Introduction

A group of unknown pneumonia cases emerged in Wuhan, China in December 2019. Most of the patients lived or worked in the local Huanan seafood wholesale market, where live wild animals were also on sale. In some patients, a clinical condition similar to acute respiratory distress syndrome (ARDS) rapidly appeared in the early stages of pneumonia. The new type of coronavirus infection with the zoonotic transition, called 2019-nCoV, has spread rapidly in China and then worldwide, causing a pandemic.

After emerging in Wuhan, Hubei province of China, the coronavirus disease-2019 (COVID-19) infection, which has rapidly spread to other countries in Asia, Pacific, Europe, and Africa, has caused a pandemic that threatens the preparation and biosafety conditions of countries worldwide (1). The world was unprepared for such a pandemic. Capacities of health facilities were insufficient.

This infection, later called COVID-19 by the World Health Organization (WHO), has caused 132,485,386 million confirmed cases and approximately 2,875,672 deaths with current data. (April 8, 2021) (2).

The outbreak is still not fully under control. COVID-19 infection, which has clinical symptoms such as fever, cough, shortness of breath, myalgia, and fatigue, causes serious lower respiratory tract infections and mortality (3-6).

Due to the rapid spread of COVID-19 infection, the health infrastructure and resources of most countries have become insufficient. As a result of excessive admissions, the number of patients has dramatically increased especially in the emergency departments (ED), which has created a need to identify markers that can help us differentiate patients with serious life-threatening clinical findings and needing urgent treatment.

The usefulness of plasma lactate level measurement in EDs as an estimation for early detection of patients with tissue hypoperfusion that can cause severe sepsis and death has been reported (5). In this study, we aimed to investigate the relationship between increased lactate values and mortality in COVID-19 patients.

Materials and Methods

This retrospective cohort study started after the local ethical approval of Clinical Research Ethics Committee (2011-KAEK-25 2020/05-05) was obtained.

The standard data entry form including information regarding the patient’s age, gender, presence of comorbid disease, plasma lactate, d-dimer, ferritin, C-reactive protein (CRP) values, Polymerase Chain Reaction (PCR) testing results of oropharyngeal and nasopharyngeal swab samples, presence of pneumonic infiltration in thorax computerized tomography (CT), outcome (hospitalization, exitus, discharge) and whether there was mortality within 28 days were used. Patients over 18 years old who were admitted to ED with symptoms of COVID-19 (fever, cough, shortness of breath, diarrhea, fatigue, muscle or joint pain) between 16.03.2020 and 16.05.2020, and recorded in the hospital automation system with COVID-19 ICD-10 codes (U07. 1 and U07. 2) were screened. A total of 348 patients were detected. Patients whose study data were not fully available (32 patients) were excluded. Totally 316 patients were included to the study.

Statistical Analysis

The data were analyzed using SPSS 22.0 for Windows (SPSS Inc., Chicago, IL, USA) computer program. Descriptive statistics were expressed as median (IQR: 25^th-75^th percentiles) for continuous numerical variables while numbers and (%) for categorical variables. Kolmogorov-Smirnov test was used for the normality of data. The significance of the difference in terms of continuous numerical variables in which parametric test statistic assumptions were not provided was evaluated with Mann-Whitney U test. Chi-square and Fisher’s exact tests were used to analyze whether there was a relationship between categorical variables. The ROC curve was plotted to investigate the diagnostic value of lactate. In the study, p<0.05 value was considered statistically significant.

Results

A total of 316 patients were included in the study and the median (IQR: 25^th-75^th percentiles) age of the patients was 69 (60-78) years and 53.5% (n=169) of the patients were male. Pneumonia was detected in thorax CT in 87.0% (n=275) of the patients. Comorbidities were found in 72.2% (n=228) of the patients. The most common comorbidity was chronic obstructive pulmonary disease (COPD) with 13.0% (n=41). While 83.5% (n=264) of the patients were hospitalized, 15.8% (n=50) were followed-up at home. Two patients (0.6%) died in ED. Mortality developed in 14.2% of the patients (n=45) within 28 days. Distribution of patients’ features are shown in Table 1. There was an increase in the mean lactate (2.05±1.45 mmol/L), CRP (52.22±65.90), D-dimer (2.65±6.96) and ferritin (344.28±524.82) values of the patients (Table 2). In the chi-square test, a statistically significant relationship was found between PCR positivity and 28-day mortality (p<0.001) (Table 3). In the Kolmogorov-Smirnov test conducted to analyze the normality distribution, it was seen that the data were not normally distributed. Within this scope, Mann-Whitney U test was conducted to investigate whether there was a difference between the lactate level and the 28-day mortality as well as PCR positivity/negativity. As a result of this test, lactate level was found to be significantly different in patients in both PCR positive and PCR negative groups who developed mortality within 28 days (p<0.001; p<0.001) (Table 3).

When the cut-off value of lactate in terms of mortality was 2.45, the sensitivity was found as 80.0%, the specificity was detected as 81.2%, and the area under the curve (AUC) was determined as 0.915 [95% confidence interval (CI): 0.876-0.955] in the ROC analysis (p<0.001). If the the cut-off value of lactate in terms of mortality was 3.22, the sensitivity decreased to 57.8%, the specificity increased to 98.2% (Table 4).

