From infections to autoimmunity: Diagnostic challenges in common variable immunodeficiency

Table 1 Definitions of common variable immunodeficiency proposed by Ameratunga et al[80], European Society of Immune Deficiencies[12] and International Consensus Document[55]

Ameratunga et al[80] 2013

Must meet all major criteria:

Hypogammaglobulinemia IgG < 5 g/L

No other cause identified for immune defect

Age > 4 yr

Sequelae directly attributable to immune system failure (ISF) (1 or more):

Recurrent, severe or unusual infections

Poor response to antibiotics

Breakthrough infections in spite of prophylactic antibiotics

Infections in spite of appropriate vaccination, e.g., human papilloma virus disease

Bronchiectasis and/or chronic sinus disease

Inflammatory disorders or autoimmunity

Supportive laboratory evidence (3 or more criteria):

Concomitant reduction or deficiency of IgA (< 0.8 g/L) and/or IgM (0.4 g/L)

Presence of B cells but reduced memory B cell subsets and/or

Increased CD21 low subsets by flow cytometry

IgG3 deficiency (< 0.2 g/L)

Impaired vaccine responses compared with age-matched controls

Transient vaccine responses compared with age-matched controls

Absent isohemagglutinins (if not blood group AB)

Serological evidence of significant autoimmunity, e.g., Coombes test

Sequence variations of genes predisposing to CVID, e.g., TNFRSF13B/TACI, TNFRSF13C/BAFFR and MSH5

Presence of relatively specific histological markers of CVID (not required for diagnosis but presence increases diagnostic certainty, in the context of category A and B criteria):

Lymphoid interstitial pneumonitis

Granulomatous disorder

Nodular regenerative hyperplasia of the liver

Nodular lymphoid hyperplasia of the gut

Absence of plasma cells on gut biopsy

ESID 2014

At least one of the following:

Increased susceptibility to infection

Autoimmune manifestations

Granulomatous disease

Unexplained polyclonal proliferation

Affected family member with antibody deficiency

AND

Marked decrease of IgG and marked decrease of IgA with or without low IgM levels (measured at least twice; < 2SD of the normal levels for their age)

AND

At least one of the following:

Poor antibody response to vaccines (and/or absent isohemaglutinins); i.e., absence of protective levels despite vaccination were defined

Low switched memory B cells (< 70% of age-related normal value)

AND

Secondary causes of hypogammaglobulinemia has been excluded:

AND

Diagnosis is established after the fourth of year of life (but symptoms can be present earlier)

AND

No evidence of profound T-cell deficiency, defined as 2 of the following (y: Year of life):

CD4 numbers/microliter:

2-6 yr < 300, 6-12 yr < 250, 12 yr < 200

% naive CD4:

2-6 yr < 25%, 6-12 yr < 20%, 12 yr < 10%

T cell proliferation absent

ICON 2016

At least 1 of the characteristic clinical manifestations: Infection, autoimmunity, lymphoproliferation

OR

Asymptomatic individuals, especially in familial cases who fulfill criteria 2 to 5, hypogammaglobulinemia should be defined according to the age adjusted reference range for the laboratory in which the measurement is performed

The IgG level must be repeatedly low in at least 2 measurements more than 3 wk apart in all patients. may be omitted if the level is very low < 100-300 mg/dL depending on age, and other characteristic features are present, IgA or IgM level must also be low

There must be a demonstrable impairment of response to at least 1 type of antigen (TD or TI), at the discretion of the practitioner, specific antibody measurement may be dispensed with if all other criteria are satisfied and if the delay incurred by prevaccination and postvaccination antibody measurement is thought to be deleterious to the patient’s health

Other causes of hypogammaglobulinemia must be excluded

Genetic studies to investigate monogenic forms of CVID or for disease-modifying polymorphisms are not generally required for diagnosis and management in most of the patients, especially those who present with infections only without immune dysregulation, autoimmunity, malignancy, or other complications

CVID: Common variable immunodeficiency; ESID: European Society of Immune Deficiencies; ICON: International consensus document.