1-year radiological, functional and quality-of-life outcomes in patients with SARS-CoV-2 pneumonia - A prospective observational study.

All over the world, SARS-CoV-2 pneumonia is causing a significant short and medium-term morbidity and mortality, with reported persisting symptoms, radiological and lung alterations up to 6 months after symptoms onset. Nevertheless, the 1-year impact on affected patients is still poorly known. In this prospective observational study, 39 patients with SARS-CoV-2 pneumonia were recruited from a single COVID-19 hospital in Southern Switzerland. They underwent a 3-month and 1-year follow-ups. At 1 year, 38 patients underwent functional follow-up through lung function tests and six minutes walking test and submitted SF-12 and SGRQ questionnaires about health-related quality of life. At 1 year most of the patients showed a persistence of the radiological and functional abnormalities and a reduction of the health-related quality of life. Thirty patients (96.8%) still presented some residual abnormalities on CT scans (31 patients at 3 months), though with a general reduction of the lesional load in all lung lobes. Twenty patients (52.6%) had persisting lung function tests impairment, with an overall improvement of DLCO. As concerning the functional status, lowest SpO2 during 6MWT increased significantly. Finally, 19 patients (50%) reported a pathological St. George's Respiratory Questionnaire, and respectively 12 (31.6%) and 11 (28.9%) patients a pathological Short Form Survey-12 in physical and mental components. At 1-year follow-up SARS-CoV-2 pneumonia survivors still present a substantial impairment in radiological and functional findings and in health-related quality of life, despite showing a progressive recovery.

Introduction

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) was first diagnosed in December 2019 in Wuhan, China, and on March 11, 2020 has been declared a pandemic by the World Health Organization. SARS-CoV-2 infection is associated with considerable short-term morbidity and mortality[1]. During the acute phase, severe cases typically have lung involvement[2,3]. The mid-term effects of SARS-CoV-2 pneumonia have been elucidated in recent publications, which flag the persistence of alterations in lung function tests and in chest imaging up to 6 months[4-6] after symptoms onset and the reduction of health-related quality of life[7]. Interestingly, similar observations were made in SARS-CoV[8] and H7N9[9] survivors. More recently, Wu et al. reported the results of a 1-year prospective trial of patients hospitalised for severe COVID-19 in China: despite most patients improved dyspnea scores and exercise capacity over time, in a subgroup of patients there was the evidence of persistent physiological and radiographic changes[10]. However, the long-term radiological and functional outcomes and the impact on quality of life in SARS-CoV-2 survivors are still not completely known. Previously, 3-month follow-up results of our cohort were reported:[11] among SARS-CoV-2 pneumonia survivors, we reported significant radiological and lung function tests abnormalities and an overall decreased quality of life. We therefore conducted a prospective observational study with 1-year follow up aiming to describe radiological and lung function parameters and self-reported health-related quality of life (HRQoL) of SARS-CoV-2 pneumonia survivors.

Methods

Case definition

Study participants were diagnosed on the result of a positive real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) assay for SARS-CoV-2.

Participants and study design

In this prospective observational single-center study we enrolled 39 consecutive laboratory-confirmed COVID-19 patients with pathological findings on a chest ultra-low dose (uld) CT scan performed at hospital admission between March 1 and April 15, 2020. A written informed consent was obtained from all participants. Exclusion criteria were age <18 years, pregnancy and absence of a written informed consent. For all included patients demographic, clinical and laboratory data were collected. Prior to hospital discharge a follow-up visit was planned at 3 months and 1 year after the admission. Patients severity at hospital admission was evaluated by the ISARIC4C score, in both mortality[12] and deterioration[13] components. ISARIC4C score is a prospectively validated model, in which higher scores indicate an higher risk of the examined outcome (respectively death and deterioration). At follow-up all patients underwent lung function tests (LFTs), 6-Minute Walk Test (6MWT), an uld chest CT scan and self-reported HRQoL questionnaires (St. George’s Respiratory Questionnaire [SGRQ] and Short Form Survey-12 [SF-12]) (Fig. 1). As stated above, 3-month data of our cohort have been presented in a recent publication[11]. The study was approved by the local ethics committee of Southern Switzerland (2020-01270 CE 3649). A written informed consent was obtained from all the patients. The study complies to the Declaration of Helsinki requirements.

