key: cord-0818506-nn59dqnl authors: Tural Onur, Seda; Altın, Sedat; Nedime Sokucu, Sinem; İleri Fikri, Burcu; Barça, Tuğçe; Bolat, Erkut; Toptaş, Mehmet title: Could ferritin level be an indicator of COVID‐19 disease mortality? date: 2020-09-23 journal: J Med Virol DOI: 10.1002/jmv.26543 sha: a005ccb81c48b15b6df8a06ba20884e3fbdf49c7 doc_id: 818506 cord_uid: nn59dqnl PURPOSE: While the number of COVID‐19 cases is increasing day by day, there is limited information known about the hematological and laboratory findings of the disease. We aimed to investigate whether serum ferritin level predicts mortality, is a marker for rapid progression for inpatients. METHODS: Our study included 56 patients who were died due to COVID‐19 as the study group, and 245 patients who were hospitalized and recovered as the control group. The laboratory data of the patients were evaluated from the first blood tests (pre) taken from the first moment of admittion to the hospital and the blood tests taken from before the patient's discharge or exitus (post) were evaluated retrospectively. RESULTS: The mean age of the nonsurvivor group was 62.0 ± 15.7 and the mean age of the control group was 54.34 ± 13.03. Age and length of stay are significantly higher in the nonsurvivor group. When comparing the pre and post values of ferritin, according to the two groups separately, there was no significant difference in the control group and a high level of significance was observed in the nonsurvivor group (p <0.01). CONCLUSION: COVID‐19 disease caused by SARS‐CoV‐2 causes high mortality with widespread inflammation and cytokine storm. Ferritin is a cheap and widespread available marker, ferritin, which can be used for its predictivity of the mortality and hope it would be a usefull marker for clinicians for the management of the disease. This article is protected by copyright. All rights reserved. The new severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), defined for the first time in China at the end of 2019, rapidly affected the world and caused a pandemic. The disease identified as COVID-19 can cause fatal acute respiratory distress syndrome (ARDS) with its severe course by severe pneumonia [1] . About 367166 people died from the beginning of the pandemic by the end of May 2020 due to COVID-19 [2] . While the number of cases is increasing day by day, there is limited information known about the hematological and laboratory findings of the disease [3] [4] [5] . It is managed in the light of clinical classification from simple pneumonia to severe respiratory failure recommended by WHO and the scientific committee in our country [6] . COVID-19 patients defined by the following criteria: (a) Epidemiology history, (b) Fever or other respiratory symptoms which is undefined by any condition, (c) Typical CT image abnormities of viral pneumonia, (d) Severe Acute Respiratory Infections, (e) Positive result of RT-PCR for SARS-CoV-2 RNA. While the disease may be asymptomatic, it can be encountered with a severe ARDS, which is thought to be due to inflammatory cytokine storm. Activation of the monocyte macrophage system is existing Accepted Article just before the disease is produces pneumonia. In this period, an increase in ferritin levels is observed in COVID-19 patients, along with an increase in many laboratory parameters such as d-dimer and fibrinogen [7] [8] [9] . In this study, we aimed to investigate whether serum ferritin level predicts mortality, is a marker for rapid progression for inpatients, and has got a cut-off level to forecast the negative affect to the treatment of the patient diagnosed with COVID-19. Three hundreds and one patients who were hospitalized for COVID-19 according to who interim guidance to our education and research hospital, which was designated as Pandemic hospital between 11 March-20 April 2020, were retrospectively analyzed. Our study included 56 patients who were died due to COVID-19 as the study group, and 245 patients who were hospitalized and recovered as the control group. This study was approved by the Clinical Research Ethics Committee of the Health Sciences University Istanbul Training and Research Hospital, the scientific board of our hospital and Turkish Republic the Ministry of Health General Directorate of Health Services. Demographic data, medical history, laboratory findings and thorax tomography of the patients were obtained from the hospital electronic information system retrospectively. The laboratory data of the patients were evaluated from the first blood tests (pre) taken from the first moment of admittion to the hospital and the blood tests taken from before the patient's discharge or exitus (post) were evaluated. The hemogram data of the patients were studied in the biochemistry laboratory with the Beckman Coulter AU2700 device with the biochemical tests with the Sysmex XT4000i device. All patient data were double checked and analyzed by the research team. PCR tests were performed in our hospital and Istanbul Cerrahpaşa Medical Faculty microbiology laboratory which were both validated as Sars-CoV-2 laboratory. Swap samples were taken from the upper respiratory tract (naso-oropharynx) when the patient was admitted to the hospital and transported via viral-transport medium to the laboratory. All RNA extraction was obtained with the Genmark RNA isolation kit (Genome) previously described for the SARS-CoV-2 duration in 2-hours [10] . All statistical analyses were performed using the SPSS 21.0 software. Categorical variables were expressed as frequency rates and percentages (%), and continuous variables were expressed as median (IQR). Categorical variables between groups were compared using the χ2 test or Fisher exact test. Kolmogorov-Smirnov test was used to check the normal distribution for continuous data. As the normal distribution hypothesis is not provided, Mann-Whitney U test was conducted for the analysis of the differences between control and death groups. The pre and post values of ferritin were compared with Wilcoxon test. In addition, logistic regression was made after determining the dependent variable as being dead or alive due to COVID-19 and independent variables as age, length of stay, favipiravir. Furtermore, receiver operating