Abstract
Background
Post-COVID-19 Interstitial Lung Disease (PC-ILD) is characterized by fibrotic-like signs at high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) abnormalities after SARS-CoV-2 infection. It is still not clear how frequent these tests should be performed to rule out long-term consequences of COVID-19 pneumonia.
Objectives
The aims of our study were to evaluate the incidence and risk factors of PC-ILD and possibly to propose a long-term follow-up program.
Method
One-hundred patients, hospitalized in our ward for moderate to critical COVID-19, underwent two follow-up visits at three and 15 months in which PFTs and HRCT were performed.
Results
At the 15-month follow-up, 8% of patients showed residual radiological and functional signs consistent with PC-ILD. All but one of these patients had already demonstrated PFTs and HRCT alterations at first follow-up visit, and the last 1 patient showed worsening of lung function during follow-up. These findings highlight the negative predictive value of PFTs at 3-month follow-up for the development of PC-ILD. Aging, severity of COVID-19, and degree of pulmonary involvement during acute infection proved to be significant risk factors for developing PC-ILD.
Conclusions
Our study highlights the importance of PFTs in the long-term follow-up of patients affected by moderate to critical COVID-19 pneumonia. Further studies are needed to confirm our hypothesis that HRCT should be performed only in patients with PFTs abnormalities.
Keywords: Infection, Post-COVID-19 Interstitial Lung Disease, Pulmonary function testing
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus that was firstly reported in Wuhan, China, in December 2019 and quickly spread worldwide bringing to coronavirus disease 19 (COVID-19). Because of its high contagiousness and rapid transmission, in March 2020 the World Health Organization (WHO) declared the pandemic status to COVID-19 [1, 2, 3]. COVID-19 pneumonia may include a diffuse alveolitis and lung interstitial inflammation [4]. This type of lung inflammation may trigger type-II alveolar epithelial cell proliferation and surfactant reduction that can lead to an alveolar collapse and, subsequently, to an acute respiratory distress syndrome [5]. Also, because of an imbalance between pro-inflammatory and anti-inflammatory responses caused by cytokine storm [5, 6], some patients may develop a systemic inflammatory response syndrome, septic shock, and/or multiple organ dysfunction syndrome.
Prior to COVID-19, three global viral outbreaks have been reported: SARS-CoV-1 in 2002, influenza A H1N1 in 2009, and Middle Eastern respiratory syndrome coronavirus in 2012 [3, 4]. For each of these infections, long-term respiratory complications in surviving patients [7, 8, 9, 10] have been described, by means of radiological and functional tests carried out months or years after the initial infection. In particular, SARS-CoV-1 residual alterations in the lung parenchyma, mainly fibrotic, have been reported in up to 30% of patients at 6 months [11]. However, an interstitial damage after 2 years of follow-up has been demonstrated in only 4–6% of patients [12].
High-resolution computed tomography (HRCT) represents the gold reference imaging tool to investigate COVID-19 pneumonia and its outcomes, with a very high sensitivity (95.5%) [13]. Different scores based on chest CT have been presented to address the diagnosis of COVID-19 pneumonia, such as the COVID-19 Reporting and Data System (CO-RADS) [14]. In our institution, we routinely use a semiquantitative chest CT score, which precisely describes the severity of lung involvement by using specific percentages of lung parenchymal involvement, with the advantage of being very reproducible [15]. A high CT score proved to be strongly correlated to short-term clinical outcomes and mortality, even more than clinically useful markers (as CRP and D-dimer blood levels) [16].
Moreover, recent studies have proposed the term “Post-COVID-19 Interstitial Lung Disease” (PC-ILD) as the condition characterized by fibrotic-like signs at HRCT of the chest associated with pulmonary function tests (PFTs) abnormalities. If the PC-ILD is a progressive disorder, a stable condition or eventually a late resolving pneumonia is still object of debate. To answer this question, long-term follow-up studies are currently lacking and desirable. Only one 12-month follow-up study is nowadays available, carried out in a small number of patients, in which respiratory function testing and lung imaging were both obtained [17]. It is still not clear how frequent lung function testing and chest imaging should be performed to rule out long-term consequences of COVID-19 pneumonia. However, this issue is of particular interest because it could provide better insights for patients' follow-up that may underlie a high cost in terms of both human and technological resources.
