Long COVID: The Next Chapter in the COVID-19 Pandemic

May 20, 2022

The United States is approaching 83,000,000 COVID-19 cases and 1 million COVID-19 deaths, with the specter of yet another surge in cases due to Omicron BA 2.12.1 variant. Effective vaccines, monoclonal antibodies against both Omicron and its BA-2 variants and antiviral agents make it likely that the numbers of hospitalization and deaths will be a fraction of those seen with the Delta and Omicron variants. However, the poorly understood complications of COVID-19 infection, initially called “Long COVID” or “long haul COVID,” but now referred to as “post-COVID-19 condition,” will continue to impact the lives of infected individuals for months-to-years to come. The U.S. General Accounting Office estimates between 7.7-23 million Americans will develop post-COVID-19 condition, and as many as 1 million will be debilitated and unable to work. In the U.K., as many as 1.3 million people, or 2% of the population, have experienced post-COVID-19 condition. Although it is clear that post-COVID-19 condition is likely to have a significant health impact on 10s of millions globally, the data on this syndrome are, at best, murky. Part of this limited understanding is due to a lack of clear definition of post-COVID 19 condition. In this article, we will address 3 questions:

  1. What is the current clinical definition of post-COVID-19 condition?
  2. What is our current understanding of the pathogenesis of post-COVID-19 condition?
  3. What is the impact of vaccination, monoclonal antibodies and antiviral agents on prevention of this syndrome?

What Is the Current Clinical Definition of Post-COVID-19 Condition (Long COVID)?

Using a Delphi consensus methodology, the World Health Organization (WHO) recently developed a definition of post-COVID-19 condition. This definition is exceedingly complex and reflects the multi-organ nature of SARS-CoV-2 infections, which can impact the lungs, brain, heart, kidney and clotting system. It also recognizes that the infection can be persistent or represent a post-infectious sequelae seen with a variety of viral infections including other coronaviruses, SAR-CoV and MERS-CoV.

Not surprisingly, in order to be diagnosed with post-COVID-19 condition, a person must have a history of SARS-CoV-2 infection, and a considerable amount of time must have passed since the initial signs or diagnosis of acute infection (3+ months). Additionally, there must not be an alternative explanation for the symptoms that the patient is experiencing. Whether this complex definition will be widely accepted, and how it will be applied in research settings, are both open questions.

Key aspects of this definition include:

  • History of SARS-CoV-2 infection, preferably with laboratory confirmation.
  • At least 3 months since the onset of acute COVID-19 symptoms, or any positive SARS-CoV-2 test in patients who were initially asymptomatic.
  • At least 2 months minimum duration of post-COVID-19 condition symptoms.
  • Symptoms do not have an alternative explanation.
  • Symptoms can be persistent from initial infection, be of new onset in both symptomatic and asymptomatically infected patients weeks after initial infection or can wax and wane over time.
  • Symptoms impact quality of life/everyday functions.

What Are the Symptoms of Post-COVID-19 Condition (Long COVID)?

To meet the WHO definition of post-COVID-19 condition, the individual should have symptoms for a minimum of 2 months. The most common symptoms are pulmonary (cough and shortness of breath), neurological (cognitive dysfunction, "brain fog," headache), psychological (anxiety, depression, sleep difficulties), cardiovascular (chest pain, heart palpitations, and myocarditis) and loss of sense of test and smell. Multiple symptoms may occur but are not required for diagnosis.

Clinical Characteristics of post-COVID-19 condition .
Clinical Characteristics of post-COVID-19 condition.

How Frequently Does Post-COVID-19 Condition (Long COVID) Occur?

A major question that has not been adequately answered about post COVID-19 condition is how frequently it occurs. Because there has not been a standard definition of what constitutes a case of post-COVID-19 condition, case counts can vary dramatically; 1 review showed prevalence of 2 to 53%, depending on whether or not the individuals were hospitalized. Even greater variance in the prevalence of this condition has been reported. Clearly, there is a range of severity for post-COVID-19 condition. Studies using the WHO case definition are desperately needed to understand the overall prevalence of this condition. In addition, classification of the spectrum of signs and symptoms in patients with post-COVID-19 condition is also needed.