Fig. 1

Study timeline.

We represent the study timeline, with the 3 phases (admission, 3-month f-up and 1-year f-up) and the exams performed in each phase.

Chest CT protocol

Uld CT has proven to be more sensitive for the detection of COVID-19 lesions than chest X-ray (CXR)[14] and international guidelines have also made recommendations in favour of CT for the diagnostic work-up of COVID-19[15]. In addition, experts highlighted the issue of exposition to radiation doses and encouraged the use of low-dose CT scans[16]. In our cohort all patients underwent uld chest CT in supine position at full inspiration, without intravenous contrast medium, using two multi-detector scanners: Siemens Somatom Definition Flash and Siemens Somatom Definition Edge (Siemens, Erlangen, Germany). Scan parameters for uld CT were optimized for a patient with a normal body mass index (BMI between 18.5 and 24.9 kg/m2) and with an effective dose varying from 0.14 to 0.5 mSv as reported in the current literature[17,18]. Image analysis and final scores were performed by consensus by two radiologists (G.A., and C.P., with 15 and 20 years of experience in thoracic radiology, respectively) who scored independently and blinded to clinical data. Images were reviewed on a professional picture archiving and communication system (PACS) PC workstation (Philips Intellispace PACS). A semiquantitative scoring system based on the method proposed by Pan et al.[19] was used to estimate the global pulmonary involvement of all abnormalities on the basis of the area involved. For each lobe the presence of a predominant pattern for ground-glass opacity (GGO), consolidation, fibrosis or parenchymal bands was determined and each of the five lung lobes was visually scored on a scale of 0 to 5, with 0 indicating no involvement; 1, less than 5% involvement; 2, 5–25% involvement; 3, 26–49% involvement; 4, 50–75% involvement; and 5, more than 75% involvement. The total CT score was the sum of the individual lobar scores and ranged from 0 (no involvement) to 25 (maximum involvement). Presence of a pleural effusion, thoracic lymphadenopathy (defined as lymph node size of 10 mm in short-axis dimension) or underlying lung disease such as emphysema or fibrosis were noted but not score. In Fig. 2 we present CT scan lesions of a typical SARS-CoV-2-related pneumonia and the evolution at 3 and 12-month.

Fig. 2

Typical SARS-CoV-2 CT scan lesions and their evolution at 3 and 12 months.

Asterisks show complete healing of the areas of consolidation at 3 months. White arrows demonstrate a slower but almost complete resolution of the areas of ground glass opacities at 3 and 12 months.

LFTs and QoL assessment

LFTs were conducted in the Division of Pneumology at the Regional Hospital of Lugano, Switzerland, using the Vyntus BODY Plethysmograph (Vyaire Medical, IL, USA) according to the European Respiratory Society (ERS) guidelines[20,21]. We measured both static and dynamic volumes, other than performing bronchodilation tests and assessing diffusing lung capacity for carbon monoxide (DLCO). Since interstitial lung disease and pulmonary vascular diseases are considered the most important lung complications of COVID-19, we defined as abnormal LFT the presence of a DLCO < lower limit of normal (LLN) and/or of a TLC < LLN. Thereafter, patients underwent a 6MWT and self-reported QoL questionnaires (SGRQ and SF-12) were submitted by all participants[22,23]. Pathological SGRQ and SF-12 scores, in their respective components, were defined by a higher score than that reported in literature and validated in the general population (normal references range values indicated in Table 5). 6MWT results were described as distance walked in metres and in % of predicted for healthy individuals of the same age, sex, height and weight and as lowest SpO2 during 6MWT. As concerning QoL questionnaires, while the SGRQ is widely used to evaluate patients with respiratory diseases, SF-12, in its physical and mental components, provides a multidimensional assessment of patients, especially with regard to their role limitations as a result of emotional problems, mental health, physical pain, and general health perception.

Table 5

Health-related quality of life assessment at three-month and 1-year follow-ups.

