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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 11  |  Issue : 3  |  Page : 116-121

Impact of single-dose systemic glucocorticoids on blood leukocytes in hospitalized adults


1 Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, AZ, USA
2 Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, AZ, USA

Date of Submission14-Mar-2020
Date of Decision28-Apr-2020
Date of Acceptance06-Apr-2020
Date of Web Publication16-Sep-2020

Correspondence Address:
Dr. Khalid Eljaaly
Department of Pharmacy Practice, King Abdulaziz University, P.O. Box 80200, Jeddah, 21589

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_24_20

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  Abstract 

BACKGROUND: Glucocorticoids (GCs) may cause leukocytosis through several mechanisms. The objective of this study was to examine the impact of a single-GCs dose on total white blood cell (WBC) count, absolute neutrophil count (ANC), and absolute lymphocyte count (ALC) in hospitalized adults without bacterial infections.
METHODS: This retrospective cohort study included hospitalized patients ≥18 years of age who received a single dose of a systemic GC (oral or intravenous methylprednisolone and hydrocortisone and oral prednisone). Total WBC count, ANC, and ALC changes over the 72 h after GC administration were evaluated.
RESULTS: A total of 99 patients were included. After the administration of a single-GC dose, ALC began to drop significantly as early as the interval of 0–<6 h (median interquartile range, 0.90 [0.60–1.10], P = 0.011). ANC increased significantly as early as the interval of 6–<12 h (6.22 [4.45–7.33], P = 0.049) and continued to be significantly increased from baseline up to 42 h from GC administration. Total WBC counts significantly decreased in the 6–<12 h interval (6.90 [5.15–8.85], P = 0.03) and then increased significantly in the 12–<18 h interval (8.80 [6.50–11.95], P = 0.002). This effect on total WBC count continued to be significant until the 36-<42 h interval (10.55 [7.23–13.03], P < 0.001).
CONCLUSIONS: ANC followed by WBC count increased significantly after a single-GC dose in hospitalized patients within 12 h of a single-GC dose, while a decrease in WBC and ALC was seen within the first few hours of GC dose.

Keywords: Corticosteroids, glucocorticoids, leukocytosis, white blood cell


How to cite this article:
Alshehri S, Eljaaly K, Alshibani M, Katz M. Impact of single-dose systemic glucocorticoids on blood leukocytes in hospitalized adults. J Appl Hematol 2020;11:116-21

How to cite this URL:
Alshehri S, Eljaaly K, Alshibani M, Katz M. Impact of single-dose systemic glucocorticoids on blood leukocytes in hospitalized adults. J Appl Hematol [serial online] 2020 [cited 2020 Sep 20];11:116-21. Available from: http://www.jahjournal.org/text.asp?2020/11/3/116/295117


  Introduction Top


Glucocorticoids (GCs) are commonly used in clinical practice for several indications. GCs often cause leukocytosis, which occurs through several mechanisms, including bone marrow mobilization of polymorphonuclear neutrophils (PMNs), shift of PMNs from intravascular marginal pools into in the circulating pool (PMN demargination), delay in migration of PMNs from blood to tissue, and prolongation of the half-lives of intravascular PMNs.[1],[2],[3]

In addition to leukocytosis, GCs are known to cause neutrophilia and lymphopenia.[4],[5],[6],[7] While previous studies have assessed the effect of multiple doses of GCs on the development of leukocytosis, neutrophilia, and/or lymphopenia, to the best of our knowledge, no studies have assessed the effect of single-GC doses. Understanding the effect of single-GC doses over time would be helpful in the differential diagnosis of leukocytosis, especially when an infection is suspected. In addition, relevant information, such as time to peak of white blood cell (WBC) count and absolute neutrophil count (ANC), time to trough of absolute lymphocyte count (ALC), change in WBC count in the first few hours after GC administration, and impact of several patient characteristics and comorbidities could guide clinicians in caring for their patients.

This study was conducted with the objective of examining the impact of a single dose of systemic GC on WBC count, ANC, and ALC in hospitalized adults without bacterial infections.


  Methods Top


Study setting and population

This retrospective cohort study was conducted at Banner-University Medical Center in Tucson, AZ. Hospitalized patients 18 years of age or older who received a single dose of systemic GC between November 2013 and November 2016 were included. Institutional review board approval was obtained from the hospital. To be included in the study, individuals had a baseline complete blood count (CBC) prior to GC administration. The GCs used in this study include oral and intravenous methylprednisolone, oral and intravenous hydrocortisone, and oral prednisone. Individuals were excluded if they received home GC therapy, concomitant GCs or antimicrobial agents during hospitalization, or multiple GC doses or if they had conditions known to cause leukocytosis.

