https://orcid.org/0000-0002-3871-7002
Abstract
Background
Limited data are available in COVID-19 patients on the prediction of treatment response to systemic corticosteroid therapy based on systemic inflammatory markers. There is a concern whether the response to systemic corticosteroid is different according to white blood cell (WBC) counts in COVID-19 patients. We aimed to assess whether WBC count is related with the clinical outcomes after treatment with systemic corticosteroids in severe COVID-19.
Methods
We conducted a retrospective cohort study and analysed the patients hospitalised for severe COVID-19 and received systemic corticosteroids between July 2020 and June 2021. The primary endpoint was to compare the composite poor outcome of mechanical ventilation, extracorporeal membrane oxygenation, and mortality among the patients with different WBC counts.
Results
Of the 585 COVID-19 patients who required oxygen supplementation and systemic corticosteroids, 145 (24.8%) belonged to the leukopoenia group, 375 (64.1%) belonged to the normal WBC group, and 65 (11.1%) belonged to the leukocytosis group. In Kaplan-Meier curve, the composite poor outcome was significantly reduced in leukopoenia group compared to leukocytosis group (log-rank p-value < 0.001). In the multivariable Cox regression analysis, leukopoenia group was significantly associated with a lower risk of the composite poor outcome compared to normal WBC group (adjusted hazard ratio [aHR] = 0.32, 95% CI 0.14–0.76, p-value = 0.009) and leukocytosis group (aHR = 0.30, 95% CI = 0.12–0.78, p-value = 0.013). There was no significant difference in aHR for composite poor outcome between leukocytosis and normal WBC group.
Conclusion
Leukopoenia may be related with a better response to systemic corticosteroid therapy in COVID-19 patients requiring oxygen supplementation.
In severe COVID-19 treated with systemic corticosteroids, patients with leukopoenia showed a lower hazard for composite poor outcome compared to patients with normal white blood cell counts or leukocytosis.
Leukopoenia may be a potential biomarker for better response to systemic corticosteroid therapy in COVID-19 pneumonia.
KEY MESSAGES
Introduction
Systemic corticosteroid therapy has been a critical component for the management of severe coronavirus disease 2019 (COVID-19) with respiratory failure [Citation1]. In previous randomised controlled trials (RCTs), administration of systemic corticosteroids improved mortality and increased ventilator free days in COVID-19 patients [Citation2,Citation3]. Especially, dexamethasone had significant benefits in the COVID-19 patients who required oxygen supplementation or mechanical ventilation [Citation2]. However, the mortality rate of severe COVID-19 patients was still as high as 26.6%, even though systemic corticosteroids were used [Citation1]. Therefore, we need to differentiate the COVID-19 patients with heterogeneous responses to systemic corticosteroids.
To provide precise and individualised management for the COVID-19 patients, it is essential to identify the subgroups who either responds well or poorly to standard treatment consisting mainly of systemic corticosteroids. Considering that the efficacy of corticosteroids on COVID-19 relies on their anti-inflammatory or immunomodulatory effects [Citation4], systemic inflammatory biomarkers may have a potential role to predict the response to corticosteroids. There have been few studies that investigated inflammatory phenotypes related with the response to systemic corticosteroids. A recent study showed that systemic corticosteroids may be less effective in the critically-ill COVID-19 patients with hypo-inflammatory phenotypes [Citation5]. A better clinical response to systemic corticosteroids has been expected in hyper-inflammatory phenotypes than hypo-inflammatory phenotypes [Citation6]. Among various systemic inflammatory markers, white blood cell (WBC) has been considered as an important indicator to differentiate hyper- and hypo-inflammatory phenotypes in acute respiratory distress syndrome (ARDS) [Citation7,Citation8]. WBC count was related with cytokine storm syndrome, higher severity, and poor prognosis in COVID-19 [Citation9–11]. Although WBC count is an important biologic marker for systemic inflammation, it has not been figured out whether treatment response to systemic corticosteroid for severe COVID-19 is different according to WBC count.
Therefore, we investigated whether the clinical outcomes after treatment with systemic corticosteroid are different according to the WBC counts in COVID-19 patients who required oxygen therapy.
Methods
We reported the present study following the guidance of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.
