key: cord-0932716-g6nhsxal authors: Cabalak, Mehmet; Doğan, Serdar; Bal, Tayibe; Dikmen, Nursel title: Serum periostin levels in COVID‐19: Is it useful as a new biomarker? date: 2021-08-21 journal: Int J Clin Pract DOI: 10.1111/ijcp.14728 sha: a5e125f80c839f2b294bb2319227e92db882f3e5 doc_id: 932716 cord_uid: g6nhsxal OBJECTIVES: Severe disease characterised by interstitial pneumonia may develop in some cases of coronavirus disease (COVID‐19). Periostin has been associated with many respiratory diseases. In this study, we aimed to investigate whether periostin could be a useful new biomarker in the follow‐up and severity assessment of the disease in patients with COVID‐19 pneumonia. METHODS: In the study, 32 patients followed up during May to July 2020 because of COVID‐19 and 24 healthy controls were included. The patients were divided into two groups, namely, mild/moderate and severe, according to the severity of the disease. Serum periostin and transforming growth factor beta (TGF‐β) levels were tested using an enzyme‐linked immunosorbent assay (ELISA) method using commercially available ELISA kits. RESULTS: It was observed that the periostin level was significantly higher in both mild/moderate cases and severe cases compared with the control group at first presentation. However, TGF‐β levels at first presentation were similar between the groups. CONCLUSIONS: The current manuscript may be the first one performing periostin ELISA on COVID serum, and we believe that periostin can be used as a new biomarker. periostin, can be induced by the cytokines transforming growth factor beta (TGFβ), interleukin (IL)-4, and IL-13. 10, 11 Periostin interacts with multiple molecules involved in signal cascades to modulate the expression of various genes such as those encoding collagen, chemokines, and TGFβ. 12, 13 In this study, we aimed to investigate whether periostin could be a useful new biomarker in the follow-up and severity assessment of the disease in patients with COVID-19 pneumonia. In addition, the current manuscript may be the first one performing periostin ELISA on COVID serum. Our study was conducted in the Infectious Diseases and Chest Diseases Clinic of our hospital between May 2020 and July 2020. For this study, three groups; namely, the mild/moderate COVID-19 group, severe COVID-19 group, and control group, were formed. Patients with symptoms of fever, muscle/joint pain, cough, and sore throat with a respiratory rate of <30/minute and a partial pressure of oxygen (SpO2) level on room air of >90% were regarded as mild/moderate cases. 1 In contrast, cases with tachypnea (respiratory rate >30/min), with an SpO2 level <90%, with bilateral diffuse pneumonia on chest Xray or tomography, or those that developed acute organ dysfunction, ARDS and/or sepsis, and/or septic shock were considered as severe cases. From the 32 patients who were hospitalised with a clinical presentation of COVID-19 and a positive real-time reverse transcription polymerase chain reaction test, a 5-cc sample of blood was collected on their first day of hospitalisation and at the first month of their Coronaviruses are among the main pathogens that mainly target the human respiratory system. Severe disease characterised by interstitial pneumonia develops in 10%-20% of patients. Periostin has recently been shown to be an indicator of disease progression in idiopathic pulmonary fibrosis. In this study, we aimed to investigate whether periostin could be a useful new biomarker in the followup and severity assessment of the disease in patients with COVID-19 pneumonia. Note: Continuous data were expressed as mean ± standard deviation (SD), while categorical data were expressed as count (percentage). P values in bold indicate values that are significant at P < .05. Abbreviation: TGFβ, transforming growth factor beta. follow-up. In our study, 24 age-and gender-matched healthy individuals without any acute/choronic infectious, chronic diseases such as coronary heart disease, chronic pulmonary disease, diabetes mellitus, and chronic kidney disease, a rheumatological disease were included as a control group. The blood samples were centrifuged at 1500 g for 10 min to obtain the serum and maintained at −80℃ until analysis. All of the statistical analyses were performed using the SPSS soft- The study comprised 56 participants, divided into three groups: mild/ moderate (n = 24), severe (n = 8), and control (n = 24). The median were males. Table 1 shows the demographic data of the groups. It was observed that the periostin level was significantly higher in both mild/moderate cases and severe cases compared with the control group at first presentation (P = .027 and P = .002, respectively) ( Figure 1 ). However, TGFβ levels at first presentation were similar between the groups (P = .302) (Figure 2 ). In the severe patient group, a significant increase was observed in serum periostin levels one month from symptom onset compared with the time of symptom onset (P = .020). In contrast, although serum periostin level increased slightly in the mild/moderate patient group, this increase was not found to be statistically significant (P = .138). Another result of our study was that there was a weak but significant negative relationship between the basal lymphocyte and periostin levels and a weak, but significant positive relationship between the basal lymphocyte and TGFβ levels (r s = −0.410, P = .020 and r s = 0.369, P = .038, respectively) ( Figure 3 and Table 2 ). While there was a weak but significant negative relationship between the basal eosinophil and periostin levels (r s = −0.341, P = .029) ( Table 2) . However, these correlations were not