Long COVID, with its chronic nature and high prevalence, has the potential to become the next major public health issue across the globe. As we learn more about this condition and its challenges, biopharmaceutical companies can help by focusing their R&D efforts on treating the long COVID symptoms with the highest health implications and developing initiatives to enable early diagnosis of the disease.

There’s growing evidence that some patients are experiencing clinical consequences long after recovery from COVID-19. This phenomenon is increasing among patients of all ages and across a wide range of risk factors. Global COVID-19 cases are approaching 150 million. Using conservative estimates of 10% of all documented infections, that means up to 15 million individuals could be afflicted with long COVID. The sheer magnitude of cases coupled with a limited understanding of the science behind long COVID and lack of curative treatment options suggest that there may be significant unmet medical need for patients with long-term afflictions.

 

The National Institutes of Health formally announced a new $1.15 billion initiative to study post-acute sequelae of SARS-CoV-2 infection, otherwise known as long COVID, although it has acknowledged that the condition still needs to be defined comprehensively. In the United Kingdom, the National Institute for Health and Care Excellence defines long COVID as symptoms that continue or develop after acute COVID-19 (figure 1).

There’s an emerging hypothesis that long COVID consists of distinct symptom clusters and syndromes. Although there’s no universally recognized typology, the current classifications of long COVID symptoms can be grouped into the following themes:

  • Ongoing acute COVID-19 symptoms four weeks after infection: A study published in, “Open Forum Infectious Diseases,” suggests that continuing symptoms from acute disease should be distinguished from new symptoms developed after recovery from acute infection. For example, researchers have observed an ongoing symptomatic COVID-19 condition in the form of continued inflammatory response in some patients who are 40 to 60 days past infection, suggesting that biochemical and inflammatory pathways within the body can remain disturbed long after SARS-CoV-2 infections.
  • Persistent organ damage: Studies have shown abnormalities in lung CT scans of COVID-19 patients 100 days past onset. Although the evidence isn’t yet conclusive, studies also indicate signs of heart damage including myocarditis, muscle scarring or infarction, and ischemia from previously hospitalized patients. Although the connection between organ damage and symptoms isn’t fully understood, persistent dysfunction may be causing long-term symptoms.
  • Post-viral syndromes: Long COVID symptoms such as fatigue, muscle or joint pain, brain fog, depressive symptoms and sleep problems were reported by patients who recovered from other acute viral infections, including SARS-CoV-1 in 2003, MERS in 2012 and Epstein-Barr virus. This finding suggests that the viruses may have a common mechanism of action.
  • Long-term effects aren’t COVID-19 specific: Long COVID symptoms such as post-intensive-care syndrome (or post critical illness syndrome) and post-traumatic stress disorder are better understood as consequences of disease characteristics associated with COVID-19, not of the disease itself.

Because COVID-19 is a relatively new disease, longitudinal data on long COVID patients is limited. However, parallels can be drawn with the long-term impact of other coronaviruses, like SARS-CoV-1 and MERS, to help understand the potential duration and impact of long COVID. Longitudinal studies on SARS patients demonstrate long-term pulmonary effects in some patients 15 years after infection, suggesting some health consequences from long COVID could possibly last years to decades.

 

Current epidemiology studies suggest a wide range of prevalence, likely due to differing definitions of long COVID and differences in patient populations. The UK’s COVID-19 symptom study, the largest scale study to date on COVID-19 patients, suggests that around 13% of patients remain unwell beyond four weeks. Studies targeting hospitalized patients show a higher long COVID prevalence. In fact, 76% of COVID-19 patients hospitalized in Wuhan, China, continued to experience symptoms six months after contracting the virus. A study from Italy found that 87% of patients still had symptoms 60 days after being discharged from the hospital. Ongoing longitudinal studies on the long-term effects of COVID-19 will provide more extensive data in the future.

While respiratory symptoms have been the leading cause of COVID-19-related hospitalization, COVID-19 symptoms take place in many other organ systems (figure 2). Long COVID has the potential to affect patient quality of life with breathing issues, overall heart and lung function, and neurological or cognitive issues.

