From April 1, 2020, to December 31, 2021, 6,656 patients were hospitalized for COVID-19 in our facilities. Among the patients who visited a follow-up outpatient clinic 3 months after disease onset, 335 patients consented to participate in this study. Finally, 74 patients completed the physical examination and SF-36 questionnaire at the two time points and the pulmonary function test at the 6-month follow-up (Fig. 1). In this cohort, 46% were over 65 years old, 73% were male, and 65% had a history of smoking. 88% received medication during hospitalization-65% with systemic steroids and 72% with antiviral drugs. 80% received supplemental oxygen, and 19% were intubated. Additional baseline characteristics are described in Table 1.
Table 1
Patient characteristics (n = 74). Categorical variables are expressed as numbers and percentages. Abbreviation: BMI Body Mass Index, COPD Chronic Obstructive Pulmonary Disease, ECMO Extracorporeal Membrane Oxygenation.
Parameter
|
n = 74
|
Parameter
|
n = 74
|
Age group
|
|
Treatment received during hospital stay
|
65 (88%)
|
< 65 years
|
40 (54%)
|
Corticosteroids
|
48 (65%)
|
≥ 65 years
|
34 (46%)
|
Chloroquine
|
3 (4%)
|
Sex
|
|
Antiviral drugs
|
53 (72%)
|
Male
|
54 (73%)
|
Remdesivir
|
25 (34%)
|
Female
|
20 (27%)
|
Favipiravir
|
32 (43%)
|
BMI
|
|
Tocilizumab
|
5 (7%)
|
< 25 (kg/m2)
|
40 (54%)
|
Macrolides
|
8 (11%)
|
≥ 25 (kg/m2)
|
27 (36%)
|
Baricitinib
|
2 (3%)
|
Unknown
|
7 (10%)
|
Medical equipment
|
|
Smoking history Yes
|
48 (65%)
|
Supplemental Oxygen
|
59 (80%)
|
No
|
26 (35%)
|
High-flow nasal cannula
|
2 (3%)
|
Comorbidity
|
54 (73%)
|
Intubation
|
14 (19%)
|
Hypertension
|
35 (47%)
|
ECMO
|
1 (1%)
|
Diabetes
|
18 (24%)
|
Data are expressed as No. (%).
|
Cardiovascular disease
|
11 (15%)
|
|
|
Cerebrovascular disease
|
6 (8%)
|
|
|
Malignant tumor
|
3 (4%)
|
|
|
Autoimmune disease
|
3 (4%)
|
|
|
Interstitial lung disease
|
3 (4%)
|
|
|
COPD
|
9 (12%)
|
|
|
Bronchial asthma
|
7 (9%)
|
|
|
At 3 months, 31 patients (42%) reported at least one symptom, the most common of which were dyspnea (22%), cough (12%), and fatigue (8%). At 6 months, there was an overall trend toward symptom improvement; however, 21 patients (28%) still experienced persistent symptoms. The most common residual symptoms were dyspnea (14%), cough (5%), and fatigue (9%) (Fig. 2).
The eight component scores and three component summary scores normalized by the Japanese national standard at each time point are shown in Table 2. At 3 months after disease onset, the average scores of five components (PF, RP, BP, SF, and RE) of the SF-36 were below the Japanese national standard (50 points). The average scores of PF and BP, which are the main components of PCS, were slightly below the national standard and had minimal change from 3 to 6 months. On the other hand, average scores of RP, SF, and RE, the main components of RCS, were the three lowest component scores among the eight components at 3 months. These three component scores showed recovery at 6 months. Reflecting on these results, RCS was the lowest of the three component summary scores at 3 months, but improvement of average scores was observed at 6 months follow-up.