The primary objective of this study was to identify the incidence and risk factors for the development of PC-ILD defined as association of fibrotic-like signs at HRCT (i.e., ground glass opacities, consolidations, interlobular and intralobular interstitial thickening, reticular opacity, traction bronchiectasis, and honeycombing) and abnormal PFTs (i.e., diffusion capacity for carbon monoxide [DLco] decrease and restrictive pattern) [17]. A secondary objective of the study was to establish which lung function test or radiological exam has the greatest predictive capacity in identifying the patients at risk of developing PC-ILD, proposing the most appropriate long-term approach.
Materials and Methods
To this end, one-hundred and fifteen patients consecutively admitted in our hospital, from March 2020 to August 2020, with a diagnosis of moderate to critical SARS-CoV-2 infection (as defined by WHO) [18], were enrolled in this prospective and single-center study. SARS-CoV-2 infection was confirmed by reverse transcription polymerase chain reaction on nasopharyngeal swab; COVID-19 pneumonia was confirmed by chest HRCT.
In accordance with a recent review [19], we anticipate a 5% incidence of PC-ILD after 15 months from COVID-19 acute infection. Assuming an alpha margin of error of 5% and a statistical power of 80%, the number of subjects to be enrolled for this survey should be at least 88.
Comorbidities and demographic data, such as age, sex, BMI, smoking habit, date of onset of symptoms and hospital admission, drug treatments, and respiratory support received by each patient were recorded. The exclusion criteria were the following: lung cancer and/or lung metastases, patients' death from causes unrelated to COVID-19 during the follow-up, patients' refusal to undergo the follow-up.
Study Design
The study design is illustrated in Figure 1. It consisted of two follow-up visits, at 3 and 15 months. Follow-up visits consisted in anamnesis, physical examination, PFTs, and HRCT of the chest.
Fig. 1.
Study design.
Pulmonary Function Tests
PFTs were performed by expert personnel using a spirometer (Quark PFT, Cosmed, Pavona, Italy), following the recommendations of American Thoracic Society and European Respiratory Society [20, 21]. The following tests were performed: spirometry with evaluation of forced vital capacity (FVC), forced expiratory volume at 1s; body plethysmography to measure total lung capacity and residual volume; alveolar-capillary DLCO by using the single breath method [20, 21].
PFTs were considered indicative of PC-ILD in the presence of restrictive ventilatory deficit and/or reduced DLCO. The restrictive pattern was defined by normal forced expiratory volume at 1s/FVC ratio (>0.70) together with a reduction in total lung capacity below 80% of the predicted value [22]. The reduction in the DLco was defined as a DLCO < 75% of the predicted value [22].
CT Protocol and Image Analysis
All examinations were performed using two multidetector CT scanners (Somatom Sensation 16 and Somatom Sensation 64; Siemens Healthineers) with the patient in a supine position. Scan parameters corresponded to the manufacturer's recommended standard pre-setting for a chest routine. In all cases, image reconstruction was made with a slice thickness of 1 mm, applying the classic filtered back projection method with a soft tissue kernel of B20 and a lung kernel of B60. Coronal and sagittal multiplanar reconstructions were available for all examinations. CT scans were performed on admission and at follow-up, after two negative results on consecutive nasal/oropharyngeal swabs.
