteria with the New Zealand hypogammaglobulinemia/CVID cohort. These criteria will need international consensus and endorsement by immunology societies. Having uniform criteria will assist with treating individual patients. It will also allow comparison of international cohorts of patients, who may have different clinical features and complications. Having a characteristic histological lesion may obviate the need to stop immunoglobulin treatment to assess vaccine responses. This process can take several months and patients may be at risk of infections during this time. These criteria will also help identify common and unusual causes of secondary hypogammaglobulinemia [8].

While we welcome the publication of our criteria in peer-reviewed journals, our main concern is that our table of diagnostic criteria has been substantially modified by Kumar and Bhatia, which will significantly alter its diagnostic utility. Our original publication had eight criteria in Category C and patients were required to meet three criteria to qualify. In the Kumar publication [1], these were shortened to five (Box 2), which will significantly reduce the probability of patients with CVID meeting three of these criteria. Furthermore, we have not suggested assessing only responses to protein (T cell-dependent) vaccines as stated in the Kumar publication. There is also no mention of mutations in genes, such as TACI or BAFF receptor, which may predispose to CVID in the modified table.

Our concern is that if patients do not meet the criteria in the Kumar publication, there is a risk that their immunoglobulin treatment may not be funded in some parts of the world. We request that any authors citing our work in the future, reproduce our criteria accurately to reduce the risk of confusion. This would be expected when citing the Jones criteria for acute rheumatic fever or the American College of Rheumatology criteria for systemic lupus erythematosus.

Financial & competing interests disclosure

R Ameratunga has received an unrestricted educational grant from Octapharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Notes