Response to Letter on “Inhaled Aviptadil for Post-COVID Lung Injury: Early Promise, Future Directions”

We thank the authors for their comprehensive commentary on our recently published study evaluating inhaled aviptadil in patients recovering from COVID-19-related lung injury [1, 2]. The authors’ recognition of the study’s design elements, particularly its prospective, randomized, double-blind, placebo-controlled methodology, and the potential clinical relevance of our findings, is encouraging and appreciated. We want to discuss the points raised in their letter further.

As noted by the authors, we observed a statistically significant improvement in dyspnea on day 7 as measured by the Modified Borg Scale. This difference among groups was insignificant at day 28, even though the radiological improvement by this time point was significantly better at the treatment arm, reflecting the anti-inflammatory or cytoprotective effect of the treatment that diminishes over time without continued dosing.

We agree that variability in oxygen supplementation and measurement conditions poses limitations in interpreting oxygenation outcomes and have mentioned this in detail in our article. As per the inclusion criteria, patients with SpO₂ levels, measured without supplementary oxygen, below 94% were eligible for recruitment, which aligns with national guidelines for COVID-19 hospitalization. Importantly, all patients discharged in the study did not require long-term oxygen therapy afterward.

The commentary highlights the novelty and theoretical advantages of inhaled delivery for aviptadil. We agree that this route offers the potential for targeted pulmonary effects with reduced systemic exposure. However, pharmacokinetic and pharmacodynamic studies specific to the inhaled formulation remain limited and will be critical to tailor the optimal dosing in future trials.

The relatively small sample size and high drop-out rate are important limitations; thus, larger, multicenter trials are necessary to confirm and extend our findings. Involving pulmonary function tests, 6-minute walk tests, and patient-reported outcomes would enrich our understanding of functional recovery. During the initial months of the COVID-19 pandemic, most centers did not perform spirometry for safety reasons, a significant obstacle to collecting the data of the pulmonary function tests of these patients. Even though we could perform these tests after COVID-19, the lack of preinfection data would still be a concern in commenting on the changes in the outcome parameters. The 6-minute walk test was planned and performed in most centers on days 28 and 180 as stated on the ClinicalTrials.gov website [3]. Due to the severity of the disease during the pandemic and the ongoing symptoms after discharge, the 6-minute walking test was only properly evaluated in 28 patients. Because of the small sample size, a meaningful statistical evaluation could not be conducted (unpubl. data).

Similarly, evaluation of biomarkers such as IL-6 and D-dimer and more detailed inflammatory profiles like exhaled nitric oxide or BAL cytokine analysis would help elucidate the mechanistic pathways of aviptadil. We acknowledge the challenge of incorporating these measurements in early-phase studies, particularly in resource-limited settings, but we fully support their integration in future trials. Among the biomarkers analyzed, D-dimer, the values did not differ statistically for both treatment and placebo groups at three different time points: baseline, day 28, and day 180 (p > 0.05) (unpubl. data).

The 25-point semi-quantitative CT scoring system used in our study has precedent in COVID-19 literature, but we recognize the limitations of interobserver variability [4]. The suggestion to integrate AI-derived or automated CT quantification tools could enhance reproducibility, reduce bias, and allow for quicker detection of treatment effects during follow-ups.

We also do appreciate the emphasis on transparency and stratification. While we included detailed baseline data in supplementary materials, we agree that subgroup analyses could yield clinically actionable insights. As mentioned in our supplementary material, having a history of immunosuppressive treatment (including corticosteroids for more than 2 weeks) was an exclusion criterion [1]. Regarding the preexisting lung disease, we had only 2 patients (one with asthma and one with COPD) stable for the last year period, and none of the patients had a previous oxygen requirement history, so as not to confuse the reason for dyspnea and desaturation that might have been related to reasons other than COVID-19 pneumonia. The proposal to include active comparator arms, such as intravenous aviptadil or standard immunomodulatory therapies, is a logical next step in determining relative efficacy.

In conclusion, we thank the authors for their insightful and constructive feedback. Their commentary underscores the complexities of studying post-COVID pulmonary recovery and highlights important avenues for future research.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This article was not supported by any sponsor or funder.

Author Contributions

Dorina Esendagli on behalf of all authors has contributed to the conception, drafting, and revision of the manuscript.

Funding Statement

This article was not supported by any sponsor or funder.