In agreement with previous publications, COVID-19 pneumonia on the baseline CTs and its outcomes on follow-up images were evaluated through the following CT findings: ground glass opacities (GGO), crazy-paving, consolidation, and interlobular septal thickening [16, 23, 24]. According to these findings, the semiquantitative CT severity score proposed by Pan et al. [15] was used to assess the total extent of disease on both baseline and follow-up CTs. Briefly, for each lobe the following score was assessed: 0, no involvement; 1, <5% involvement; 2, 5–25% involvement; 3, 26–50% involvement; 4, 51–75% involvement; 5, >75% involvement. The resulting global CT score was obtained by summing all lobar scores, ranging from 0 to 25. HRCT was considered normal in the absence of lesions or in the presence of alterations involving less than 5% of the lung parenchyma. Since the presence of interlobular septal thickening, traction bronchiectasis, bronchioloectasis, honeycombing, crazy-paving pattern, and parenchymal bands may be suggestive of interstitial pneumonia outcomes [24], their presence was also assessed as sign indicative of PC-ILD. We referred to these radiological alterations secondary to acute pneumonia as “fibrotic-like lesions,” because of their similarity with chronic fibrotic disease, which can also represent an immature fibrosis which may undergo regression [25].
Baseline and follow-up images were anonymized, randomized, and analyzed separately by two different radiologists (the first with more than 15 years of experience and the second more than 5 years in chest imaging), who were blinded from clinical information. Differences in opinion were resolved by consensus. Radiological terms such as GGO, pulmonary consolidation, interlobular septal thickening, parenchymal bands, and bronchiectasis were adopted according to the Fleischner Society's glossary for thoracic imaging [26].
Group Assignment
Based on PFTs and HRCT results at 3-month follow-up, the patients were divided into 4 groups:
A: patients with normal PFTs and HRCT.
B: subjects with obstructive, restrictive, or mixed ventilatory deficit and/or reduced DLco in the absence of radiological alterations.
C: patients with evidence of radiological abnormalities at HRCT but normal PFTs.
D: patients with alterations in both PFTs and HRCT.
Group A patients did not continue follow-up and were considered as completely recovered. Group B, C, and D subjects underwent a second follow-up visit at 15 months after the hospitalization for COVID-19. All patients repeated the PFTs, while HRCT was performed only in group C and group D subjects. Chest CT was not executed in group A and B patients to avoid exposure to ionizing radiation, considering the absence of radiological alterations.
Statistical Analysis
Descriptive statistics were obtained using the median and interquartile range or mean and standard deviation (SD) for continuous variables whereas proportions for dichotomous and categorical variables. A multivariable logistic regression model was built to identify independent predictors of PC-ILD at 15-month follow-up. Each variable was first examined by univariable analysis using Pearson's χ2 test or Fisher's exact test for categorical variables and the Mann-Whitney U test for continuous variables. Variables were then included in the model when the p value <0.20 or when they were considered relevant to the outcome based on expert opinion. The final model was chosen using the Akaike information criterion, while the Hosmer and Lemeshow test was used to evaluate the goodness of fit. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. All analyses were performed using STATA version 17.0 (StataCorp LLC, College Station, TX, USA). A two-sided p value of <0.05 was considered statistically significant.
The capacities of PFTs and HRCT to identify subjects with PC-ILD at 3-month follow-up (i.e., sensibility) were calculated as follows:
The capacities of PFTs and HRCT to rule out at 3-month follow-up healthy patients (i.e., specificity) were calculated as follows:
The probabilities of PFTs and HRCT to correctly identify at 3-month follow-up patients with PC-ILD (i.e., positive predictive value) were calculated as follows:
The probabilities of PFTs and HRCT to correctly rule out at 3-month follow-up patients without PC-ILD (i.e., negative predictive value) were calculated as follows:
Results
Patients' Characteristics at Baseline
One-hundred of one-hundred and fifteen patients consecutively admitted in our hospital were enrolled, since 15 patients were excluded (fourteen for lung cancer or lung metastases and one for death). Clinical and demographic data of patients enrolled in the study are summarized in Table 1.
Table 1.
