Patient characteristics
Between February 7 and February 17, 2020, a total of 83 patients with severe or critical COVID-19 were screened for inclusion. Of these patients, 11 patients were excluded, including eight critical COVID-19 patients with less than two serial CT scans during hospital stay, two patients receiving systemic corticosteroids or immunosuppressive therapy in the previous 6 weeks, and one patient with solid malignancy. Within the study period, 72 patients with severe COVID-19 were finally included in this study (Fig. 1).
Thirty-one patients (43.1%) received steroid therapy. Table 1 presents the baseline characteristics of the patients. The median age of the 72 patients was 63 years [IQR 49 to 69 years], and 51.4% of the patients were male. Fever was the most common symptom (90.3%), followed by fatigue (87.5%), cough (73.6%), and dyspnea (55.6%). The baseline characteristics between patients receiving steroid therapy and those not receiving steroid therapy were similar (Table 1). The vital signs and the PaO2/FiO2 ratio on admission were also similar between the two groups.
Table 1
Clinical characteristics of patients with severe COVID-19
| Entire cohort | Steroid group | Standard care group | P value |
Number of patients | 72 | 31 | 41 | |
Age (years) | 63[49,69] | 65[55,72] | 62[48,69] | 0.31 |
Gender (male), n (%) | 37(51.4) | 14(45.2) | 23(56.1) | 0.48 |
Smoking history, n (%) | 9(12.5) | 4(12.9) | 5(12.2) | 1.00 |
Comorbidities | | | | |
Hypertension, n (%) | 22(30.6) | 11(35.5) | 11(26.8) | 0.45 |
Diabetes mellitus, n (%) | 16(22.2) | 7(22.6) | 9(22.0) | 1.00 |
CAD, n (%) | 4(5.6) | 2(6.5) | 2(4.9) | 1.00 |
COPD, n (%) | 1(1.4) | 0(0) | 1(2.4) | 1.00 |
Cerebrovascular disease, n (%) | 1(1.4) | 1(3.2) | 0(0) | 1.00 |
Chronic renal disease, n (%) | 2(2.8) | 1(3.2) | 1(2.4) | 1.00 |
Signs and symptoms | | | | |
Fever, n (%) | 65(90.3) | 30(96.8) | 35(85.4) | 0.23 |
Cough, n (%) | 53(73.6) | 24(77.4) | 29(70.7) | 0.60 |
Sputum production, n (%) | 10(13.9) | 4(12.9) | 6(14.6) | 1.00 |
Fatigue, n (%) | 63(87.5) | 28(90.3) | 35(85.4) | 0.72 |
Headache, n (%) | 4(5.6) | 1(3.2) | 3(7.3) | 0.63 |
Dyspnea, n (%) | 40(55.6) | 20(64.5) | 20(48.8) | 0.23 |
Nausea or vomiting, n (%) | 13(18.1) | 6(19.4) | 7(17.1) | 1.00 |
Diarrhea, n (%) | 15(20.8) | 7(22.6) | 8(19.5) | 0.77 |
Anorexia, n (%) | 4(5.6) | 3(9.7) | 1(2.4) | 0.31 |
Myalgia or arthralgia, n (%) | 7(9.7) | 4(12.9) | 3(7.3) | 0.45 |
Onset of symptom to first CT scan (days) | 14[11, 17] | 14[11, 19] | 13[11, 16] | 0.16 |
Vital signs at hospital admission | | | | |
Altered mental status, n (%) | 2(2.8) | 2(6.5) | 0(0) | 0.18 |
Heart rate (beats/minute) | 88[78,102] | 85[77,105] | 90[81,100] | 0.83 |
Respiratory rate (breaths/minute) | 24[23, 31] | 25[24, 32] | 24[23, 29] | 0.20 |
Systolic blood pressure (mm Hg) | 132[122,145] | 132[123,147] | 131[120,144] | 0.44 |
Diastolic blood pressure (mm Hg) | 78[71,83] | 79[72,83] | 76[70,84] | 0.54 |
Respiratory status assessment | | | | |
PaO2 on admission (mmHg) | 67[61,86] | 66[59,84] | 68[63,87] | 0.49 |
PaCO2 on admission (mmHg) | 39[34, 42] | 39[33, 41] | 40[36, 43] | 0.36 |
