AMSTERDAM — Five years after the COVID-19 pandemic began, millions of people worldwide continue to live with its long-term consequences. For clinicians, managing long COVID remains one of the “most challenging clinics,” said Rachael A. Evans, PhD, clinical associate professor at the University of Leicester, Leicester, England, at the European Respiratory Society (ERS) 2025 International Congress. Long-term consequences of COVID continue to have a significant impact on patients who find it difficult to identify themselves, she said. “People lose their own identity. They say ‘I’m not the same person, I don’t feel like me anymore.’” 

Persistent scientific uncertainty exacerbates the clinical challenge. Without a definitive biomarker or a universally effective treatment, clinicians are left to navigate a complex landscape of nonspecific symptoms and a rapidly evolving body of evidence. Key questions remain about the underlying mechanisms, the true risk for long-term organ damage, and how to safely and effectively guide patients toward recovery.

Defining an ‘Undefinable’ Condition

Over the past 5 years, the volume of research on long COVID has grown exponentially, with more than 40,000 papers published. Some traits have become clearer. An estimated 400 million people worldwide are thought to have long COVID. According to demographics, the ailment is more prevalent in middle-aged people, women, and those from lower socioeconomic backgrounds. Preexisting conditions are also a significant risk factor.

Yet a clear, universally accepted definition and diagnostic pathway remain elusive. “Long COVID is very real,” said Joan B. Soriano, MD, PhD, senior scientist at the La Princesa University Hospital in Madrid, Spain. However, its heterogeneity, with more than 200 different symptoms reported, makes it difficult to define the condition uniquely. “We need to define the problem to start to identify the solution,” Soriano urged.

The World Health Organization defines the condition as a “condition occurring in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction, and other symptoms that typically affect every day functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.”

The Search for Personalized Care

A one-size-fits-all approach is inadequate for long COVID, and experts are increasingly looking toward personalized care. “We’ve learned from other long-term conditions over the last few decades that a more personalized medicine approach has been very fruitful,” said Evans.

Research has begun to uncover distinct phenotypes of long COVID, moving the field beyond treating it as a single entity. Initial studies clustered patients by symptom severity and found that the group with the most severe and ongoing physical and mental impairments also had higher levels of inflammatory markers, such as C-reactive protein and interleukin 6, Evans explained.

More recent work using machine learning is identifying protein profiles that may eventually serve as biomarkers to better classify patients and inform treatment decisions. This effort on understanding the underlying biology has led to several potential mechanisms that could be driving the condition, including:

• Immune dysregulation and inflammation. Research suggests that in some patients, the immune system becomes overactive or misdirected, attacking the body’s healthy cells and leading to ongoing inflammation. This can cause symptoms such as fatigue and joint pain.
• Persistent virus or viral reactivation. One theory is that fragments of the SARS-CoV-2 virus or a reactivated latent virus, such as the Epstein-Barr virus, remain in the body, triggering a continuous immune response. However, Evans said that “finding the virus has been really, really hard.”
• Micro-clots and disrupted hemostasis. The acute phase of COVID-19 is known to be a hypercoagulable state, and some researchers hypothesize that persistent microscopic blood clots may be impairing oxygen transport to tissues, contributing to long-COVID symptoms.
• The role of obesity. Obesity, a known risk factor for severe acute COVID-19, is also associated with more severe long COVID. It is thought that the preexisting proinflammatory state in obesity may exacerbate the inflammatory response to the virus.

A Shadow on the Lungs?

One of the earliest concerns with long COVID was the potential for lasting lung damage, specifically pulmonary fibrosis. Claudia Valenzuela, MD, pulmonologist at the La Princesa University Hospital in Madrid, Spain, said that while many patients show gradual improvement in radiologic abnormalities, persistent issues remain a concern for a subset.

Key findings from longitudinal studies include:

• An early Italian study from 2020 found that 25% of post-hospitalization patients presented with signs of pulmonary fibrosis at their follow-up.
• At 18 months, one study found that 11% of patients referred to a specialized clinic had persistent lung abnormalities.
• Studies extending to 3 years have shown contradictory results, with some patients continuing to improve while others show persistent fibrotic-like changes. However, one analysis noted “stability over 3 years of the lesions,” suggesting that for many, the condition is not progressive.

Valenzuela stressed the importance of differentiating “fibrotic sequelae…from post-COVID ILD [interstitial lung disease]…that sometimes has functional impairment.” Currently, there is insufficient evidence to guide the management of post-COVID ILD.

A Path to Recovery

Recent evidence suggests that rehabilitation can be beneficial. A review of 24 randomized controlled trials (RCTs) found that cognitive behavioral therapy and combined physical and mental health programs improved symptoms of long COVID. Another review of 37 RCTs found that programs lasting 4-8 weeks, which included breathing exercises and multicomponent training, were effective in improving physical and functional capacity, respiratory function, anxiety, and quality of life.

A major challenge in rehabilitation is post-exertional malaise (PEM), a worsening of symptoms after physical or mental exertion, affecting an estimated 25% of people with long COVID. A recent review found no change in PEM score between the interventional groups and the control groups, while those in the interventional groups experienced significant improvement in exercise capacity. However, quality of life did not improve.

Tessa Schneeberger, PhD, physiotherapist and researcher at Schön Klinik Berchtesgadener Land in Munich, Germany, tailors rehabilitation interventions to patients based on the severity of their PEM. Patients with severe PEM start with pacing strategies, while those with mild-to-moderate PEM undergo a symptom-titrated exercise approach, she explained. “In our rehabilitation center, our approach is multimodal, combining pacing or symptom-titrated exercise with respiratory therapy, education, and psychological support, tailored to each patient’s individual symptom cluster,” she said. This personalized method has yielded positive outcomes. “We saw that a symptom-titrated program is experienced well and also leads to an increased quality of life,” she said.

New research presented by Enya Daynes, PhD, rehabilitation specialist and physiotherapist at the University Hospitals of Leicester, England, provided a potential mechanism for why exercise can be beneficial for the immune system, which is thought to be dysregulated in long COVID. In an RCT, an 8-week program of treadmill walking, cycling, and strength training for hospitalized patients with long COVID was compared to a control group receiving usual care. The study found that the exercise program helped to restore a more normal, well-regulated immune system.

Daynes explained that the exercise group showed “significant improvements in their naive immune cells,” whose role is to recognize and respond to new infections. In contrast, the immune function in the usual care group seemed to get worse over the same period, she said.

The program also bolstered the body’s immunologic memory. “We found improvements in central memory CD4+ T cells,” Daynes said, which are “responsible for providing a quick response to any infections that the body has encountered before.” Additionally, central and effector memory CD8+ T cells improved, enabling them to identify and fight future infections more rapidly.

Where Will We Be in 5 Years?

“The problem will remain,” said Soriano, although the incidence and severity might decrease because newer variants seem to cause fewer long-COVID cases, and vaccination is protective.

Schneeberger offered a more cautious view. Even if acute infections are milder, that “does not mean that they suffer less” from long-term symptoms. “It is a problem that is going to stay,” she said.

Evans, Soriano, Valenzuela, Schneeberger, and Daynes reported having no relevant financial relationships.

Manuela Callari is a freelance science journalist specializing in human and planetary health. Her work has been published in The Medical Republic, Rare Disease Advisor, New Scientist, The Guardian, MIT Technology Review, and others.