The study—published in *Anesthesiology, Anaesthesia, Critical Care & Pain Medicine*—identifies two types of critically ill patients, which has significant implications for the design of clinical trials involving antiviral drugs.
This study is a subproject of the CIBERUCICOVID project under CIBERES and is co-funded by UNESPA and the ISCIII COVID-19 Fund.
The strategy developed could be applied to other severe respiratory viral infections, such as seasonal or pandemic influenza.
A new study answers one of the major unanswered questions left by the pandemic: whether, when a person with COVID-19 reached a critical condition and required invasive mechanical ventilation, the virus was still actively replicating in the lungs, or whether the respiratory damage was solely a consequence of the inflammatory response. The answer is clear: 60% of critically ill patients have live virus in their lungs at the time of intubation.
This study is a subproject of the CIBERUCICOVID project of the Biomedical Research Network Center for Respiratory Diseases (CIBERES), which investigates personalized prognostic risk factors and one-year follow-up of patients admitted to Spanish intensive care units who are infected with the SARS-CoV-2 virus. The study is coordinated by a CIBERES research team based at the Salamanca Institute for Biomedical Research (IBSAL) and co-funded through UNESPA’s “Estar Preparados” Program and the ISCIII’s COVID-19 Fund.
The research, published in *Anaesthesia Critical Care & Pain Medicine*, was based on a study conducted in collaboration with the Jerez University Hospital. The study included 159 critically ill patients admitted to its ICU and was conducted, among others, in collaboration with the Institute of Medical Microbiology at Jena University Hospital (Germany), where viral cultures were performed to confirm the presence of replicating virus.
Two Distinct Profiles of Critically Ill Patients
In addition to demonstrating the persistence of live virus in most critically ill patients, the research team identified two clearly distinct patterns regarding the timing of the initiation of invasive mechanical ventilation.
On the one hand, there are patients who progress rapidly from the onset of symptoms to respiratory failure and the need for mechanical ventilation. This group exhibits high levels of live virus in the lungs and clear evidence of active replication.
On the other hand, patients whose disease progresses more slowly and who are placed on mechanical ventilation at a later stage, when the pulmonary viral load is low or the virus is no longer detectable by culture.
“This distinction has profound implications for the design of future clinical trials with antivirals. The results suggest that not all critically ill patients would benefit equally from these treatments and that stratification based on the presence of viable virus could be key to optimizing their administration,” explain Jesús F. Bermejo-Martin —study coordinator and researcher at CIBERES at the Institute of Biomedical Research of Salamanca (IBSAL) and the University of Salamanca— and Ángel Estella, —first author at the University Hospital of Jerez.
Recognizing that viral culture is not available in most hospitals, the research team developed and refined an alternative method based on digital PCR to identify patients with replicating virus in the lungs. This technology, already implemented in numerous centers, makes it possible to detect viable virus without the need for specialized cell culture infrastructure.
This breakthrough makes it easier to identify critically ill patients who might benefit from antiviral treatment and paves the way for more personalized medicine in the ICU setting.
Implications Beyond COVID-19
Ferrán Barbé, the project coordinator and a researcher at CIBERES at the Institute for Biomedical Research of Lleida (IRBLleida), emphasizes that the strategy developed is not limited to SARS-CoV-2: “It could be applied to other severe respiratory viral infections, such as seasonal or pandemic influenza, as well as to future emerging threats.”
Overall, this study represents a significant advance in our understanding of the pathophysiology of severe respiratory failure caused by respiratory viral infections and lays the groundwork for improving future clinical trials of antiviral drugs in critically ill patients.
From left to right: Jesús Bermejo, Ferrán Barbé, Ángel Estella, and Stephanie Deinhardt-Emmer.
Article reference:
Estella A, Tedim AP, Häder A, Ortega A, García-Mateo N, de la Fuente A, et al. Poor control of pulmonary viral replication in COVID-19 patients with early respiratory failure. Anaesth Crit Care Pain Med. February 25, 2026:101779. doi: 10.1016/j.accpm.2026.101779. Published online ahead of print. PMID: 41759657.
