The Failure of Pulmonary Oxygen Exchange in Severe Viral Lung Disease: Pneumolysis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In their manuscript, the authors describe a suggestive but unproven hypothesis of pneumolysis in COVID-19.
The figures are interesting, and the test is written in good English.
However, I believe that the phenomenon of probable pneumolysis as a cause of alveolar damage is too simple to draw definitive conclusions on the pathophysiology of COVID-19.
I therefore suggest considering other important data that cause pulmonary fibrosis and hypoxemia in COVID-19, a topic that is still under discussion due to the lack of clarity in the scientific data.

I therefore believe that only the help of clinical studies with large numbers of patients can provide a better understanding of the disease and its causative mechanisms, as well as its anomalies.
I do not recommend publication of the manuscript in the Journal

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The authors present a distinctive pathophysiological framework,pneumolysis to describe severe lung compromise in COVID-19, positioning it as mechanistically different from classical pneumonia or conventional ARDS.

I would like to particularly commend the authors for the extraordinary effort involved in obtaining post-mortem ultrasound-guided lung biopsies from 19 patients. Collecting such histological material during the peak of the pandemic represents exceptionally challenging and high-risk clinical work. The integration of these pathological findings (notably Figure 5) with the authors’ long-standing expertise in high-altitude medicine and HAPE-related mechanisms offers a valuable and unconventional perspective that is rarely captured in the mainstream COVID-19 pathology literature.

Conceptual Positioning of Pneumolysis (Section 3.1)

The definition of pneumolysis as progressive alveolar-capillary destruction is clearly articulated. At the same time, many of the histopathological features described such as hyaline membrane remnants, fibroblast proliferation, and Masson bodies are also well recognized components of the organizing or proliferative phases of diffuse alveolar damage (DAD). Explicitly acknowledging this histological overlap while emphasizing the authors’ proposed mechanistic distinction (i.e., direct viral cytopathic injury and/or immune-mediated pneumocyte destruction) would help place the concept of pneumolysis more clearly within the existing pathological landscape.

Therapeutic Interpretation (Section 6)

The discussion regarding the potential detrimental effects of mechanical ventilation in fragile lung tissue, as well as the proposed role of erythropoietin based on high-altitude physiology, reflects substantial clinical experience. However, these observations arise from pathological interpretation and clinical reasoning rather than controlled interventional evidence. Framing these elements as hypothesis-generating or exploratory therapeutic considerations would better align them with the evidentiary basis presented in the manuscript.

Clinical and Visual Documentation

The histological documentation in Figure 5 is of high quality and strongly supports the descriptive pathology presented. Figure 6, depicting the Kawasaki-like tongue, is also a striking clinical observation. Where available, additional contextual information in the figure legends such as timing relative to symptom onset or disease stage would further enhance the interpretability of these images.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The article describes pneumolysis, which can be a cause of hypoxemia in COVID-19.
In this new version, the Authors clearly describe the topic with further revisions at the reviewers' suggestion.
The article is interesting and may help improve knowledge of this disease, both in research and clinical settings, for both specialists and non-specialists.