Study design and participants
We conducted a retrospective cohort study and analysed the patients who were hospitalised for severe COVID-19 at Boramae Medical Centre between July 2020 and June 2021. All the eligible patients were: (1) age >18 years old, (2) diagnosed with COVID-19 through quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assays using respiratory tract samples, (3) treated with systemic corticosteroids for severe COVID-19. Systemic corticosteroids were administrated when the COVID-19 patients required oxygen therapy or had a significant desaturation (room-air percutaneous arterial oxygen saturation [SpO2] < 90%). Exclusion criteria were immunosuppressive conditions including haematologic malignancy or current chemotherapy for active cancer, administration of systemic corticosteroids or immunosuppressive drugs for other conditions, pregnant status, and terminal stage disease with documented Do Not Resuscitate order.
Variables
Baseline demographic data were collected including age, sex, body mass index (BMI), cigarette smoking status, cigarette pack-years, and comorbidities (hypertension, diabetes, chronic obstructive pulmonary disease (COPD), asthma, interstitial lung disease (ILD), history of tuberculosis, lung cancer, other malignancy, chronic kidney disease, chronic liver disease, cardiovascular disease, cerebrovascular disease, cognitive disorder, and connective tissue disease). Symptomatic manifestation data was systematically recorded in electronic medical records including smell or taste abnormalities, myalgia, sore throat, cough, sputum, chest discomfort, dyspnoea, fever, rhinorrhea or nasal congestion, and diarrhoea. Information on vital signs and parameters for oxygen status including systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), respiratory rate (RR), SpO2, oxygen requirement (L/min), fraction of inspired oxygen (FiO2), SpO2/FiO2 (SF ratio), and ROX index (SF ratio/RR) were obtained. Laboratory and radiologic examinations were routinely performed for the hospitalised patients with oxygen requirement including complete blood count (CBC) with differential count, haemoglobin, platelet, C-reactive protein (CRP), procalcitonin, lactate dehydrogenase (LDH), D-dimer, troponin I, NT-proB-type natriuretic peptide (NT-proBNP), blood urea nitrogen (BUN), creatinine, aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, prothrombin time international normalised ratio (PT INR), and chest X-ray. Information on treatment including Lopinavir/Ritonavir, hydroxychloroquine, remdesivir, antibiotics, duration or cumulative dose of corticosteroids were collected. Information on clinical outcomes including high flow nasal cannula (HFNC), mechanical ventilation (MV), extracorporeal membrane oxygenation (ECMO), mortality, and hospital length of stay (LOS) were obtained.
Study outcomes
The primary endpoint was to compare the composite poor outcome including mechanical ventilation, ECMO and mortality among three groups classified based on different WBC counts: leukopoenia, normal leukocyte, and leukocytosis groups. The patients with WBC <4000 were defined as leukopoenia group, those with WBC from 4000 to 9999 were defined as normal WBC group, and those with WBC ≥10,000 were defined as leukocytosis group.
Statistical analyses
Demographic information, symptomatic manifestation, vital signs and parameters for oxygen status, laboratory and radiologic results, treatments and clinical outcomes were compared among the different three groups. We analysed categorical variables using Pearson’s chi-squared test or the Fisher’s exact test and continuous variables using ANOVA test or Kruskal-Wallis test. To analyse linear trend among the three groups, the Cochran-Armitage test was used for categorical variables, and linear regression analysis was used for continuous variables. We conducted repeated-measure ANOVA tests to evaluate the changes of WBC counts. We performed survival analysis with Kaplan-Meier estimation. To minimise the potential risk of bias due to confounding factors, multivariate Cox regression analysis was conducted with statistically significant covariables selected through backward elimination. Statistical significance was determined as p-values <0.05. All the statistical analyses were conducted using R statistical software, version 4.1.1 (R Core Team, [2021], Vienna, Austria).
Ethics
This study was conducted in accordance with the principles of the Declaration of Helsinki. The Institutional Review Board of Seoul Metropolitan Government-Seoul National University Boramae Medical Centre approved the study protocol waived the need for informed consent for access to the electronic medical records (IRB No. 30-2022-40).
