Residual Lung Abnormalities in Survivors of Severe or Critical COVID-19 at One-Year Follow-Up Computed Tomography: A Narrative Review Comparing the European and East Asian Experiences

The literature reports that there was a significant difference in the medical impact of the coronavirus disease (COVID-19) pandemic between European and East Asian countries; specifically, the mortality rate of COVID-19 in Europe was significantly higher than that in East Asia. Considering such a difference, our narrative review aimed to compare the prevalence and characteristics of residual lung abnormalities at one-year follow-up computed tomography (CT) after severe or critical COVID-19 in survivors of European and East Asian countries. A literature search was performed to identify articles focusing on the prevalence and characteristics of CT lung abnormalities in survivors of severe or critical COVID-19. Database analysis identified 16 research articles, 9 from Europe and 7 from East Asia (all from China). Our analysis found a higher prevalence of CT lung abnormalities in European than in Chinese studies (82% vs. 52%). While the most prevalent lung abnormalities in Chinese studies were ground-glass opacities (35%), the most prevalent lung abnormalities in European studies were linear (59%) and reticular opacities (55%), followed by bronchiectasis (46%). Although our findings required confirmation, the higher prevalence and severity of lung abnormalities in European than in Chinese survivors of COVID-19 may reflect a greater architectural distortion due to a more severe lung damage.


Introduction
Almost four years have elapsed since the first outbreak of the coronavirus disease (COVID-19) that occurred in Wuhan at the end of 2019 [1].Although a few sporadic cases of COVID-19 were registered in Europe at the end of December 2019, the first European COVID-19 outbreak was identified on 21 February 2020, in Northern Italy [2,3].After this first cluster of COVID-19, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection quickly spread throughout Europe.On 3 October 2023, the World Health Organization (WHO) reported a number of confirmed cases of SARS-CoV-2 infection totaling 277,468,232 in Europe with 2,253,849 deaths, resulting in an overall mortality rate of 0.8% [4].
Fortunately, following the massive introduction of COVID-19 vaccination programs in European countries-on 1 October 2023, the total number of vaccine doses administered in Europe was 1,736,552,311 [4]-the severity of the disease has significantly decreased, and the situation is gradually returning to normalcy [5][6][7][8].Specifically, the WHO declared on 5 May 2023 that the global emergency caused by SARS-CoV-2 was over-and we hope it will be forever.
To date, the number of papers reporting the long-term sequelae of COVID-19 one year or more after infection is progressively increasing, particularly those related to residual lung abnormalities observed on follow-up chest CT .The frequency of lung parenchymal abnormalities on chest CT examinations performed at one-year follow-up varies according to the severity of COVID-19 (it is greater in patients with severe or critical disease), age (it is greater in patients aged 50 years or older), sex (it is greater in men), length of hospitalization (it is greater in longer hospitalization lengths), invasive ventilation use (it is greater in patients who required invasive ventilation), and sample selection .
Knowledge of the frequency and CT characteristics of residual lung abnormalities in survivors of COVID-19 is of paramount importance, as it can aid radiologists and clinicians in differentiating long-term post-COVID-19 sequelae from other interstitial lung diseases, preventing future misdiagnoses.
Currently, several systematic reviews and meta-analyses on long-term CT lung abnormalities in survivors of COVID-19 have been published [18,26,31,[47][48][49].However, to the best of our knowledge, no literature review has yet compared the pulmonary sequelae in survivors after severe or critical COVID-19 at one-year follow-up CT in the European and East Asian populations.
In a previous study, Yamamoto and Bauer [51] reported a significant difference in the medical impact of the COVID-19 pandemic between European countries (such as Spain, Italy, United Kingdom, France, and Germany) and East Asian countries (such as China, Japan, South Korea, and Taiwan).In particular, the authors found that the mortality rate of COVID-19 in Europe was significantly higher than that in East Asia [51].
Considering such a difference, it is plausible to assume that the frequency and severity of the residual lung abnormalities observed on follow-up chest CT in the European population are greater than those observed in the East Asian population.Therefore, our narrative review aimed to compare the frequency and CT characteristics of residual lung abnormalities at one-year follow-up in patients of European and East Asian countries by focusing the analysis on survivors of severe or critical COVID-19.