What Is Our Current Understanding of the Pathogenesis of Post-COVID-19 Condition (Long COVID)?

Our current knowledge of pathogenesis of post-COVID-19 condition is exceedingly complex and based on 4 interacting mechanisms:

  1. Viral persistence in tissue, particularly those rich in ACE-2 receptors, such as the lungs, nasopharynx and gastrointestinal tract.
  2. Dysregulation of the inflammatory response, resulting in tissue damage.
  3. Dysregulation of the clotting system that results in thrombotic-induced tissue damage, including strokes and pulmonary emboli.
  4. Viral mimicry potentially resulting in cross-reactive antibodies that may cause tissue damage.

Viral persistence in tissue results in dysregulation of the inflammatory response. SARS-CoV-2 infected patients with long-term pulmonary symptoms such as cough, dyspnea and fatigue have been shown to have increased levels of pro-inflammatory cytokines including IL-6 and TNF factor. Similar events may also explain heart palpitations and myocarditis. Thrombotic-induced tissue injury in the brain or persistent inflammatory response may cause the neurologic sequelae seen in this condition. Although viral mimicry has been described with SARS-CoV-2, its actual role in the pathogenesis of post-COVID-19 condition is currently uncertain.

One of the mysteries of post-COVID-19 condition is that the severity of the acute infection does not predict whether the individual will develop post-COVID-19 condition. Unravelling the pathogenesis of post-COVID-19 condition—are there other predisposing host risk factors and/or specific virulence factors at play—will be necessary to develop effective, science-based interventions to post-COVID-19 condition.

Pathogenesis of post–COVID-19 condition.
Pathogenesis of post–COVID-19 condition.

Can Vaccines, Monoclonal Antibodies and Antiviral Agents Prevent Post-COVID-19 Condition (Long COVID)?

One of the shortcomings of attempting to address this question is the paucity of data available. Most of the data about the impact of these interventions were collected when the Alpha variant was dominant. Only a small amount of data has been collected while delta and omicron variants were dominant. With the arrival of the BA.2 variants of Omicron, and the continuing emergence of new BA.2 subvariants, it is a near certainty that data on the efficacy of various interventions will lag behind what is occurring in real time.

​Impact of Vaccines
The best way to prevent development of post-COVID-19 condition is to prevent infection in the first place, and vaccination remains the most reliable tool to do so. One of the robust studies that examined development of post-COVID-19 condition in a fully vaccinated population (2 injections of the BNT162b2 mRNA vaccine) was conducted during a period when Alpha was the dominant variant. In the population studied, only 2% of those vaccinated developed an infection post-vaccination. Most of these infections were asymptomatic or mild. Unfortunately, 19% of those with post-vaccination infections also developed post-COVID-19 condition, although the study’s case definition was not consistent with proposed WHO post-COVID-19 condition. Long-term follow up was not reported.

The U.K. Health Security Agency released a literature review on the effectiveness of vaccination in preventing post-COVID-19 condition. In this study, the likelihood of post-COVID-19 condition development in partially or fully vaccinated individuals who experienced post-vaccination infections was compared to the likelihood of post-COVID-19 condition development in unvaccinated individuals.  It was estimated that vaccinated individuals were half as likely to develop post-COVID-19 condition than unvaccinated ones. However, this review did not address the question of how effective vaccination was in preventing post-COVID-19 condition with an appropriately matched control group that was unvaccinated.

A recent CDC study which evaluated the effectiveness of mRNA vaccines during both the Delta and Omicron surges showed vaccination had an overall 95% effectiveness in preventing death compared to an unvaccinated population, and a 94% effectiveness in preventing death in those specifically infected with Omicron. It should be noted that the vaccinated population was older, had complex medical conditions and was more likely to be immunocompromised. Protection was higher in those who received a third dose of vaccine. These data suggest that a third dose mRNA regimen is effective at preventing severe disease against current variants.

separate study showed a 3-dose mRNA vaccine regimen was effective at preventing symptomatic Delta and Omicron infections, although the 2 vaccines were less effective against the Omicron variant. Taken together, these data suggest that the mRNA vaccines may be protective against post-COVID-19 condition. However, neither study was designed to specifically answer the question of whether these vaccines prevent l post-COVID-19 condition.  We need better data to determine how effective vaccine are at protecting against both symptomatic infections, but also asymptomatic ones. The reason why this is important is if vaccination prevents SARS-CoV-2 infection, it prevents post-COVID-19 condition. Unfortunately, individuals with asymptomatic infections can develop post-COVID-19 condition. We need to know the best vaccine to prevent any COVID infection to best prevent post-COVID-19 condition.

