Comment on “Common variable immunodeficiency in adults: current diagnostic protocol and laboratory measures”

Abstract

Response to: Ameratunga R, Woon S-T, Gillis D et al. Challenges in diagnosis of CVID. Expert Rev. Clin. Immunol. 10(2), 000–000 (2014).

We appreciate the issues raised by Ameratunga et al. in the Letter to the Editor and are pleased to respond to their comments. Common variable immunodeficiency (CVID) is a heterogeneous disorder, which is often misdiagnosed or its presentation recognized at a much later age. One of the reasons could be that because majority of primary immunodeficiency disorders (PIDs) occur in the pediatric age group, a possibility of CVID in adults is sometimes ignored. Also the criteria for diagnosis of CVID were laid down way back in the 1990s, and thereafter, significant addition has been made to the understanding of CVID. Hence, a need for modifications in the original diagnostic criteria proposed by European Society for Immunodeficiencies and Pan-American Group for Immunodeficiency has been felt by the PIDs experts from time to time [1–3]. Each of them has their own opinions and suggestions for inclusion in diagnostic criteria for CVID. So far, none of them have been validated. We reviewed the suggestions of all the past and present major groups working on CVID. Till any one set of criteria is formally revised and approved, we intended to compile proposed modifications from different experts with an aim to provide all the important diagnostic features of CVID in one box without giving preference to any particular group. The recently proposed modifications by the Ameratunga et al. group were incorporated and given due importance to appreciate all the hard work done by them in formulating the guidelines that are likely to assist in deciding an appropriate therapy for CVID patients [4]. At the end of the box, authors clearly mention the source(s) of the information since the criteria mentioned have been collected from different papers.

We have mentioned the cutoff levels for serum IgG as ‘<4.5 g/l for adults or 2.5th percentile for the age.’ This implies that a cutoff should be below 4.5 g/l, and if not, then <2.5th percentile for the age. This does not mean that it excludes those with higher IgG levels but the levels should be below the levels found in general population at that age (2.5th percentile for the age or less than those found in 2.5% of general population). This will exclude inclusion of normal individuals in a population that has higher cutoff levels. Further, lower cutoff limit (<4.5 g/l) has been strongly supported by larger European and US studies in which majority of CVID patients were found to have serum IgG below 4.5 g/l [1,5,6]. In a way, the cutoff levels are flexible and more population-specific.

It is agreed that assessment of responses to protein vaccines is difficult; however, the same has been strongly recommended by Chapel and Cunningham-Rundles [1] and also by Yong et al. [3]. Reason for omitting the mutations in genes as one of the criteria is because in a recent update on classification system for PIDs by the International Union of Immunological Societies expert committee for PID (2011), the genetic defects in ICOS, BAFFR, TACI, CD19, CD20 and CD81 have been labeled as separate entities, and CVID is categorized as a disorder with unknown genetic defects [7].

Concomitant deficiency of IgA and/or IgM is usually seen along with IgG deficiency as suggested in original European Society for Immunodeficiencies/Pan-American Group for Immunodeficiency classification and also in the suggested modifications of other authors; hence, they have not been considered as separate criteria. Moreover, presence of three out of five is less likely to miss or neglect CVID cases compared with three out of eight minor criteria.

The intention of the authors is not to promote or criticize any group or the criteria laid by them. We believe that the people working on CVID should use their jurisdiction to judiciously use the criteria that are most useful and suited to their diagnostic requirements.

Financial & competing interests disclosure

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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