Literature Search Strategy
A literature search of the PubMed/MEDLINE, Scopus, and Web of Science databases was performed to identify articles focusing on the frequency and CT characteristics of long-term CT lung abnormalities in survivors of COVID-19.Different combinations of the following terms were used in the search: COVID-19; SARS-CoV-2; chest CT; CT; one year/one-year; 1 year/1-year; long term; and follow-up.The final search of the three databases was conducted on 29 September 2023.

Study Selection Criteria
For this literature search, the following inclusion criteria were considered: (a) articles written in English, (b) articles focused on residual lung abnormalities on CT images in survivors of COVID-19 at one-year follow-up, and (c) studies conducted in European and East Asian countries.Only studies that reported the CT characteristics of residual lung abnormalities and their respective frequencies at one-year follow-up after severe or critical COVID-19 in detail were included.Data regarding patients with mild to moderate disease were not considered in this review as the monitoring strategies for this group of patients differed significantly between countries and healthcare institutions.
Case reports, case series, letters to the editor, editorials, commentaries, conference papers, and review articles were excluded from this review.In addition, articles on longterm residual lung abnormalities that specifically focused on survivors of COVID-19 with underlying comorbidities were excluded.
The CT findings considered for this review included the following lung abnormalities: ground-glass opacities; reticular opacities; linear opacities; consolidations; bronchiectasis; traction bronchiectasis; and honeycombing (Figure 1).
A literature search of the PubMed/MEDLINE, Scopus, and Web of Science databases was performed to identify articles focusing on the frequency and CT characteristics of long-term CT lung abnormalities in survivors of COVID-19.Different combinations of the following terms were used in the search: COVID-19; SARS-CoV-2; chest CT; CT; one year/one-year; 1 year/1-year; long term; and follow-up.The final search of the three databases was conducted on 29 September 2023.

Study Selection Criteria
For this literature search, the following inclusion criteria were considered: (a) articles written in English, (b) articles focused on residual lung abnormalities on CT images in survivors of COVID-19 at one-year follow-up, and (c) studies conducted in European and East Asian countries.Only studies that reported the CT characteristics of residual lung abnormalities and their respective frequencies at one-year follow-up after severe or critical COVID-19 in detail were included.Data regarding patients with mild to moderate disease were not considered in this review as the monitoring strategies for this group of patients differed significantly between countries and healthcare institutions.
Case reports, case series, letters to the editor, editorials, commentaries, conference papers, and review articles were excluded from this review.In addition, articles on longterm residual lung abnormalities that specifically focused on survivors of COVID-19 with underlying comorbidities were excluded.
The CT findings considered for this review included the following lung abnormalities: ground-glass opacities; reticular opacities; linear opacities; consolidations; bronchiectasis; traction bronchiectasis; and honeycombing (Figure 1).Using the term reticular opacities, we also included the following chest CT findings: reticulations, reticular abnormalities, reticular lesions, and reticular patterns.Using the term linear opacities, we also included the following chest CT findings: bands; curvilinear bands; interlobular thickening; interlobular septal thickening; irregular lines; lines; parenchymal bands; subpleural curvilinear opacities; and subpleural lines.In the case Using the term reticular opacities, we also included the following chest CT findings: reticulations, reticular abnormalities, reticular lesions, and reticular patterns.Using the term linear opacities, we also included the following chest CT findings: bands; curvilinear bands; interlobular thickening; interlobular septal thickening; irregular lines; lines; parenchymal bands; subpleural curvilinear opacities; and subpleural lines.In the case where more than one of these linear opacities were reported, only the one with the highest prevalence was considered.
The three databases were searched by an experienced thoracic radiologist (A.B.) assisted by two radiology residents (P.C. and E.A.) with three and four years of experience in CT imaging, respectively.

Data Extraction
For each included article, we collected the following data: (a) article details (first author, month/year of submission/publication, country of origin, and design); (b) study sample characteristics (number of patients, age, number/percentage of men, and number/percentage of survivors of severe or critical COVID-19); and (c) prevalence, CT characteristics, and extent of residual lung abnormalities at one-year follow-up grouped by European and East Asian countries.