Impact of Monoclonal Antibodies 
With the emergence of the Omicron BA.2, only 2 monoclonal products are recommended for use. EVUSHELD is a combination of the monoclonals, tixagevimab and cilgavimab, which bind to the SARS-CoV-2 spike protein. There is animal model evidence that it is effective in protecting against Delta, Omicron and Omicron BA.2 variants. EVUSHELD is used as pre-exposure prophylaxis in people who cannot receive COVID-19 vaccines, or are immunocompromised and unlikely to mount an immune response to the COVID-19 vaccines. Because the purpose of this monoclonal antibody combination is to prevent the development of infection, it may also prevent post-COVID-19 condition.

Bebtelovimab is a recently developed monoclonal antibody for use in patients 12 years of age or older who have tested positive for SARS-CoV-2 and have mild to moderate COVID-19 symptoms. It is effective against Omicron and Omicron BA.2 variant. Since the patients are already infected at the time of administration, it is not clear what impact this monoclonal would have at preventing or modifying any post-COVID-19 condition if it were to occur since there is no clear association between acute disease severity and the disease state in post-COVID-19 condition.

Impact of Antiviral Agents
Three antiviral agents are available for treatment of SARS-CoV-2 infections. All 3 agents are most effective when given as close to the onset of clinical symptoms as possible. Remdesivir is the only antiviral that is approved by the Food and Drug Administration (FDA) for treatment of SARS-CoV-2. Because it is given intravenously, it is used to treat hospitalized patients. In a single center, observational study, patient treated with remdesivir had a 36% reduction in post-COVID-19 condition compared to non-treated ones. It should be noted that the definition of post-COVID-19 condition in this study was quite different than the WHO proposed case definition.

Two oral antiviral agents, nirmatrelvir with ritonavir (Paxlovid) and molnupiravir, have recently received Emergency Use Authorization by the FDA for those over 12 years of age (Paxlovid) or adults (molnupiravir). Both are for outpatient use, and both are recommended to be used within 5 days of symptom onset. There are many drug-drug interactions recognized with ritonavir, a component of Paxlovid. For those prescribed Paxlovid who are taking other medications, a pharmacist should be consulted about any potential interactions. There are no data on the impact of these 2 agents on the prevention of post-COVID-19-condition.

Unanswered Questions About Post-COVID-19 Condition:

  • Will the WHO definition of post-COVID-19 condition be broadly accepted to bring some order to research on this topic?
  • What is the natural history of post-COVID-19 condition? Is it self-limiting or will symptoms persist for months to years?
  • What will be the associated long-term morbidity and mortality of post-COVID-19 condition?
  • Will a million people in the U.S. be permanently disabled by this condition, as the General Accounting Office suggests?
  • Based on the complexity of post-COVID-19 condition, does it represent a single disease state with a unifying pathology, or several disease states with varying pathologies?
  • Are current treatment and prevention methods effective at preventing post-COVID-19 condition? Better designed studies are needed to determine the effectiveness of vaccines, monoclonals, and antivirals in preventing post-COVID-19 condition.
  • As our understanding of this condition matures, will there be interventions that shorten the course of this condition or enhance an affected individual’s quality of life?

Acknowledgement: The author would like to thank M. Lynn Smiley, M.D., for her useful discussion and critical review of this manuscript.

Author: Peter Gilligan, Ph.D., D(ABMM), F(AAM)

Peter Gilligan, Ph.D., D(ABMM), F(AAM)
Peter Gilligan, Ph.D., D(ABMM), F(AAM) is the former Director of the Clinical Microbiology-Immunology Laboratories at the University of North Carolina Hospitals.