PaO2/FiO2 on admission (mmHg) | 256[226,277] | 246[195,279] | 258[228,277] | 0.40 |
Respiratory support | | | | |
High flow nasal oxygen, n (%) | 14(19.4) | 11(35.5) | 3(7.3) | < 0.01 |
Non-invasive mechanical ventilation, n (%) | 2(2.8) | 2(6.5) | 0(0) | 0.18 |
Invasive mechanical ventilation, n (%) | 1(1.4) | 1(3.2) | 0(0) | 0.43 |
Renal replacement therapy, n (%) | 1(1.4) | 0(0) | 1(2.4) | 1.00 |
Hospital mortality, n (%) | 0(0) | 0(0) | 0(0) | - |
Duration of viral shedding after COVID-19 onset (days) | 25[18, 31] | 27[22, 34] | 23[17, 29] | 0.03 |
Hospital length of stay (days) | 33[27, 39] | 36[31, 42] | 29[24, 36] | < 0.01 |
Data are expressed as the median with interquartile range (IQR) in square brackets for non-normally distributed data. Continuous variables are shown as the mean ± SD or median [IQR], as appropriate. Categorical variables are shown as number (%). COVID-19, coronavirus disease 2019; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; FiO2, fraction of inspired oxygen; PaO2, partial pressure of oxygen. |
During hospital stay, more patients in the steroid therapy group were treated with high-flow nasal oxygen than standard care group (35.5% vs. 7.3%, P < 0.01). However, the proportion of invasive or noninvasive ventilation between the two groups was comparable. All patients survived to discharge from hospital in this study. The length of hospital stay was higher in patients receiving steroid therapy than in those not receiving steroid therapy (36 vs. 29 days, P < 0.01).
Quantitative CT parameters over time in the steroid therapy group and the standard care group
Three hundred chest CT scans were longitudinally collected from 72 patients with severe COVID-19. All CT scans were classified into five stages according to the interval between hospital admission and follow-up CT scans: Stage 1 (T1, at admission); Stage 2 (T2, 3–7 days); Stage 3 (T3, 8–14 days); Stage 4 (T4, 15–21 days); and Stage 5 (T5, 22–31 days).
The quantitative percentages and volumes of compromised lung (CL), nonaerated lung (NNL), poorly aerated lung (PAL), normally aerated lung (NAL), and hyperinflated lung (HI) were extracted from CT scans according to the recommended protocols (Fig. 2 and Table 2). Quantitative CT parameters over time in the steroid therapy group and the standard care group are shown in Fig. 3. At baseline (Stage 1), the percentages of CL, NNL, PAL, and HI were higher in the steroid therapy group than in the standard care group (all P < 0.05; Table 2). The percentages of %CL, %PAL, and %HI were significantly decreased in the steroid therapy group as compared to those in the standard care group during the follow-up period (all P < 0.05 by repeated-measures ANOVA; Fig. 3A, 3C, and 3E), whereas the percentage of %NNL and %NAL did not significantly differ between the groups (P > 0.05 by repeated-measures ANOVA; Fig. 3B and 3D). Examples of quantitative lung CT analysis for patients with severe COVID-19 receiving steroid therapy and with no steroid therapy were presented in Fig. 4 and Fig. 5, respectively.
