Immune System in Single Ventricle Patients—A Complex Nexus

Even in patients whose anatomic abnormalities are restricted to the heart, it is widely recognized that single ventricle heart disease is physiologically a systemic disease. Pulmonary vascular abnormalities are common and the pulmonary and cardiac systems reciprocally affect each other’s status. Long-term neurodevelopmental issues are common and may or may not be related to the need for multiple cardiac surgeries, bypass runs, and long periods of cyanosis. The higher abdominal venous pressure that is inevitable with a Fontan circulation can lead to congestive hepatopathy, gastrointestinal derangements, and renal dysfunction. In this issue of the journal, Kovacikova et al ¹ report abnormalities in the immune system that cannot be readily reconciled with known circulatory derangements in single ventricle physiology.

There are a number of reasons why single ventricle patients can have immune abnormalities. Thymectomy is routinely performed during the vast majority of pediatric cardiac surgeries. Single ventricle patients often have associated syndromes, such as DiGeorge or Down Syndromes, which can affect immune homeostasis. Heterotaxy and associated poly- or asplenia are also known to impact immune status. Prior infections, chylous effusions, and malnutrition can all play an important role. However, to this date, one of the best-recognized etiologies of immune abnormalities in single ventricle patients continues to be protein-losing enteropathy, a late complication of Fontan circulation. Kovacikova et al sought to analyze the immunologic characteristics from neonates to immediate post-Fontan patients, with the goal of identifying early onset immune abnormalities. To this end, they performed a battery of tests on 177 patients who were prospectively enrolled in their study over a six-year period.

And, as is usually the case, when carefully evaluated, an impressive array of results unfolds. Immune abnormalities were noted even before Glenn procedure. By the time Fontan circulation is reached, there appears to be a relative reduction in T-lymphocyte levels, spread across both CD4 and CD8 subtypes, with an increase in B-lymphocyte counts. Although no formal correlative analyses were undertaken, the spread of the data would suggest that no specific association with underlying cardiac or noncardiac pathology is discernible. Interestingly, lower lymphocyte counts correlated with increased length of stay and pleural effusions. The most plausible explanation for this association is that low lymphocyte counts served as a surrogate for overall health quality and hence were linked to recovery parameters following major cardiac surgery.

As in any well-designed work, this study raises more questions than it answers. Firstly, this report is at best a catalog of a variety of immunologic abnormalities. Despite its prospective design, this study does not include longitudinal data from patients across the various stages of single ventricle palliation. This precludes an understanding of the “natural” history of these immunologic abnormalities. The univariate analyses are oversimplified and do not account for the myriad of confounding variables that can impact the immune system. Although comprehensive and extending over all stages of surgical palliation, these data are purely cross-sectional and represent spot measurements at each respective time point. Whether they would bear the test of repeated measures still remains to be known. Regardless of these limitations, the authors should be commended for drawing our attention with data to the obvious fact that immunologic abnormalities are linked in a complex fashion to single ventricle physiology. It would be naive to imagine that they are exclusively late Fontan events.

Future efforts should be aimed at placing these laboratory aberrations in a clinical context to more comprehensively correlate their impact on outcomes. And the bigger question that needs to be answered is why in the first place do these abnormalities result, and how, if at all, can we intervene to redirect the trend favorably.