	Normal reference range values in general population	Overall at 3 mo (n = 39)	Overall at 12 mo (n = 38)	P-value	CT improvement or normalised at 1 year (n = 32)	CT not improving at 1 year (n = 6)	P-value
St. George symptoms (median and 25th–75th)	12 (9–15)	16.3 (10.4–29.8)	13.5 (3.6–20.25)	0.07	13.5 (5.4–19.6)	7 (0–22.6)	0.43
St. George activity (median and 25th–75th)	9 (7–12)	19 (12.2–41.4)	8.7 (0–41.5)	0.28	14.7 (0–47.2)	3.1 (0–18)	0.32
St. George impact (median and 25th–75th)	2 (1–3)	4 (0–11.5)	0 (0–5.6)	0.04	0 (0–8.6)	0.95 (0–2.5)	0.62
St. George total (median and 25th–75th)	6 (5–7)	9.9 (7.7–21)	6.9 (1.1–19.8)	0.07	8.1 (1–22.8)	5.2 (1.5–8.8)	0.38
Abnormal St. George total (n and %)	-	31 (79.5)	19 (50)	0.009	15 (46.9)	4 (66.7)	0.66
SF-12 physical (median and 25th–75th)	>50	50.5 (36.1–55)	53.5 (47–55.5)	0.005	52.8 (43.5–55.4)	55.1 (52.3–57.1)	0.16
SF-12 mental (median and 25th–75th)	>50	54.9 (43.5–59.8)	57.1 (47.6–59.9)	0.4	56.5 (46.7–60.5)	58.8 (49–60.4)	0.54
Abnormal SF-12 physical (n and %)	-	19 (48.7)	12 (31.6)	0.16	11 (34.4)	1 (16.7)	0.64
Abnormal SF-12 mental (n and %)	-	12 (30.8)	11 (28.9)	>0.99	10 (31.3)	1 (16.7)	0.65

Statistical analysis

Quantitative data are reported as mean ± standard deviation (SD) or as median with the 25th and 75th percentile, unless otherwise indicated, whereas qualitative data are summarized as absolute values with the corresponding percentages. Parametric or non-parametric paired tests were used to compare two time-points estimates (paired Student t-test, or Wilcoxon-rank test). A repeated-measures analysis of variance (ANOVA) was used to compare variables assessed at three different time-points after checking for normality and homoscedasticity with the conventional tests. By violation of these assumptions the non-parametric repeated ANOVA (Friedman test) was used. When the F-ratio of the ANOVA or the Friedman test reached a critical level (corresponding to a P < 0.05) post hoc analysis with P-value adjustment for multiple comparison was used. Categorical paired nominal data at two time-points were compared with the McNemar test. By three time-points P-values were adjusted for multiple comparisons. All tests were performed two-sided and a P-value < 0.05 was considered statistical significant. Statistical analysis was performed using Stata Version 15 (StatCorp.LP, College Station, TX, USA).

Table 1

Clinical characteristics of included patients.