Results
Baseline characteristics
Of the 2690 patients hospitalised for COVID-19 infection, 708 patients required oxygen therapy. Among these patients with oxygen requirement, 585 patients who received systemic corticosteroid therapy for severe COVID-19 were eligible. In the eligible study patients, 145 (24.8%) belonged to the leukopoenia group, 375 (64.1%) belonged to the normal WBC group, and 65 (11.1%) belonged to the leukocytosis group (). The time intervals from symptom onset, diagnosis of COVID-19, and hospital admission to oxygen requirement were median 7 (interquartile range [IQR] = 5–10), 3 (IQR = 1–6), and 1 (IQR = 1–3) days, respectively.
Figure 1. Flow diagram of the study population.
The baseline characteristics of the included patients are presented in . Leukocytosis group was older with mean age of 74.2 years compared to 68.1 and 68.5 years in leukopoenia and normal WBC group, respectively. The proportion of hypertension and asthma showed a positive linear trend according to the WBC status. Otherwise, there were no significant differences across the groups.
Table 1. Baseline demographic characteristics according to different white blood cell counts.
Clinical characteristics and initial laboratory indices
The clinical characteristics and initial laboratory indices are presented in . For initial vital signs and parameters, SBP, HR, and oxygen requirement or FiO2 showed positive linear trends according to the WBC status while SpO2, SF ratio, and ROX index showed negative linear trends. For initial laboratory indices, neutrophil-to-lymphocyte ratio (NLR) showed a positive linear trend according to the WBC status while monocytes showed a negative linear trend. Platelet counts, CRP, procalcitonin, LDH, D-dimer, BUN, AST, ALT, total bilirubin, and PT INR also showed positive linear trends. In the analysis of WBC changes during 5 days of steroids, WBC count and neutrophil count increased in leukopoenia and normal WBC group, while decreased in leukocytosis group (supplemental Figure S1). In addition, lymphocyte count of leukopoenia group was more increased compared with that of leukocytosis group, although lymphocyte counts at D1 were similar. There was no difference in the presence of pneumonic infiltration in chest X-rays across the groups.
Table 2. Clinical manifestation according to different white blood cell counts.
Treatment and clinical outcomes for COVID-19
Treatment of COVID-19 infection across the groups showed difference in the duration of steroid therapy; it was the longest in leukocytosis group with the mean of 12.5 days compared to 9.5 days in both leukopoenia and normal WBC group (). The use of remdesivir or antibiotics was similar across the groups. The hospital length of stay was the longest in leukocytosis group with 31.3 days compared to 16.7 days and 15.7 days in leukopoenia and normal WBC group, respectively. In Kaplan-Meier curve, the composite poor outcome of mechanical ventilation, ECMO and mortality was significantly reduced in leukopoenia group compared to leukocytosis group (log-rank p-value < 0.001), but not compared to normal WBC group (log-rank p-value = 0.060) ().
Figure 2. Probability of mechanical ventilation, ECMO, or mortality. Red line (
) = normal WBC (WBC count = 4000–9999), blue line (
) = leukocytosis (WBC count ≥10,000). Log-rank test in comparison with leukopoenia (
) vs. normal WBC (
) resulted p-value of 0.060. Log-rank test in comparison with leukopoenia (
) vs. leukocytosis (
) resulted p-value of <0.001. Log-rank test in comparison with normal WBC (
) vs. leukocytosis (
) resulted p-value of 0.024.
Table 3. Treatment and clinical outcomes according to different white blood cell counts.
Multivariable analysis to evaluate risk factors of composite poor outcome
In the univariable Cox regression analysis, leukopoenia group showed a lower hazard ratio (HR) for composite poor outcome compared to normal WBC group. In addition, age greater than 65 years, connective tissue disease, febrile manifestation, a higher systolic blood pressure, procalcitonin greater than 0.5 ng/mL, a lower ROX index, neutrophilia (≥7500, 103/µL), NLR, a lower haemoglobin, and a lower platelet count were associated with a higher HR for composite poor outcome. In the multivariable Cox regression analysis, leukopoenia group was significantly associated with a lower risk of composite poor outcome compared to normal WBC group (adjusted HR (aHR)=0.32, 95% CI = 0.14–0.76, p-value = 0.009) and leukocytosis group (aHR = 0.30, 95% CI = 0.12–0.78, p-value = 0.013) in COVID-19 patients who were treated with systemic corticosteroids (). On the other hand, leukocytosis group was not associated with composite poor outcome (aHR 1.08, 95% CI 0.52–2.21, p-value = 0.845) compared to normal WBC group. In the multivariable analyses according to the differential count of white blood cells, neutrophilia was related with a higher risk of composite poor outcome, but there was no association between neutropenia or lymphopenia and composite poor outcome (supplemental Table S3 and S4). In addition, we found no association between NLR and composite poor outcome in the multivariable analysis (supplemental Table S5). Nomogram of variables on composite poor outcome is described in supplemental Figure S2.