Clinical and demographic data
| Demographic data | (N = 100) | Clinical data | (N = 100) |
|---|---|---|---|
| Age, years | 59.6±12.8 | WHO severity disease, n (%) | |
| Gender, n. (%) | Moderate illness | 60 (60) | |
| W | 38 (38) | Severe illness | 3 (3) |
| M | 62 (62) | Critical illness | 37 (37) |
| Body mass index a | 26.5±4.5 | CCS | |
| Comorbidities, n. (%)b | Mean (DS) | 6.7 (4.8) | |
| Arterial hypertension | 43 (43%) | Median (IQR) | 6.0 (2.0–10.0) |
| Respiratory disease | Hospitalization ICU, n (%) | 17 (17) | |
| COPD | 7 (7) | Oxygen therapy, n (%) | 81 (81) |
| Asthma | 14 (14) | Respiratory therapy, n (%) | |
| ILD | 0 (0%) | HNFO | 7 (7%) |
| Obesity/overweight | 64 (64%) | CPAP | 33 (33%) |
| NIV | 1 (1%) | ||
| Current smoker | 6 (6%) | IMV | 13 (13%) |
| Prior smoker | 33 (33%) | Pharmacological Therapy, n (%) | |
| Non-smoker | 61 (61%) | Steroids | 26 (26%) |
| Tocilizumab | 46 (46%) | ||
| Hospitalization, days | 25.0±15.1 |
Values indicated as plus-minus are means ± SD. Values in parenthesis express percentages of patients. CCS, chest CT score; CPAP, continuous positive airway pressure; HFNO, high flow nasal oxygen; ICU, intensive care unit; ILD, interstitial lung disease; IMV, invasive mechanical ventilation; NIV, non-invasive ventilation.
Body mass index (BMI) is denoted as weight in kilograms divided by the square of the height into meters.
Values and percentages are reported singularly for each item, allowing for more than one choice for each patient.
The mean age was 59 years, and 62 patients were males (62%). Thirty-nine patients were current or former smokers, and eighty suffered from comorbidities, such as systemic arterial hypertension (43%), obesity/overweight (64%), and bronchial asthma (14%). During hospitalization, disease severity was moderate in sixty patients (60%) and critical in the other forty patients (40%).
Three-Month Follow-Up Visit
At 3-month visit (90 ± 22 SD days), thirty-seven patients (37%) showed PFTs abnormalities consistent with PC-ILD (Table 2). At HRCT, lung parenchymal abnormalities were still present in 22% patients mainly consisting in GGO and fibrotic-like alterations (63% and 78%, respectively) with ubiquitous involvement (Table 3); a combination of both was found in 61% of subjects.
Table 2.
Pulmonary function tests at 3-and at 15-month follow-up
| 3 months (N = 100), n (%) | 15 months (N = 48), n (%) | |
|---|---|---|
| Normal | 54 (54) | 26 (54.2) |
| 6 (12.5) | ||
| Obstructive ventilatory defect | 9 (9) | |
| Post-COVID-19 interstitial lung alteration | 37 (37) | 16 (33.3) |
| Restrictive ventilatory defect | 10 (10) | 5 (10.4) |
| Decrease of DLCO | 13 (13) | 11 (22.9) |
| Restrictive ventilatory defect and decrease of DLCO | 14 (14) | 0 (0) |
DLCO, diffusion lung of carbon monoxide.
Table 3.
