key: cord-0840686-jx1ws18b
authors: Gong, Yuan; Guan, Li; Jin, Zhu; Chen, Shixiong; Xiang, Guangming; Gao, Baoan
title: Effects of methylprednisolone use on viral genomic nucleic acid negative conversion and CT imaging lesion absorption in COVID‐19 patients under 50 years old
date: 2020-05-22
journal: J Med Virol
DOI: 10.1002/jmv.26052
sha: ba1f2b131c888bb51ea8c5c1422bc31ab64f0435
doc_id: 840686
cord_uid: jx1ws18b

The use of corticosteroids has been controversial in viral pneumonia. In most cases, application of methylprednisolone in severe and critical viral pneumonia patients can quickly alleviate the symptoms of dyspnea and prevent disease progression. However, some scholars have confirmed that corticosteroids delayed the body's clearance of the virus. In our retrospective non‐randomised study, 34 patients under 50 years old and diagnosed with coronavirus disease 2019 (COVID‐19) were included, according to given methylprednisolone treatment (n = 18) or not (n = 16), they were separated into 2 groups. By comparing the clinical data we concluded that corticosteroids therapy can effectively release COVID‐19 symptoms such as persistent fever and difficult breathing, improve oxygenation and prevent disease progression. However, it can prolong the negative conversion of nucleic acids. This article is protected by copyright. All rights reserved.

In Yi Chang City, Hu Bei Province, the first outbreak of COVID-19 commenced on 24 January 2020 in the Yichang Third People's Hospital. With 931 persons becoming infected and the increasing number of COVID-19 patients, the medical resources of the Yichang Third People's Hospital were in short supply. In this case, Jiangnan District of Yichang Central People's Hospital has been put into use urgently, and nearly 30 percent of COVID-19 confirmed patients in Yichang have been treated in our hospital. Until date, this highly contagious respiratory disease has caused infections worldwide, 211 countries have found confirmed patients until 29 April 2020 [1] . Unfortunately, there is no specific drug for this disease at present. As one of the drugs for the treatment of interstitial pneumonia, corticosteroid have been studied in many epidemic viral pneumonia. Arabi YM et al [2] found that corticosteroid therapy can relieve respiratory symptoms in middle east respiratory syndrome (MERS) patients, and this treatment was not related to mortality, but related to MERS coronavirus RNA clearance replacement. Peiris JS et al [3] reported that corticosteroid treatment in early stage of severe acute respiratory syndrome (SARS) was associated with a higher subsequent plasma viral load. Christian B [4] analyze the clinical impact of corticosteroids therapy on 208 H1N1 influenza-related ARDS patients and found no beneficial effect. During the progression of viral pneumonia, an outbreak of inflammation may cause acute respiratory distress syndrome (ARDS). Despite the controversial role of corticosteroids, they are often used as a supportive approach to minimize inflammatory response in viral pneumonia [5, 6] .As a type of corticosteroids, methylprednisolone is widely used in clinic because of its large distribution, high concentration and long retention time in alveolar epithelial cells [7] . However, there is fierce debate about whether corticosteroids slow down the clearance of coronaviruses [8] and increase the chance of opportunistic infections [9] , but still the use of corticosteroids seems to be indispensable in the treatment of with severe and especially critical COVID-19 patients [10] [11] [12] . 

A retrospective comparison study was performed on COVID-19 patients under 50 years old who were admitted between 30 January and 20 February 2020. Regardless of whether the patient has a positive nucleic acid test result before hospital admission, we re-tested the nasopharyngeal swabs for COVID-19 on the first day of admission. All of them were diagnosed by positive result of real-time fluorescent RT-PCR detection of nasopharyngeal swabs, of which 18 patients who had persistent high fever (body temperature> 39 ℃) for three consecutive days, or progress in CT imaging within 2 days (that is, the number of affected lung segments increased by 50%, or the range of the original affected lung segments increased by 50%) or with hypoxia and difficulty breathing were treated with methylprednisolone, the initial dose was calculated based on their body weight (1-2mg/kg/d) [13] and gradually halved every 3 days, the total treating course range from 5 to 10 days. In addition, all the 34 patients have received antiviral therapy (200mg of arbidol three times a day, 400mg/100mg of lopinavir and ritonavir twice daily) for 7-10 days. In the end, all these patients recovered smoothly and were discharged according to the standard, that is, the symptoms were significantly relieved, the CT imaging lesions were obviously absorbed, and the two consecutive nucleic acid detection were negative. Most importantly, there was no death. Based on whether they were treated with methylprednisolone or not, they were divided into two groups, the basic information and disease typology are described in the table below: CT images of 20 days before and after treatment in those 2 groups were compared. Good CT imaging lung lesion absorption is defined as: the number of affected pulmonary segments is reduced by half, or the CT density of the lesion is significantly reduced. The time of viral nucleic acid negative conversion is calculated as the time interval between two consecutive negative detections of new coronavirus nucleic acid and the onset of illness (Table1).