Table 4. Cox regression analysis to identify risk factors of mechanical ventilation, ECMO, or mortality.
Discussion
Our study investigated treatment response of systemic corticosteroid therapy in COVID-19 patients who required oxygen therapy according to the blood leukocyte counts. Leukopoenia group showed a significantly lower hazard of composite poor outcome consisting of mechanical ventilation, ECMO and mortality compared to normal WBC or leukocytosis group in multivariable analysis. Leukocytosis group showed an increased risk of composite poor outcome in survival analysis, but did not increase the hazard of composite poor outcome compared to normal WBC group after adjustment for disease severity. Neutrophilia was related with an increased hazard of composite poor outcome, while neutropenia, lymphopenia, and NLR were not associated with composite poor outcome in multivariable analyses. Therefore, a better treatment response may be expected in the patients with leukopoenia who were treated with systemic corticosteroids for severe COVID-19 pneumonia.
There has been a growing interest in identifying clinical sub-phenotypes of COVID-19 pneumonia or COVID-19-related ARDS for establishing individualised therapy. Especially, phenotyping with various inflammatory profiles has been expected useful in predicting treatment response to systemic corticosteroid in COVID-19. A previous study conducted cluster analysis using inflammatory biomarkers to investigate hyper- and hypo-inflammatory phenotypes in critically ill COVID-19 patients who used systemic corticosteroids [Citation5]. This study reported that a better efficacy of systemic corticosteroid therapy was observed in the patient group with hyper-inflammatory phenotypes. Although systemic corticosteroid treatment was not randomised, another study conducted latent class analysis to find a better response to systemic corticosteroid in the patients with hyper-inflammatory phenotypes [Citation8]. COVID-19 can cause systemic hyper-inflammation with features of cytokine storm syndrome [Citation12,Citation13], and systemic corticosteroids are thought to be effective because they down-regulate systemic hyper-inflammatory response.
Our study figured out that there may be a difference in the response to systemic corticosteroids according to the WBC profiles, which is one of the important inflammatory markers. WBC count reflected the immunologic response in COVID-19 that was different from other respiratory viral infections and was related to the prognosis in COVID-19 patients. The leukocyte expression profiles were different between hypo- and hyper-inflammatory ARDS [Citation14]. In our study, the hazard of composite poor outcome was lower in leukopoenia group compared to normal WBC or leukocytosis group in severe COVID-19 patients who used systemic corticosteroid. Leukopoenia has been frequently found in the hyperinflammatory syndromes including secondary haemophagocytic lymphohistiocytosis, macrophage activation syndrome, and cytokine release syndrome [Citation15]. Therefore, leukopoenia may be a biologic marker for hyper-inflammatory phenotype in COVID-19 with a better response to systemic corticosteroid [Citation16–18].
Lymphopenia has been suggested as a poor prognostic factor in COVID-19. Compared to the cytokine storm syndromes caused by other diseases, COVID-19 induced hyper-inflammation is different in its haematologic manifestation as decreased lymphocyte count was related with poor outcomes [Citation19,Citation20]. The mechanism behind the development of lymphopenia in COVID-19 is suggested to be multi-factorial: direct cell infection by the virus, indirect destruction by hyper-inflammation caused via IL-6 and TNF-α pathways, and lymphocytes recruitment to the inflammatory lung tissues [Citation21]. Our study showed that lymphopenia was not a prognostic factor in COVID-19 patients who used systemic corticosteroids. Systemic corticosteroids are reported to increase lymphocyte counts in clinically responsive COVID-19 patients [Citation22]. Immunomodulating effect of systemic corticosteroids may recover T-cell dysregulation and or alleviate the inflammatory process [Citation23,Citation24].
