Risk Factors and Clinical Impact of Fibrotic-Like Changes and the Organizing Pneumonia Pattern in Patients With COVID-19- and Non-COVID-19-Induced Acute Respiratory Distress Syndrome

Authors’ full names: Enric Barbeta1,2,3,4,5, Mariana Benegas6, Marcelo Sánchez6, Anna Motos2,3,5, Miquel Ferrer1,2,3,5 Adrián Ceccato2,3,4,5, Rubén Lopez2,3,5, Leticia Bueno2,3,5, Ricard Mellado -Artigas7, Carlos Ferrando7, Laia Fernández-Barat2,3,5, Nuria Albacar1,5, Joan Ramon Badia1,3,5, Teresa López8, Elena Sandoval9, David Toapanta10, Pedro Castro2,5,11, Alex Soriano12, Antoni Torres1,2,3,5, The Covid Clinic Critical Care Group*.

withdrawn in <24 h; refusal of study participation on behalf of relatives; and the presence of previously known interstitial lung disease. Patients were divided into two groups according to the cause of ARDS (i.e., COVID-19 and non-COVID-19 cohorts).
We compared the presence of persistent or new-onset diffuse pulmonary opacities in chest X-rays (CXRs) beginning day 7 of ARDS diagnosis to death or intensive care unit (ICU) discharge. Furthermore, we assessed the presence and severity of pulmonary fibrotic-like changes and organizing pneumonia pattern in thoracic computed tomography (CT) scans during the same time frame. Patients with COVID-19-related ARDS were further divided into those who presented with fibrotic-like changes and those who did not. We analyzed risk factors for its development and compared clinical outcomes between both groups.
Attending doctors ordered thoracic CT scans without following any research protocol. Time (days) from ARDS diagnosis to CT scan was recorded. CXRs were performed every 24-48 h per protocol until ICU discharge. A pulmonologist and experienced thoracic radiologist independently and blindly assessed CT features to diagnose fibrotic-like changes and organizing pneumonia pattern. Additionally, two pulmonologists independently and blindly assessed CXRs to diagnose persistent or new-onset diffuse pulmonary opacities. Agreement between evaluators was assessed for CT scans and CXRs using Cohen's Kappa. After the first independent analysis, and without unblinding the cohort, evaluators met to discuss the radiological images on which there was a disagreement.
Persistent or new onset diffuse pulmonary opacities were defined as the presence of any of the following criteria between day 7 since ARDS diagnosis and death or ICU discharge: (1) persistence of ≥50% of radiological opacities found at ARDS diagnosis (2) an increase in or new-onset bilateral pulmonary opacities between day 7 since ARDS diagnosis and death or ICU discharge. An increase in radiological opacities had to be identified in both lungs. New-onset unilateral opacities did not meet this definition.
Fibrotic-like changes were defined as the presence of traction bronchiectasis, reticulation, parenchymal bands and/or honeycombing in thoracic CT scans performed between day 7 since ARDS diagnosis and death or ICU discharge. 11 Extension of fibrotic-like changes in thoracic CT scans was classified into one of three categories based on visual assessment and the percentage of bilateral lung involvement: mild (<25%), moderate (25%-50%) and severe (>50%).
An organizing pneumonia pattern was defined as peribronchovascular consolidations with perilobular distribution and/or the reverse halo sign between day 7 since ARDS diagnosis and death or ICU discharge. 11      the study (Supplementary Fig. 1). Of the 101 patients included in the analysis, 81 had sequential CXRs beginning day 7 since ARDS diagnosis to death or ICU discharge. In addition, and within the same time frame, fifty patients underwent a thoracic CT scan. Table 1 shows the demographic and clinical characteristics of these patients. Patients with COVID-19-induced ARDS (n = 24, 71%) presented with a higher incidence of fibrotic-like changes when compared to those with non-COVID-19-induced ARDS (n = 2, 12%) (P = .001). All patients with COVID-19 and fibrotic-like changes also presented with an organizing pneumonia pattern in thoracic CT scans. With respect to assessments of CT scan features, agreement between the thoracic radiologist and pulmonologist was 0.64; regarding assessments of CXRs, agreement between pulmonologists was 0.73. Table 2 and Supplementary Table 1 show the characteristics of patients with COVID-19-induced