Imaging characteristics of high-resolution computed tomography at 3- and at 15-month follow-up
| 3 months (N = 100) | 15 months (N = 19) | |
|---|---|---|
| Radiological alterations, n (%) | ||
| Consolidation | 11 (11) | 0 (0) |
| GGO | 63 (63) | 7 (36.8) |
| Fibrotic-like change | 78 (78) | 19 (100) |
| Fibrotic parenchymal bands | 9 (9) | 1 (5.3) |
| Interlobular septal thickening | 14 (14) | 0 (0) |
| Traction bronchiectasis | 2 (2) | 0 (0) |
| Honeycombing | 0 (0) | 0 (0) |
| At least 2 patterns | 53 (53) | 18 (94.7) |
| None | 22 (22) | 0 (0) |
| Pulmonary parenchymal involvement | ||
| Mean CCS (DS) | 1.6 (2.2) | 1.9 (1.9) |
| Median CCS (IQR) | 1.0 (1.0–1.0) | 1.0 (1.0–3.0) |
| Mean extension, n (%) | 5.2 | 7 |
| Bilateral, n (%) | 83 (83) | 18 (94.7) |
| Monolateral, n (%) | 17 (17) | 1 (5.3) |
| Involved lobes, n (%) | ||
| 0 | 19 (19) | 1 (5.3) |
| 1 | 15 (15) | 1 (5.3) |
| 2 | 25 (25) | 5 (26.3) |
| 3 | 10 (10) | 4 (21.0) |
| 4 | 5 (5) | 3 (15.8) |
| 5 | 26 (26) | 5 (26.3%) |
| Mean | 2.5 (1.8) | 3.2 (1.5) |
| Median | 2 (1–5) | 3 (2–5) |
GGO, ground glass opacities; CCS, chest CT score.
Based on PFTs and HRCT, patients were divided into the aforementioned four groups:
A (n = 45): patients with normal PFTs and HRCT.
B (n = 33): subjects with obstructive, restrictive, or mixed ventilatory deficit and/or reduced DLco and the absence of radiological alterations.
C (n = 9): patients with evidence of radiological lesions at HRCT and normal PFTs.
D (n = 13): patients with alterations in both PFTs and HRCT.
Fifteen-Month Follow-Up Visit
Out of fifty-five patients, eligible for the follow-up visit, seven did not attend the second follow-up visit due to patient refusal or inability to go to the center for logistical reasons. Thus, forty-eight patients (group B = 29, group C = 7, group D = 12) underwent the 15-month follow-up visit (months 14.6 ± 1.1 SD).
At PFTs, sixteen patients (33.3%) showed a residual respiratory functional impairment consistent with PC-ILD (group B = 8; group C = 1; group D = 7) (Table 2). Of them, 8 patients (group C + D) also underwent a chest HRCT. At HRCT, residual fibrotic-like abnormalities were found in all patients of group C and group D (n = 19) with ubiquitous involvement in most of cases; on the other hand, we observed an almost complete reduction of GGO and consolidation (from 62% at 3 months to 7% at 15 months).
Post-COVID-19 Interstitial Lung Disease
During the 15-month follow-up period, 8 patients (∼8%) showed residual radiological and functional signs consistent with PC-ILD (Table 4). Chest CT scans of 2 patients are shown in the supplementary Figures 1 and 2 (for all online suppl. material, see www.karger.com/doi/10.1159/000529441). It should be noted that, of the 8 patients with PC-ILD, 6 showed a progressive improvement in PFTs (i.e., an improvement greater than 10% in FVC and/or 15% improvement in DLco), 1 subject showed a progressive worsening in his functional pulmonary tests (i.e., reduction greater than 10% in FVC and/or 15% reduction in DLco), and 1 remains stable.
Table 4.
