Chest CT images are critical for the evaluation of lung abnormalities in COVID-19 patients. While the early phase of disease progression has been well-characterized [7, 8], our study enhances our understanding the time course and pattern of lung recovery of the disease using intensity-based CT image analysis. The key findings of our study are that the IWS system more closely tracked with resolution of disease symptoms than the ABS analysis, suggesting intensity-weighted scoring is more sensitive to evaluate temporal changes in lung abnormalities during late-phase recovery in COVID-19 patients. Second, D-dimer and C-reactive protein (CRP) levels on admission were strong independent risk factors for high-level lesion burden during late-phase recovery, indicating that a strong inflammatory response to the virus may be predictive of long-lasting lesion burden in COVID-19 patients.
Chest CT imaging has become one of the most important evaluation approaches for assessing COVID-19 severity, progression, and guiding effective management [6]. The specific chest CT changes of COVID-19 patients have been described by several previous studies [6, 18, 19], with lung abnormalities including ground glass opacities, consolidation, reticular pattern and crazy paving patterns found to be common hallmarks at symptom onset into peak illness in both COVID-19 [7, 8, 20] and asymptomatic patients [21]. Our findings confirm that these typical patterns persist throughout the late-phase of the disease, even showing up in some scans in week 8, which has been observed in COVID-19 [5, 22, 23] and (commonly) SARS-CoV-1 [17, 24] patients. Indeed, the presence of ground glass opacities in the CT scans of COVID-19 patients has been linked to accumulating lung damage [22], and have been observed in asymptomatic COVID-19 patients [25]. While these lung patterns were consistent between early- and late-phase disease, their presence alone was not indicative of the time course of resolution of lung abnormalities from symptom onset. As different CT patterns and the intensity and extent of lesion burden would indicate different pathophysiological changes in the lungs [26–28], taking these factors into consideration is necessary for assessing the severity of COVID-19-mediated lung abnormalities and may be predictive of long-term adverse pulmonary consequences of COVID-19. The semi-quantitative visual CT grading approaches used in the current study have been previously indicated, with both area-based (ABS)[10, 29, 30] and intensity-weighted (IWS)[16] grading systems having been used to assess various pulmonary abnormalities. It is clear from our findings that the IWS approach aligned with symptom presentation and showed progressive reductions in lesion burden. By contrast, the ABS approach suggested less recovery over time, with the pattern and time course of changes in many patients lagging behind the recovery implied by symptom scores and the IWS approach. These differences in the ability to capture subtle changes in lung abnormalities may reflect the ability of IWS to simultaneously assess both density and range changes in pulmonary lesions, which avoids overestimation or underestimation in lesion burden scores caused by simple density and/or range constant changes [16]. Given the IWS approach encapsulates the specific nature of the lung abnormalities in its semi-quantitative scoring of lesion extent and intensity, this method is more dynamic than ABS and may possess greater sensitivity to detect subtle lesion resolution and more adequately assess recovery, especially in those patients in which lesion area remains unchanged.
The time course of resolution of pulmonary lesion burden during the late phase of recovery is of great concern in COVID-19 patients [31]. Although there is no evidence of delayed virus elimination in patients with higher lesion burden in the current study, our data suggest that elevations in inflammatory markers on admission, specifically D-dimer and CRP, may be predictive of a higher and more prolonged lesion burden in COVID-19 patients. Indeed, elevated pro-inflammatory cytokines has been linked to impaired type 2 pneumocyte function and lung cell damage [32, 33]. The link between elevated lesion burden and inflammatory markers is not surprising [17]. Indeed, CRP levels have been shown to be elevated in the early stages of COVID-19 [34] and is being increasingly linked to clinical outcomes in COVID-19 patients [35]. Moreover, D-dimer, which has been linked to thromboembolic disease, has been increasingly recognized as a biomarker for disease severity and mortality [23, 35–37], consistent with D-dimer being a prognostic biomarker in other pulmonary diseases [38, 39]. Thus, targeting the early inflammatory response may be important to managing the long-term pulmonary effects of COVID-19.
Of concern, late pulmonary fibrosis, which is a severe complication after recovery for other coronavirus infections, is highly linked to inflammation [40–42], thus there is a concern that elevated pro-inflammatory markers and high lesion burden on admission may be a harbinger for pulmonary interstitial fibrosis and permanent lung injury in COVID-19 patients in the long-term [33, 43]. Thus, CRP and D-dimer levels may be important for risk stratification and identifying those patients that may have long-term adverse outcomes to COVID-19, which requires further study. However, there is currently limited [44, 45] evidence showing severe fibrosis in recovered COVID-19 patients, including our own patient cohort, with much of the long-term concern extrapolated from SARS-CoV-1 patients [17, 46] in which conservative estimates expect one-third of COVID-19 patients to have significant pulmonary fibrosis [24, 47]. Nonetheless, the results of our AUC analysis suggest recovery from COVID-19 is slower compared to other forms of viral pneumonia that typically resolve within 2–3 weeks [48–50], with lung abnormalities detectable in some patients 8 weeks after symptom onset. Hence, given the paucity of studies examining the long-term pulmonary effects of COVID-19 [51] and as our understanding of the complexity and pathophysiology of COVID-19 and its variants continues to evolve, late-phase CT follow-up should be indicated and a standardized approach for identifying, differentiating, and reporting interstitial lung fibrosis [52] in this cohort is needed, especially in those patients with persistent respiratory symptoms and high-levels of inflammatory markers on admission.