ARDS, presenting with or without fibrotic-like changes. Those patients who later developed fibroticlike changes or an extensive manifestation of these changes had higher dead space (ventilatory ratio) on day 3 since the ARDS diagnosis. In addition, we more frequently identified ventilation with higher tidal volume and positive end-inspiratory pressure upon ARDS diagnosis in patients who later presented with fibroticlike changes or its extensive manifestation, respectively. Likewise, administering mechanical ventilation with a higher tidal volume and driving pressure on day 3 since ARDS diagnosis was associated with the development of fibrotic-like changes and the extensive manifestation of such changes thereafter.
Clinical outcomes from COVID-19 and non-COVID-19-induced ARDS according to the presence or absence of fibrotic-like changes are shown in Supplementary Tables 2 and 3, as well as Supplementary Fig. 2.
The main findings of this study are the following: first, patients with COVID-19-induced ARDS more frequently presented with fibrotic-like changes and an organizing pneumonia pattern than those with non-COVID-19-induced ARDS. Second, higher dead space ventilation (i.e., ventilatory ratio), tidal volume, endinspiratory pressure and driving pressure during the early course of ARDS were associated with the development of fibrotic-like changes in patients with COVID-19-induced ARDS. Finally, the manifestation of fibrotic-like changes in its extensive form occurred in 36% of patients, being associated with longer mechanical ventilation and ICU length of stay.
Pulmonary fibrotic-like changes are a radiological manifestation of a defective healing process of the lung, which is related to higher mortality. 12,13 As in ARDS caused by other risk factors, exudative or fibroproliferative DAD is already known to be the main histological pattern in COVID-19-induced ARDS. 14 In our study, we identified an organizing pneumonia pattern in all patients with COVID-19 who also presented with fibrotic-like changes. The fact that DAD can have regions with organizing pneumonia or acute fibrinous organizing pneumonia has been well-established. 14 However, it remains unknown as to whether COVID-19-induced ARDS includes larger lung areas of these two histological patterns (organizing pneumonia or acute fibrinous organizing pneumonia). Our findings raise concerns about whether SARS-CoV-2 more frequently elicits a transition from inflammation to an organizing process. Further, our findings invite the consideration of whether steroids would confer a benefit even if DAD is present as well.
We found that, during the early course of ARDS, several variables related to VILI (i.e., tidal volume, positive end-inspiratory pressure and driving pressure) were associated with the development of fibrotic-like changes. Interestingly, this association was identified even when all of these parameters were within the range that is currently believed to be protective.
The degree of impairment in oxygenation at days 1 and 3 since ARDS diagnosis was not related to the development of fibroticlike changes. Conversely, on day 3, higher dead space ventilation was found in patients who developed extensive and non-extensive fibrotic-like changes. In comparison to oxygenation, dead space ventilation is a better marker of lung inhomogeneities and is strongly related to a higher mortality risk. 15 This study has several limitations. First, due to the observational design of the study, there was no specific protocol to perform CT scans. A selection bias may therefore have overestimated the presence of fibrotic-like changes in COVID-19-induced ARDS. Indeed, patients with COVID-19 underwent more thoracic CT scans and at a different time point than those without COVID-19. Second, as a result of the low sample size of patients with available CT scans, a large type II error may have occurred. Third, organizing pneumonia is a pathological diagnosis, and information provided by CT scans should be interpreted with caution.

Ethics Approval and Consent to Participate
The study was approved by the Institution's Internal Review Board (HCB/2018/0231)

Consent for Publication
Informed written consent was obtained from the patients for publication of this article.

Availability of Data and Material
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.