Table 2
Quantitative chest CT parameters (%) during the follow-up period
| Stage 1 | Stage 2 | Stage 3 | Stage 4 | Stage 5 |
Quantitative chest CT parameters (%) | Entire cohort(n = 72) | Steroid group(n = 31) | Standard care group(n = 41) | Entire cohort(n = 62) | Steroid group(n = 27) | Standard care group(n = 35) | Entire cohort(n = 65) | Steroid group(n = 29) | Standard care group(n = 36) | Entire cohort(n = 56) | Steroid group(n = 29) | Standard care group(n = 27) | Entire cohort(n = 45) | Steroid group(n = 25) | Standard care group(n = 20) |
%CL | 23.90[19.83,36.11] | 36.45[25.12,48.53] * | 22.29[18.81,24.36] | 22.38[19.89,29.54] | 28.35[22.47,40.52] * | 20.57[18.63,24.13] | 21.92[18.88,31.81] | 24.95[20.90,34.29] * | 19.30[17.91,26.73] | 21.44[18.18,27.84] | 23.91[19.80,29.57] * | 19.61[17.73,26.50] | 22.49[18.44,30.80] | 22.49[18.56,30.80] | 22.65[17.85,30.37] |
%NNL | 18.02[15.91,21.35] | 20.22[17.72,24.37] * | 17.05[15.71,18.53] | 17.26[16.01,20.15] | 18.93[17.19,23.28] * | 16.52[15.60,18.03] | 17.03[15.62,20.75] | 17.35[16.35,22.23] | 16.20[15.50,20.13] | 16.72[15.52,19.40] | 16.56[15.78,20.92] | 16.88[15.28,18.94] | 17.10[15.35,22.47] | 17.10[15.40,22.53] | 17.00[15.31,22.08] |
%PAL | 5.92[3.81,13.59] | 13.73[7.06,20.00] * | 4.18[2.97,5.97] | 5.10[3.47,8.74] | 8.98[5.88,17.93] * | 3.63[2.78,5.67] | 4.67[2.87,9.79] | 7.05[4.57,14.42] * | 3.24[2.31,6.38] | 4.28[2.63,8.49] | 4.92[3.83,10.69] * | 2.97[2.20,7.46] | 5.41[2.66,8.15] | 5.41[2.95,8.38] | 5.16[2.37,7.12] |
%NAL | 59.23[50.79,67.26] | 57.20[46.68,66.59] | 61.69[53.69,68.51] | 61.31[55.10,70.01] | 62.25[53.28,70.09] | 60.78[55.65,69.75] | 58.72[51.95,67.24] | 61.96[54.71,71.88] * | 57.59[49.00,62.34] | 58.46[53.41,68.98] | 62.01[55.39,70.18] * | 55.64[45.57,62.51] | 60.32[53.37,66.56] | 61.72[56.39,68.62] * | 56.25[44.75,62.06] |
%HI | 7.62[2.12,19.40] | 2.39[1.40,7.72] * | 14.11[6.90,23.29] | 7.93[3.44,19.27] | 4.65[2.13,7.23] * | 17.58[7.17,25.27] | 10.57[3.50,22.23] | 5.87[2.57,11.79] * | 20.12[5.72,30.17] | 12.81[5.64,25.04] | 9.42[4.46,14.46] * | 21.78[8.42,34.32] | 13.21[3.45,23.48] | 6.38[2.22,17.04] ** | 19.90[4.28,33.03] |
Data are expressed as the median with interquartile range in square brackets for non-normally distributed data. The Kruskal–Wallis analysis of variance was used for non-normally distributed data comparison. %CL, percentage of compromised lung volume, considered as the sum of %PAL and %NNL; %NNL, percentage of nonaerated lung volume; %PAL, percentage of poorly aerated lung volume; %NAL, percentage of normally aerated lung volume; %HI, percentage of hyperinflated lung volume. * denotes P < 0.05 between two groups at each stage. |
Associations between steroid administration and changes in quantitative chest CT parameters during the follow-up period
Main Effect Associations
GEE models were used to assess the effect of steroid on changes in quantitative chest CT parameters during the follow-up period. The main effect analyses, without interactions in the GEE model, are shown in Table 3. Across the entire cohort, univariate GEE analysis revealed that steroid administration was associated with decrease in %CL (-7.44% [95% CI, -10.01 to -4.87, P < 0.001]) and increase in %NAL (7.46% [95% CI, 4.03 to 10.88, P < 0.001]). After adjusting for duration and baseline quantitative CT parameters (%), steroid administration was still associated with decrease in %CL (-3.27% [95% CI, -5.86 to -0.68, P = 0.01]) and increase in %NAL (6.17% [95% CI, 3.51 to 8.83, P < 0.001]). There were no significant associations between steroid administration and changes in %NNL, %PAL, and %HI (Table 3, all P > 0.1).