	Normal range	Overall – 1 year (n = 38)	CT improvement or normalised at 1 year (n = 32)	CT not improving at 1 year (n = 6)	P-value
Age (years, median and IQR)		64.5 (52.7–72.2)	65.5 (55–72.75)	53.5 (49.5 –71.25)	0.28
Sex (female, n and %)		8 (21)	24 (75)	0 (0)	0.001
BMI > 25 kg/m2 (n and %)		30 (78.9)	20 (62.5)	6 (100)	0.15
Active smokers (n and %)		3 (7.9)	3 (9.4)	0 (0)	1
Previous smokers (n and %)		12 (30.8)	11 (34.4)	1 (16.7)	0.64
Length of stay (days, median and IQR)		15 (12–22.5)	14.5 (12–20.75)	22 (7.2–39.5)	0.49
Hypertension (n and %)		14 (36.8)	13 (40.6)	1 (16.7)	0.38
Diabetes (n and %)		5 (13.1)	5 (15.6)	0 (0)	0.57
Cardiovascular diseases (n and %)		7 (18.4)	6 (18.7)	1 (16.7)	1
Coronary heart disease (n and %)		4 (10.5)	3 (9.4)	1 (16.7)	0.51
Chronic respiratory diseases (n and %)		8 (21)	8 (25)	0 (0)	0.32
COPD (n and %)		3 (7.9)	3 (9.4)	0 (0)	1
Asthma (n and %)		5 (13.1)	5 (15.6)	0 (0)	0.57
Chronic kidney disease (n and %)		3 (7.9)	2 (6.2)	1 (16.7)	0.41
Malignancy (n and %)		4 (10.5)	4 (12.5)	0 (0)	1
Depression (n and %)		4 (10.5)	3 (9.4)	1 (16.7)	0.51
Intensive care unit admission (n and %)		10 (26.3)	7 (21.9)	3 (50)	0.31
Invasive mechanical ventilation (n and %)		7 (18.4)	5 (15.6)	2 (33.3)	0.61
Rehabilitation after discharge (n and %)		7 (18.4)	5 (15.6)	2 (33.3)	0.61
ISARIC4C score – mortality on admission (mean ± SD)		6.1 ± 2.9	6.3 ± 2.8	4.8 ± 3.5	0.26
ISARIC4C score – deterioration on admission (mean ± SD)		421.6 ± 73.8	429.5 ± 65	379.3 ± 107.7	0.13
Peak PCR on admission (mg/l) (mean ± SD)	1–5	185.7 ± 147.4	179.3 ± 142.3	230.8 ± 189.5	0.44
Peak LDH on admission (U/l) (mean ± SD)	< 500	653.2 ± 348.5	644.6 ± 351.4	690.5 ± 394.1	0.77
Peak leukocytes on admission (G/l) (mean ± SD)	4.2–10	8.9 ± 4.8	9 ± 4.6	8.7 ± 4.4	0.90
Peak lymphopenia on admission (G/l) (mean ± SD)	1.5–2.5	0.7 ± 0.2	0.7 ± 0.2	0.6 ± 1.2	0.53
Peak thrombopenia on admission (G/l) (mean ± SD)	150–400	185.5 ± 81.9	191.6 ± 87.9	149 ± 33.6	0.25
Peak d-dimer on admission (mg/l) (mean ± SD)	< 0.5	4.8 ± 10	3.7 ± 6.3	9.8 ± 20.4	0.19
Lymphocytes on admission (G/l) (mean ± SD)	1.5–2.5	0.8 ± 0.3	0.8 ± 0.3	0.9 ± 0.4	0.61
Leukocytes on admission (G/l) (mean ± SD)	4.2–10	5.5 ± 2.3	5.8 ± 2.4	4.2 ± 1	0.14
Thrombocytes on admission (G/l) (mean ± SD)	150–400	189.9 ± 74.7	195.1 ± 79	156.7 ± 45.1	0.26
PaO2 on admission (kPa) (mean ± SD)	> 8	9.3 ± 1.4	9.2 ± 1.2	9.9 ± 2.1	0.27
nt-proBNP on admission (ng/l) (mean ± SD)	< 450	275.7 ± 253.7	277.9 ± 225.6	261 ± 453.5	0.91
D-dimer on admission (mg/l) (mean ± SD)	< 0.5	1.1 ± 0.8	1.2 ± 0.9	0.9 ± 0.8	0.43
Antibiotics (n and %)		24 (61.5)	20 (62.5)	3 (50)	0.66
Hydroxychloroquine (n and %)		32 (82)	27 (84.4)	4 (66.7)	0.30
Remdesevir (n and %)		2 (5.1)	1 (3.1)	0 (0)	1
Tocilizumab (n and %)		4 (10.2)	3 (9.4)	0 (0)	1
Lopinavir-Ritonavir (n and %)		21 (53.8)	15 (46.9)	5 (83.3)	0.18
ACE-I, ARB treatment (n and %)		11 (28.2)	10 (31.3)	1 (16.7)	0.65
Corticosteroids during hospitalisation (n and %)		0 (0)	0 (0)	0 (0)	-
Oxygen therapy during hospitalisation (n and %)		36 (94.7)	31 (96.9)	5 (83.3)	0.29
Immunosuppressive therapy on admission* (n and %)		1 (2.6)	1 (3.1)	0 (0)	1
Anticoagulation on admission (n and %)		4 (10.2)	4 (12.5)	0 (0)	1
Antiplatelet therapy on admission (n and %)		7 (17.9)	6 (18.7)	1 (16.7)	1

*Immunosuppressive therapy on admission was defined as the habitual intake of more than 20 mg/day of prednisone or of an equivalent dose of other corticosteroids, and/or of calcineurin inhibitors, and/or of antiproliferative agents, and/or of mTOR inhibitors and/or of any treatment that interferes with the physiological immune response.

Table 2

Radiological characteristics on admission, at three-month and 1-year follow-ups.

