INTRODUCTION
Coronaviruses are a large family of viruses that cause illness ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome Coronavirus (MERS-CoV) emerged in 2012 and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) emerged in 2002 (1). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain that has been firstly identified in a series of pneumonia cases linked to a seafood and wet animal wholesale market emerged in Wuhan, Hubei, China in December 2019 (2–4). Corona Virus Disease 2019 (COVID-19) caused by SARS-CoV-2, which possessed an estimated basic reproductive number of 2.2 (5), has become a global epidemic. As of March 16, 2020, a total of 167,511 confirmed cases had been reported in 152 countries, of which the vast majority were non-severe cases (6).
Till now, little data are available that describe the pharmacological therapies of proven efficacy and the pathological features of COVID-19. Corticosteroid was a double-edged sword, inhibiting inflammatory injury of lung while prolonging virus shedding as well as bringing potential complications, thus its treatment for COVID-19 was controversial (7, 8). The physicians from Chinese Thoracic Society have developed an expert consensus statement on the use of corticosteroid in COVID-19 pneumonia, recommending a prudent use in a short course of corticosteroid at low-to-moderate dose for critically ill patients (9). However for the non-severe cases, the vast majority of COVID-19 patients, should corticosteroid treatment be absolutely forbidden? In the early stage of the epidemic in Wuhan, corticosteroid was used in partial non-severe cases in our hospital, and we herein compared the clinical and radiographic outcomes of non-severe pneumonia cases treated with and without corticosteroid in this retrospective study.
METHODS
Patients
This retrospective study was approved by the Institutional Review Boards of Hubei Public Health Clinical Center, the central Hospital of Wuhan, and written informed consent was waived. Between 20 January 2020 and 25 February 2020, 132 patients who were diagnosed as non-severe COVID-19 pneumonia and discharged with recovered symptoms or developed to severe cases in the hospitalization were included. Patients who were treated before admission but without available specific treatment data were excluded. Diagnosis of COVID-19 was made according to the criteria established by the WHO interim guidance (10). That is a positive test for SARS-CoV-2 viral RNA, in throat-swab specimens collected from patients by real-time reverse transcription polymerase chain reaction (RT-PCR) using standard RT-PCR protocol at Hubei Provincial Center for Disease Control and Prevention (CDC) or our hospital laboratory. According to the coronavirus pneumonia diagnosis and treatment plan (trial version 7) developed by the National Health Committee of the People's Republic of China, non-severe pneumonia was defined as COVID-19 cases with pneumonia on radiological images, but did not meet any of the followings: respiratory distress, respiratory rate per min≥30; in the resting state, means oxygen saturation≤93%; arterial blood oxygen partial pressure/oxygen concentration ≤300 mm Hg (1 mm Hg = 0.133 kPa); progress of chest radiological manifestations> 50% within 24–48 h.
Data collection
Until the patients progressed to severe cases, their demographic, clinical, laboratory, radiological, treatment, and outcome data were extracted from electronic medical records by three physicians (CS, MY, and XX). Fever was defined as axillary temperature of above 37.3°C. Secondary infection was diagnosed when patients showed clinical symptoms or signs of pneumonia or bacteraemia and a positive culture of a new pathogen was obtained from lower respiratory tract specimens or blood samples after admission. The duration of virus shedding was defined as the time from illness onset to twice continuous negative tests for SARS-CoV-2 viral RNA with at least 24 h intervals. Temperature, laboratory data were recorded about every 3 days, and chest computed tomography (CT) imaging data were recorded about every 7 days.
CT imaging score
The technical parameters included 64-section scanner with 1 mm collimation at 5 mm intervals. All CT examinations were performed with the patient in the supine position and with breath-holding following inspiration, without administration of contrast material. Images were obtained with both mediastinal (width 350 HU; level 40 HU) and parenchymal (width 1,500 HU; level −600 HU) window settings.
Two experienced pulmonologists (CS, MY) reviewed the images independently, with a final finding reached by consensus when there was a discrepancy. CT findings included ground-glass opacity (GGO), consolidation, air bronchogram, and nodular opacities. GGO is characterized by hazy regions of increased lung opacity or attenuation in which vessels remain visible. Consolidation was defined as homogeneous opacification of the parenchyma obscuring the underlying vessels. The CT scans were scored on the axial images referring to the method described previously (11, 12). The extent of involvement of each abnormality was assessed independently for each of three zones: upper (above the carina), middle (below the carina and above the inferior pulmonary vein), and lower (below the inferior pulmonary vein). The CT findings were graded on a 3-point scale: 0 as normal attenuation, 1 as fibrous stripes, 2 as GGO, and 3 as consolidation. Each lung zone, with a total of six lung zones in each patient, was assigned a following scale according to distribution of the affected lung parenchyma: 0 as normal, 1 as < 25% abnormality, 2 as 25% to 50% abnormality, 3 as 50% to 75% abnormality, and 4 as > 75% abnormality. The four-point scale of the lung parenchyma distribution was then multiplied by the radiologic scale described above. Points from all zones were added for a final total cumulative score (Fig. 1).
