Researchers led by UVA School of Medicine scientist Jie Sun, PhD, discovered that severe respiratory infections can alter immune cells in the lungs in ways that support tumor growth months or even years later. Based on these findings, the scientists recommend that doctors closely watch patients who recover from severe COVID, flu, or pneumonia so lung cancer can be detected early, when treatment is most effective.

“A bad case of COVID or flu can leave the lungs in a long-lasting ‘inflamed’ state that makes it easier for cancer to take hold later,” said Sun, co-director of UVA’s Carter Center and a member of UVA’s Division of Infectious Diseases and International Health. “The encouraging news is that vaccination largely prevents those harmful changes for cancer growth in the lung.”

Severe Respiratory Infections and Long Term Lung Damage

Respiratory illnesses such as influenza and COVID are among the most common sources of lung injury. However, scientists have not fully understood how this type of damage might influence cancer risk years later. To explore this question, Sun and his team studied the effects of severe lung infections in both laboratory mice and human patients.

The findings were striking. Mice that experienced severe lung infections were more likely to develop lung cancer later and were also more likely to die from the disease. When the researchers analyzed patient data, they found a similar pattern. People who had previously been hospitalized with COVID-19 showed a higher rate of lung cancer diagnoses.

The analysis revealed a 1.24-fold increase in lung cancer incidence among patients who had been hospitalized for COVID-19. This elevated risk was seen regardless of whether the individuals smoked or had other medical conditions, which doctors refer to as “comorbidities.”

“These findings have important immediate implications for how we monitor patients after severe respiratory viral infection,” said Jeffrey Sturek, MD, PhD, a UVA physician-scientist who collaborated on the study. “We’ve known for a long time that things like smoking increase the risk for lung cancer. The results from this study suggest that we may need to think about severe respiratory viral infection similarly. For example, in some patients who are at high risk for lung cancer based on smoking history, we recommend close monitoring with routine screening CT scans of the lungs to catch cancer early. In future studies, we may want to consider a similar approach after severe respiratory viral infection.”

Immune Changes That Create a Pro Tumor Environment

Experiments in mice helped the researchers uncover why severe infections may increase cancer risk. The team observed major changes in immune cells known as neutrophils and macrophages, which normally help defend the lungs.

After severe infection, some neutrophils began behaving abnormally and contributed to a persistent inflammatory environment described as “pro-tumor,” meaning it supports cancer growth. The scientists also found significant changes in epithelial cells that line the lungs and the tiny air sacs responsible for breathing.

Vaccination May Protect the Lungs

The study also produced encouraging findings about prevention. Prior vaccination appeared to block many of the lung changes linked to cancer development. Vaccines help the immune system respond more effectively to infections, which reduces how severe the illness becomes.

The researchers observed the increased cancer risk mainly in people who had severe COVID-19. Individuals who experienced only mild infections did not show this elevated risk and actually had a slight decrease in lung cancer incidence.

Even so, the scientists warn that many people who survived severe COVID-19 or other serious respiratory infections could face a higher risk of lung cancer in the future.

“With tens of millions of people globally experiencing long-term pulmonary [COVID-19] sequelae, these findings carry significant implications for clinical care,” the researchers wrote in their scientific paper. “Individuals recovering from severe viral pneumonia, particularly those with smoking history, may benefit from enhanced lung cancer surveillance, and preventing severe infection through vaccination may confer indirect cancer protection benefits.”

Implications for Early Detection and Treatment

Sun and his colleagues hope their work will help doctors better identify patients who may face an increased risk of lung cancer after severe respiratory infections. Earlier detection could allow treatment to begin sooner and improve patient outcomes.

The team also believes their findings could guide the development of new strategies to prevent or treat lung cancer linked to prior lung infections.

“Our goal is to help doctors identify who may be at higher risk of lung cancer after a severe infection, and develop targeted ways to prevent and treat lung cancer after prior pneumonia,” Sun said. “We also believe that vaccines don’t just prevent acute hospitalization after contracting the virus. They may also reduce the long-term fallout of severe infection, including the kind of immune scarring that can increase cancer risk.”

Advancing Biomedical Research at UVA

Improving the understanding and treatment of complex diseases is a central mission of UVA’s Paul and Diane Manning Institute of Biotechnology. The institute focuses on accelerating innovative research like Sun’s work and helping translate laboratory discoveries into new treatments more quickly.

UVA’s Beirne B. Carter Center for Immunology Research (CIC) was established through the generosity of Beirne B. Carter, and the Beirne Carter Foundation continues to support its research efforts. Scientists at CIC study infections, cancer, cardiovascular disease, chronic lung conditions, the microbiome, and autoimmune disorders to develop new therapies and cures.

The UVA Comprehensive Cancer Center is one of only 57 cancer centers in the United States to receive the National Cancer Center’s “comprehensive” designation, recognizing excellence in patient care and advanced cancer research.

Findings Published in Cell

Sun and his collaborators published their findings in the scientific journal Cell. The research team included Wei Qian, Xiaoqin Wei, Andrew J. Barros, Xiangyu Ye, Haibo Zhang, Qing Yu, Samuel P. Young, Eric V Yeatts, Yury Park, Chaofan Li, Sijie Hao, Gislane Almeida-Santos, Jinyi Tang, Harish Narasimhan, Nicole A Kirk, Valeria Molinary, Ying Li, Li Li, Bimal N. Desai, Peter Chen, Kwon-Sik Park, Anny Xiaobo, Jeffrey M. Sturek, Wei Chen, In Su Cheon and Sun.

Funding for the research came from the National Institutes of Health, grants AI147394, AG069264, AI112844, HL170961, AI176171, AG090337, R01HL179312, F31HL170746, T32AI007496, T32CA009109, R01AI155808 and R01HL162783; a UVA Comprehensive Cancer Center Collaborative Grant, U01CA224293; a UVA Pinn Scholar Award; a UVA Shannon Fellowship; a UVA Comprehensive Cancer Center Lung TRT Pilot Grant; an American Lung Association Catalyst Grant, T32GM139787-01; and a UVA Parsons-Weber-Parsons Fellowship.