Dear Editor,

We read with interest McGroder et al’s study on the radiographic findings of patients four months after severe COVID-19 and the associated risk factors. Hürsoy and colleagues’ comment (1) on the paper was equally thought-provoking. We would like to further this discussion by contributing some of our observations from the pulmonology clinic at a major academic medical center in South East Asia.

It has been tremendously challenging globally to achieve precision in the diagnosis of Interstitial Lung Disease (ILD) post-COVID as invasive testing such as lung biopsies are performed sparingly. Histopathological pulmonary findings have largely remained inaccessible since COVID survivors are hypoxic so biopsies pose a high risk for the patient, and healthcare personnels are reluctant to perform such high-risk procedures. Hence, we are left to derive our diagnosis from radiological data and pulmonary function tests (PFTs) of the patient.

We propose that a consensus definition be reached for the diagnosis of post-COVID ILD, one that incorporates well-accepted radiological terms (used to represent any interstitial lung disease). We recommend that lung fibrosis only be classified as ILD if the lung parenchymal abnormalities persist for a minimum of six months after the COVID infection has resolved. Post-COVID ILD should then be further subclassified based on distinct radiological patterns. In our retrospective cohort study, four patterns of post-COVID lung parenchymal changes were exhibited by patients with no preexisting lung disease: persistent ground-glass opacities; interlobular septal thickening; reticulation and honeycombing; interlobular septal thickening and reticulations; and patchy consolidation with or without ground-glass opacity (2).

In terms of outcome, within our cohort of severe to critically ill patients, most developed persistent ground-glass opacities or patchy consolidation (with or without ground-glass opacity); a majority of these participants significantly improved (clinically and radiologically) upon administration of corticosteroids (2). Radiological improvement was defined as clearance of at least 50% of lung infiltrates. Reiterating our findings, Han et al. reported ground-glass opacities as the predominant pattern observed in follow-up CT scans of patients with fibrotic-like changes within six months of disease onset (3). Three of the five patients in our study who died had progressive disease with reticulation and honeycombing. To achieve greater accuracy in disease severity assessment and risk stratification, we suggest employing PFTs, particularly to obtain diffusion capacity of the lungs for carbon monoxide (DLCO) and forced vital capacity (FVC) measurements. For the eight out of thirty patients in our cohort who had significant HRCT findings, PFTs were ordered to assess physiological function; three presented with low FVCs (2). In Han et al’s study, abnormal DLCO (less than 80%) at 6-month follow up was a common occurrence in those with fibrotic-like changes (3).

Similar to McGroder et al’s findings, we concluded that the male gender was a significant predisposing factor for post-COVID pulmonary fibrosis. Moreover, like Li et al. and Han et al., we found diabetes mellitus and hypertension to be prevalent comorbidities in patients who developed fibrotic changes (2-4). Interestingly, in our cohort, disease severity did not significantly influence the development of any particular pattern of lung parenchymal abnormality. In light of these observations, we can conclude that the reported lung microstructure changes are not only a ramification of post-ARDS fibrosis or ventilator-induced lung damage but also a consequence of direct virus attack and aberrant local immune response. This is further evidenced by the finding that the Coronavirus induced fibrosis even in moderately ill patients who did not require invasive mechanical ventilation or ICU stay (2).

We hope that prospective studies will further enrich and broaden the global dialogue on post-COVID lung fibrosis.

References:

1. Hürsoy et al. 2021. e-letter https://thorax.bmj.com/eletters
2. Zubairi ABS, Shaikh A, Zubair SM, Ali AS, Awan S, Irfan M. Persistence of post-COVID lung parenchymal abnormalities during the three-month follow-up. Adv Respir Med. 2021;89(5):477–83. Available from: https://pubmed.ncbi.nlm.nih.gov/34612504/
3. Han X, Fan Y, Alwalid O, Li N, Jia X, Yuan M, et al. Six-month Follow-up Chest CT Findings after Severe COVID-19 Pneumonia. Radiology. 2021;299(1):E177-E186.
4. Li Y, Wu J, Wang S, Li X, Zhou J, Huang B, et al. Progression to fibrosing diffuse alveolar damage in a series of 30 minimally invasive autopsies with COVID-19 pneumonia in Wuhan, China. Histopathology. 2021;78(4):542-55.

To the editor,

We thank N. Hürsoy and colleagues for their interest in our study of patients four months after severe COVID-19 [1]. We agree that there needs to be continued development of terms describing the radiographic appearance of post-COVID fibrotic-like patterns. We acknowledge that without the benefit of histopathology or serial imaging, our ability to define pulmonary fibrosis is limited.

The authors posit that parenchymal bands, irregular densities, and ground glass opacities, may be considered fibrotic-like patterns. We have included irregular densities, characterized as reticulations or traction bronchiectasis, as fibrotic-like changes. We did not include parenchymal bands [2], as these can be associated with atelectasis, which is common in COVID and can disappear over time [3]. Similarly, we did not include isolated ground glass opacities as fibrotic-like changes, as these have been found to decrease over time in CT lung cancer screening cohorts [4] and in other post COVID-19 cohorts [5, 6].

