Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis.

Coronavirus disease 2019 (COVID-19), a new form of respiratory and systemic disorder sustained by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is now producing an outbreak of pandemic proportions, whereby nearly 110,000 people have already been infected around the world, 10–15% of whom with severe disease and over 3800 already died [1]. A severe form of pneumonia, potentially evolving towards adult respiratory distress syndrome (ARDS) and occasionally associated with multiorgan failure, are the leading complications of this respiratory virus [2]. Since laboratory medicine provides an essential contribution to the clinical decision making in this and many other infectious diseases [3], we aim to investigate here whether procalcitonin, whose values are not substantially modified in patients with viral infections [4], may play a role in distinguishing patients with or without severe COVID-19.

We carried out an electronic search in Medline (PubMed interface), Scopus and Web of Science, using the keywords “procalcitonin” AND “2019 novel coronavirus” OR “2019-nCoV” OR “COVID-19” without date (i.e., up to March 3, 2020) and language restrictions. The title, abstract and full text of all documents identified according to these search criteria were scrutinized by the authors, and those reporting data in COVID-19 patients with or without severe disease (defined as needing admission to intensive care unit or use of mechanical ventilation), were finally included in our meta-analysis. The reference list of each article was reviewed (forward and backward citation tracking) for identifying other potentially eligible documents. A meta-analysis was then carried out for calculating the individual and pooled odds ratios (OR) with their relative 95% confidence interval (95% CI), using MetaXL software Version 5.3 (EpiGear International Pty Ltd., Sunrise Beach, Australia). Procalcitonin values were entered as dichotomous variable, i.e., below or above the locally defined reference range (typically ≥ 0.50 ng/mL). Since the heterogeneity (I2 statistics) did not exceed 50%, a fixed effects model was finally used.

Overall, 27 articles could be originally identified using our search criteria, 24 of which were excluded after title, abstract or full text reading, because they did not report procalcitonin values in patients with or without severe COVID-19. An additional document could be identified from the reference list of one of selected articles. Overall, 4 studies were finally included in our meta-analysis [5], [6], [7], [8]. The pooled OR of these studies is summarized in Fig. 1 , which shows that increased procalcitonin values are associated with a nearly 5-fold higher risk of severe SARS-CoV-2 infection (OR, 4.76; 95% CI, 2.74–8.29). The heterogeneity among the different studies was found to be modest (i.e., 34%) [9].

Fig. 1

Odds ratio (OR) and 95% confidence interval (95% CI) of procalcitonin values above the normal reference range for predicting severe coronavirus disease 2019 (COVID-19).

Although the overall number of COVID-19 patients with increased procalcitonin values seems limited, as highlighted in a recent article [10], the results of this concise meta-analysis of the literature would suggest that serial procalcitonin measurement may play a role for predicting evolution towards a more severe form of disease. There is a plausible explanation for this evidence. The production and release into the circulation of procalcitonin from extrathyroidal sources is enormously amplified during bacterial infections, actively sustained by enhanced concentrations of interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6. Nevertheless, the synthesis of this biomarker is inhibited by interferon (INF)-γ, whose concentration increases during viral infections. It is hence not surprising that the procalcitonin value would remain within the reference range in several patients with non-complicated SARS-CoV-2 infection, whereby its substantial increase would reflect bacterial coinfection in those developing severe form of disease, thus contributing to complicate the clinical picture, as recently shown in children with viral lower respiratory tract infections [11]. Additional studies are compellingly needed to verify the putative bacterial origin of procalcitonin increase in patients with severe COVID-19.