Neutropenia was only found in leukopoenia group but neutrophilia was not. Low neutrophil count was related with a higher mortality, and there was an insignificant trend of decreasing mortality after administration of systemic corticosteroid in COVID-19 patients with neutropenia [Citation25]. In our study, neutropenia was not significantly associated with the hazard of composite poor outcome after treatment with systemic corticosteroid. Neutrophilia is another haematologic marker associated with poor outcome in COVID-19 [Citation26–28]. Neutrophilia is related with the increased release of proinflammatory cytokines, activation of neutrophil, induction of oxidative stress, and formation of neutrophil extracellular traps, resulting in inflammatory lung injury [Citation29]. Neutrophilia has been a predictive marker of progression of ARDS associated with a systemic hyper-inflammatory response [Citation29]. However, even though systemic corticosteroid was administered, the patients with neutrophilia showed a higher hazard of the composite poor outcome in our study. Therefore, additional therapeutic intervention combined with systemic corticosteroid may be necessary to further modify dysregulation of excessive inflammatory response to COVID-19 pneumonia in the patients with neutrophilia.
The present study has several limitations. First, our study is a retrospective cohort study in a single medical centre. For generalisation, external validation within a larger cohort is needed. Second, different prognosis according to WBC counts may be related with a different severity of COVID-19, rather than the response to systemic corticosteroid. Therefore, we included only severe COVID-19 patients who required oxygen therapy and analysed them with adjustment for age, comorbidities, ROX index, and other laboratory findings. Even considering this limitation, lymphopenia is speculated as a biologic indicator for favourable outcomes in COVID-19 patients treated with systemic corticosteroid. Third, to properly estimate the different efficacy of systemic corticosteroid according to WBC counts, clinical outcomes should be compared according to whether or not steroids were administered in each group. However, it is not feasible in real-world to compare prognosis between the patients who used steroids and those who did not because of the considerable difference in disease severity between them. In addition, random allocation for steroid administration according to specific biomarkers in the patients with severe COVID-19 who requires oxygen is considered ethically violated under current treatment consensus. Therefore, our study evaluated clinical outcomes as an indirect indicator for treatment response to systemic corticosteroids in severe COVID-19 patients. Fourth, further in vivo or in vitro study is needed to elucidate the pathophysiological background behind WBC changes with corticosteroid therapy during severe COVID-19 infection.
Conclusion
Leukopoenia group showed a lower hazard for composite poor outcome compared to normal WBC or leukocytosis group in severe COVID-19 patients who were treated with systemic corticosteroids. Leukopoenia may be a potential biomarker for better response to systemic corticosteroid therapy in COVID-19 pneumonia.
Author contributions
HWL developed the study concept and design. HWL, DHK, KNJ and BR completed the acquisition of data. HWL, KYC, DHK, KNJ, HJL, TYP and BR made contributions to data analysis. HWL, KYC, JKL, EYH and DKK made contributions to data interpretation. KYC and HWL drafted the manuscript. All authors critically revised the manuscript for important intellectual content. All authors read and approved the final version of the manuscript, and agreed to be accountable for the work.
Guarantor statement
HWL accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Supplemental Material
Download TIFF Image (659 KB)Supplemental Material
Download TIFF Image (838.2 KB)Supplemental Material
Download MS Word (27.1 KB)Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
References
- Sterne JAC, Murthy S, Diaz JV, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324(13):1330–1341.
- RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with covid-19. N Engl J Med. 2021;384(8):693–704.
- Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020;324(13):1307–1316.
- Rizk JG, Kalantar-Zadeh K, Mehra MR, et al. Pharmaco-immunomodulatory therapy in COVID-19. Drugs. 2020;80(13):1267–1292.
- Chen H, Xie J, Su N, et al. Corticosteroid therapy is associated with improved outcome in critically ill patients with COVID-19 with hyperinflammatory phenotype. Chest. 2021;159(5):1793–1802.
- Reddy K, Hardin CC, McAuley DF. COVID-19-related acute respiratory distress syndrome subphenotypes and differential response to corticosteroids: time for more precision? Am J Respir Crit Care Med. 2021;204(11):1241–1243.