	CT on admission (n = 39)	CT at 3 months (n = 39)	CT at 12 months (n = 31)
Ground glass opacities (n and %)	34 (87.1)	23 (59)	21 (67.7)
Consolidations (n and %)	17 (43.6)	1 (2.6)*	3 (9.7)*
Fibrous bands (n and %)	28 (71.8)	27 (69.2)	23 (74.2)
Pathological CT scans (n and %)	39 (100)	32 (82)	30 (96.8)

*P-value < 0.05 as compared with on admission.

Table 3

CT score (0–5) per lobe and overall (0–25) on admission, at three-month and at 1-year follow-ups.

	CT on admission (n = 39)	CT at 3 months (n = 39)	CT at 12 months (n = 31)
Right upper lobe (mean ± SD)	2.5 ± 1.2	1.4 ± 1.2#	1.2 ± 1.1#§
Middle lobe (mean ± SD)	2 ± 1.3	1.2 ± 1.1#	0.7 ± 0.6#§
Right lower lobe (mean ± SD)	2.7 ± 1.1	1.5 ± 1.2*	1.3 ± 1.1#§
Left upper lobe (mean ± SD)	2.4 ± 1.4	1.4 ± 1.3*	1.1 ± 1#§
Left lower lobe (mean ± SD)	2.7 ± 1	1.5 ± 1.3#	1.3 ± 1#§
CT score overall (mean ± SD)	12.9 ± 4.5	8.6 ± 4.3#	5.5 ± 3.9#§

*P-value < 0.05 as compared with on admission.

#P-value < 0.001 as compared with on admission.

§P-value < 0.05 as compared with 3 months.

Table 4

Lung function tests and functional tests at three-month and 1-year follow-ups.

	Overall at 3 mo (n = 39)	Overall at 12 mo (n = 38)	P-value	CT improvement or normalised at 1 year (n = 32)	CT not improving at 1 year (n = 6)	P-value
FEV 1 (l) (mean ± SD)	2.9 ± 0.7	3 ± 0.8	0.07	3 ± 0.7	3.1 ± 0.9	0.6
FEV 1 (% of predicted) (mean ± SD)	93.4 ± 16.1	96.5 ± 17.9	0.02	97 ± 18	94 ± 17.9	0.71
FVC (l) (mean ± SD)	3.7 ± 0.9	3.9 ± 0.9	0.008	3.9 ± 0.9	3.9 ± 1.3	0.91
FVC (% of predicted) (mean ± SD)	92.5 ± 13.6	96.2 ± 14.6	0.25	97.5 ± 13.5	89.5 ± 19.3	0.22
Obstruction (n and %)	3 (7.7)	4 (10.5)	1	4 (12.5)	0 (0)	1
Restriction (n and %)	3 (7.7)	2 (5.3)	1	1 (3.1)	1 (16.7)	0.29
TLC (%) (mean ± SD)	98.5 ± 13.6	100.4 ± 14	0.11	101.8 ± 14.5	93.2 ± 9	0.17
Abnormal DLCO (n and %)	22 (56.4)	18 (47.4)	0.50	16 (50)	2 (33.3)	0.66
DLCO (% of predicted) (mean ± SD)	71.3 ± 15.5	75 ± 15.8	0.002	74.9 ± 16.8	76 ± 9.8	0.87
LFTs abnormalities (n and %)	25 (64.1)	20 (52.6)	0.36	20 (62.5)	3 (50)	0.66
6MWT (m) (mean ± SD)	539.3 ± 102.8	556.4 ± 92.1	0.09	559.6 ± 90.1	538.2 ± 108.8	0.6
6MWT (% of predicted) (mean ± SD)	99 ± 13.6	104.6 ± 12.7	0.07	105.8 ± 13.3	98.8 ± 7.6	0.23
SpO2 at rest (%) (median and 25th–75th)	96 (95–97)	96 (95–97)	0.17	96 (95–97)	97 (95.5–98)	0.16
Lowest SpO2 during 6MWT (%) (median and 25th–75th)	92 (90–94)	93 (92–94)	<0.001	93 (92–94)	93 (88.5–95.25)	0.86
mMRC score (≥2) (n and %)	6 (15.4)	6 (15.8)	0.34	6 (18.7)	0 (0)	0.56

LFTs lung function tests.