Coronavirus disease 2019 (COVID-19) was first encountered in Wuhan, China in December 2019, as a case of unexplained pneumonia caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was quickly followed by a global outbreak that was declared a pandemic by the World Health Organization (WHO) on March 11, 2020 (Guan et al., 2020; Zhu et al., 2020). According to the WHO, as of the time of the writing of this article, there have been 766,440,796 confirmed cases of COVID-19 worldwide, resulting in 6,932,591 deaths (WHO COVID-19 Dashboard, 2020). COVID-19, therefore, poses a serious threat to public health worldwide[3]. Viruses are highly diverse, due to their susceptibility to mutations and recombination (Huo et al., 2020), and during the last three years of the COVID-19 pandemic, numerous variants have been identified by the WHO, including Alpha, Beta, Gamma, Delta, and Omicron. The common mechanism by which COVID-19 invades the body is by targeting angiotensin-converting enzyme 2 (ACE2), exerting a pathogenic effect (Mathioudakis et al., 2022).

Lactate (LAC) is the final product of cellular glycolysis under anaerobic conditions, and is a metabolic waste product removed from the blood by the liver and kidneys (Rabinowitz and Enerbäck, 2020). Conventional wisdom has been that increased LAC levels are due to anaerobic metabolism caused by hypoxia in the body. Bakker et al (Bakker et al., 2013; Gupta, 2022) proposed that the cause of hyperlactatemia may be multifactorial, as it can also occur under completely aerobic conditions. It has been shown that the level of LAC can be significantly higher in patients hospitalized with COVID-19 compared to those that are not hospitalized, that the initial LAC level in deceased patients is higher than that in those that survive (Trebuian et al., 2024; Velavan et al., 2021), and that lactate dehydrogenase (LDH), a key enzyme in the conversion of pyruvate to LAC, can be used as a significant independent risk factor for predicting the occurrence respiratory failure in severe COVID-19 patients (Wang et al., 2024). Based on a multifactorial analysis of the increase in LAC levels, it is necessary to further explore whether the increase in LAC in patients with COVID-19 is due only to hypoxia from impaired ventilation and air exchange resulting from pulmonary changes, or if it is also due to a combination of local ischemia, which may result in an imbalance in the ventilation-to-blood flow ratio.

Significant changes can be observed in the immune systems of patients with COVID-19, which primarily manifest as a continuous and significant decrease in peripheral blood lymphocyte (LYM) count, the majority of which are CD4+T and CD8+T cells. These changes are significantly related to complications and poor prognoses (Zhou et al., 2020); therefore, changes in the LYM count should be dynamically observed in clinical practice. As such, we proposed using the rate of change in LYM over the course of one week (changes in LYM counts during the first week after admission)/(LYM counts on the day of admission) to determine the predictive value of LYM count for prognoses. LYM counts and its correlation with other test indicators, such as Neutrophil (NEU)-to- Lymphocyte ratio (NLR), Platelet-to- Lymphocyte ratio (PLR), and Lymphocyte-to-Monocyte ratio (LMR) have been studied extensively, of which NLR is considered an independent predictor of the risk of death in COVID-19 patients (Colaneri et al., 2024), with a higher ratio being associated with an increased risk of thrombosis (Pivina et al., 2024).

The present study, therefore, aimed to explore the predictive value of LAC and the weekly rate of change in LYM on the prognosis of patients, through a retrospective analysis of the clinical data of COVID-19 patients admitted to the intensive care unit (ICU), and whether there was any relationship with other clinical indicators.

In a retrospective analysis of patients with COVID-19 admitted to our comprehensive, respiratory, and infection ICUs during the COVID-19 pandemic, the predictive value of LAC level combined with the weekly LYM change rate for determining prognoses was greater than that of either alone, which is of practical value for judging the prognosis of ICU patients with COVID-19. The risk of death in patients with a LAC level >1.75 mmol/L on the day of admission to the ICU was significantly higher than that in patients with lower LAC levels. The increase in LAC, however, was not found to be associated with respiratory-related indicators, which may, in turn, be related to microcirculation disorders due to SARS-CoV-2 infection.