Imaging studies suggest that damage to the heart or lungs is common in previously hospitalized COVID-19 patients. Conditions like myocardial edema and myocarditis often go undiagnosed and eventually can lead to cardiac fibrosis, heart failure or death. Similarly, neurological and psychological symptoms of long COVID also can adversely affect overall quality of life and deserve medical attention.

Anyone infected with SARS-CoV-2 is at risk for experiencing long COVID. This is supported by clinical evidence demonstrating that long COVID is seen in asymptomatic, symptomatic and hospitalized individuals who tested positive for COVID-19. However, there are patient demographics that have a higher likelihood of developing the condition. The characteristics that have been attributed to an increased risk include advanced age, gender, higher than average BMI, asthma and a high number of symptoms during the first week of infection.

 

Pediatric patients generally are less likely to develop serious illness. However, there’s early evidence to suggest that children who had mild or asymptomatic COVID-19 may experience long-term effects that are similar to those experienced by adults following COVID-19. Multisystem inflammatory syndrome in children, a rare but potentially life-threatening condition, is characterized by severe inflammation in one or more parts of the body and high mortality rates.

Long COVID may be a result of several processes, such as an elevated immune system reaction or a direct result of damage from SARS-CoV-2 infected organs. Research into what causes long COVID is ongoing, but here are a couple of predominant theories:

  • Immune overreaction: One of the most common theories for what causes long COVID is an immune overreaction following acute infection. Cytokines are proteins that signal the immune system to begin fending off intrusions and are released when the virus is detected. In some cases, abnormally large amounts of these proteins are released and become a cytokine storm that can damage the body. Data suggests that patients with a more severe case of acute COVID-19 have a significantly higher level of cytokines. However, there’s growing evidence that autoantibodies, antibodies that damage organs and interfere with the immune system’s response instead of attacking the virus, may be the source of longer term problems. Autoantibodies can persist for months after the infection has cleared, potentially contributing to long COVID symptoms.
  • Direct infection in organs with ACE2 expression: Organ damage caused by direct infection from SARS-CoV-2 virus may also contribute to some long COVID symptoms. The angiotensin-converting enzyme 2 (ACE2) receptor acts as a cellular doorway for SARS-CoV2’s spike protein, which binds to the receptor prior to the entry and infection of the host cell. ACE2 receptors are expressed in multiple organs, including the lungs, heart and kidneys, and are responsible for regulating the angiotensin II protein (ANG II). Unbalanced ACE2 receptors allow ANG II proteins to increase blood pressure and inflammation, which could cause additional damage to the lining of blood vessels, destroy cells in the alveoli, and contribute to other tissue injury. Continued presence of SARS-

Long COVID remains a poorly understood condition with few treatment options. There’s no cure for long COVID or many of the symptoms associated with the disease. For example, some associated pulmonary and cardiovascular conditions may be addressed by existing treatments, but unmet need remains in myocarditis patients and treating fibrosis in the lungs and heart. Therapies to address neurological concerns including, chronic fatigue and brain fog—which affect a large proportion of patients—are extremely limited. To ensure patients are getting the right support, manufacturers could consider building awareness across stakeholders, conducting clinical trials broadly using existing treatments, as well as investing in research for relevant sub-populations.

 

It’s also important to address the challenge in the diagnosis of long COVID, especially for patients who were asymptomatic or didn’t test positive for COVID-19. To ensure timely diagnosis, manufacturers could consider building awareness among physicians and payers to allow for appropriate clinical testing for patients demonstrating any of the symptoms associated with long COVID. Additionally, there may be a need to develop appropriate testing and treatment guidelines to ensure systematic identification and treatment of patients. At the moment, long COVID patients are most commonly identified if previously hospitalized for COVID-19. Routine bloodwork, including testing for COVID-19 antibodies, may help identify long COVID patients more quickly for appropriate treatment when available.