characteristic (ROC) analysis was used to evaluate the cut-off value of ferritin. P-value <.05 was considered statistically significant. The demographic characteristics of our patients are summarized in Table-1 , from the 301 patients, 56 (18.6%) of the them died during the study. The mean age of the nonsurvivor group was 62.0 ± 15.7 and the mean age of the control group was 54.34 ± 13.03, and the nonsurvivor group was significantly older than the control group (p <0.01). There was no significant difference in male / female ratio in the nonsurvivor group compared to the control group (p> 0.05). As can be seen in Table 1 , age, length of stay, CVD (Cardiovascular disease), and number of patients taken favipiravir treatment were statistically significant in the control and nonsurvivor group comparisons. Age and length of stay are significantly higher in the nonsurvivor group. In addition, when looking at categorical variables, the rates of CVD and number of patients taken favipiravir treatment were found significantly higher in the nonsurvivor group. While comorbidity was present in 39.8% of the patients, only CVD was found to be significantly higher as comorbidity in the exitus group. When Table 2 In Table 3 , when comparing the pre and post values of ferritin, according to the two groups separately, there was no significant difference in the control group and a high level of significance was observed in the nonsurvivor group. In the nonsurvivor group, post ferritin values are quite high compared to the pre ferritin. A statistically significant difference was found in the comparison of the ferritin values of favipiravir users among the groups. Ferritin values are higher in the nonsurvivor group despite treatment (p<0,01). In Table 4 , according to the results of logistic regression analysis, age, length of stay, CVD, lung cancer, and favipiravir are effective factors on the risk of death. However, when ORs are examined, this effect is low at the age and length of stay, and others are more effective in the risk of death. According to ROC Curve analysis results for Ferritin, the Cut-Off value was 304.30 and the area under the curve was 0.762 (95% CI: 0.690-0.835). Sensitivity and specificity values are 71.4% and 70.6%, respectively. COVID-19, caused by the new coronavirus SARS-Cov-2, is a new disease for humanity and also contains many unknowns. During the course of the disease, besides hematological abnormalities, variabilities are observed in many biochemical parameters. With the excessive activation of the immune system and monocyte-macrophage system activation, damage occurs in many organs, especially the lungs. While variety in immunological response cannot be explained only by viral load, epidemiological and molecular differences play a role in the manifestation of the clinical presentation, and there are a limited number of studies to explain this in the literature [11, 12] . In our study, we have shown that ferritin which is an indicator of systemic inflammation can be a predictor of disease severity and mortality. In current literature, it has been stated that COVID-19 disease progresses more seriously, especially in elderly and male patients with comorbidity. While patients often have dyspnea, cough, fever, malaise and myalgia, in severe cases clinical course can go up to ARDS and patients have to be intubated in intensive care [4] . In our study, the frequency of ARDS development and hematological abnormality was found to be increased in patients with longer hospital stay, elderly and patients whose radiological involvement in CT is extensive so that treated with favipravir. Our duration of hospital stay was determined in accordance with a multicenter study, and patients with increased hospital stay had higher ARDS and increased ferritin levels [13] . While the correlation of lymphopenia from hematological abnormalities with disease severity is supported by the literature, it is emphasized that it is the first parameter that can be used due to being inexpensive, easy and economical [1, 14] . In our study, we think that lymphopenia may also be used with high ferritin levels in patients who has widespread inflammation leading to ARDS. In a metaanalysis in which a limited number of literature is examined, hematological findings detected in COVID-19 patients are considered as an indication of the increase in values such as d-dimer, troponin, IL-6, and the diffuse cytokine release in patients that led to multiple organ damage [15] . In our study, we have shown that the increase in the biochemical parameters such as ferritin, fibrinogen, d-dimer, troponin, measured at the first time of hospital admission, as well as the detection of lymphopenia are associated with mortality. Favipravir which is effective on viral RNA is activated with the host's enzyme system [16] . Favipravir whose efficacy was determined at the level of observation without clinical study, was used primarily in patients in the intensive care unit and in desaturated patients in clinics in accordance with the recommendation of the scientific committee of our country. Since the course of the disease was poor in our patients using Favipiravir, the change in ferritin value was clinically significant in these patients. As a result, COVID-19 disease caused by SARS-CoV-2 causes high mortality with widespread inflammation and cytokine storm. A serious fight against the disease is active all around the world because of high mortality of this pandemic. In this pandemic period, we wanted to contribute to the literature with our study done with a cheap and widespread available marker, ferritin, which can be used for its predictivity of the mortality and hope it would be a usefull marker for clinicians for the management of the disease. All authors declare that they have no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Report of the Coronavirus Disease 2019 (COVID19). 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Version 2. Signal Transduct Target Ther Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis The mechanism of resistance to favipiravir in influenza WBC: White blood cell count, ×10e3/uL; HGB: Hemoglobin, g/dL; HCT: Hematocrit, %; LY: Lymphocyte count, ×10e3/uL; LY%: Lymphocyte count %