Study outcomes

The primary endpoints in this study were total WBC count, ANC, and ALC changes over the 72 h after GC administration. Blood samples were divided into the following intervals: 0–<6 h, 6–<12 h, 12–<18 h, 18–<24 h, 24–<30 h, 30–<36 h, 36–<42 h, 42–<48 h, 48–<54 h, 54–<60 h, 60–<66 h, and 66–<72 h. Secondary endpoints included the extent of leukocytosis, neutrophilia, and lymphopenia, as measured by a change in WBC count, ANC, and ALC, respectively, from baseline over the 72 h after GC administration, as well as time to WBC and ANC peak, and time to ALC trough.

Statistical analysis

Continuous data were analyzed using means and standard deviations for normally distributed data and as medians and interquartile ranges (IQR) for nonnormally distributed data. The two-tailed Wilcoxon–Signed rank test was used for nonnormally distributed continuous paired data. Statistical significance was considered as P < 0.05. The association between the degree of WBC count elevation and GC dose (high vs. low) and the presence of autoimmune disease was examined using multivariable linear regression models. High-GC doses were defined as prednisone ≥60 mg, methylprednisolone ≥48 mg, and hydrocortisone >240 mg. Preliminary analyses were conducted to ensure there were no violations of the assumptions of normality, linearity, multicollinearity, and homoscedasticity. Data were analyzed with SPSS software, version 24 (IBM, Chicago, IL, USA).


  Results Top


A total of 11,137 records were retrieved for patients who received the included GCs between 11/1/2013 and 11/1/2016. After excluding patients who received systemic antibiotics on the same admission, we were left with 5700 individuals, of whom 2399 had CBC results during the same admission, and 1022 had at least 3 consecutive CBC readings during the admission. Of these, patients were excluded for the following reasons: not receiving the ordered GC (n = 34); lack of baseline blood cell counts prior to GC administration (n = 40); receiving another type of GC medication either during the admission (n = 52) or prior to the admission (n = 552); having a condition that causes leukocytosis (n = 5); and receiving multiple doses of GCs (n = 240). A final total of 99 patients was included in the study [Figure 1].
Figure 1: Inclusion flowchart

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The baseline characteristics of included patients are presented in [Table 1]. The median age (IQR) was 61 (50–73), 60.6% were male, 76.8% were white/Caucasian, and 18.2% were smokers. Methylprednisolone was used in 67.7% of patients, 24.2% received prednisone, and 8.1% received hydrocortisone. Doses ranged from 60 mg to 1000 mg for methylprednisolone, 15 mg to 80 mg for prednisone, and 50 mg–100 mg for hydrocortisone.
Table 1: Baseline characteristics

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At baseline, the median (IQR) ALC, ANC, and WBC counts were 1.51 (1.00–2.00), 5.18 (3.96–7.18), and 7.50 (6.40–9.90), respectively. After a single-GC dose, ALC decreased significantly as early as 0-<6 h (median [IQR], 0.90 [0.60–1.10], P = 0.011) and continued to be significantly lowered compared to baseline for up to 24 h. ANC increased significantly as early as 6-<12 h (median [IQR], 6.22 [4.45–7.33], P = 0.049) and continued to be significantly elevated for up to 42 h after GC administration. During the period of 6–<12 h, an initial significant decrease in WBC count (median [IQR], 6.90 [5.15–8.85] P = 0.03) was correlated with a significant decrease in ALC (median [IQR], 0.60 [0.40–0.70] P < 0.001). As ANC started to increase, offsetting the ALC effect on the total WBC count, the WBC count increased significantly over the 12–<18 h interval (median [IQR], 8.80 [6.50–11.95], P = 0.002) and continued to be significantly elevated until 36–<42 h (median [IQR], 10.55 [7.23–13.03], P < 0.001) [Table 2] and [Figure 2], [Figure 3], [Figure 4].
Table 2: Primary outcome

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Figure 2: White blood cell count trends

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Figure 3: Absolute neutrophil count trends

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Figure 4: Absolute lymphocyte count trends