Table 2
SF-36 scores normalized by the Japanese national standards at each time point. Scores are expressed as mean ± standard deviations (SD). Abbreviation: PF : Physical Function, RP : Role Physical, BP : Bodily Pain, GH : General Health, VT : Vitality, SF : Social Functioning, RE : Role Emotional, MH : Mental Health, PCS : Physical Component Summary, MCS : Mental Component Summary, RCS : Role/Social Component Summary
|
3 months
|
6 months
|
SF-36 Scale
|
Mean score (± SD)
|
Mean score (± SD)
|
PF
|
46.6 ± 9.7
|
47.9 ± 8.1
|
RP
|
43.9 ± 13.1
|
46.7 ± 11.7
|
BP
|
49.8 ± 11.9
|
48.8 ± 11.1
|
GH
|
51.2 ± 7.6
|
51.9 ± 8.01
|
VT
|
54.3 ± 10.0
|
53.8 ± 10.1
|
SF
|
42.8 ± 14.3
|
47.6 ± 11.4
|
RE
|
45.0 ± 12.8
|
48.1 ± 11.3
|
MH
|
52.6 ± 9.1
|
53.9 ± 8.71
|
PCS
|
48.4 ± 11.0
|
47.5 ± 9.8
|
MCS
|
56.1 ± 8.5
|
55.5 ± 9.1
|
RCS
|
40.7 ± 13.9
|
45.7 ± 12.3
|
We further investigated the patient characteristics associated with a low RCS score at each time point. Patients with residual respiratory-related symptoms (dyspnea, cough or fatigue) tended to have a low RCS score at 3 months (P = 0.037). In addition, although the difference did not reach statistical significance, the RCS score tended to be lower in patients who had any symptoms (P = 0.090), respiratory-related symptoms (P = 0.088), or dyspnea symptoms (P = 0.086) at 6 months. Diarrhea and fever were not analyzed because no participants had these symptoms at either time point (Table 3). Several pulmonary function tests such as FVC, and FEV1 measured at the 6-month follow-up were also significantly associated with the RCS score (Table 3).
Table 3
Association of PASC, pulmonary function tests and RCS score. Dyspnea, cough or fatigue were defined as respiratory symptoms. Abbreviation: PASC Post-acute sequelae of SARS-CoV-2 infection, FVC Forced vital capacity, FEV1 Forced expiratory volume in 1 second. “-” indicates no comparative patients. Significant values are in [bold].
|
Role/Social Component Summary Score
|
|
3 months
|
6 months
|
|
coefficient
|
95% C.I.
|
p-value
|
coefficient
|
95% C.I.
|
p-value
|
PASC at each time points (yes/no)
|
|
|
|
|
|
|
|
|
any symptoms
|
-4.76
|
-11.3
|
1.78
|
0.151
|
-5.52
|
-11.91
|
0.87
|
0.090
|
respiratory symptoms
|
-6.99
|
-13.54
|
-0.44
|
0.037
|
-5.74
|
-12.35
|
0.88
|
0.088
|
dyspnea
|
1.20
|
-6.76
|
9.14
|
0.766
|
-7.57
|
-16.23
|
1.10
|
0.086
|
cough
|
-6.86
|
-16.30
|
2.58
|
0.152
|
-2.94
|
-15.71
|
9.82
|
0.647
|
fatigue
|
-8.85
|
-20.67
|
2.96
|
0.140
|
-4.42
|
-14.25
|
5.40
|
0.372
|
numbness
|
-1.70
|
-16.17
|
12.78
|
0.816
|
2.50
|
-10.27
|
15.28
|
0.697
|
joint pain
|
-13.47
|
-33.41
|
6.48
|
0.182
|
2.88
|
-22.14
|
27.90
|
0.819
|
olfactory disorder
|
13.82
|
-6.11
|
33.75
|
0.171
|
-
|
-
|
-
|
-
|
Pulmonary Function Test at 6 months after onset
|
|
|
|
|
|
|
|
|
FVC (L)
|
-
|
-
|
-
|
-
|
3.59
|
0.395
|
6.78
|
0.028
|
%FVC (%)
|
-
|
-
|
-
|
-
|
0.19
|
0.01
|
0.38
|
0.045
|
FEV1 (L)
|
-
|
-
|
-
|
-
|
3.99
|
0.24
|
7.73
|
0.037
|
FEV1/FVC (%)
|
-
|
-
|
-
|
-
|
-0.07
|
-0.31
|
0.17
|
0.554
|
Comparisons were determined by simple regression analysis.
|
We used univariate analysis to examine whether the clinical history and disease course in the acute phase of illness may have influenced the RCS score. Age (over 65 years) was related to a low RCS score at both time points (3 months; P = 0.016, 6 months; P = 0.016). The use of a high-flow nasal cannula and a high CT score on admission (median value ≥ 10 points) were associated with a low RCS score at 3 months (P = 0.007) and 6 months (P = 0.014), respectively (Table 4). The association between CT score on admission and a low RCS score was also confirmed by the significant negative linear relationship between the CT score and the RCS score at both time points, while no relation between the CT score and the PCS or MCS score was observed (Fig. 3a). Concerning the trajectory of the RCS score, the group with a high CT score showed poorer recovery (average of score change between 3 and 6 months: 3.4 points) than the group with a low CT score (average of score change between 3 and 6 months: 7.1 points) (Fig. 3b). Multiple regression analysis was conducted that included age (older than 65 years), sex (male), history of smoking, history of intubation, and CT score (median value ≥ 10 points). The results showed that older age (greater than 65 years) (P = 0.037) and a history of intubation (P = 0.042) were independent factors of a low RCS score at 3 months, and a high CT score (median value ≥ 10 points) (P = 0.026) was an independent factor of a low RCS score at 6 months (Table 5).