Table 3
Associations between steroid administration and changes in quantitative chest CT parameters (%) in the entire cohort
Outcome | Unadjusted | Adjusted |
Changes in quantitative CT parameters (%) | Coefficient | 95% CI | P value | Coefficient | 95% CI | P value |
Changes in CLa | -7.44 | -10.01 to -4.87 | < 0.01 | -3.27 | -5.86 to -0.68 | 0.01 |
Changes in NNLb | -1.75 | -3.01 to -0.48 | < 0.01 | -0.68 | -1.61 to 0.24 | 0.15 |
Changes in PALc | -5.71 | -7.66 to -3.77 | < 0.01 | -1.44 | -3.46 to 0.57 | 0.16 |
Changes in NALd | 7.46 | 4.03 to 10.88 | < 0.01 | 6.17 | 3.51 to 8.83 | < 0.01 |
Changes in HIe | 0.06 | -2.81 to 2.92 | 0.97 | -1.86 | -4.73to 1.01 | 0.20 |
Analyses using generalized estimating equations to implement linear regression models. Coefficients represent differences in changes in quantitative chest CT parameters associated with steroid administration. All analyses were adjusted for duration and baseline quantitative chest CT parameters. a Model adjusted for duration and baseline %CL; b Model adjusted for duration and baseline %NNL; c Model adjusted for duration and baseline %PAL; d Model adjusted for duration and baseline %NAL; e Model adjusted for duration and baseline %HI. %CL, percentage of compromised lung volume, calculated as the sum of %PAL and %NNL; %NNL, percentage of nonaerated lung volume; %PAL, percentage of poorly aerated lung volume; %NAL, percentage of normally aerated lung volume; %HI, percentage of hyperinflated lung volume. |
Interaction By Duration
Statistically significant interactions were observed between steroid administration and duration for quantitative chest CT parameters (all interactions, P < 0.05). Therefore, we analyzed the association between steroid administration and change in quantitative chest CT parameters at each stage separately (Table 4). At stage 2, steroid administration was not associated with changes in %CL (-2.02%, [95% CI, -4.55 to 0.51], P = 0.12). However, after stage 3, steroid administration was significantly associated with decreases in %CL. Steroid administration was associated with a 3.73% decrease in %CL ([95% CI, -7.18 to -0.29], P = 0.03) at stage 3, a 3.95% decrease in %CL ([95% CI, -7.57 to -0.33], P = 0.03) at stage 4, and a 5.01% decrease in %CL ([95% CI, -8.95 to -1.08], P = 0.01) at stage 5. Steroid administration at each stage was significantly associated with changes in %NAL. Steroid administration was associated with a 3.65% increase in %NAL ([95% CI, 0.68 to 6.63], P = 0.02) at stage 2, a 8.23% increase in %NAL ([95% CI, 4.50 to 11.96], P = 0.000) at stage 3, a 7.82% increase in %NAL ([95% CI, -3.41 to 12.23], P = 0.001) at stage 4, and a 9.59% increase in %NAL ([95% CI, 4.65 to 14.53], P = 0.000) at stage 5. No associations were observed between steroid administration and changes in %NNL or %HI after analyzing each stage separately. Steroid administration was also not associated with changes in %PAL at all stages, except stage 5.
Table 4
Associations between steroid administration and changes in quantitative CT parameters (%) at different stages
Outcome | Stage 2 | Stage 3 | Stage 4 | Stage 5 |
Changes in quantitative CT parameters (%) | Coefficient | 95% CI | P value | Coefficient | 95% CI | P value | Coefficient | 95% CI | P value | Coefficient | 95% CI | P value |
Changes in CL a | -2.02 | -4.55 to 0.51 | 0.12 | -3.73 | -7.18 to -0.29 | 0.03 | -3.95 | -7.57 to -0.33 | 0.03 | -5.01 | -8.95 to -1.08 | 0.01 |
Changes in NNL b | -0.23 | -1.49 to 1.02 | 0.71 | -0.83 | -2.34 to 0.68 | 0.28 | -1.15 | -2.99 to 0.69 | 0.22 | -1.07 | -3.06 to 0.92 | 0.28 |
Changes in PAL c | -1.01 | -2.74 to 0.72 | 0.25 | -2.31 | -4.71 to 0.08 | 0.06 | -1.85 | -4.10 to 0.40 | 0.11 | -2.99 | -5.24 to-0.75 | 0.01 |
Changes in NAL d | 3.65 | 0.68 to 6.63 | 0.02 | 8.23 | 4.50 to 11.96 | < 0.01 | 7.82 | 3.41 to 12.23 | < 0.01 | 9.59 | 4.65 to 14.53 | < 0.01 |