Results
Based on the predefined selection criteria, 16 original research articles were included in this review (9 from Europe and 7 from East Asia).
The main characteristics of the included articles are listed in Tables 1 and 2.  The European articles were published in the following countries: Italy, four; Spain, two; France, one; Belgium, one; and the Netherlands, one.Conversely, all articles selected from East Asia were conducted in China.The submission dates of the included studies ranged from April 2021 to September 2022.
As shown in Tables 1 and 2, all articles except one presented data from a prospective analysis.Only one study, conducted in Europe (specifically, in one of the hot spots of the pandemic in Northern Italy), presented data from a retrospective analysis [28].
Among the 16 selected articles, 7 (43.8%)were multicenter (5 from Europe and 2 from China) [11,20,29,[33][34][35]39]. The selected studies included a total of 3683 patients after COVID-19 infection (1515 patients from Europe and 2168 patients from China).The mean or median age of the survivors of COVID-19 reported in these articles ranged from 39 to 68 years (59 to 68 years in European studies and 39 to 60 years in Chinese studies).The overall percentage of men was 56%, ranging from 19 to 79% (55 to 79% in European studies and 19 to 57% in Chinese studies).However, considering only severe or critical COVID-19 and excluding patients from the study of Liao et al. (performed on health care workers) [44], the mean/median age of the Chinese patients ranged from 51 to 60 years with a percentage of men ranging from 50 to 67%.
As reported in Tables 1 and 2, 7/16 (43.8%) studies (5 from Europe and 2 from China) included only survivors of COVID-19 after severe or critical infection, whereas the remaining 9/16 (56.2%) studies included survivors of COVID-19 after both mild to moderate and severe to critical infections.
Overall, the selected studies comprised a total of 1383 survivors of COVID-19 after severe or critical infection (843 patients from Europe and 540 patients from China).Considering only such a group of patients, although the mean or median age of survivors of COVID-19 was similar, the overall percentage of men increased from 56% to 62%.
Among the survivors of COVID-19 after severe or critical infection, 923/1383 (66.7%) had a one-year chest CT follow-up (477 patients from European countries and 446 patients from China).Only the residual lung abnormalities on CT images from this group of 923 patients were included in our analyses (Tables 3 and 4).
* CT images analysis performed by at least one thoracic radiologist; ˆCT images analysis performed by at least one experienced radiologist; † CT images analysis performed by at least radiologist; • Not specified who analyzed the CT images; GGOs, ground-glass opacities; NA, not available.
As shown in Table 3, the reported prevalence of any CT lung abnormalities at one-year follow-up ranged from 64% to 100% in the European studies.Among the European articles, only one study (prospective multicenter) from Italy did not report the overall prevalence of any CT lung abnormalities [39].A total of 362/440 (82%) European patients had residual lung abnormalities on CT images performed one year after severe or critical COVID-19.
As shown in Table 4, the reported prevalence of any CT lung abnormalities at oneyear follow-up ranged from 24% to 87% in the Chinese articles.Among the Chinese articles, only one study (prospective single-center) did not report the overall prevalence of any CT lung abnormalities [45].A total of 210/403 (52%) Chinese patients had residual lung abnormalities on CT images performed one year after severe or critical COVID-19.Excluding the study of Liao et al. [44], the percentage of Chinese patients with residual lung abnormalities was 60%.
Consolidation and honeycombing were the less frequent CT findings at one-year follow-up, with an overall prevalence of 4% (17/432 survivors of COVID-19) and 1% (2/289 patients), respectively (Table 4 and Figure 3).As shown in Table 4, the prevalence of consolidation was reported in 6/7 (86%) studies; the prevalence of consolidation on CT images was not reported in the study by Zhou et al. [20].The prevalence of honeycombing was reported in 3/7 (43%) studies (Table 4); in these articles, the prevalence of honeycombing in the CT images ranged from 0 to 2% [38,43,44].
Regarding the quantitative assessment of the extent of residual lung abnormalities on CT images, only 5/16 (38%) studies (3 from Europe and 2 from China) estimated the overall percentage of lung involvement: 3 with dedicated software [20,28,44], and 2 with a visual method [25,42] (Table 5).As shown in Table 5, the overall percentage of lung volume affected by residual lung abnormalities on CT images ranged from 0 to 12%, with As shown in Table 4, the prevalence of reticular and linear opacities was reported in 6/7 (86%) studies, reticular opacities were not reported in the study by Zhou et al. [20], and linear opacities were not included in the study by Han et al. [11].The prevalence of bronchiectasis (including traction bronchiectasis) at one-year follow-up CT was reported in 5/7 (71%) Chinese studies (Table 4); bronchiectasis was not reported in the studies by Zhao et al. [45] and Huang et al. [21].
Consolidation and honeycombing were the less frequent CT findings at one-year follow-up, with an overall prevalence of 4% (17/432 survivors of COVID-19) and 1% (2/289 patients), respectively (Table 4 and Figure 3).As shown in Table 4, the prevalence of consolidation was reported in 6/7 (86%) studies; the prevalence of consolidation on CT images was not reported in the study by Zhou et al. [20].The prevalence of honeycombing was reported in 3/7 (43%) studies (Table 4); in these articles, the prevalence of honeycombing in the CT images ranged from 0 to 4% [38,43,44].