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The time to WBC count peak and ANC peak after a single dose of GC ranged from 2.90 to 66.95 h (median [IQR] 30.88 [17.31–36.99]) and 2.45–66.95 h (median [IQR], 29.37 [15.79–37.29]) respectively. The time to ALC trough ranged from 1.70 to 54.42 h (median [IQR], 12.57 [8.36–17.30]). The extent of elevation from baseline in WBC count and ANC was as high as 12,400/mm3 and 12,100/mm3, respectively, whereas the extent of reduction from baseline in ALC was as low as 3630/mm3. The median (IQR) extents of elevation from baseline in WBC count and ANC were (2700 [1680–4890])/mm3 and (2600 [1830–4950])/mm3, respectively, while the (median [IQR] extent of reduction from baseline in ALC was (0.80 [400–1200])/mm3 [Table 3].
Table 3: Secondary outcomes

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We found statistically significant associations of the extent of WBC count elevation with high dose of GC (β, 1.131; 95% confidence interval [CI]: 0.021–2.241; P = 0.046) and presence of an autoimmune disease (β, 2.324; 95% CI: 0.506–4.142; P = 0.013) but not an association with age (β, −0.005; 95% CI −0.035–0.024; P = 0.724) or being a smoker (β, 0.400; 95% CI −1.645–0.845; P = 0.524).


  Discussion Top


Our study is the first to report that total WBC counts are reduced significantly in the first few hours (6–<12 h interval) following GC administration. It appears that this early reduction is caused by a significant decrease in ALC. WBC counts then significantly increased during the 12–<18 h interval, while ANC significantly increased during the 6–<12 h interval, indicating that ANC elevation precedes total WBC elevation after GC dose.

This study focused only on the effect of a single dose of systemic GC. Unlike previous studies,[4],[5],[6] our study included adult patients with various conditions that might require GC therapy during hospitalization. We used 6-h intervals to detect early responses in ANC, ALC, and WBC counts instead of the 24-h interval used in some previous studies.[5],[8]

A reduction in ALC in the 0–<6 h interval was seen in a previous study,[9] which found that the ALC trough occurred in the first 4–6 h. However, the ALC trough in our study was more delayed, occurring after approximately 12 h. Moreover, ALC continued to be significantly reduced for up to 24 h in our study but returned to normal within 24 h in the Fauci and Dale study.[9] This variation may be explained by two key differences between the studies. First, the GC doses were higher in our study, and second, most patients in our study received methylprednisolone and prednisone, which have longer durations of action than then the hydrocortisone used in the Fauci and Dale study.[9] It is worth mentioning that the delay in the normalization of ALC in the Fauci andDale study was found in patients who received higher doses of hydrocortisone.

Our finding of the early decrease in WBC count within 6–<12 h after GC dose might be explained by the statistically significant drop in ALC. This new observation is likely due to the use of 6-h intervals to detect early responses in ANC, ALC, and WBC count instead of the 24-h intervals used in some previous studies.[5],[8] For later time intervals, the WBC results were in concordance with previous studies, which have shown that WBC counts start to rise significantly within 12-<18 h[4],[8] and then return to normal the next day.[8]

Contrary to a previous study by Velthove et al.,[10] our results confirm the phenomenon of GC-induced leukocytosis. However, that study examined the effect of multiple GC doses both chronically and acutely and compared individuals to a control group rather than comparing individuals to their own baselines. Velthove et al. also categorized the GC effect on WBC counts rather than using the counts as continuous variables.

The findings from our study confirm the variation of responses among patients in terms of peak counts and times to peak. We observed the WBC count peaking as early as 3 h after GC administration, whereas Shoenfeld et al.[4] found that the peak can occur as early as 5 h after administration. This variation is likely due to dosage form differences, since Shoenfeld et al. included only oral prednisone while we included both oral and intravenous GC formulations.

WBC count is widely used as an indicator of bacterial infection and sometimes guides the decision to initiate empiric antimicrobial therapy. Our data show that the increase in WBC following a single-GC dose is variable in its extent and timing among individuals. An elevated WBC count could be observed for up to 2 days after the patient received even a single dose of GC. This information could potentially prevent unnecessary initiation of antimicrobial therapy in some patients without other signs of new bacterial infection.

