New Insights in Laboratory Testing for COVID-19 Patients: Looking for the Role and Predictive Value of Human epididymis secretory protein 4 (HE4) and the Innate Immunity of the Oral Cavity and Respiratory Tract

Annalisa Schirinzi, Angela Pia Cazzolla, Roberto Lovero, Lorenzo Lo Muzio, Nunzio Francesco Testa, Domenico Ciavarella, Giuseppe Palmieri, Pietro Pozzessere, Vito Procacci, Francesca Di Serio, Luigi Santacroce, Annalisa Schirinzi, Angela Pia Cazzolla, Roberto Lovero, Lorenzo Lo Muzio, Nunzio Francesco Testa, Domenico Ciavarella, Giuseppe Palmieri, Pietro Pozzessere, Vito Procacci, Francesca Di Serio, Luigi Santacroce

Abstract

COVID-19 is a viral pandemic caused by the new coronavirus SARS-CoV-2, an enveloped positive stranded RNA virus. The mechanisms of innate immunity, considered as the first line of antiviral defense, is essential towards viruses. A significant role in host defense of the lung, nasal and oral cavities is played by Human epididymis secretory protein 4 (HE4) HE4 has been demonstrated to be serum inflammatory biomarker and to show a role in natural immunity at the level of oral cavity, nasopharynx and respiratory tract with both antimicrobial/antiviral and anti-inflammatory activity. Several biomarkers like IL-6, presepsin (PSP), procalcitonin (PCT), CRP, D-Dimer have showed a good function as predictor factors for the clinical evolution of COVID-19 patients (mild, severe and critical). The aim of this study was to correlate the blood levels of CRP, IL-6, PSP, PCT, D-Dimer with He4, to identify the predictive values of these biomarkers for the evolution of the disease and to evaluate the possible role of HE4 in the defense mechanisms of innate immunity at the level of oral cavity, nasopharynx and respiratory tract. Of 134 patients admitted at COVID hospital of Policlinico-University of Bari, 86 (58 men age 67.6 ± 12.4 and 28 women age 65.7 ± 15.4) fulfilled the inclusion criteria: in particular, 80 patients (93%) showed prodromal symptoms (smell and/or taste dysfunctions) and other typical clinical manifestations and 19 died (13 men age 73.4 ± 7.7 and 6 women age 74.8 ± 6.7). 48 patients were excluded because 13 finished chemotherapy and 6 radiotherapy recently, 5 presented suspected breast carcinoma, 5 suspected lung carcinoma, 6 suspected ovarian carcinoma or ovary cyst, 1 cystic fibrosis, 3 renal fibrosis and 9 were affected by autoimmune diseases in treatment with monoclonal antibodies. The venous sample was taken for each patient on the admission and during the hospital stay. For each patient, six measurements relating to considered parameters were performed. Significant correlations between He4 and IL-6 levels (r = 0.797), between He4 and PSP (r = 0.621), between He4 and PCT (r = 0.447), between He4 and D-Dimer (r = 0.367), between He4 and RCP (r = 0.327) have been found. ROC curves analysis showed an excellent accuracy for He4 (AUC = 0.92) and IL-6 (AUC = 0.91), a very good accuracy for PSP (AUC = 0.81), a good accuracy for PCT (AUC = 0.701) and D-Dimer (AUC = 0.721) and sufficient accuracy for RCP (AUC = 0.616). These results demonstrated the important correlation between He4, IL6 and PSP, an excellent accuracy of He4 and IL6 and showed a probable role of He4 in the innate immunity in particularly at the level of oral cavity, nasopharynx and respiratory tract. Besides He4 together with IL6 might be involved in the onset of smell and/or taste disorders and it might be used as innovative biomarker to monitor clinical evolution of COVID-19 because He4 could indicate a multi-organ involvement.

Keywords: COVID-19; Human epididymis secretory protein 4 (HE4); SARS-CoV-2; innate immunity; interleukin-6 (IL-6); laboratory test; presepsin (PSP); procalcitonin (PCT).

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
IL-6 and He4 sex distributions showed an increase in females compared to males; PSP, D-Dimer, RCP and PCT sex distributions showed an increase in males compared to females (Mann Whitney U test p < 0.05).
Figure 2
Figure 2
Area under curve/AUC) of considered biomarkers: in all patients (a) excellent accuracy for He4 (AUC = 0.92), IL-6 (AUC = 0.91), and very good accuracy for PSP (AUC = 0.81); (b) good accuracy for PCT (AUC = 0.701) and D-Dimer (AUC = 0.721), sufficient accuracy for RCP (AUC = 0.616); in mild patients (c) excellent accuracy for He4 (AUC = 0.978), IL-6 (AUC = 0.96), very good accuracy for PSP (AUC = 0.873); (d) good accuracy for RCP (AUC = 0.705), D-Dimer (AUC = 0.753); sufficient accuracy for PCT (AUC = 0.622); in severe patients (e) very good accuracy for He4 (AUC = 0.897), IL-6 (AUC = 0.851), good accuracy for PSP (AUC = 0.738); (f) a sufficent accuracy for PCT (AUC = 0.622) and D-Dimer (AUC = 0.6.83); a bad accuracy for RCP (AUC = 0.513).

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