Arterial blood LAC level is used as a routine parameter of clinical evaluation in ICU patients, as increased LAC levels are common in critically ill patients, and are often used to assess disease severity, monitor and guide treatment, and determine prognosis. For example, The Sepsis-3 guidelines include high LAC levels (> 2 mmol/L) as a diagnostic criterion for septic shock, and recommend normalizing LAC levels as a goal during early fluid resuscitation (Rhodes et al., 2017). Traditionally, it has been believed that an increase in blood LAC is the result of anaerobic metabolism due to tissue hypoxia; however, increased LAC concentrations can also be found in non-hypoxic states of the body, such as a decrease in clearance due to kidney or liver dysfunction (Kumar et al., 2025), an increase in aerobic glycolysis (Chen et al., 2025), and beta-adrenergic stimulation (Rimachi et al., 2012), as a result of the interaction of oxygen supply, tissue metabolism, and blood clearance. In the early stages of the COVID-19 epidemic in Wuhan, it was found that about 84% of elderly patients (≥ 60 years old) had elevated LAC levels (Li P. et al., 2020). A data analysis of 2,860 elderly patients admitted to the ICU with COVID-19 showed that the initial LAC levels of those that did not survive were significantly higher than in those that did survive, increased serum lactate on the first day was related to a significant increase in ICU mortality, as well as 30-day and 3-month mortality, and ICU mortality was negatively correlated with a decrease in the LAC level (Bruno et al., 2021). In a Greek single-center study, Alice et al (Vassiliou et al., 2020) proposed that a cut-off value of 1.85 mmol/L for LAC level could predict mortality in ICU patients with COVID-19. The statistical analysis performed in the present retrospective study found that 1.75 mmol/L could be used as a critical value to judge the prognosis of ICU patients with severe COVID-19, and found that lactate >1.75 mmol/L was significantly correlated with the patients’ prognoses (P < 0.001). The difference in this cut-off value may be due to regional differences, different prevalent strains, or other factors.

Researchers have studied the pathogenic mechanism of SARS-CoV-2, the pathogen that causes COVID-19, and have found that the virus mainly exerts its toxic effect by binding to the host receptor membrane ACE2 through its spike S-glycoprotein (Gheblawi et al., 2020), while ACE2 is expressed in a variety of cells in the respiratory tract, so that the SARS-CoV-2 directly infects the bronchial and alveolar epithelial cells, causing lung tissue damage and affecting the ventilation and air exchange function of the body (Sungnak et al., 2020). In the present study, however, we found that partial pressure of oxygen (PO₂) and Oxygen saturation(SO₂)were lower, while partial pressure of carbon dioxide (PCO₂) and FIO₂ were higher, in patients who died of severe COVID-19 than in the surviving patients, although none of the differences were significant. Additionally, we observed no significant relationship between these values and prognosis, even after excluding interference from other factors through multifactorial regression analysis (P > 0.05), while LAC was found to be significantly associated with prognosis (P = 0.047). In regards to the source and clearance of LAC, an increase in LAC throughout the body may be caused by insufficient tissue perfusion. (Li H. et al., 2020) found that approximately 71.4% of patients who died of COVID-19 had disseminated intravascular coagulation, evidenced by the observation of a thrombus in the microvascular system upon autopsy (Wichmann et al., 2020). Tang et al (2020a; 2020b). reviewed coagulation parameters in COVID-19 patients, and proposed that FDP and DD levels were significantly higher in deceased than surviving patients, and that patients with DD levels exceeding six times the upper limit of normal had an increased mortality rate, suggesting that although other factors may contribute to the elevation of LAC in the body, reduced tissue perfusion due to thrombosis caused by microcirculatory thrombi may be the primary cause of increased LAC levels in patients with COVID-19.