The extent of WBC count changes in this study was measured as the increase from baseline, unlike in previous studies in which the WBC count was presented as an absolute number and not compared to the patients' baseline values.[4],[5],[6]

As expected and similar to findings in other studies[4],[6] we observed a relationship between GC dose and extent of WBC count elevation. Our results suggest that we would expect a WBC count elevation that was 1.131/mm3 higher in patients who received a high dose of GC compared to those who received a low dose of GC. Unlike other studies.[4],[10] our study considered high doses to be equal to or more than 60 mg for prednisone or equivalent doses of other GCs.

Interestingly, we found a statistically significant association between the extent of WBC count elevation and presence of an autoimmune disease. We would expect a 2.324/mm3 higher WBC count elevation in patients with an autoimmune disease compared to those without. Previous studies have examined the GC effect on WBC counts in either healthy volunteers[4],[9] or patients with an autoimmune disease[5],[6] while our study examined both patients with and without autoimmune disease. This difference may explain some of the variation between previous studies and our study in several outcomes. It is unclear why patients with autoimmune diseases experienced a higher WBC count elevation, but this response could be attributed to baseline hyperactivity of their immune systems.

Since our study focused only on the acute effect of one dose of GC, our method of using 6-h intervals following GC dose allowed us to identify the impact on WBC counts earlier than in previous studies. We did not use more frequent intervals because that would have reduced the sample size and statistical power. In addition, we excluded patients with several confounding factors that cause leukocytosis and included 3 GCs at various doses, as well as a mixed patient population, to mimic real-life use of these agents.

This study has some limitations primarily because it was based on a retrospective chart review. Our study did not include a control group of patients who did not receive a GC. Furthermore, the number of individuals included was relatively small for us to properly assess the effect of several factors, including indication for GC treatment, race, and asthma, on the extent of leukocytosis.


  Conclusions Top


Our study found that ANC increases significantly 12 h after a single-dose administration of GC in hospitalized patients and that WBC count increases significantly following this initial elevation in ANC. Variability in timing and extent of WBC count and ANC elevation was observed. A decrease in WBC count and ALC was seen within the first few hours of GC dose. High doses of GC and autoimmune disease were associated with a greater elevation in WBC counts.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Nakagawa M, Terashima T, D'yachkova Y, Bondy GP, Hogg JC, van Eeden SF. Glucocorticoid-induced granulocytosis: Contribution of marrow release and demargination of intravascular granulocytes. Circulation 1998;98:2307-13.  Back to cited text no. 1
    
2.
Bishop CR, Athens JW, Boggs DR, Warner HR, Cartwright GE, Wintrobe MM. Leukokinetic studies. 13. A non-steady-state kinetic evaluation of the mechanism of cortisone-induced granulocytosis. J Clin Invest 1968;47:249-60.  Back to cited text no. 2
    
3.
Athens JW, Haab OP, Raab SO, Mauer AM, Ashenbrucker H, Cartwright GE, et al. Leukokinetic studies, 4: The total blood, circulating, and marginal granulocyte pools and the granulocyte turnover rate in normal subjects. J Clin Invest 1961;40:989-95.  Back to cited text no. 3
    
4.
Shoenfeld Y, Gurewich Y, Gallant LA, Pinkhas J. Prednisone-induced leukocytosis. Influence of dosage, method and duration of administration on the degree of leukocytosis. Am J Med 1981;71:773-8.  Back to cited text no. 4
    
5.
John TJ. Leukocytosis during steroid therapy. Am J Dis Child 1966;111:68-70.  Back to cited text no. 5
    
6.
Floyd M, Muckle TJ, Kerr DN. Prednisone-induced leucocytosis in nephrotic syndrome. Lancet 1969;1:1192-3.  Back to cited text no. 6
    
7.
Serra-Bonett N, Al Snih S, Rodriguez MA. Effect of low-dose prednisone on leukocyte counts and subpopulations in patients with rheumatoid arthritis. J Clin Rheumatol 2009;15:148-9.  Back to cited text no. 7
    
8.
Denison FC, Elliott CL, Wallace EM. Dexamethasone-induced leucocytosis in pregnancy. Br J Obstet Gynaecol 1997;104:851-3.  Back to cited text no. 8
    
9.
Fauci AS, Dale DC. The effect ofin vivo hydrocortisone on subpopulations of human lymphocytes. J Clin Invest 1974;53:240-6.  Back to cited text no. 9
    
10.
Velthove KJ, Leufkens HG, Souverein PC, Schweizer RC, Bracke M, van Solinge WW. Effects of glucocorticoids on the neutrophil count: A cohort study among hospitalized patients. Pulm Pharmacol Ther 2010;23:129-34.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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