Lung was the primary organ affected by SARS-CoV-2 infection. Most of patients had mild symptom, but part of them can develop to severe or critical symptom. The risk of death significantly increased with the progress of heart failure, acute kidney injury and ARDS[2, 5, 6]. However, the pathogenesis of SARS-CoV-2 infection was still unclear. It was documented that the C-reaction protein, IL-6 and TNF-a are all significantly upregulated in COVID-19 patients[7]. Among the secondarily symptoms, cytokine storm was identified as the inducer, which could be association with excessive activation of immune cells[8]. Based on these, some researchers presumed that excessive immune response promote cytokine storm and further evoke MOF[9, 10]. However, so far, the role of neutrophils is not clear in lung injury induced by SARS-CoV-2.
We found that, in the early stage of the disease, patient’s leucocytes, including neutrophils, lymphocytes and monocytes, decreased with the disease progresses. Although the patient's lung damaged, he did not develop significant hypoxemia. After the treatment with recombinant human GSF, the patient’s leucocytes increased rapidly, especially with a significant increase in neutrophils. Afterwards, the patient's condition further deteriorated and developed to moderate ARDS. Considering that leukocyte elevation was not associated with other infections such as secondary bacterial infections, we supposed that the iatrogenic elevation of neutrophils might aggravate lung injury.
In addition, there are several issues that need to be clarified. Firstly, promoting leukocytes, especially neutrophils, may worsen lung injury induced by SARS-CoV-2 infection in early progression stage. In classical pathogenesis of ARDS, the activation of alveolar-macrophages resulted in persistent inflammation and tissue damage, which contributed to produce proinflammatory factor, recruit leucocyte (neutrophils, monocytes/macrophages, effector T cells), and activate alveolar epithelial cells[11-13]. Moreover, many literatures had shown that neutrophils played an important role in the development of ARDS[14-17]. It was shown that chemokines CCL2 and CCL7 synergized with C-X-C Motif Chemokine Ligand 8(CXCL8) to promote neutrophils migration into the pulmonary interstitium and alveoli, aggravating lung injury[18]. Up to now, few studies focused on the role of neutrophils in lung injury induced by viral infection. It was documented that the number of neutrophils in the lower respiratory tract is correlated with disease severity during severe influenza pneumonia and highly pathogenic avian influenza infection[16]. Therefore, improper promotion of neutrophils may aggravate lung injury in SARS-CoV-2 infection early stage.
Secondly, it was considered that the mechanism of organ damage caused by virus infection was related to the inducted immune response. The overactivated leucocytes (monocytes, T lymphocytes, and macrophages) can lead to ARDS and sequential organ failure[9, 19]. At present, the detection results from clinical lab showed that SARS-CoV-2 infection usually led to the decrease of leucocytes (including neutrophils, monocytes and lymphocytes)[4]. Maybe the cytokine storm was also weakened with the decrease of inflammatory cells, which may conducive to delaying the progress of the disease. Thus, enhancing leukocytes, especially neutrophils may accelerate the deterioration of illness at this moment.
Finally, it was difficult for us to find the direct evidence of the increase of neutrophils in lung tissue and exclude the possibility of progress of the disease itself. This case report showed that there is a certain correlation between the progress of the lung injury and the rise of iatrogenic leukocytes, especially neutrophils. Further studies are warranted to confirm this correlation.
This case report showed that iatrogenic increase of leucocytes (especially neutrophils) may worsen lung injury and leucocyte increasing agents were used with caution in the early stage of COVID-19 patients. At the same time, the phenomenon remains to be further confirmed in the future study.