Discussion
As reported by Yamamoto and Bauer [51], strong evidence indicates the presence of significant differences in the spread of SARS-CoV-2 infection and COVID-19 severity between European and East Asian countries.Specifically, the authors reported that the mortality rate of COVID-19 in Europe was significantly higher than that in East Asia.
To explain such differences between European and East Asian countries, Yamamoto and Bauer [51] proposed four possible hypothesis, as follows: (a) differences in sociobehavioral aspects and lifestyle between the two regions (e.g., shaking hands, kissing, or hugging one another is an uncommon behavior in East Asian countries); (b) differences in SARS-CoV-2 virulence due to multiple viral infections, with a greater virulence in Europe, probably due to inadequate protection and underestimation of SARS-CoV-2 contagiousness in combination with antibody-dependent enhancement and mutation of the viral RNA genome; (c) differences in individual resistance to SARS-CoV-2 infection (e.g., East Asian populations may have an immune system genetically trained to defend themselves from novel viruses, including coronavirus; and (d) differences in hygiene aspects.
Based on the data reported by Yamamoto and Bauer [51], we considered it plausible to hypothesize that the prevalence and severity of residual lung abnormalities on CT scans after COVID-19 were higher in European than in East Asian patients.
In line with this hypothesis, our review found that the prevalence and severity of residual lung abnormalities on CT images at one-year follow-up after severe or critical COVID-19 were significantly higher in European than in Chinese patients (Tables 3 and 4).Notably, while the overall prevalence of any CT lung abnormality in European studies was 82%, that in Chinese studies was 52% (60% excluding the study of Liao et al. [44]).
In European studies, the most prevalent lung abnormalities after severe or critical COVID-19 were linear (59%) and reticular opacities (53%), followed by bronchiectasis (46%) and ground-glass opacities (44%) (Figure 2).In contrast, in Chinese studies, the most prevalent lung abnormalities after severe or critical infection were ground-glass opacities (35% or 40% if the study of Liao et al. [44] was excluded).Additionally, the observed prevalence of reticular opacities (17%), linear opacities (13%), and bronchiectasis (11%) in Chinese patients was significantly lower than in European patients (Figure 3).This difference remained even when the patients from the study of Liao et al. [44] were excluded.
The differences between the prevalence and type of residual lung abnormalities among European and Chinese studies likely reflect the different severities of the disease (higher in Europe), as suggested by Yamamoto and Bauer [51].
The residual lung abnormality that mostly reflected the severity and fibrotic evolution of lung damage was bronchiectasis, and its prevalence was significantly higher in European than in Chinese patients (46% in European vs. 11% in Chinese studies).Honeycombing, traditionally considered a CT feature of established pulmonary fibrosis (end-stage pulmonary fibrosis), was more prevalent in European than in Chinese patients (4% in European vs. 1% in Chinese studies).Additionally, we found that the percentage of lung volume affected by residual lung abnormalities on CT images was significantly greater in European than in Chinese patients (Table 5).
The differences between our findings and those reported previously [26,31,[47][48][49] are probably due to a different method of analyses.
Unlike previous systematic reviews [26,31,[47][48][49], our study included only chest CT abnormalities in survivors of COVID-19 after severe or critical SARS-CoV-2 infection, and the CT findings were grouped based on the region of origin (Europe vs. China).
The literature also reports that the second most common lung abnormalities in survivors of COVID-19 were fibrotic-like changes [26,31].In contrast to previous systematic reviews [26,31,47,48], we excluded fibrotic and fibrotic-like changes from our analysis, as this term is rather ambiguous and is affected by the wide variability in its definition across various studies [18,49].
The higher prevalence of linear and reticular opacities, bronchiectasis (including bronchial dilatation and traction bronchiectasis), and honeycombing observed in European than in Chinese patients may reflect a greater architectural lung distortion with a possible evolution to fibrosis due to a more severe lung damage.
Although further studies are required to confirm our data, the major strength of the present review is that it is the first to compare the pulmonary sequelae and their prevalence after severe or critical COVID-19 at one-year follow-up CT in the European and Chinese population.
This study had several limitations.First, it was a narrative (non-systematic) review, and only descriptive statistics were performed.Second, the number of selected articles was relatively small because the inclusion criteria were rather strict, and only papers that reported the CT characteristics of residual lung abnormalities after severe or critical COVID-19 in detail were included.Third, there was heterogeneity in the data of the selected studies; however, to reduce the heterogeneity of the subgroups, only survivors of COVID-19 after severe to critical infection were included.Fourth, there were differences in the age and proportion of men between European and Chinese studies; however, these differences cannot explain the higher prevalence and severity of residual lung abnormalities in Europeans compared to Chinese, and also because all patients were severely or critically ill and the differences in age and proportion of men between European and Chinese survivors were significantly smaller when the patients from the study of Liao et al. (performed on health care workers) [44] were excluded.Fifth, no information regarding underlying comorbidities, smoking history, pulmonary functional tests, or laboratory parameters was assessed, as this review focused only on residual lung abnormalities detected at one-year follow-up CT.

