Koen et al report on a laboratory “back story” that played out during a randomized, double-blind, placebo-controlled trial of immunogenicity and safety of a new monovalent parenteral subunit rotavirus vaccine in Soweto, South African infants and toddlers. Measurement of white blood cell (WBC) count with 5-part differential count (along with basic metabolic tests) was required by protocol prior to enrollment/injection as well as 7 days following the first injection. WBC count and differential were performed in an accredited laboratory using a Beckman Coulter LH-750 Analyzer. So far so good. Abnormal absolute neutrophil counts were graded according to the laboratory's routine practice (which was not age specific) on a scale of 1-4; screening neutropenia ≥grade 2 excluded subjects from participation. When during the early course of the study 28% of healthy HIV-uninfected 1-2 month old infants were excluded because of ≥grade 2 neutropenia (<1500 cells/mm3), the Safety Review Committee reviewed the study's grading table and well established alternative grading scales. When the protocol was revised subsequently to use an alternative grading scale for neutropenia, only 12% of healthy infants were excluded because of neutropenia >grade 2 (<1000 cells/mm3). Because children of African descent have lower WBC and absolute neutrophil counts than those of European descent, interpretation of neutropenia had major impact in this particular geoethnic setting.
Laboratory testing at baseline and during conduct of clinical trials of drugs and vaccines is a standard, “automatic” part of research protocols. Over-reaching interpretation of “abnormalities” at screening can threaten generalizability of results, and at time points during the study can lead to halting trials prematurely or to misleading conclusions of potential adverse events. Even exclusion of 12% of healthy infants in the current study is unfortunate. One might ask what immunogenicity or safety hypotheses underpinned the necessity to measure the WBC count in healthy infants prior to or during potential exposure to a parenteral subunit vaccine? Experienced clinicians recognize the substantial variability in absolute neutrophil count in healthy and mildly ill children, the lack of untoward consequences even with high grade neutropenia if it is the singular finding, and the folly of seeking a clinically meaningful pathologic explanation or pursuing an altered course of care.
Be careful for what you ask, and be prepared to interpret what you find appropriately.
Read the related article “Neutrophil Counts in Healthy South African Infants: Implications for Enrollment and Adverse Event Grading in Clinical Trials in an African Setting” by Koen et al, The Journal of Pediatrics: X 2019;1:100005. https://doi.org/10.1016/j.ympdx.2019.100005.