CLSI-Derived Hematology and Biochemistry Reference Intervals for Healthy Adults in Eastern and Southern Africa

Abstract

BackgroundClinical laboratory reference intervals have not been established in many African countries, and non-local intervals are commonly used in clinical trials to screen and monitor adverse events (AEs) among African participants. Using laboratory reference intervals derived from other populations excludes potential trial volunteers in Africa and makes AE assessment challenging. The objective of this study was to establish clinical laboratory reference intervals for 25 hematology, immunology and biochemistry values among healthy African adults typical of those who might join a clinical trial.Methods and FindingsEqual proportions of men and women were invited to participate in a cross sectional study at seven clinical centers (Kigali, Rwanda; Masaka and Entebbe, Uganda; two in Nairobi and one in Kilifi, Kenya; and Lusaka, Zambia). All laboratories used hematology, immunology and biochemistry analyzers validated by an independent clinical laboratory. Clinical and Laboratory Standards Institute guidelines were followed to create study consensus intervals. For comparison, AE grading criteria published by the U.S. National Institute of Allergy and Infectious Diseases Division of AIDS (DAIDS) and other U.S. reference intervals were used. 2,990 potential volunteers were screened, and 2,105 (1,083 men and 1,022 women) were included in the analysis. While some significant gender and regional differences were observed, creating consensus African study intervals from the complete data was possible for 18 of the 25 analytes. Compared to reference intervals from the U.S., we found lower hematocrit and hemoglobin levels, particularly among women, lower white blood cell and neutrophil counts, and lower amylase. Both genders had elevated eosinophil counts, immunoglobulin G, total and direct bilirubin, lactate dehydrogenase and creatine phosphokinase, the latter being more pronounced among women. When graded against U.S.-derived DAIDS AE grading criteria, we observed 774 (35.3%) volunteers with grade one or higher results; 314 (14.9%) had elevated total bilirubin, and 201 (9.6%) had low neutrophil counts. These otherwise healthy volunteers would be excluded or would require special exemption to participate in many clinical trials.ConclusionsTo accelerate clinical trials in Africa, and to improve their scientific validity, locally appropriate reference ranges should be used. This study provides ranges that will inform inclusion criteria and evaluation of adverse events for studies in these regions of Africa.

Laboratory Reference Intervals in Africa

“…White Blood Cell (WBC) components A high proportion of participants in the African studies have WBC counts below the lower range of the Massachusetts General Hospital US population-derived values [9,20]. This phenomenon is consistent with a number of studies that have reported lower WBC counts in…”

“…(MCH) by gender have been observed in several African studies, with adult males having higher values than adult females in East Africa [9,16,20,31,39,40], Southern Africa [20,36], West Africa [41] and Central Africa [42]. These gender differences in RBC parameters as illustrated in our findings (Table 2), are consistent with previously established evidence that males have higher values than females for these parameters and is partly attributed to the influence of the androgen hormone on erythropoiesis [43,44] and to menstrual blood loss in women [16,25,39,42,45].…”

“…A majority of clinically healthy participants have been excluded from several clinical trials in Africa because laboratory hematological and biochemical parameters are classified as abnormal [18][19][20]. Unnecessary exclusion of potential participants generally results in increased cost for study recruitment to achieve the target sample size.…”

“…The normal values of red cell counts and indices (i.e., hemoglobin concentration, hematocrit, mean corpuscular volume, red blood cell count), white cell counts and platelet counts are known to vary with age, sex and pregnancy [9,16,20,31,36]. In addition, genetic and environmental factors can also affect the reference intervals in certain populations [32][33][34]37].…”

AIDS Vaccines and Preexposure Prophylaxis: Is Synergy Possible?

“…In a survey of men and women who were healthy by history and physical examination, from potential vaccine trial populations, 10-35% of volunteers would not be eligible. 103,104 However, data from current PrEP testof-concept trials may allow these criteria to be less stringent.…”