News & Views: SARS-Cov-2 Is Not the Only Virus to Cause Lingering Effects

Long COVID has been an ongoing issue related to SARS-CoV-2 infections. Following an infection, many people have reported experiencing lingering symptoms. The symptoms affect a variety of organs and can last for many months or even more than a year. Scientists and clinicians continue to work to understand why this happens, to whom, and how to treat the effects. The lingering, sometimes life-changing, symptoms have been one of the scarier aspects of COVID-19.

But many people don’t realize that other viral — and some bacterial — infections can also cause lingering effects. Indeed, lingering effects are so common as to have been generally categorized as “post-acute infection syndrome,” and sometimes more specifically, such as post-polio syndrome, post-Ebola syndrome, Q fever fatigue syndrome, sub-acute sclerosing panencephalitis (SSPE), Guillain-Barré syndrome (GBS), post-dengue fatigue syndrome, post-chikungunya chronic inflammatory rheumatism, rheumatic fever, and post-treatment Lyme disease syndrome. Further, conditions that cause a similar series of manifestations, but for which a consistent cause remains elusive, have also been attributed to previous viral infection, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Lingering effects of other infections

Lingering effects have been described following numerous viral infections, including some coronaviruses, adenoviruses, herpesviruses, enteroviruses, paramyxoviruses, and orthomyxoviruses. Bacterial infections caused by pneumococcus, Coxiella burnetii, Borrelia, and Giardia lamblia have also been associated with long-term effects.

For example,

• Mononucleosis is characterized by extreme fatigue and can last for weeks or months following infection with Epstein-Barr virus.
• Rheumatic fever, which is caused by infection with streptococcus, is characterized by joint pain and fatigue. But the infection can also cause long-term damage to the heart that occurs up to five weeks after the initial bacterial infection.
• Following infections with either influenza or pneumococcus, patients in Scotland were found to be at increased risk of having a stroke up to 28 days later.
• Influenza infection has been associated with lingering symptoms of fatigue, depression and sleep disorders, which were often characterized after pandemics (e.g., 1918 and 2009 H1N1).
• When viruses reach the brain and cause encephalitis, patients can experience long-term consequences, such as recurrent headaches, sleep or motor disorders (including tics or speech disorders), epilepsy, or behavioral, memory or learning disorders (e.g., ADHD, depression, irritability, confusion, or loss of concentration). Some examples of viruses that can cause encephalitis include arboviruses, rhabdoviruses, enteroviruses, herpesviruses, retroviruses, orthomyxoviruses, orthopneumovirus and coronaviruses.
• Ebola infection has been shown to cause lingering tiredness, joint and muscle pain, issues with vision and hearing, headaches and sleep disorders, among others. These effects can last years.
• Muscle weakness following recovery from polio can reappear decades later as survivors age.
• A delayed, yet fatal, outcome of measles and rubella infections is subacute sclerosing panencephalitis (SSPE). Symptoms start with cognitive signs, like forgetfulness, lack of concentration, and sleep disorders before progressing to muscle jerking, seizures and, eventually, muscle rigidity, including in some cases inability to swallow.

Potential causes of lingering effects

The causes of lingering effects may differ among pathogens, and in some cases, may overlap within a class of pathogen, but in many cases remain only partly understood. Causes may include:

• Remaining pathogen – In some cases, reservoirs of the pathogen remain in the body. This can be caused by ongoing viral replication (e.g., hepatitis B virus) or periods of latency with intermittent reactivation (e.g., HIV and Epstein-Barr virus).
• Immune system disfunction – These effects can be caused by development of autoimmunity, persistence of inflammatory state due to lingering immune response (e.g., elevated levels of inflammation-inducing cytokines), or dysregulation of the balance between the microbiome and the individual (e.g., so-called “gut-brain axis”).
• Permanent damage to tissues – If tissues damaged during the acute infection are not repaired, or reparable, long-term effects could result, such as lung damage resulting in long-term respiratory dysfunction.

Back to COVID-19

As we relate what we know about other infections to long COVID, three important considerations emerge:

1. Any (or all) of the causes listed above could be contributing to what people with long COVID are experiencing. Some evidence exists for each, and depending upon which is the cause, different approaches to treatment may emerge. For example, if reservoirs of pathogen remain, antivirals may improve outcomes. In contrast, if the symptoms are the result of immune system disfunction, generalized treatments targeted at inflammation (e.g., steroids) or more targeted biologics may be needed.
2. When lingering symptoms to other infections have been described over time, the numbers of people affected decreased. Some early data suggest a similar pattern for COVID-19, but one study found only a small percentage (15%) of people recovered after one year. More work will be needed to understand whether certain symptoms linger longer than others, whether certain individuals are prone to a longer recovery timeline, and how their recovery may be affected by future infections with this virus, particularly since it continues to change and reinfect people.
3. The current situation with long COVID is compounded by the numbers of affected people. As lingering effects of influenza were often better characterized following pandemics, one result of the COVID-19 pandemic may be to have shone a light — and research attention — on the potential for lingering effects following this infection. Indeed, when no one in the world is immune to an infection and billions of people are affected during the same period, many will also experience lingering effects around the same time. We can hope that as we gain a collective immunity against this new virus, we will also decrease our populational susceptibility to its lingering effects; however, for those whose lives have been affected and for those who will be in the future, it is important to better characterize and be able to treat this condition.

For a review of the current understanding of long COVID, including limitations of the current research and areas for further study, check out this recent article in Nature Reviews Microbiology by Hannah E. Davis and colleagues.