The effect of pegbovigrastim on circulating neutrophil count in dairy cattle: A randomized controlled trial

Abstract

Previous research in various species has shown that granulocyte-colony stimulating factor stimulates the production and release of neutrophils from bone marrow. The objective of this study was to characterize the effects of polyethylene glycol-bound bovine granulocyte colony-stimulating factor (pegbovigrastim; Imrestor, Elanco) on circulating leukocyte counts. Thirty-four Holstein cows were randomly assigned to receive 2 injections of either physiologic saline (n = 16) or pegbovigrastim (n = 18), 7 days before expected calving (d -7) and within 24 hours after calving (d 0). Cows were sampled at d -7, d -6, d 0, d +1, d +7, and d +21, relative to calving. Only cows for which the interval from the first injection to calving was ≥ 4 d and ≤ 10 d were included, such that the interval (mean ± SD) from first treatment to calving was 6.7 ± 1.9 d. Treatment effects were assessed with mixed linear regression models. After the first injection, neutrophil counts (×109/ L) in pegbovigrastim-treated cows increased from 4.3 (95% CI 3.8 to 4.8) at d -7 to 18.2 (CI 16.3 to 20.3) at d -6 (P < 0.0001). Their counts then decreased from d -6 to d 0, when the second injection was administered, at a rate of -0.31 ×109 neutrophils/L/day (P < 0.0001). After the second injection, neutrophil counts increased from 16.4 (CI 13.7 to 19.6) at d 0 to 32.8 (CI 25.2 to 42.7) at d +1 (P < 0.0001), after which counts decreased at a rate of -3.73 ×109 neutrophils/L/day until d +7 (P < 0.0001). Counts continued to decrease from d +7 to d +21 at a slower rate of -0.43 ×109 neutrophils/L/day (P < 0.0001), until baseline levels were reached. Conversely, in control cows, neutrophil counts were unchanged from d -7 to d -6 (P = 0.86) after the first injection and then decreased from 6.1 (CI 5.0–7.3) at d 0, to 3.2 (CI 2.4–4.2) at d +1 (P < 0.0001) after the second injection. Neutrophil count was greater (P < 0.001) in pegbovigrastim-treated than in control cows at days -6, 0, +1 and +7. Area under the curve (cells ×109/ L per 28 d) for neutrophil counts in the pegbovigrastim group was 429, versus 99 in the control group (P < 0.0001). The response to each injection of pegbovigrastim was additive and consisted of 95% segmented neutrophils, suggesting that the effect of the treatment was to release mature neutrophils from a substantial pool available in the bone marrow. The sustained increase in circulating neutrophil count around the time of calving may contribute to improved health during the peripartum transition period.

Review: Relationships between metabolism and neutrophil function in dairy cows in the peripartum period

“…A small study with that product (Imrestor; Elanco Animal Health Greenfield, IL, USA) demonstrated substantial increases in circulating neutrophil count and an increase in myeloperoxidase exocytosis, but not phagocytosis or oxidative burst (Kimura et al, 2014). Those effects have been confirmed in subsequent studies (McDougall et al, 2017;Van Schyndel et al, 2018). Blood neutrophils from cows treated with PEG-rbG-CSF had greater expression of 3 (ICAM1, TLR2 and PTGS2) of a panel of 20 genes selected to represent the chain of functional steps of neutrophils (Heiser et al, 2018).…”

“…General neutrophil biology Neutrophils are differentiated and proliferated in the bone marrow under the influence of granulocyte colonystimulating factor (G-CSF), a process that appears to take about 7 to 10 days from myeloblast to release of a neutrophil into circulation (Paape et al, 2003;Kubes, 2018). The turnover and production of neutrophils are impressive, estimated at 10 9 cells/kg body weight per day (Kubes, 2018) or >10 11 cells per day in cattle, which can increase 10-fold during acute inflammation or administration of G-CSF (Van Schyndel et al, 2018). The process and regulation of granulopoiesis have recently been reviewed in detail (Yvan-Charvet and Ng, 2019), highlighting differences in the process between homeostatic and acute response states, including diurnal patterns, at least in mice.…”

“…In cattle, the circulating half-life was estimated to be 9 h (Paape et al, 2003). Neutrophils in dairy cows in the transition period may have a shorter-than-normal lifespan due to early activation of apoptosis, but administration of recombinant bovine G-CSF stimulates production and release of neutrophils (Van Schyndel et al, 2018). In humans, G-CSF delayed apoptosis by inhibiting caspase-9 and -3 (van Raam et al, 2008).…”

Outcomes from Experimental Testing of Nonsteroidal Anti-Inflammatory Drug (NSAID) Administration during the Transition Period of Dairy Cows

“…Several studies have shown that in cattle, the administration of Pegbovigrastim provides a well-tolerated approach to overcoming periparturient immune suppression, making it possible to restore normal neutrophil function [ 62 , 75 ]. The administration of Pegbovigrastim induces a state of neutrophilia, characterized by a ‘left-shift’ towards progenitor cells with a release of mature neutrophils and band cells from storage pools in bone marrow [ 76 , 77 ]. Pegbovigrastim is found to induce a slight decrease of red cell count and hematocrit in cows treated 7 and 21 days after calving [ 62 , 77 ].…”

Alternative Anti-Infective Treatments to Traditional Antibiotherapy against Staphylococcal Veterinary Pathogens

“…For example, dairy cows suffer a reduction in immune function during lactation, with a subsequent predisposition to infectious disease [ 37 , 80 ]. This immunosuppression could be reversed to avoid staphylococcal infections with pegbovigrastim, a recombinant DNA-derived bovine granulocyte colony-stimulating factor (G-CSF) analog ( Table 2 ).…”