Since ACE2 is highly expressed in arteriovenous endothelia, viruses cause damage and apoptosis to the vascular endothelia by binding to ACE2, triggering endothelial inflammation, and subsequently, thrombus formation (Varga et al., 2020). Simultaneously, ACE2, as a key link in the renin-angiotensin-aldosterone system (RASS), plays a role in vasodilation and anti-inflammatory actions; therefore, when ACE2 is blocked by the virus and its expression is downregulated, the microcirculatory blood flow decreases, resulting in inadequate circulatory perfusion of the tissue (Patel et al., 2016; Hanff et al., 2020), as oxygen exchange occurs in the microcirculatory system, and oxygen consumption is limited when systemic oxygen delivery is reduced (Wang et al., 2023). Moreover, SARS-CoV-2 infection can cause mitochondrial reactive oxygen species (ROS) production and dysfunction, inducing hypoxia-inducible factor-1 (HIF-1) activation, reduced oxidative phosphorylation, and increased aerobic glycolysis, resulting in an increase in LAC levels (Kumar et al., 2021; Tian et al., 2021; Yang et al., 2022). Additionally, a leftward shift in the oxygen dissociation curve can be observed in COVID-19 patients (Böning et al., 2021), indicating an increased affinity between hemoglobin and oxygen. Even if the oxygen content in a patient’s blood is guaranteed, the ability of the tissue to utilize oxygen decreases, which might explain the lack of significant difference in PO₂ between the deceased and surviving patients in the results of the present study, although there was a significant difference in LAC levels. In another retrospective study of COVID-19 patients, (Tang et al. 2020b) found that mortality in patients with COVID-19-associated coagulopathy who were treated with heparin was significantly lower than in those who did not receive anticoagulation. Li et al (Ma et al., 2022) demonstrated, for the first time, that low molecular weight heparin (LMWH) can reduce plasma LAC levels in patients with COVID-19, which may be associated with a reduction of microthrombus formation. Therefore, the authors of the present study suggest that even in patients with COVID-19 whose initial and most severely affected organ is the lungs, the elevation of LAC may not be entirely to ventilation and air exchange dysfunction caused by pulmonary thrombi, but may also be due to inflammation and immune response-induced alterations in the coagulation system of the body. These changes affect the microcirculatory blood flow, leading to insufficient tissue blood supply and reduced oxygen utilization, subsequently resulting in increased LAC production due to increased aerobic glycolysis.

The body’s immune system is composed of an innate immune response, which is induced by neutrophils and is the body’s first line of defense against invading pathogens, and an adaptive immune system, which is dominated by lymphocytes, including B-cells as well as T-cells, which provide specific antigenic responses to the body (Song et al., 2021; Buonacera et al., 2022). The two coordinate with each other and reflect the balance of the body ‘s immunity. Under normal conditions, T cells activated in response to inflammation, such as regulatory T cells (Treg), inhibit the production of the pro-inflammatory cytokine IL-6 by neutrophils, and transform into a large number of anti-inflammatory factors, such as IL-10, TGF-β, and indoleamine 2,3-dioxygenase (IDO)), which induce apoptosis in neutrophils and counteract the excessive inflammatory process mediated by neutrophils (Lewkowicz et al., 2013; Schönrich et al., 2020). In the early stage of SARS-CoV-2 infection, neutrophils are stimulated to activate and secrete large amounts of reactive oxygen species (ROS) (Jiang et al., 2025; Schönrich et al., 2020), which induces oxidative stress and increases the formation of neutrophil extracellular traps (NET), thereby suppressing the activity of T lymphocytes (Tripathi et al., 2018). Moreover, SARS-CoV-2 can directly affect lymphoid organs and cells through ACE2, causing the destruction and apoptosis of lymphocyte (Gu et al., 2005). The virus can also cause an innate immune system overreaction and cytokine storm in the body, resulting in a substantial decrease in peripheral lymphocyte counts (Colantuoni et al., 2020). Similar to the results of previous studies, the results of the present study found that the majority of ICU patients diagnosed with COVID-19 had lymphopenia, and that there were significant differences in LYM counts between the deceased and surviving patients. To better determine the relationship between LYM counts and disease prognosis, we collected LYM counts on the first and seventh days of the ICU admission, and calculated the rate of over the course of one week (change in LYM count throughout the week/LYM count on day of admission) to define the immune dysregulation caused by COVID-19. Statistical analysis revealed that the LYM change rates were significantly correlated with patients’ prognoses (P < 0.001), and that the predictive value of this index combined with LAC for prognosis was greater than that of either index alone. Similar studies have been conducted on the impact of LAC and LYM counts on the prognosis of patients with COVID-19. For example, Wang et al. (2021) have pointed out that LYM counts were nonlinearly associated with the risk of death in patients hospitalized with COVID-19. With the decrease of LYM counts (< 0.95 × 109/L), the risk of death in hospitalized patients with COVID-19 will gradually increase. Vassiliou et al. (2020) found that initial blood lactate in COVID-19 patients admitted to the ICU served as an independent outcome predictor and that the time course of LAC reflected changes in organ dysfunction during hospitalization, which correlated with adverse clinical outcomes. Unlike previous studies, considering the continuous changes of lymphocytes in patients with severe COVID-19, the change rate of lymphocytes within one week was calculated, and the patient data collected in this study were from the pandemic period after the implementation of the COVID-19 open management policy in China. At this time, the popular strain was mainly Omicron, which had higher infection rate and immune evasion than other strains (Parsons and Acharya, 2023).

