News & Resources
December 1, 2022

Like It? Share It

The Long COVID Pathophysiology Part 2 – General Concepts

COVID-19 Resources

The term “Long COVID” is one of many terms with variable definitions. As with many emerging disease processes, the terms used have evolved along with our perspectives and understanding of the disease. Long COVID and other associated terms currently serve as more of an umbrella moniker for a wide range of physical and mental health consequences experienced by some patients after COVID-19 infections.

Defining Long COVID

Despite calls for a unified definition from national and global groups, the clinical issues experienced by individuals following COVID-19 infections remain varied. Much of the current difficulty in defining it revolves around the multiple definitions used by clinicians and scientists.

The CDC typically focuses on persistent symptoms four weeks after initial COVID-19 infection. Symptoms before four weeks are generally considered to be associated with acute infection with SARS-CoV-2. Long COVID is typically thought of as a lack of return to a usual state of health following acute COVID-19 illness.

Prevalence of Long COVID

A specific prevalence for Long COVID is difficult to determine. Likely the most reliable estimates lie between ten to 30% of individuals who experience a COVID-19 infection. More recent studies put the prevalence estimate towards the lower end of this spectrum. A study out of The Netherlands evaluated a pre-Omicron (mostly Delta) infected group contrasted with a control group and put Long COVID prevalence at around 12% at six weeks. The CDC cites 13% at 30 days and 2.5% at 90 days.

In addition, prevalence seems to be altered by variant. A study out of the United Kingdom was able to compare Delta versus Omicron-infected cohorts and reported prevalence of the Delta cohort at 10% versus an Omicron cohort of 5%. However, the much larger number of overall Omicron infections still increased the number of patients with Long COVID complaints. The number of Omicron-related Long COVID complaints outnumbered the cumulative number of complaints from all other SARS-CoV-2 variants combined.

What are Symptoms of Long COVID?

Many symptoms have been reported as associated with Long COVID. Fatigue, dyspnea, chest pain or tightness and cough are by far the most common symptoms. The somewhat ill-defined complaint of “brain fog,” or difficulty in concentration and focus, is very commonly reported. It is however more likely that individuals do not seek medical care for this problem, and it is therefore likely quite under-reported.

The less common complaints span a wider range of problems. Despite being less commonly reported, these complaints can still be quite disconcerting for the patient. Up to 20-33% of individuals with Long COVID will have more than one symptom. Diagnostic testing for some of these complaints does exist, but for the most part, Long COVID is a syndrome that is complaint-based and otherwise not verifiable by discrete testing.

What are the Possible Risk Factors for Long COVID?

Severity of illness with COVID-19 is one factor associated with increased risk. Higher severity of illness is likely the most significant risk factor for Long COVID. Studies have shown that hospitalization for COVID-19 increased the risk of Long COVID five times over non-hospitalization. Admission to critical care increased risk by over seven times over non-hospitalization. Comorbidities are also linked to an elevated risk of Long COVID and span the spectrum through diabetes mellitus to hypertension. This also includes some psycho-emotional conditions including depression.

Gender also seems to have an impact on the incidence of Long COVID. Males have a higher overall risk for contracting, developing serious illness and dying from COVID-19 (50-60% higher). In 2021, approximately 60,000 more men than women died from COVID-19, according to the CDC. At the same time, women have a substantially higher reporting rate of Long COVID complaints than men; women are estimated to be 50-60% more likely to develop Long COVID than men.

Vaccination Status and Long COVID

Several studies have addressed the questions of COVID-19 vaccination status and Long COVID. A case-control study in Lancet from 2022 reported that COVID-19 symptom intensity during the first week of illness, and the persistence of symptoms were less common in individuals who had been vaccinated when compared to those who were unvaccinated.

An observational cohort study published in JAMA included nine Italian health centers with 2,560 patients and noted that the prevalence of Long COVID decreased in a vaccine dose-dependent manner. All of these patients were defined as “mild” COVID-19. Unvaccinated patients developed Long COVID 42% of the time compared to 30% in individuals who had received a single dose of vaccine. A cohort with two doses (the full primary series) experienced a 17% rate and three doses (one booster) dropped the rate to about 1%. These results were all associated with reasonably narrow confidence intervals.

Who is Taking Ownership of Long COVID?

Many post-COVID conditions can and are being managed by primary care providers. Because of the pervasive impacts Long COVID has on some individuals, a patient-centered approach to optimize function and quality of life is important. Primary care can effectively manage specialty referrals as needed to neurology, pulmonology, cardiology, mental health, rehabilitation and other medical domains.

Primary care management may also help impact the readmission rates for COVID-19 cases currently reported at about 10% at 30 days and 20% at 60 days. Of note, there has also been a proliferation of “Long COVID Rehabilitation Centers” over the last year.

Prevention of Long COVID

The primary way to prevent Long COVID is to prevent COVID-19. Once the disease is contracted, there is no currently known way to decrease the chance of developing Long COVID symptoms. At this time the primary preventive measures consist of the standard public health measures of vaccination, masking, social distancing and hand hygiene.

What Areas of Focus and Research are Needed?

Patient-centered care and support systems need to be integrated to improve quality of life and recovery. Also, education on Long COVID needs to be developed and deployed to clinicians, patients, families and the public. Better analysis and characterization need to be done on post-COVID symptoms and definitions. Identification of risk factors along with the potential mechanisms involved will likewise help us better understand how to prevent Long COVID. Understanding the characteristics of any groups that are disproportionately affected by Long COVID will also help inform clinical decisions. In addition, a better assessment and understanding of the disease burden along with the associated healthcare cost and resource needs will help.

Finally, identification of successful interventions for COVID-19 and Long COVID will help prevent and decrease the impact of these conditions. Increasing access and promotion to vaccination will prevent COVID-19 and any subsequent outcomes. Importantly, we must focus on equity in healthcare around this issue to promote more balanced access and utilization.

Pathophysiology of Long COVID General Concepts

Further studies need to be conducted to investigate the underlying pathophysiology of COVID-19 and Long COVID. These studies will more specifically inform us regarding potential preventive, restorative and rehabilitative methods and agents for Long COVID. Find more COVID-19 resources, see a full list of references and read part one of our Pathophysiology of Long COVID series.