Changes in HI e | -2.54 | -5.96 to 0.88 | 0.14 | -2.73 | -6.91 to 1.45 | 0.20 | -1.77 | -7.01 to 3.47 | 0.50 | -3.27 | -8.67to 2.12 | 0.23 |
Analyses were performed using linear regression models adjusted for baseline quantitative chest CT parameters. Coefficients represent differences in changes in quantitative CT parameters associated with steroid administration. a Model adjusted for duration and baseline %CL; b Model adjusted for duration and baseline %NNL; c Model adjusted for duration and baseline %PAL; d Model adjusted for duration and baseline %NAL; e Model adjusted for duration and baseline %HI. %CL, percentage of compromised lung volume, calculated as the sum of %PAL and %NNL; %NNL, percentage of nonaerated lung volume; %PAL, percentage of poorly aerated lung volume; %NAL, percentage of normally aerated lung volume; %HI, percentage of hyperinflated lung volume. |
Interaction By Disease Severity
Associations between steroid administration and changes in %CL, %NNL, %PAL, %NAL, or %HI during the follow-up period varied between different baseline quantitative CT parameters (all interactions, P < 0.01). All patients were classified into high (> median level) and low groups (< median level) according to baseline quantitative CT parameters. On the basis of the analysis of different quantitative parameters separately, the associations between steroid administration and changes in quantitative CT parameters are shown in Table 5. Steroid administration was associated with more significant decrease in %CL in the high CL group (-9.67%, [95% CI, -13.12 to -6.22], P < 0.001), but there was no significant association between steroid administration and %CL decrease in the low CL group (0.81%, [95% CI, -1.72 to 3.34], P = 0.53). Similarly, steroid administration was associated with a greater decrease in NNL or PAL in the high NNL or PAL group, but the association was not significantly different in the low NNL or PAL group. For NAL, steroid administration was associated with a more significant increase in NAL in both high NAL group (5.92%, [95% CI, 1.88 to 9.95], P = 0.004) and low NAL group (7.28%, [95% CI, 2.59 to 11.97], P = 0.002). Steroid administration was, however, not associated with changes in HI in both high and low HI groups (all P > 0.1).
Table 5
Associations between steroid administration and changes in quantitative chest CT parameters (%) according to baseline parameters.
Outcome | | Coefficient | 95% CI | P value |
Changes in CL (%) | | | | |
High CL group (≥ 23.90) | N = 144 | -9.67 | -13.12 to -6.22 | < 0.01 |
Low CL group (< 23.90) | N = 144 | 0.81 | -1.72 to 3.34 | 0.53 |
Changes in NNL (%) | | | | |
High NNL group (≥ 18.02) | N = 144 | -1.88 | -3.63 to -0.12 | 0.04 |
Low NNL group (< 18.02) | N = 144 | -0.17 | -1.20 to 0.86 | 0.75 |
Changes in PAL (%) | | | | |
High PAL group (≥ 5.92) | N = 144 | -6.74 | -9.29 to -4.19 | < 0.01 |
Low PAL group (< 5.92) | N = 144 | 0.96 | -1.00 to 2.92 | 0.34 |
Changes in NAL (%) | | | | |
High NAL group (≥ 59.23) | N = 144 | 5.92 | 1.88 to 9.95 | < 0.01 |
Low NAL group (< 59.23) | N = 144 | 7.28 | 2.59 to 11.97 | < 0.01 |
Changes in HI (%) | | | | |
High HI group (≥ 7.62) | N = 144 | -1.84 | -8.12 to 4.44 | 0.57 |
Low HI group (< 7.62) | N = 144 | -0.35 | -3.73 to 3.02 | 0.84 |
Analyses using generalized estimating equations to implement linear regression models. Coefficients represent the differences in changes in quantitative CT parameters associated with steroid administration. All analyses were adjusted for duration. %CL, percentage of compromised lung volume, calculated as the sum of %PAL and %NNL; %NNL, percentage of nonaerated lung volume; %PAL, percentage of poorly aerated lung volume; %NAL, percentage of normally aerated lung volume; %HI, percentage of hyperinflated lung volume. |