LAC is considered a functional chemical that can affect the body’s immune response, which may also explain why NLR mediated the of LAC on the mortality of severe patients in the causal mediation analysis of this study; The study found that in severe COVID-19 patients, NK cells were strongly activated but their function was significantly reduced, mainly manifested as dim ­CD56dim phenotype cells, compared to bright phenotype ­CD56bright cells, and the former has a significant-inflammatory and cytotoxic effects (Maucourant et al., 2020; Osuchowski et al., 2021). While under low lactate levels, such as in the recovery period after exercise, the ratio of CD56bright to CD56dim cells increased significantly (Timmons and Cieslak, 2008; Gupta, 2022). In cancer patients, it was found that the acidosis induced by elevated LAC can significantly inhibit NK cell activity and reduce the level of interferon-γby it, while correcting acidosis can promote the degeneration of tumor cells (Greppi et al., 2024); T cells have specific transport proteins to sense lactate, inhibit its mobility, and increase the conversion of CD4+ T cells to an IL-17+ fraction, while reducing the cytolytic activity of CD8+ T cells (Pucino et al., 2019). In sepsis patients, increasing glycolysis, promoting ATP production, and relieving lactic acidosis can significantly offset the immunosuppressive effects of LAC and enhance the immune function of the body (Liu et al., 2024), so may be possible to explore the treatment of severe COVID-19 patients through corresponding LAC blocking strategies, so as to improve their prognosis.

Multivariate analysis revealed that the SOFA score also had a predictive value for the prognosis of patients with COVID-19; however, considering that the present study was retrospective in nature, the SOFA score included a subjective evaluation of the state of consciousness, and the SOFA score, as well as LAC, both indicated organ dysfunction in the body. Therefore, the present study did not include an evaluation of lactic acid combined with the SOFA score on the prognosis of patients with COVID-19; however, we did evaluate the predictive value of the combination of clinical detection indicators. In the present study, an increased NLR, when associated with increased LAC levels, mediated an increased risk of poor prognosis in ICU patients with COVID-19, which may be attributed to the body’s systemic inflammatory and excessive immune response, with an increase in NEUs and a decrease in LYMs, while LAC regulates the immune and inflammatory responses of the body.

The present study analyzed clinical indicators of patients admitted to the ICU during the Omicron variant phase of the COVID-19 pandemic, and found that clinical tests, such as LAC level, LYM change rate, and NLR, had predictive value for the prognosis of ICU patients with COVID-19. The cut-off value of LAC was found to be 1.75 mmol/L, and the prognosis of patients with a LAC level >1.75 mmol/L was significantly worse than that of patients with a LAC level <1.75 mmol/L. LAC level, combined with the weekly LYM change rate, had the greatest predictive value for the prognosis of patients in the ICU diagnosed with COVID-19. We suggest, therefore, that the elevated LAC levels may be caused by insufficient tissue blood supply due to microcirculatory thrombosis, rather than impaired pulmonary ventilation.

The present study had a few limitations. First, the patient data collected in the present study came from different ICUs within the same hospital and all the patients included were from China; therefore, selection bias and variability in detection may be present. Secondly, the present study was retrospective in nature, encompassing a smaller sample size, which may limit the interpretation of the results. Moreover, because the subjects were ICU patients who may have been treated in the general ward prior to being admitted to the ICU, not all patients were admitted directly from the emergency department, which may have affected the results of the present study. Finally, the patients’ viral loads were not measured or statistically analyzed. Additionally, whether or not patients received the vaccine before the onset of the disease was not included in the present study. These factors, therefore, may have impacted our results.