High procalcitonin levels associated with increased intensive care unit admission and mortality in patients with a COVID-19 infection in the emergency department

Coronavirus disease (COVID-19) caused by the novel Coronavirus (SARS-CoV-2) was declared a pandemic on the 11th of March 2020 by the World Health Organization [1]. Ever since, COVID-19 caused a high burden on hospital and intensive care unit capacity [2]. Patients with COVID-19 often require hospitalization and treatment at an intensive care unit (ICU) when they develop acute respiratory distress syndrome (ARDS). The exact underlying pathophysiology of ARDS in these severe COVID-19 infections is under research with an exponentially growing amount of studies on this topic [3, 4]. Many studies have found that hyperinflammation, caused by an overwhelming upregulation of the immune system, and immune thrombosis play a major role in the development of ARDS in COVID-19 [5].

When patients with a COVID-19 infection present at the emergency department (ED), it is important to be able to identify patients who are at high risk of developing a severe COVID-19 infection. These patients may benefit from more extensive monitoring or early ICU admission.

Different biomarkers have been identified as predictors of disease severity in COVID-19 [6], including procalcitonin (PCT). PCT is a biomarker previously used for distinguishing viral infections from bacterial infections [7], although its use in the ED for this purpose is controversial [8, 9]. Elevated PCT levels are often seen in patients with a bacterial infection. PCT is the prohormone of calcitonin and in a physiological state produced by C-cells of the thyroid gland. During inflammation, PCT is synthesized in all tissues. Bacterial toxins are well known triggers of synthesis of PCT. Other triggers of synthesis include interleukin-6 and tumor necrosis factor alpha (TNF-alpha) [10, 11]. High levels of these cytokines have been reported in severe COVID-19 infections [12]. For this reason, PCT may also be elevated in a hyperinflammatory state in the absence of a bacterial pathogen. ARDS is clinically the most important severe complication of COVID-19, therefore PCT may be predictive of hyperinflammation and the development of ARDS [13]. This may aid physicians in the ED to identify patients that are at risk of developing ARDS early.

The goal of this study is to investigate the association between PCT levels and severe COVID-19 infections in the ED.

In this retrospective single center cohort study we included patients with a confirmed COVID-19 infection who visited the ED of Erasmus University Medical Center, in Rotterdam, the Netherlands, between 1 March 2020 and 31 December 2020. Erasmus University Medical Center is an academic hospital with 40.000 ED visits annually. This study was conducted in accordance with the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013). The institutional review board waivered informed consent for the retrospective use of clinical data of COVID-19 patients. The study was performed following the STROBE guidelines (Additional file 1).

Between 1 March 2020 and 31 December 2020, a total of 23,195 patients visited the ED of which 2188 were clinically suspected of having a COVID-19 infection. Of these patients, 477 patients had a positive COVID-19 PCR-test at the day of the ED visit. Procalcitonin was measured in 339 of these patients. Four patients were excluded due to an invalid procalcitonin measurement, two patients were excluded because the ED visit was not related to the COVID-19 infection and one patient was excluded because there was no follow up data available. A total of 332 patients were included in the analysis of this study (Fig. 1). There were missing data in 3% of the data These missing data were imputated using multiple imputation. A specification of missing data per variable is shown in Additional file 2.

A total of 105 (32%) patients reached the composite outcome of a severe COVID-19 infection. Of these 105 patients, 44 (13%) were admitted to the ICU and 61 (18%) patients died. The non-severe COVID-19 infection group consisted of 227 (68%) patients, of which 67 (20%) were discharged directly from the ED and 158 (48%) were discharged from the general ward after an uncomplicated hospital admission. Baseline characteristics and differences between both groups including unadjusted ORs are shown in Table 1. The severe COVID-19 group was significantly older, more often male and had more frequently diabetes mellitus and any form of immunodeficiency as comorbidity. In vital parameters there were significant differences in heartrate, respiratory rate, oxygen saturation and diastolic blood pressure. In laboratory testing there were significant differences in PCT, CRP, leukocyte count, RDW, ASAT, ALAT, lactate, D-dimer and creatinine. Patients with severe COVID-19 infections had a bacterial coinfection more often.

PCT showed an unadjusted OR of 4.19 (95%CI: 2.52–7.69) on a severe COVID-19 infection with an AUC of 0.82 (CI: 0.76–0.87). Corrected for bacterial coinfection, high PCT remained associated with an increase in severe COVID-19 infections with an adjusted OR of 4.05 (95% CI: 2.45–7.41). In the multivariable model adjusted for sex, bacterial coinfection, age, any comorbidity, CRP and d-dimer, PCT was still significantly associated with a severe COVID-19 infection with an adjusted OR of 2.11 (95% CI: 1.36–3.61) (Table 2). The AUC of the multivariable model was 0.85 (95% CI: 0.81–0.90).