statistically significant when controlled for age (P = .812, P = .470 and P = .375, respectively). Periostin levels showed a reasonable ability to distinguish COVID 19 patients from controls (AUC: 0.765, 95%Cl: 0.638-0.892, P = .001). The optimal cut-off value for the periostin to be able to differentiate COVID 19 patients from controls were 7.04 (specificity: 96%, sensitivity: 48%) (Figure 4 ). In another result of our study, the amount of eosinophils at the first admission was found to be lower in both the mild/moderate and severe groups compared with the control group. In our study, high periostin levels were detected in both mild/ moderate and severe cases after the first month of their follow-up. The periostin level was higher especially in severe cases than in mild cases, and this was statistically significant. We believe that the periostin level can be used in the follow-up of disease severity. In the case of inflammation and/or stress, the release of cytokines such as IL-4, IL-13, and TGFβ increases from inflammatory cells, and they, in turn, cause the release of periostin from the airway epithelial cells. [9] [10] [11] In our study, although the periostin level was found to be high, no significant change was found in TGFβ level. This may be because the regulation of periostin is affected not only by the expression of TGFβ but also by IL-4 and IL-13 in patients with COVID-19. We believe that further studies are needed to understand the molecular mechanisms behind the host response. In addition, we believe that the high level of periostin in the first month of the disease despite the clinical improvement may be a guide for complications that may develop in the future, which can be assessed in a longer follow-up period. In another study, the proinflammatory factor tenascin C and extracellular factor mucin-1 in bronchoalveolar lavage and serum samples were found to be higher in patients with COVID-19 compared with healthy controls. It has been suggested that these molecules can be used as potential biomarker candidates or therapeutic targets. 14 Based on the results of our study, we believe that periostin can be used to assess disease severity in patients with COVID-19; however, we recommend conducting further studies with a longer duration and a larger number of cases. In our study, ferritin level was found to be significantly higher in severe cases. D-dimer, LDH and CRP levels were also found to be higher. In another study, lactate dehydrogenase, ferritin, D-dimer, and IL-6 levels were found to be associated with mortality. 15 In yet another study, especially the levels of D-dimer and fibrin degradation products were found to be higher in patients with COVID-19 who died. 16 The reason for finding higher levels only for ferritin in our study can be explained by the low number of cases. In a study analysing severe cases, lymphopenia was detected in 85% of the cases with COVID-19 pneumonia. 4 Older patients with lower lymphocyte and platelet counts were found to have a higher risk of disease and an increased duration of hospital stay. 17 A notable result of our study was that there was a weak but significant negative relationship between basal levels of lymphocytes and periostin and a weak, but positive relationship between the basal levels of lymphocytes and TGFβ. In another study, it was shown that lymphopenia in CD8 + T cells was an independent predictor for COVID-19 severity and treatment effectiveness. 18 In yet another study, lymphocyte percentage was proposed as a predictive biomarker for disease severity or recovery. 19 In the light of these results, lymphopenia associated with COVID-19 has been identified as a key pathological biomarker and a criterion that marks the severity of the disease. Our data also support this finding. A detailed investigation of 140 hospitalised patients suggested that eosinopenia with lymphopenia may be both a diagnostic and prognostic indicator for COVID-19. 20 In another study, the combination of eosinopenia with high sensitivity CRP could effectively distinguish patients with suspected COVID-19 from other patients with fever. 21 Eosinopenia indicated poor prognosis also in another study. 22 The amount of eosinophils in our study was found to be lower in both mild/ moderate and severe groups compared with the control group. In the light of these studies, it can be thought that eosinopenia can be used both diagnostically and prognostically in patients with COVID-19. The limitations of our study included the small number of cases and short duration of the study. Another limitation was that only TGFβ level was investigated, although the level of periostin is affected by many cytokines. Our study is the first one performing periostin ELISA on COVID serum in patients with COVID-19, and it was found to be significantly higher in patients with COVID-19. Periostin can be used as a new biomarker; however, we believe that further studies with larger numbers of cases and longer follow-up periods are needed for its use in the follow-up and severity prediction of the disease. Mehmet Cabalak https://orcid.org/0000-0003-1148-2247 Serdar Doğan https://orcid.org/0000-0001-6854-2197 Tayibe Bal https://orcid.org/0000-0002-5315-122X Nursel Dikmen https://orcid.org/0000-0002-5923-400X Clinical management of COVID-19: interim guidance Pathogenicity and transmissibility of 2019-nCoV-A quick overview and comparison with other emerging viruses COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? Clinical features of patients infected with 2019 novel coronavirus in Wuhan Periostin and TGF-β-induced protein: Two peas in a pod? 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