Conclusions and Future Directions
In conclusion, the prevalence, severity, and extent of residual lung abnormalities at one-year follow-up CT after severe to critical COVID-19 infection were higher in European compared to Chinese patients.In contrast to the Chinese studies, the most frequently reported abnormalities in European articles were linear and reticular opacities, and bronchiectasis, which probably reflect greater architectural lung distortion with possible evolution to fibrosis because of a more severe lung damage.
The findings observed in the present narrative review must be verified in future systematic analyses with a larger number of studies and longer follow-up periods (i.e., beyond one year).However, we believe that our results, together with those of Yamamoto and Bauer [51], are clinically relevant, as they suggest that the European population may be at a greater risk both for death and severe post-infectious sequelae if a pandemic from a new virus were to occur.While hoping that this does not happen, this information could be useful not only for clinicians but also for governments by facilitating the introduction of appropriate measures to prevent infection, and, thereby, reduce deaths and infectious sequelae.

Figure 1 .
Figure 1.Cropped axial thin-section CT images with lung window setting show some examples of long-term chest CT findings in survivors of COVID-19: (a) ground-glass and subpleural curvilinear opacities; (b) reticular opacities with architectural distortion and bronchiectasis; (c) reticular opacities with architectural distortion and traction bronchiectasis.

Figure 1 .
Figure 1.Cropped axial thin-section computed tomography (CT) images with lung window setting show some examples of long-term chest CT findings in survivors of coronavirus disease (COVID-19): (a) ground-glass and subpleural curvilinear opacities; (b) reticular opacities with architectural distortion and bronchiectasis; (c) reticular opacities with architectural distortion and traction bronchiectasis.

Table 1 .
Study details and patient characteristics in the selected European studies.
Data are presented as number (percentages in round brackets); † Month and year of paper submission; MC, multicenter study; SC; single-center study; * Age is presented as mean or median; ˆpatients who have received invasive mechanical ventilation.

Table 2 .
Study details and patient characteristics in the selected East Asian studies (all from China).
Data are presented as number (percentages in round brackets); † Month and year of paper submission; MC, multicenter study; SC; single-center study; * Age is presented as mean or median.

Table 3 .
Residual lung abnormalities on chest CT images (European studies).

CT Lung Abnormalities at 1-Year Follow-Up after Severe or Critical COVID-19
* CT images analysis performed by at least one thoracic radiologist; ˆCT images analysis performed by at least one experienced radiologist; † CT images analysis performed by at least radiologist; • Not specified who analyzed the CT images; GGOs, ground-glass opacities; NA, not available.

Table 4 .
Residual lung abnormalities on chest CT images (Chinese studies).

Table 5 .
Extent of CT lung abnormalities in survivors of severe or critical COVID-19.