Functional and radiological modification in 8 subjects identified with PC-ILD
| FVC T3 | FVC TI5 Δ | TLC T3 | TLC TI5 Δ | DLCO T3 | DLCO TI5 | HRCT T0 | HRCT T3 | HRCT TIS Δ | |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 77% 2.95 | 94% 3.10 +22.1 | 74% 4.51 | 93% 5.69 +24.6 | 57% 15.24 | 71% 18.79 +24.6% | 35% | 10% | 2% |
| 2 | 70% 2.06 | 70% 2.05 0% | 79% 3.79 | 79% 3.79 0% | 68% 16.24 | 82% 19.4 +20.6% | 40% | 10% | 5% |
| 3 | 111% 2.6 | 139% 3.23 +25.2 | 81% 4.3 | 83% 4.4 2.5% | 47% 9.67 | 65% 13.06 38.2 | 20% | 15% | 10% |
| 4 | 98% 3.84 | 88% 3.4 −10.2% | 81 5.56 | 76% 5.16 −6.2% | 84% 22.24 | 108% 28.21 + 28.6% | 30% | 10% | 5% |
| 5 | 135% 5.18 | 148% 5.63 +9.6% | 99% 6.98 | 102% 7.09 +3% | 52% 13.14 | 64% 16.04 +23.1% | 50% | 40% | 15% |
| 6 | 90% 3.99 | 115% 4.5 +27.8% | 93% 7.01 | 96% 7.27 +3.2% | 42% 12.1 | 63% 28.71 +50% | 50% | 40% | 15% |
| 7 | 93% 3.32 | 115% 4.07 +23.7% | 97% 6.32 | 103% 6.69 +6.2% | 83% 20.1 | 74% 17.68 −10.8% | 60% | 40% | 5% |
| 8 | 112% 3.01 | 119% 2.93 −1.8% | 73% 3.71 | 93% 4.72 +27.4% | 77% 17.13 | 60% 13.2 −22.1 | 25% | 10% | 2% |
T0, baseline; T3, 3-month follow-up; T15, 15-month follow-up. DLCO, diffusion lung of carbon monoxide; FVC, forced vital capacity; TLC, total lung capacity.
Statistical Analysis
The analyses were conducted on 97 patients, since three subjects belonging to groups C and D who should have repeated HRCT did not complete the follow-up and it was not possible to predict the outcome. Univariate analysis did not identify any significant difference between patients with PC-ILD and those without PC-ILD at 15 months of follow-up in demographic characteristics (age, sex, BMI, smoking history) and comorbidities. Conversely, COVID-19 disease severity during hospitalization, using none of respiratory support (continuous positive airway pressure, high flow nasal oxygen, non-invasive ventilation, invasive mechanical ventilation), and the degree of parenchymal involvement (at baseline and at 3-month follow-up visit) were associated with the presence of PC-ILD at the 15-month follow-up visit (Tables 5, 6).
Table 5.
Univariate analysis on the characteristics of SARS-CoV-2 acute infection
| PC-ILD N = 8 | NO PC-ILD N = 89 | p value | |
|---|---|---|---|
| COVID-19 severity, n (%) Moderate-severe | 2 (25) | 61 (68.5) | 0.021 |
| Critical | 6 (75) | 28 (31.5) | |
| CCS | |||
| Mean (DS) | 11.5 (3.1) | 6.1 (4.5) | 0.001 |
| Median (IQR) | 11.5 (9.0–14.5) | 5.0 (2.0–9.0) | |
| ICU stay | 3 (3.8) | 13 (14.6) | 0.123 |
| Oxygen therapy | 8 (100) | 70 (78.7) | 0.349 |
| Respiratory therapy, n (%) | |||
| CPAP | 5 (62.5) | 25 (28.1) | 0.102 |
| HFNC | 0 (0.0) | 7 (7.9) | 0.999 |
| NIV | 1 (12.5) | 0 (0.0) | 0.082 |
| IMV | 2 (25) | 11 (11.4) | 0.291 |
| At least 2 features | 2 (25) | 13 (14.6) | 0.605 |
| None | 2 (25) | 59 (66.3) | 0.049 |
| Pharmacological therapy, n (%) | |||
| Steroids | 2 (25.0) | 23 (25.8) | 0.999 |
| Tocilizumab | 5 (62.5) | 40 (44.9) | 0.466 |
| Both | 2 (25) | 17 (19.2) | 0.653 |
| None | 3 (37.5) | 43 (48.3) | 0.718 |
| Length of hospital stay, n (%) | |||
| Mean (SD) | 31.6 (11.4) | 24.1 (15.1) | 0.065 |
| Median (IQR) | 30.5 (21.5–42.5) | 20.0 (13.0–31.0) | |
CCS, chest CT score.