Statistical analyses were performed using the SPSS 21.0 (IBM, USA). Data were shown as mean values ± standard deviation (SD). Two-tailed Student's t-test was used to compare the two groups of means in this study, P values were ≤ 93% at a rest state; arterial partial pressure of oxygen (PaO2)/oxygen concentration (FiO2) ≤ 300 mmHg. Patients with > 50% lesions progression within 24 to 48 hours in lung imaging should be treated as severe cases. Critical: meeting any of the following criteria: occurrence of respiratory failure requiring mechanical ventilation; presence of shock; other organ failure that requires monitoring and treatment in the ICU. Critical cases are further divided into early, middle and late stages according to the oxygenation index and compliance of respiratory system [13] . determined to measure the significance. P values < 0.001 were considered extremely significant (Expressed as ***), < 0.01 were considered very significant (Expressed as **), < 0.05 were considered significant (Expressed as *), ≥ 0.05 were considered not significant (Abbreviated as N.S).

We compared the changes of CT imaging at 20 days before and after treatment, and found out that most lung lesions were presented as follows: ground glass opacity, cloudy, interstitial changes and fibrous stripes, consolidation (Figure 1 ). After 20 days of antiviral treatment, 4 cases in the non-methylprednisolone treatment group completely absorbed the lung lesion on CT image, 12 cases partially absorbed the lung lesion ( Figure 2 A and B) . In the methylprednisolone treatment group, compared with CT image 20 days before antiviral and methylprednisolone treatment, 2 cases completely absorbed the lung lesion on CT image, 14 cases partially absorbed the lung lesion, and 2 cases enlarged the lung lesion ( Figure 2 C and D) . However, there was no statistical difference in the total number of pulmonary segments with lesion before and after 20 days of treatment in both 2 groups. The time that needed for viral nucleic acid negative conversion in the non-methylprednisolone treatment group (24.44 ± 5.21) was shorter than that in the methylprednisolone treatment group (29.11 ± 6.61, P = 0.03). 15 patients in the methylprednisolone treatment group developed hypoxia before treatment (ie, the percentage of finger oxygen saturation without oxygen inhalation was less than or equal to 97%). However, after these patients were discharged and isolated for 14 days, the blood oxygen saturation returned to normal levels ( Figure 3 ). 

COVID-19 is an animal-derived virus [14] , bats may be the host of the virus and intermediate hosts may include pangolins [15] . To date, 237 cases of COVID-19 diagnosed patients in Yichang City, Hubei Province have been treated in our hospital. These patients range from 0.5 to 87 years old, and there is no significant difference between the male and female ratios, which indicates that COVID-19 is susceptible to all the population with no obvious gender differences and can cause disease at all ages. Unfortunately, there are still no specific drug to treat COVID-19 at present. According to the diagnosis and treatment guideline issued by the Chinese National Health Council on March 3, 2020, corticosteroids are recommended for severe, especially critically ill patients [13] , which can effectively alleviate the symptoms of patients such as dyspnea and high fever, but also can prevent patients from rapid progress in lung imaging. However, due to the well-known reasons, corticosteroids are highly controversial in the treatment of viral pneumonia. Some scholars believe that corticosteroids can slow down the clearance of the virus [8] , and long-term use of corticosteroids will also cause a series of such as opportunistic fungal infection, femoral head necrosis, etc [16] .

In our study, we found that the time required for nucleic acid negative conversion in the corticosteroids treatment group was longer than that in the non-corticosteroids treatment group, which is consistent with the opinion that the use of corticosteroids can slow down the clearance of the virus [4, 12, 17] . But more importantly, although the proportion of severe and critical typology patients in the methylprednisolone treatment group is higher than that in the non-Methylprednisolone treatment group, the percentage of good CT imaging lung lesion absorption in methylprednisolone treatment group (88.9%) is comparable to that in the non-corticosteroids treatment group (100%), and oxygen-deficiency of the hypoxic patients are gradually improved in the corticosteroids treatment group. Despite the fact that two severe patients in methylprednisolone treatment group had larger lung lesions after 20 days treatment, they did not turn into critical cases and both of them recovered and successfully discharged with no complications.

Based on the result of retrospective analysis of clinical data, we concluded that corticosteroids are a safe and effective treatment for COVID-19. In the early stage of the disease, the use of corticosteroids may affect the clearance of the virus, but in the period of rapid disease progression, the use of corticosteroids can inhibit the further deterioration of the disease and create opportunities for treatment. From the perspective of the treatment for critical and severe patients in our hospital, corticosteroids plays a very important role in saving patients' lives and rapidly suppressing the progress of the disease. Considering that the majority typology of COVID-19 patients under 50 years old are moderate typology, the use of corticosteroids requires individualized selection. Corticosteroids need to be used promptly when disease progression changes rapidly and may develop into severe or critical cases. If there is insufficient evidence, it is best to avoid the use of corticosteroids, as nucleic acid negative transformation takes longer after treatment, which may be due to slower virus removal.

This study have limitations because it was not a randomized study and also just the patients under 50 years old and just one type of corticosteroids were included in the study, due to the urgency, there are difficulties in carrying out a rigorous large-scale clinical trial. Although corticosteroids therapy is widely controversial in viral pneumonia, it is safe and effective in clinical applications. Therefore, larger randomized studies are needed to confirm our preliminary results.

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The authors declare that they have no competing financial interests.

Yuan Gong, Zhu Jin collected and analyzed the data, and prepared the manuscript. Shixiong Chen contributed to the collecting and interpretation of radiological materials. Guangming Xiang, Li Guan were involved in the patient management and organization work. Baoan Gao designed the study and reviewed the manuscript.