Reply to Vijayakumar and Shah

From the Authors:

We thank Vijayakumar and Shah for their letter regarding our report on the high prevalence of pulmonary sequelae at 3 months in mechanically ventilated survivors of coronavirus disease (COVID-19) assessed by pulmonary function testing and high-resolution computed tomography (HRCT) (1). They raise some important points that are discussed below.

Vijayakumar and Shah rightfully point out that the definition of fibrosis used is relevant for interpretation of our data. Almost all patients had parenchymal bands with a pattern of fibrous residual changes at the 3-month follow-up, and in approximately half, these were accompanied with other signs of fibrosis on chest CT such as parenchymal distortion, volume loss, and/or bronchiolectasis. The evolution of the fibrous bands over time is interesting but not yet systematically screened for. Currently, around one-fifth of our cohort has had a repeated chest CT after the 3-month follow-up in which the fibrous bands were still unchanged.

Pulmonary embolism was diagnosed in 14 out of 22 participants in whom a CT angiogram was performed during admission. As noted, there was no systematic screening for pulmonary embolism during the initial wave, which limits any judgments about relations. Both macro- and microthrombosis with hypoperfusion are common during COVID-19 admission, but their role in long-term pulmonary dysfunction and responsiveness to anticoagulants is unclear (2). Perfusion defects are difficult to assess on HRCT, which was the standard modality in our follow-up. Follow-up data with dual-energy contrast-enhanced CT would potentially be of added value in this regard.

New low-attenuation areas with pattern of emphysematous destruction or cavitation were present in a quarter of the survivors, which we agree with Vijayakumar and Shah is very interesting. To elucidate its pathophysiology, we aimed to compare the follow-up scan with any available CT scan performed during the admission. Although these data need to be interpreted with caution, they suggest that these lesions evolve either from affected areas showing a vacuole sign or from unaffected areas without infiltration or destruction. Thus, we agree that these new lesions may not be COVID-19 specific but rather a consequence of acute respiratory distress syndrome severity and/or ventilator-induced injury.

The etiology of ground-glass opacifications, either inflammatory or fibrotic, may indeed be of relevance for therapeutic intervention and further recovery. Radiological follow-up to assess their evolution over time will be key to address this issue.

The 6-minute-walk test (6MWT) represents an integrated measure of both cardiopulmonary and skeletal muscle function (3), the latter likely being an equally significant contributor to impaired 6MWT results. The four patients in our cohort with significant (>4%) desaturation during the 6MWT were similarly affected in terms of pulmonary function test, HRCT results, and self-reported shortness of breath.

Small airway disease was indirectly assessed by the presence of air trapping on the expiration HRCT scan (4). Although many patients showed some air trapping, defined as more than 2–3 secondary lobules per lobe, the extent of air trapping was limited. Furthermore, we had no previous expiration CT scans in this study cohort, so we were not able to judge this finding as new. In contrast to its prevalence, the extent of air trapping was limited. This is in agreement with the absence of reversibility in pulmonary function test: no significant effect of bronchodilation on either FEV₁ or FVC (median change 1.0 [−1.0 to 4.0] and 0.0 [−2.0 to 2.0] % of predicted, respectively). In addition, none of the patients met the criteria for bronchodilator reversibility (change in FEV₁ and/or FVC >12% and >200 ml), demonstrating that restriction, not obstruction, was the dominant spirometry feature seen in the survivors of COVID-19.

We appreciate the remarks of Vijayakumar and Shah, which in our view highlight two key challenges that remain to be addressed in future work: 1) the long-term follow-up of these respiratory sequelae and their evolution/persistence over time and 2) unraveling the role of (micro)thrombosis in the respiratory sequelae as observed in survivors of COVID-19.