Table 6.
Univariate analysis on functional and radiological data at 3 months of follow-up
| PC-ILD (N = 8) | NO PC-ILD (N = 89) | p value | |||
|---|---|---|---|---|---|
| CT lung | CCS | Mean (DS) Median (IQR) |
5.5 (3.8) 4.0 (2.5–8.5) |
1.2 (1.6) 1.0 (1.0–1.0) |
0.001 |
|
|
|||||
| Fibrotic-like signs | Fibrotic parenchymal bands | 0 (0.0%) | 8 (9.0%) | 0.147 | |
| Interlobular septal thickening | 0 (0.0%) | 14 (15.8%) | |||
| Traction bronchiectasis | 0 (0.0%) | 1 (1.1%) | |||
| At least 2 features | 8 (100%) | 44 (49.4%) | |||
| None | 0 (0.0%) | 22 (24.7%) | |||
|
|
|||||
| GGO | Present | 8 (100%) | 52 (58.4%) | 0.022 | |
| Absent | 0 (0.0%) | 37 (41.6%) | |||
|
| |||||
| PFTs | Normal/obstructive | 2 (25%) | 58 (65.2%) | 0.020 | |
| Restrictive | 0 (0.0%) | 10 (11.2%) | |||
| Reductions of DLCO | 3 (37.5%) | 10 (11.2%) | |||
| Reduction of DLCO and restrictive | 3 (37.5%) | 11 (12.4%) | |||
CCS, chest CT score; GGO, ground glass opacities.
At multivariable analysis, two factors showed a significant relationship with the likelihood of PC-ILD at 15 months of follow-up: age (OR: 1.10, 95% CI: 1.00–1.21) and pulmonary involvement (i.e., chest CT score) at baseline (OR: 1.50, 95% CI: 1.04–2.16) (Table 7). At 3-month follow-up, functional tests were able to identify subjects with PC-ILD and to rule out healthy patients in 75% and 66% of cases, respectively. On the other hand, HRCT was able to identify residual interstitial alterations in 100% of cases, while healthy subjects were correctly found in 24.7% or 41,6% of cases, depending on the radiological pattern that was considered (fibrotic-like lesion or GGO, respectively).
Table 7.
Multivariable logistic regression analysis of predictors of PC-ILD at 15 months of follow-up
| PC-ILD | OR | 95% CI | p value |
|---|---|---|---|
| Gender (female) | 5.17 | 0.56–47.83 | 0.148 |
| Age, years | 1.11 | 1.01–1.22 | 0.039 |
| Obesity/overweight (yes) | 0.30 | 0.05–1.86 | 0.195 |
| COVID-19 severity (critical) | 9.49 | 0.75–120.48 | 0.083 |
| CCS | 1.50 | 1.04–2.17 | 0.031 |
| Steroids (yes) | 0.73 | 0.073–7.22 | 0.785 |
| Tocilizumab (yes) | 1.62 | 0.15–17.58 | 0.692 |
| Length of hospitalization (days) | 0.95 | 0.86–1.05 | 0.280 |
CCS, chest CT score.
At 3-month follow-up, the probabilities to correctly identify patients with PC-ILD diagnosed at 15-month follow-up were 16.5% for PFTs and 10,6%–13,3% for HRCT, depending on the radiological pattern considered (fibrotic-like lesion or GGO, respectively). The probabilities to correctly rule out patients without PC-ILD at 15-month follow-up were 96.7% for PFTs and 100% for HRCT.