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Fig. 1: A sample scoring on CT images of a 42-year-old man from corticosteroid group demonstrated a total score of 14 on admission. It is calculated as: for upper zone (A), 2 (ground-glass opacity) × 1 (< 25% distribution of the right lung); for middle zone (B), 2 (ground-glass opacity) × 1 (< 25% distribution) × 2 (both right and left lungs); for lower zone (C), 3 (consolidation) × 1 (< 25% distribution) × 2 (both right and left lungs) + 2 (ground-glass opacity) × 1 (< 25% distribution of the right lung).
Statistical analysis
Propensity score matching was used to adjust for differences in baseline characteristics of patients between corticosteroid group and non-corticosteroid group. Propensity scores methods are a powerful tool for comparing groups with similar observed characteristics without specifying the relationship between confounders and outcomes (13). Propensity scores for all patients were estimated according to some essential covariates (Table 1) that might have affected patient assignment to a corticosteroid or non-corticosteroid group, as well as clinical outcomes. A one-to-one matched analysis using nearest-neighbor matching was performed based on the estimated propensity scores of each patient and the caliper was set as 0.25. Continuous variables were expressed as median (interquartile range (IQR)) and compared with the Mann–Whitney U test or Wilcoxon test; categorical variables were expressed as number (%) and compared by χ2 test or Fisher exact test if appropriate. A two-sided α of less than 0.05 was considered statistically significant. Statistical analyses were done using the SPSS version 22.0 (IBM SPSS, Armonk, NY).
Table 1: Baseline characteristics of patients treated with or without corticosteroid before and after propensity score matching.
RESULTS
One hundred thirty-two patients who satisfied the inclusion criteria were categorized into corticosteroid group (n = 74) and non-corticosteroid group (n = 58). As significant baseline characteristics differences existed, 35 pairs were generated according to propensity score matching. Table 1 shows the characteristics of patients before and after matching. As shown in the unmatched groups, patients who had more fever before admission and who had lower lymphocyte counts were more likely to be treated with corticosteroid. Moreover ribavirin and lopinavir/ritonavir were more frequently used in corticosteroid group, while arbidol treatment was more common in non-corticosteroid group. After propensity score matching, the baseline characteristics of patients were well balanced between the groups.
The details of corticosteroid treatment are shown in Table 2. All patients in corticosteroid group were administrated methylprednisolone. Corticosteroid was initiated within a median of 8.3 days (IQR, 5.0–10 d) of the onset of illness, and they were initiated within a median of 1.9 days (IQR, 0–2.25 d) of hospital admission. The maximum dose of corticosteroid administered was 52.2 mg methylprednisolone (IQR, 40–50 mg) and the initial dose was 44.6 mg (IQR, 40–40 mg). Patients were treated with corticosteroid for a median duration of 10.8 days (IQR, 8–13 d). Details of corticosteroid administration in the matched 35 patients are also shown in Table 2. The details of comorbidities and other medications in the matched groups are shown in Supplementary Table 1, https://links.lww.com/SHK/B54.
Table 2: Details of administration of corticosteroid before and after propensity score matching.
Comparisons of clinical outcomes between patients treated with or without corticosteroid in propensity-matched groups are shown in Table 3. More patients in corticosteroid group progressed to severe cases than in non-corticosteroid group (11.4% versus 2.9%, P = 0.353); meanwhile compared to non-corticosteroid group, there was a prolonged hospital stay (23.5 days (IQR, 19–29 d) versus 20.2 days (IQR, 14–25.3 d), P = 0.079) and duration of viral shedding (20.3 days (IQR, 15.2–24.8 d) versus 19.4 days (IQR, 11.5–28.3 d), P = 0.669), and a shortened fever time (9.5 days (IQR, 6.5–12.2 d) versus 10.2 days (IQR, 6.8–14 d), P = 0.28) in corticosteroid group. However all these data revealed no statistically significant differences. None of the patients, either treated with or without corticosteroid, suffered to secondary infection.
Table 3: Comparison of outcomes in patients treated with or without corticosteroid in matched groups.
Figure 2 exhibits dynamic comparisons of body temperature, lymphocyte count, and CT score between COVID-19 patients with and without corticosteroid treatment after propensity score matching. There were no differences in dynamic changes of body temperature between groups. On the whole, the lymphocyte count increased over time in both groups, and although no significant difference, the numbers of lymphocytes were slightly higher in non-corticosteroid group than in corticosteroid group on the first 6 days and on the fifteenth day of hospitalization. In corticosteroid group, the CT score elevated slightly on day 7 and then declined subsequently, while the score of non-corticosteroid group exhibited a trend of continuous decline. Moreover, compared to non-corticosteroid group, the CT score on day 7 was significantly higher in corticosteroid group (8.6 (IQR, 2.8–11.5) versus 12.0 (IQR, 5.0–19.3), P = 0.046).