A priori, we evaluated for both previously established interstitial lung abnormality categories [7], as well as categories of radiographic abnormalities reported in Acute Respiratory Distress Syndrome (ARDS) survivors using an established scoring system [8]. This inclusive approach should facilitate meta-analyses and comparisons with future studies of COVID-19 survivors, interstitial lung disease studies, and studies of non-COVID ARDS survivors. Furthermore, it allows for future post-hoc analyses if alternate definitions of fibrotic-like patterns in COVID-19 survivors are established. Additionally, we showed that objective quantitative analyses closely agreed with visual assessments (Figure S2). These types of quantitative imaging analyses may facilitate the convergence of data from multiple centers if imaging protocols become more standardized [9].

Efforts are underway to characterize pulmonary impairments and radiographic abnormalities in our cohort over time in order to assess longitudinal evolution. We acknowledge that our findings do not exclude the possibility of pre-existing lung disease and we therefore look forward to reviewing independent studies, such as the Collaborative Cohort of Cohorts for COVID-19 Research (C4R) [10] project, which will provide better understanding of radiographic changes by comparing chest imaging studies before and after SARS-CoV-2 infection.

1. McGroder, C.F., et al., Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length. Thorax, 2021.
2. Pulmonary Parenchymal Band. Available from: https://www.ncbi.nlm.nih.gov/medgen/978776.
3. Kong, M., et al., Evolution of chest CT manifestations of COVID-19: a longitudinal study. J Thorac Dis, 2020. 12(9): p. 4892-4907.
4. Jin, G.Y., et al., Interstitial lung abnormalities in a CT lung cancer screening population: prevalence and progression rate. Radiology, 2013. 268(2): p. 563-71.
5. Nagpal, P., et al., Case Studies in Physiology: Temporal Variations of the Lung Parenchyma and Vasculature in Asymptomatic COVID-19 Pneumonia: A Multi-Spectral CT Assessment. J Appl Physiol (1985), 2021.
6. Liu, D., et al., The pulmonary sequalae in discharged patients with COVID-19: a short-term observational study. Respir Res, 2020. 21(1): p. 125.
7. Hatabu, H., et al., Interstitial lung abnormalities detected incidentally on CT: a Position Paper from the Fleischner Society. Lancet Respir Med, 2020. 8(7): p. 726-737.
8. Burnham, E.L., et al., Chest CT features are associated with poorer quality of life in acute lung injury survivors. Crit Care Med, 2013. 41(2): p. 445-56.
9. Nagpal, P., et al., Quantitative CT imaging and advanced visualization methods: potential application in novel coronavirus disease 2019 (COVID-19) pneumonia. BJR Open, 2021. 3(1): p. 20200043.
10. Collaborative Cohort of Cohorts for COVID-19 Research. Available from: https://c4r-nih.org/content/overview.

We thank Dr Abdulqawi for interest in our work (1). He comments that the referral, uptake and completion rates for pulmonary rehabilitation in the current study were lower than in a previous study by Jones and colleagues (2). We would caution against retrospective comparison with unmatched historical controls due to confounding factors such as differences in patient characteristics and practice pathways that may contribute to inaccurate point estimates.

We hypothesised that the COPD discharge bundle would impact on referral rates. Strengths of the current work include the prospective real-world nature of the study, with the research team having no involvement in treatment allocation. The clinical team delivering the bundle were blinded to the study objectives, thus minimising any Hawthorne effect.

Dr Abdulqawi raises the point that pulmonary rehabilitation completion rates were low in the current study (albeit based on a low denominator). The reasons for non-completion of PR are often complex and multi-factorial (3) and may not be directly related to referral source. However, what is clear is that without a referral for pulmonary rehabilitation, uptake and completion rates are zero.

1. Barker RE BL, Maddocks M, Nolan CM, Patel S, Walsh JA, Polgar O, Wenneberg J, Kon SSC, Wedzicha JA, Man WDC, Farquhar M. Integrating Home-Based Exercise Training with a Hospital at Home Service for Patients Hospitalised with Acute Exacerbations of COPD: Developing the Model Using Accelerated Experience-Based Co-Design. Int J Chron Obstruct Pulmon Dis. 2021;16:1035-49.
2. Jones SE, Green SA, Clark AL, Dickson MJ, Nolan AM, Moloney C, et al. Pulmonary rehabilitation following hospitalisation for acute exacerbation of COPD: Referrals, uptake and adherence. Thorax. 2014;69(2):181-2.
3. Jones SE, Barker RE, Nolan CM, Patel S, Maddocks M, Man WD. Pulmonary rehabilitation in patients with an acute exacerbation of chronic obstructive pulmonary disease. J Thorac Dis. 2018;1(1):S1390-S9.