Discussion
The major result of this prospective single-center study was the finding of PC-ILD in ∼8% of a large population after 15-month follow-up from onset of acute infection. To our knowledge, this is the longest study available in the literature so far. In addition, we were able to demonstrate that PC-ILD is likely to occur in older patients that had a more severe COVID-19 pneumonia on CT during acute infection. Also, we were able to demonstrate that some patients (group B) may show an alteration in PFTs, at 15-month follow-up visit, despite a complete resolution of lung infiltrate at HRCT while others (group C) may still have lung parenchymal alteration at HRCT in the presence of normal PFTs. Finally, our study clearly demonstrates the progressive resolution of lung infiltrates at HRCT with concomitant progressive improvement in lung function at PFTs in the vast majority of patients affected by moderate to critical COVID-19 pneumonia.
In agreement with recent published studies [27, 28, 29, 30, 31, 32, 33], risk factors for the development of PC-ILD appear to be age, severity of acute infection, and degree of pulmonary involvement at HRCT. The identification of these risk factors may have clinical relevance in particular on the selection of patients to be enrolled in a post-COVID-19 follow-up program. We did not find a correlation between mechanical ventilation and the development of PC-ILD, as suggested in other studies, probably because of the small number of patients treated with such respiratory support.
It should be noted that the combination of PFTs and HRCT evaluation at 3-month follow-up visit was able to identify a significant number of patients that will not need further HRCT evaluation, 45% of patients with both normal PFTs and HRCT (group A), and 33% with abnormal PFTs and normal HRCT (group B). We also found that only 1 patient of group C (normal PFTs and abnormal HRCT) developed PC-ILD at 15-month follow-up while 7 patients out of twelve of group D (both abnormal PFTs and HRCT) developed PC-ILD at 15 months. These findings highlight the negative predictive value of PFTs, at 3-month follow-up visit, for a long-term presence of PC-ILD after COVID-19 pneumonia.
Study Limitation
Possible limitations of the present study are the following. First, the lack at baseline of PFTs and chest HRCT performed prior to COVID-19 pneumonia does not allow to exclude a pre-existent chronic condition. The “fibrotic-like alterations” observed in our patients after COVID-19 pneumonia could represent the flare of a pre-exiting ILD [34]. Second, in the present study we cannot rule out the possible negative influence of the ventilatory support utilized during hospitalization in the development of PC-ILD.
Conclusions
In conclusion, our study demonstrates that PC-ILD is likely to occur in less than 10% of patients affected by severe COVID-19 pneumonia. It also highlights the importance of PFTs in the long-term follow-up of these patients given the high negative predictive value of PFTs for the development of PC-ILD. Further studies are needed to confirm our hypothesis that HRCT should be performed only in patients with PFTs abnormalities. Based on the results of our study, we believe that in the long-term post-COVID-19 follow-up program it is reasonable to propose an initial evaluation at 3 months only based on PFTs while HRCT should be obtained in those patients still presenting PFTs abnormalities at 15 months.
Statement of Ethics
This study protocol was reviewed and approved by Ethical Committee Sapienza of Policlinico Umberto I in Rome, approval number protocol no. 0290/2022. All participants agreed by signing the informed consent.
Conflict of Interest Statement
The authors declare that they have no competing interests.
Funding Sources
The authors declare that this study has received no financial support.
Author Contributions
Concept − Sanna Arianna, Pellegrino Daniela, D'Antoni Letizia, and Palange Paolo; design and writing − Sanna Arianna, Pellegrino Daniela, and Palange Paolo; supervision − Paolo Palange, Villari Paolo, Catalano Carlo, Panebianco Valeria, D'Antoni Letizia, Landini Nicholas, and Baiocchi Pia; materials and data collection and/or processing − Sanna Arianna, Pellegrino Daniela, and Messina Emanuele; analysis and/or interpretation − Siena Leonardo Maria, Baccolini Valentina, Panebianco Valeria, and Palange Paolo; literature review − Sanna Arianna and Pellegrino Daniela; −critical review − Sanna Arianna, Pellegrino Daniela, Panebianco Valeria, and Palange Paolo.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.
Supplementary Material
Supplementary data
Funding Statement
The authors declare that this study has received no financial support.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary data
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.