Table 4
Association of patient backgrounds, status during hospitalization and RCS score.Abbreviation: BMI Body Mass Index, ECMO Extracorporeal Membrane Oxygenation. Significant values are in [bold].
|
Role/Social Component Summary Score
|
|
3 months
|
6 months
|
|
coefficient
|
95% C.I.
|
p-value
|
coefficient
|
95% C.I.
|
p-value
|
Background (yes/no)
|
|
|
|
|
|
|
|
|
Age ≥ 65 (years old)
|
-7.74
|
-14.0
|
-1.45
|
0.016
|
-6.91
|
-12.5
|
-1.32
|
0.016
|
Sex, male
|
-4.61
|
-11.9
|
2.68
|
0.212
|
-0.32
|
-6.84
|
6.21
|
0.923
|
BMI ≥ 25 (kg/m2)
|
2.0
|
-5.31
|
9.31
|
0.586
|
-3.25
|
-9.58
|
3.07
|
0.308
|
Smoking history
|
0.85
|
-6.01
|
7.71
|
0.806
|
-3.69
|
-9.70
|
2.33
|
0.226
|
Any comorbidities
|
-3.60
|
-3.59
|
-10.9
|
0.332
|
-6.23
|
-12.58
|
0.13
|
0.055
|
Status during hospitalization (yes/no)
|
|
|
|
|
|
|
|
|
Treatment
|
|
|
|
|
|
|
|
|
Corticosteroids
|
0.73
|
-6.13
|
7.59
|
0.833
|
-1.39
|
-7.46
|
4.67
|
0.648
|
Chloroquine
|
-9.21
|
-25.67
|
7.25
|
0.268
|
4.22
|
-10.4
|
18.84
|
0.567
|
Antiviral drugs
|
-0.07
|
-7.34
|
7.19
|
0.984
|
-0.88
|
-7.30
|
5.55
|
0.786
|
Tocilizumab
|
-5.13
|
-18.12
|
7.86
|
0.434
|
-5.06
|
-16.52
|
6.39
|
0.381
|
Macrolides
|
1.99
|
-8.55
|
12.52
|
0.708
|
7.34
|
-1.82
|
16.49
|
0.114
|
Baricitinib
|
11.72
|
-8.55
|
31.99
|
0.253
|
1.32
|
-16.71
|
19.36
|
0.884
|
Medical equipment
|
|
|
|
|
|
|
|
|
Supplemental Oxygen
|
-7.80
|
-15.73
|
0.14
|
0.054
|
-5.76
|
-12.83
|
1.31
|
0.109
|
High-flow nasal cannula
|
-26.57
|
-45.78
|
-7.37
|
0.007
|
-6.74
|
-24.50
|
11.01
|
0.452
|
Intubation
|
-6.88
|
-15.08
|
1.33
|
0.099
|
1.34
|
-6.04
|
8.73
|
0.718
|
ECMO
|
-2.03
|
-30.39
|
26.33
|
0.887
|
2.90
|
-22.14
|
27.91
|
0.819
|
CT score (≥ 10 points) on admission
|
-4.08
|
-10.87
|
2.7
|
0.233
|
-7.76
|
-13.88
|
-1.65
|
0.014
|
Comparisons were determined by simple regression analysis.
|
Table 5
Multivariate analysis results of factors predicting low RCS. Analyses were conducted using a multiple regression model. Objective variables were RCS score. The following dichotomized explanatory variables were entered into the model simultaneously; age (older than 65 years), sex (male), history of smoking, history of intubation and CT score (cut-off by median value, ≥ 10 points). Abbreviation: RCS Role/Social Component Summary. Significant values are in [bold].
|
3 months
|
6 months
|
|
coefficient
|
95% C.I.
|
p-value
|
coefficient
|
95% C.I.
|
p-value
|
Age ≥ 65 (years old)
|
-7.60
|
-14.74
|
-0.46
|
0.037
|
-5.12
|
-11.75
|
1.49
|
0.127
|
Sex, male
|
-0.71
|
-8.77
|
7.35
|
0.861
|
1.07
|
-6.41
|
8.58
|
0.776
|
History of smoking
|
3.42
|
-3.93
|
10.78
|
0.356
|
-2.45
|
-9.27
|
4.38
|
0.476
|
History of intubation
|
-9.42
|
-18.51
|
-0.34
|
0.042
|
2.38
|
-6.05
|
10.81
|
0.574
|
CT score (≥ 10 points)
|
-1.09
|
-8.07
|
5.88
|
0.755
|
-7.39
|
-13.86
|
-0.92
|
0.026
|