Clinical utility of avidity assays

Abstract

IgM may persist for months, presenting a risk of an erroneous diagnosis where serology is the only available tool. Indeed, IgM may be detected in secondary infection as a result of crossreactivity and/or nonspecific stimulation of the immune system. One test that can aid the serologist is IgG avidity testing, in that the avidity of IgG is low early in infection with the avidity of IgG antibodies increasing over time. Congenital toxoplasmosis can induce serious sequelae. Detectable IgM usually persists long after the acute infection. IgG avidity can be an important aid in diagnosis and assessing the risk to the fetus. Another infection that is of concern in pregnancy is cytomegalovirus (CMV). In pregnant women it is very important to differentiate primary from secondary infection, as primary infection presents the highest risk to the fetus. Serologic detection of IgM alone is not a specific marker of primary CMV infection. IgG avidity can have utility in identifying or excluding primary CMV infections during pregnancy. Outside of pregnancy, IgG avidity testing is increasingly recognized as a valuable tool. During the recent West Nile virus (WNV) epidemic in the US, it was recognized that WNV-specific IgM may persist for 6 - 12 months following exposure. Thus, a person presenting to their clinician with nonspecific symptoms may be tested and return a positive WNV IgM that may be the product of exposure during the previous period. In this environment, WNV IgG avidity testing is able to provide some assistance. IgG avidity testing should not be used alone and without an understanding of the limitations of the technique. Serology remains an important tool for the diagnosis and management of infectious disease. Classically, IgM is defined as a marker of acute infection and IgG, in the absence of clinical disease, is often considered a marker of past infection. However, the clinical reality can be quite different.

Role of Cytomegalovirus (CMV) IgG Avidity Testing in Diagnosing Primary CMV Infection during Pregnancy

“…Avidity is defined as the aggregate strength with which a mixture of polyclonal IgG molecules binds to multiple antigenic epitopes of proteins (12). It gradually matures over several months, reflective of antigen-driven selection of B cells producing IgG of increasing affinity (3,11,12).…”

“…It gradually matures over several months, reflective of antigen-driven selection of B cells producing IgG of increasing affinity (3,11,12). IgG antibodies produced during the first few months following primary infection exhibit low avidity (i.e., they bind weakly to the antigen), whereas antibodies produced by 6 months postinfection exhibit high avidity (i.e., they bind tightly to the antigen) (3,11,12).…”

“…The most straightforward indicator of primary CMV infection is documentation of seroconversion during pregnancy, but this approach is rarely effective due to the lack of preconception antibody screening programs allowing the identification of seronegative women (3, 9). Initial studies thus focused on detection of CMV IgM, due to its known utility as a transient marker of primary infection (3,9,12). These studies showed that CMV IgM detection is a sensitive marker for primary CMV infection, but its specificity is relatively poor; only about 50% of CMV IgM-positive individuals have primary infection (the reasons for this low specificity will be discussed later) (3,5,9,(13)(14)(15).…”

“…Studies assessing CMV IgG avidity showed that low CMV IgG avidity is both a sensitive and a specific marker of primary CMV infection (1-3). Indeed, CMV IgG avidity is increasingly considered the "gold standard" for distinguishing primary from nonprimary CMV infection (1,11,12,16) and is being used worldwide to identify primary CMV infection during pregnancy (14,(17)(18)(19)(20)(21).…”

“…Studies assessing CMV IgG avidity showed that low CMV IgG avidity is both a sensitive and a specific marker of primary CMV infection (1-3). Indeed, CMV IgG avidity is increasingly considered the "gold standard" for distinguishing primary from nonprimary CMV infection (1,11,12,16) and is being used worldwide to identify primary CMV infection during pregnancy (14,(17)(18)(19)(20)(21).This minireview focuses on 4 aspects of CMV IgG avidity testing: (a) the definition of avidity and the basic methodology used in initial studies linking CMV IgG avidity and primary infection; (b) a summary of results from the major studies demonstrating the utility of CMV IgG avidity assessment in pregnancy, including the advantages of avidity testing over CMV IgM testing alone; (c) a discussion of commercially available CMV IgG avidity assays, including newer automated assays; and (d) current issues and controversies in diagnosing primary CMV infections during pregnancy. …”