On the univariate analysis of PCT on a severe COVID-19 infection, the Hosmer-Lemshow test showed a bad fit (p = 0.003) and the calibration plot showed a slope of 1.00 (95% CI: 0.64–1.42) and intercept of 0.00 (95% CI: − 0.42–0.48) (Fig. 2A). The Hosmer-Lewshow test of the multivariable logistic regression model showed a good fit (p = 0.16) and the calibration plot showed a slope of 1.00 (CI: 0.76–1.27) with an intercept of 0.00 (CI: − 0.35–0.36) (Fig. 2B).

For the primary outcome, the OR of PCT at these cutoff points were respectively 9.76 (95% CI: 5.79–16.83), 12.12 (95% CI: 6.61–23.2) and 14.40 (95% CI: 6.45–36.77). The ORs of PCT at the different cut-off points of 0.25 ng/mL, 0.5 ng/mL and 1.0 ng/mL for the secondary outcomes are shown in Table 3. On hospital admission, the OR of PCT was 14.68 (95% CI: 5.27–61.11) at a cutoff point of 0.25 ng/mL and 22.78 (95% CI: 4.88–406.11) at a cutoff point of 0.5 ng/mL. Since there were no patients who were discharged home with a PCT of higher than 1.0, we could not calculate the OR of PCT at a cutoff of 1.0. For ICU admission, the OR of PCT at the previously mentioned cutoff points were 5.94 (95% CI: 3.36–10.79), 7.7 (95% CI: 4.24–14.2) and 8.93 (95% CI: 4.42–18.51) respectively. For mortality the ORs were 9.72 (95% CI: 5.2–19.08), 9.38 (95% CI: 5.08–17.68) and 7.93 (95% CI: 3.92–16.29) respectively.

In this study we found that elevated PCT levels are associated with an increase in the combined outcome of ICU admission and mortality. When treating a COVID-19 patient in the ED with an elevated PCT, the treating physician should not only look for possible bacterial coinfections but also be cautious of disease progression. Based on these findings, physicians should beware that patients with elevated PCT levels in the ED may have an increased risk of becoming severely ill. Although these findings need to be validated before PCT levels can be used to guide clinical decision-making on disposition of COVID-19 patients, PCT levels may serve as an early warning sign of possible clinical deterioration. Due to a low sensitivity of PCT on all outcomes, normal PCT levels should not be used in disposition decisions in COVID-19 patients in the ED.

Our findings are supported by other studies, that showed that hospitalized COVID-19 patients with severe infections had higher PCT levels [15‐17]. Only a few studies focused on the use of PCT in patients with a COVID-19 infection in an ED setting. Nazerian et al. found that PCT was not useful in diagnosing COVID-19 in the ED. However, the association PCT and of disease severity was not analysed [18]. Surme et al. investigated predictors of ICU admission and mortality and also found that high PCT were associated with an increase of the composite outcome of ICU admission and mortality [19]. Kaal et al. also showed similar results in a cohort of 142 patients, and showed that patients with PCT levels above 0.1 ng/mL have an elevated risk of a severe infection [20].

PCT is primarily used as biomarker for bacterial infections. The findings of this study show a new use for PCT in the specific group of COVID-19 patients as marker of disease severity. Even after correcting for bacterial coinfections and inflammatory markers CRP and d-dimer, elevated PCT levels remained associated with a severe COVID-19 infection. Our finding that PCT is highly elevated in severe COVID-19 infections can be explained when looking at the pathways of synthesis of PCT [10]. PCT synthesis is upregulated by different cytokines such as interleukine-6 and TNF-alpha. Because hyperinflammation is shown to be an important factor in progression of COVID-19 infections, the dysregulated immune response may also trigger PCT production [4]. Similar results of elevated PCT levels were found in patients with isolated severe influenza virus infections, findings that support the hypothesis that PCT is a marker of hyperinflammation [21].

At different cut-off values, PCT levels showed a high specificity for the hospital admission, ICU admission and mortality. On hospital admission, the lowest cut-off value of 0.25 ng/mL resulted in a specificity of 95%. This finding could be used as an argument to use PCT as support tool for hospital disposition decisions, because the majority of patients with a PCT above 0.25 ng/mL were admitted to the hospital. The sensitivity of PCT on all outcomes was low. Therefore, PCT is less suitable for being incorporated it in a rule out decision support tool of severe COVID-19 infections in the ED. Different cut-off values of PCT are recommended in distinguishing bacterial from viral infections, also ranging from 0.25 to 1.0 ng/mL [14]. The OR of PCT on hospital admission was 1667 (95% CI: 68–98,005). This high OR can be explained by the exponential increase in PCT levels in patients with severe infections. In our cohort, only 67 (20%) patients were discharged from the ED and the highest PCT level measured in these patients was 0.82 mg/mL. The patients that were admitted to the hospital also included the group that required ICU admission or died and several patients had a PCT levels above 10 ng/mL. This large difference in PCT levels between these groups resulted in the high OR.

High PCT levels are associated with high rates of severe COVID-19 infections in patients with a COVID-19 infection in the ED. The routine measurement of PCT in patients with a COVID-19 infection in the ED may assist physicians in the clinical decision-making process regarding ICU disposition. These results should be validated in a prospective multicenter cohort.