Fig. 2: Temporal changes in clinical parameters in hospitalized patients after propensity score matching. Dynamic comparisons of body temperature (A), lymphocyte count (B), and CT score (C) between corticosteroid group and non-corticosteroid group are presented. ∗ P < 0.05 determined by Mann–Whitney U test. CS indicates corticosteroid.
DISCUSSION
Although interim guidance from WHO on clinical management of severe acute respiratory infection when COVID-19 disease is suspected (released March13, 2020) advises against routinely giving corticosteroid for treatment of viral pneumonia outside of clinical trials (14), the adherence to this suggestion remained poor. About 56.1% of non-severe COVID-19 pneumonia patients in our study were administrated methylprednisolone. Another retrospective cohort study of 201 confirmed COVID-19 patients from Wuhan revealed that corticosteroid was used as adjunctive therapy in 30.8% of the cases (15). The pathogenesis of SARS-CoV-2 has not been well elucidated yet, it has been speculated that diffuse alveolar damage caused by persistent inflammation might play important roles in disease severity, just similar to Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) (16, 17). Many front-line physicians from China thought that corticosteroid could efficiently inhibit the inflammation and rapidly relieve the symptoms, thus corticosteroid was widely used during the early stage of the outbreak when little was understood about this disease.
There were controversial opinions on the effects of corticosteroid treatment on virus pneumonia. A recent systematic review in influenza-associated acute respiratory distress syndrome (ARDS) and severe pneumonia, which included 18 observational studies and one randomized controlled trial, showed that corticosteroid therapy was associated with significantly higher mortality and incidence of nosocomial infection; however, the result showed no statistically significant difference in adjusted estimates (18). Contrarily, a prospective cohort study enrolling 2,141 patients with influenza A (H1N1) showed that low-to-moderate dose of corticosteroid reduced mortality in patients with hypoxemia (19). A systematic review of observational studies of corticosteroid administered to patients with SARS reported no survival benefit and possible harms (avascular necrosis, psychosis, diabetes, and delayed viral clearance) (20). In contrast, a retrospective study pointed out that proper use of corticosteroid reduced mortality and shortened the length of stay in hospital for critically ill patients with SARS without causing secondary infection and other complications (21). In patients with MERS, no survival benefit but delayed lower respiratory tract clearance of MERS-CoV was observed in corticosteroid group (22). Limited data focusing on the effects of corticosteroid on COVID-19 cases showed that among patients with ARDS, treatment with methylprednisolone decreased the risk of death (15). A retrospective review in Wuhan Union Hospital showed that in patients with severe COVID-19 pneumonia, early, low-dose and short-term application of corticosteroid was associated with a faster improvement of clinical symptoms and absorption of lung focus (23).
To the best of our knowledge, no data are available that describe the effects of corticosteroid on non-severe COVID-19. Our study suggested that corticosteroid might have a negative effect on lung injury recovery, as patients in corticosteroid group were estimated a lower CT score than in non-corticosteroid group on day 7 after admission. We speculated the reason for this negative effect was that corticosteroid treatment might result in delayed viral clearance, for host immune defense played important roles in viral clearance when no pharmacological therapies of proven efficacy existed, just as it was reported in SRAS cases (24). Another reason may be related to angiotensin-converting enzyme 2 (ACE2). SARS-CoV-2 gains access to its target cell by exploiting the membrane-bound ACE2 (25). It is believed that viral infection downregulates ACE2, resulting in disproportionate angiotensin II activity, which may be a possible mechanism for organ injury in COVID-19. Animal studies have showed that glucocorticoids increase angiotensin II precursor processing, and upregulate angiotensin II receptors in vascular smooth muscle cells (26, 27). As angiotensin II seems to play a key role in the pathophysiology of COVID-19, its potentiation by corticosteroids might have a detrimental effect. However, our study has not observed any statistically significant effect of corticosteroid on delaying the time of viral shedding, and the conclusion was similar to an observational study (28). It is notable that the estimated duration of viral shedding is limited by the frequency of respiratory specimen collection, lack of quantitative viral RNA detection, and relatively low positive rate of SARS-CoV-2 RNA detection in throat swabs (29). Also, corticosteroid has not significantly altered the percentages of patients progressing to severe cases, the duration of fever or hospital stay.
Our study has several limitations. First, the retrospective nature of our study resulted in few missing values despite the effort in data collection, and might also bring many confounders, such as confounding by indications of corticosteroid treatment. Despite that propensity score matching was used to mitigate some confounding factors, this potential problem could not be totally solved. The results of this study must therefore be interpreted with caution. Second, there was a lack of information regarding interobserver agreement on evaluating CT score, because the study emphasizes on the final consensus interpretation rather than independent reading.
Conclusively, considering no benefits but potential harms of corticosteroid on non-severe cases, we suggest that the front-line physicians should adhere to the expert consensus statement from Chinese Thoracic Society, that is corticosteroid should be only used prudently in critically ill patients with 2019-nCoV pneumonia after the benefits and harms being carefully weighed (9).
Acknowledgments
The authors highly appreciate many members of the front-line medical and nursing staff who demonstrated selfless and heroic devotion to duty in the face of this outbreak.
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