Hypogammaglobulinemia In Children Undergoing SCT: An Immunoglobulin Isotype Class Switch Arrest?

Treatment-requiring hypogammaglobulinemia is common early after allogeneic hematopoietic stem cell transplantation (SCT) in children. Usually, it resolves but in several children it persists, demanding long-term immunoglobulin (Ig) G replacement therapy. By IgG replacement, the morbidity risk may not be reduced, but infectious complications are decreased.

Here we studied clinical events, Ig and immune cell recovery, IgG2m allotypes and dynamics of cytokines important for B-lymphocytes and Ig production in 84 children undergoing SCT. The aim was to identify risk factors for ≥3 months IgG replacement need as well as studying the biology behind the hypogammaglobulinemia seen post-SCT. Clinical data were collected from charts. Interleukin (IL)-4, -5, -6, -7 and -10, BAFF and APRIL were analyzed in patient sera pre- and post-SCT. Donors and patients were IGHG2 genotyped. Uni- and multivariate statistic analyzes were applied.

As many as 48% of the children needed ≥3 months IgG replacement. These were commonly younger (<5 years) and had acute GvHD grade II-IV. However, children with ≥3 months IgG replacement had better overall survival (88 vs. 69%, P=0.036). Significantly lower Ig levels post-SCT, but equal immune cell recovery were seen when comparing the ≥3 vs. <3 months IgG replacement groups. Significantly higher rates of mixed chimerism in CD3 and C33 populations was seen in the <3 months IgG replacement group. IGHG2 genotyping showed no significant frequencies between the groups. Pre-SCT IL-6 and -7 and post-SCT BAFF and APRIL levels were significantly higher in the ≥3 months IgG replacement group. This suggests an unfavorable cytokine milieu for graft-derived immune recovery with possibly later Ig isotype class switch arrest. Age <5 years (OR 8.16, 95% CI 2.62-25.4, P<0.001), acute GvHD grade II-IV (OR 5.61, 95% CI 1.78-17.6, P=0.038) and pre-SCT IL-6 levels >50 pg/mL (OR 8.03, 95% CI 1.26-51.0, P=0.024) were identified as significant risk factors for ≥3 months IgG replacement need.

To conclude, requiring ≥3 months IgG replacement does not need to be unfavorable and could be an effect of deteriorated cytokine signaling resulting in impaired Ig production. Further prospective studies investigating post-SCT hypogammaglobulinemia with and without IgG replacement are warranted.