DISCUSSION
The current study involving a large number of patients showed that a CG
cut-off value of <2.0 mg/dl had a sensitivity of 83.8% and a
specificity of 74.9% in order to detect AD in Turkish adult patients.
Our results also showed that CG is useful to detect low IgG levels in
parallel to low gamma globulin values in protein electrophoresis.
Furthermore, its usefulness was confirmed in identifying almost 80% of
adult PAD patients tested.
Since CG is easily accessible, simple, and inexpensive, it is suitable
for usage as a screening test12,13. Furthermore, it is
frequently used as part of routine laboratory testing in patients. It
has a high potential to facilitate early diagnosis of PAD or SAD because
of its widespread use, high sensitivity and specificity. The use of CG
as a screening test in AD was first suggested by Jolles S. et
al2. In their study, CG was obtained by subtracting
albumin, which is measured by both BCG and bromocresol purple (BCP)
methods, from total protein. They defined different cut-off values for
these two methods2. Similar to the study of Pecoraro
A. et al. 8, the Italian version of this study, we
measured albumin only with the BCG method in our study.
In the study of Jolles S. et al., a CG value of <1.8 obtained
by using the BCG method, predicted a sensitivity of 66% and a
specificity of 78% for IgG levels lower than 500
mg/dL2. In the current study, we accepted the IgG
value of 600 mg/dL as a limit for
hypogammaglobulinemia14. Therefore, the aim of our CG
cut-off value is to predict patients with a IgG value lower than 600
mg/dL. In addition, we also calculated cut-off values for different IgG
levels. The most appropriate CG cut-off value for predicting patients
with IgG <500 mg/dl was <1.9 which showed a
sensitivity of 82.7% and a specificity of 79.3%. Our study revealed
better sensitivity and specificity but with consistent results when
compared to the original study by Jolles S. et al2.
In the study of Pecoraro, A. et al., a CG value of <1.9
predicted a sensitivity of 70.0% and a specificity of 75.0% for IgG
values lower than 600 mg/dL8. In our study, the most
appropriate CG cut-off value, which we selected as <2.0, had a
sensitivity of 83.8% and a specificity of 74.9% for predicting
patients with this IgG value. Since CG value of 1.9 with a sensitivity
of 75.4% and a specificity of 84.4% was also an appropriate cut-off
value according to Youden’s index, we could have selected it similar to
Pecoraro et al. However, for screening tests, since it is recommended to
select a sensitivity higher than 80.0%11, we accepted
the cut-off value of <2.0 as the most appropriate.
CG contains other globulins such as alpha 1, alpha 2, beta 1 and beta 2
as well as gamma globulins which are mostly formed by
immunoglobulins15,16. Considering the presence of
proteins in alpha and beta bands which can act as acute phase reactants,
the CG value may remain high despite the presence of low gamma globulin
value in cases with chronic disease associated with inflammation and or
infection15-17. In addition, the gamma globulin level
might be normal while the CG value is low due to the conditions that can
decrease the production or increase the catabolism of the alpha and beta
bands15. In order to observe this difference, we also
measured the gamma globulin values of the patients participating in
our study, unlike previous studies performed on adults. Gamma globulin
cut-off value of <0.7 which best predicted IgG levels lower
than 600 mg/dL, had a higher sensitivity and specificity than the CG
cut-off value of <2.0 as expected. In the study of Piza C. et
al. conducted on pediatric and adolescent patients, in parallel with our
study, it was stated that gamma globulin had a higher sensitivity and
specificity than CG and it would be appropriate to use it as a screening
test like CG9. However, since CG is obtained in
clinics much more frequently and cheaper than gamma globulin, it has the
potential to screen a larger number of patients.
In our study, we were able to analyze the distribution of the clinical
characteristics of the patients according to the cut-off value of CG. We
observed that patients with a CG cut-off value of <2.0 had a
significantly higher rate of recurrent parenteral antibiotic use than
the others (p=0.025). To date, the CG has been defined as a screening
test by the previous studies to predict the possibility of AD. In the
current study, we have extended this to demonstrate the clinical
implications, importance and utility CG.
The most frequent source clinics of the patients with low IgG values
were nephrology and hematology. Excluding diseases such as hypertension
and diabetes, which were similar in the whole patient population and not
directly related to antibody deficiency, the patients were mostly
diagnosed as having chronic renal disease, nephrotic syndrome, multiple
myeloma and renal transplantation. In the study of Jolles S. et al., the
hematology clinic was the biggest source for the patients with IgG
values lower than 400 mg/dL2. However, nephrology
was the biggest source for this patient group in our study. We attribute
this result to the fact that Istanbul Faculty of Medicine has a large
renal transplantation center because patients can receive intensive
immunosuppression especially in the early stages of renal
transplantation. Not surprisingly, apart from antihypertensives and
statins, the most frequent medications were corticosteroids,
chemotherapeutics and other immunosuppressive drugs.
The retrospective analyses of the data of 47 patients with primary AD
(IgG<600) followed in our clinic showed that 78.7% had a CG
value of <2.0 at the time of diagnosis. Pecoraro A. et al.
found this rate to be 97.3% (37/38) in a similar analysis performed in
their study8. This difference may be due to the
clinical conditions of the patients such as the presence of infection
and acute phase elevation at the time of admission. Furthermore, in all
the patients whose protein electrophoresis were measured at the time of
the diagnosis, gamma globulin level was less than 0.7 supporting this
possibility.
Besides infections, the wide range of heterogeneous clinical
noninfectious presentations of CVID may cause delays in
diagnosis2,18. These delays may result in ongoing
recurrent infections and irreversible organ damage2.
However, early diagnosis which can be achieved by using the CG method
might prevent chronic and irreversible complications associated with AD
in this patient group19,20. On the other hand,
hematological diseases including B cell-associated lymphoproliferative
disease, chronic lymphocytic leukemia, multiple myeloma; diseases
associated with impaired lymphoid circulation or increased
immunoglobulin catabolism; treatments including mofetil mycophenolate,
cyclophosphamide, corticosteroids, antiepileptics, rituximab and
chemotherapeutics can all lead to SAD. CG represents an unbiased
screening approach and could prevent complications that may occur due to
delayed diagnosis, not only in PAD but also in SAD7,8.
A potential limitation of our study is that the homogeneity of the
patient population could have been affected due to the fact that
Istanbul Faculty of Medicine is a tertiary hospital which is considered
as a reference center for many diseases. Most of the people whose
biochemical analyses were performed in our hospital were ill and there
were almost not any healthy people who came just for a check-up.
Therefore, numbers of less acutely unwell patients such as those seen
most often in primary care may be less well represented in our study.
In conclusion, the current study indicated that a CG level of less than
2.0 mg/dl should be a warning sign for undetected AD in our population.
Therefore, given the various manifestations of antibody deficiency and
the potential presentations to both primary care and different secondary
care services, low CG can alert clinicians for possible AD to prevent
diagnostic delay and optimize therapy. CG screening represents a cheap
and simple means of detecting primary and secondary antibody deficiency
across a range of healthcare settings and we have established cut-off
values for both CG and electrophoretic gamma globulin in out Turkish
population.