Discussion

Excessive intense referral to healthcare facilities has led to the need to identify markers that can help us differentiate patients with serious life-threatening clinical findings needing urgent treatment.

Clinical, laboratory, and image findings, and factors related to the evolution of the disease and its consequences constitute critical information that must be carefully examined when a new infectious disease occurs. It is important to distinguish which COVID-19 patients are at risk. Some patients can be safely managed as an outpatient. Reliable prognostic markers should be used to identify patients who will need more aggressive treatment. Advancing age, male gender, pre-existing coronary artery diseases (CAD), diabetes mellitus (DM), hypertension (HT), asthma, COPD, malignancies, and immunosuppressive diseases have been reported to adversely affect clinical prognosis in patients with COVID-19 (7,8).  Similarly, in our study, 53.5% (n=169) of patients with COVID-19 were male, the mean age was 69 (min-max: 19-99) years, and the most common comorbidities were COPD, HT, DM, and CAD.

In a meta-analysis, clinical symptoms and findings such as fever (88.7%, 95% CI: 84.5-92.9), cough (57.6%, 95% CI%: 40.8-74.4), dyspnea (45.6%, 95% CI%: 10.9-80.4), myalgia or fatigue (29.4%, 95% CI: 19.8-39.0), sputum (28.5%, 95% CI%: 10.8-46.3) and sore throat (11%, 95% CI: 2.8-19.2) were reported in patients with COVID-19, which was statistically significant (p<0.001). In laboratory tests, the decrease in albumin (75.8%, 95% CI%: 30.5-100.0), increase in CRP (58.3%, 95% CI: 21.8-94.7), increase in lactate dehydrogenase (LDH) (95% CI: 38.0-76.0), increase in Iymphopenia (43.1%, 95% CI: 18.9-67.3) and erythrocyte sedimentation rate (ESR) (41.8%, 95% CI: 0.0-92.8) were reported to be statistically significant (p<0.001) (9). In our study, CRP, D-dimer, ferritin, and lactate were studied and it was seen that CRP (52.22± 65.9), D-dimer (2.66 ± 6.96), ferritin (344.29 ± 524.82) and lactate (2.05±1.45 mmol/L) levels increased. In addition, lactate value over 4 mmol/L in patients with sepsis was reported to be associated with high mortality (10). As a biomarker in critical diseases and even as a therapeutic target, lactate attracts attention (11).

In patients with sepsis, widespread tissue hypoxia is found when the plasma lactate value is above 4 mmol/L, even if patients are normotensive (12). Lactate is a by-product of anaerobic cellular metabolism. In the case of hypoperfusion, blood lactate level increases due to insufficient oxygen. Since anaerobic metabolism is predominant in global hypoperfusion states or shock, lactate metabolism increases in the liver and kidneys, and as a result, the lactate level in the blood increases. In some studies, increased lactate concentration has been associated with high mortality, irrespective of the presence of lactic acidosis (13). In our study, it was found that there was a relationship between high lactate values and mortality in patients with COVID-19. Lactate level was found to be statistically significantly different in both PCR positive and PCR negative groups in which mortality developed within 28 days (p<0.001), p=0.004). When the cut-off value of lactate in terms of mortality was 2.45, the sensitivity was found as 80.0%, the specificity was detected as 81.2%, and the area under the curve (AUC) was determined as 0.915 (95% CI: 0.876-0.955) in the ROC analysis (p<0.001).

When the first COVID-19 patients were detected in our hospital, we started to perform PCR testing to the oropharyngeal and nasopharyngeal swab samples of the patients. However, Thorax CT was performed in all patients with COVID-19 suspicion, since PCR was not concluded immediately and the accuracy rate was reported as low (30%-60%) in the literature (5). In our study, 38.6% of the patients had positive PCR testing, and pneumonia was detected via thorax CT in 87% of patients admitted to ED with COVID-19 symptoms. Thorax CT is a conventional, noninvasive, fast, and highly accurate imaging method. In accordance with the literature, there were characteristic CT findings (ground-glass opacification, bilateral multilobar involvement, posterior and peripheral distribution, consolidation) in our patients with COVID-19 (14). Thorax CT is considered as a routine imaging method for the monitoring and diagnosis of patients with COVID-19 pneumonia. Thorax CT may help to screen patients with suspected disease, particularly symptomatic patients with the first negative PCR scan result, and early detection of lung abnormalities (15).

Study Limitations

The main limitations of our study were the relatively low number of patients, being retrospective, not considering lactate clearance, and not investigating the treatment methods that may affect mortality.

Conclusion

In conclusion, the blood lactate level examined at the first admission to ED in patients with COVID-19 can be used as a beneficial screening test to predict mortality.

Ethics

Ethics Committee Approval: This study was approved by Bursa Yüksek İhtisas Training and Research Hospital Clinical Researches Ethics Committee (decision no: 2011-KAEK-25 2020/05-05, date: 13.05.2020).

Informed Consent: Retrospective study.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Surgical and/or Medical Practices: M.Y., Ş.İ., Concept: Y.İ., H.K., M.O.A., M.B., Design: H.K., M.Y., M.B., Data Collection and/or Analysis: H.K., M.O.A., Ş.İ., M.B., Literature Search: Y.İ, M.Y., Ş.İ, M.B., Writing: H.K., M.O.A., Ş.İ.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.