- Sinha P, Churpek MM, Calfee CS. Machine learning classifier models can identify acute respiratory distress syndrome phenotypes using readily available clinical data. Am J Respir Crit Care Med. 2020;202(7):996–1004.
- Sinha P, Furfaro D, Cummings MJ, et al. Latent class analysis reveals COVID-19-related acute respiratory distress syndrome subgroups with differential responses to corticosteroids. Am J Respir Crit Care Med. 2021;204(11):1274–1285.
- Melo AKG, Milby KM, Caparroz A, et al. Biomarkers of cytokine storm as red flags for severe and fatal COVID-19 cases: a living systematic review and meta-analysis. PLoS One. 2021;16(6):e0253894.
- Huang G, Kovalic AJ, Graber CJ. Prognostic value of leukocytosis and lymphopenia for coronavirus disease severity. Emerg Infect Dis. 2020;26(8):1839–1841.
- Yamada T, Wakabayashi M, Yamaji T, et al. Value of leukocytosis and elevated C-reactive protein in predicting severe coronavirus 2019 (COVID-19): a systematic review and meta-analysis. Clin Chim Acta. 2020;509:235–243.
- Mehta P, McAuley DF, Brown M, et al. HLH across speciality collaboration, COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–1034.
- Fajgenbaum DC, June CH, Storm C. Cytokine storm. N Engl J Med. 2020;383(23):2255–2273.
- Bos LDJ, Scicluna BP, Ong DSY, et al. Understanding heterogeneity in biologic phenotypes of acute respiratory distress syndrome by leukocyte expression profiles. Am J Respir Crit Care Med. 2019;200(1):42–50.
- Webb BJ, Peltan ID, Jensen P, et al. Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study. Lancet Rheumatol. 2020;2(12):e754–e763.
- Li Y, Wang J, Wang C, et al. Characteristics of respiratory virus infection during the outbreak of 2019 novel coronavirus in Beijing. Int J Infect Dis. 2020;96:266–269.
- Zhu B, Feng X, Jiang C, et al. Correlation between white blood cell count at admission and mortality in COVID-19 patients: a retrospective study. BMC Infect Dis. 2021;21(1):574.
- Urbano M, Costa E, Geraldes C. Hematological changes in SARS-COV-2 positive patients. Hematol Transfus Cell Ther. 2022;44(2):218–224.
- Zhao Q, Meng M, Kumar R, et al. Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a systemic review and meta-analysis. Int J Infect Dis. 2020;96:131–135.
- Tan L, Wang Q, Zhang D, et al. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct Target Ther. 2020;5(1):33.
- Vabret N, Britton GJ, Gruber C, et al. Immunology of COVID-19: current state of the science. Immunity. 2020;52(6):910–941.
- Wang F, Nie J, Wang H, et al. Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia. J Infect Dis. 2020;221(11):1762–1769.
- Yang L, Liu S, Liu J, et al. COVID-19: immunopathogenesis and immunotherapeutics. Signal Transduct Target Ther. 2020;5(1):128.
- Ye F, Liu J, Chen L, et al. Time-course analysis reveals that corticosteroids resuscitate diminished CD8+ T cells in COVID-19: a retrospective cohort study. Ann Med. 2021;53(1):181–188.
- Sereno M, Jimenez-Gordo AM, Baena-Espinar J, et al. A multicenter analysis of the outcome of cancer patients with neutropenia and COVID-19 optionally treated with Granulocyte-Colony stimulating factor (G-CSF): a comparative analysis. Cancers (Basel). 2021;13(16):4205.
- Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061–1069.
- Hu L, Chen S, Fu Y, et al. Risk factors associated with clinical outcomes in 323 coronavirus disease 2019 (COVID-19) hospitalized patients in Wuhan, China. Clin Infect Dis. 2020;71(16):2089–2098.
- Wang K, Zuo P, Liu Y, et al. Clinical and laboratory predictors of in-hospital mortality in patients with coronavirus disease-2019: a cohort study in Wuhan, China. Clin Infect Dis. 2020;71(16):2079–2088.
- Yang SC, Tsai YF, Pan YL, et al. Understanding the role of neutrophils in acute respiratory distress syndrome. Biomed J. 2021;44(4):439–446.