Long COVID: What we have learned so far

Long COVID, also known as post-acute COVID-19 sequelae (PACS), can present as a single or several symptom(s) mainly pertaining to the respiratory, central nervous and cardiovascular systems, manifesting as decreased exercise tolerance, cough, chest tightness, breathlessness, myalgia, fatigue, inability to concentrate, impaired memory, and faster or slower than usual heart rate. [Int J Environ Res Public Health 2022;19:9566; Asian J Psychiatr 2023;81:103438] Approximately 10–30 percent of individuals affected by COVID-19 (including asymptomatic cases) and approximately 80 percent of hospitalized patients may experience PACS. [Lancet Infect Dis 2022;22:e102-e107; Clin Neurophysiol 2023;145:81-88]

“As its symptoms are nonspecific, and may fluctuate or relapse over time, long COVID remains underrecognized and underreported by patients and physicians alike. However, as physicians become more aware of long COVID and less likely to dismiss the symptoms as psychosomatic, its reported prevalence is likely to increase,” explained Dbaibo.

Predisposing factors

“Unexpectedly, certain factors that increase the risk of contracting COVID-19 appear to be inversely associated with long COVID,” said Dbaibo. “For instance, several studies have found that male gender is a risk factor for COVID-19, yet there is a higher prevalence of long COVID symptoms among women. Although the elderly are at higher risk of severe COVID-19 than any other age groups and were therefore prioritized for vaccination in many regions, older age does not appear to be associated with greater risk of long COVID.” [BMJ Open 2021;11:e044640.; Hong Kong Med J 2022;28:215-222; MMWR Morb Mortal Wkly Rep 2020;69:1-5; Science 2021;71:916-921; Glob Health Med 2022;4:129-132]

According to the UK’s Office for National Statistics (ONS), in March 2023, the prevalence of self-reported long COVID was the highest in people aged 35–69 years and females, followed by people living in more deprived areas, those working in social care, those aged ≥16 years who were not working and not looking for work, and those with another activity-limiting health condition or disability. [ONS, 30 March 2023] While correlation of long COVID with age is somewhat ambiguous, female gender was identified as one of the main predisposing factors for long COVID in a number of recent studies. [PLoS Med 2021;18:e1003773; Int J Infect Dis 2022;125:287-293; JMIR Public Health Surveill 2023;9:e42315; Clin Microbiol Infect 2022;28:611.e9-611.e16; JAMA Netw Open 2022;5:e2238804]

Although a third of people with long COVID have no known pre-existing conditions, type 2 diabetes, obesity, and connective tissue disorders have been linked to increased risk in adults, while attention deficit hyperactivity disorder, chronic urticaria, and allergic rhinitis appear to be associated with long COVID in children. [FAIR Health 2022: An Analysis of Private Healthcare Claims Using the Official ICD-10 Diagnostic Code; Cell 2022;185:881-895; Diabetes Obes Metab 2021;23:2183-2188; Front Cell Neurosci 2022;16:888232; Int J Environ Res Public Health 2022;19:5993]

“The important thing to realize is that while there are certain predisposing factors for long COVID, it can affect anyone, including previously healthy adults and children,” pointed out Dbaibo. [Infect Dis (Lond) 2021;53:737-754; Lancet Child Adolesc Health 2022;6:614-623]

Potential causes

“There are multiple, possibly overlapping, causes of long COVID,” said Dbaibo. “The key themes are the disturbance of the immune system, including the dysregulation of immune response and reactivation of existing pathogens; persistence of SARS-CoV-2 infection or viral fragments in tissues; and the impact of SARS-CoV-2 on the microbiota, with resulting effects on the gut-brain axis. Pre-existing weaknesses in any of these biological systems likely increase the risk of long COVID.”

Research into immune dysregulation in individuals with long COVID after mild acute COVID-19 has found T-cell alterations, including exhausted T-cells and reduced CD4+ and CD8+ effector memory cell numbers. [J Neurosci Res 2021;99:2367-2376; J Investig Med 2022;70:61-67] Reactivated viruses, including Epstein-Barr virus and human herpesvirus 6, that have been found in patients with long COVID (and have been implicated in myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]) can lead to mitochondrial fragmentation and severely affect energy metabolism. [Pathogens 2021;10:763; Rheumatol Int 2022;42:1523-1530; J Med Virol 2020;92:3682-3699; Immunohorizons 2020;4:201-215]

In another model of long COVID, persistent SARS-CoV-2 triggers a dysregulated immune system with subsequent heightened release of proinflammatory cytokines that can lead to chronic low-grade inflammation and multiorgan symptomatology. [Allergy Asthma Proc 2022;43:187-193] In one study (n=63), circulating SARS-CoV-2 spike antigen was found in 60 percent of patients with long COVID up to 12 months after diagnosis vs none of the infected patients who experienced no long-term symptoms. [Clin Infect Dis 2023;76:e487-e490] Similarly, another small-scale study (n=46) has identified persistent S1 protein in CD16+ monocytes of patients with PACS up to 15 months post-infection. [Front Immunol 2022;12:746021]

The gut microbiota composition is significantly altered in patients with acute COVID-19 and those with long COVID. At 6 months, patients without PACS showed recovered gut microbiome profile comparable to that of non–COVID-19 controls, while the gut microbiome of patients with PACS continued to be characterized by higher levels of Ruminococcus gnavus and Bacteroides vulgatus and lower levels of Faecalibacterium prausnitzii. Additional evidence suggests a strong correlation between dysbiosis and ME/CFS, providing a potential explanation for some of the neurocognitive symptoms associated with long COVID. [Sci Rep 2021;11:704]

Protective effect of vaccination

While avoiding COVID-19 infection is the best way to protect oneself against long COVID, no COVID-19 vaccine has been shown to be 100 percent effective against infection. “Reassuringly, vaccination does offer protection against long COVID,” stated Dbaibo. “In addition to minimizing the risk of severe illness [one of the strongest risk factors for PACS], receiving ≥2 COVID-19 vaccine doses of also considerably reduces the risk of long COVID.” [PLoS Med 2021;18:e1003773]

A recent systematic review and meta-analysis of six observational studies involving 536,291 unvaccinated and 84,603 vaccinated patients found that two-dose vaccination before SARS-CoV-2 infection was associated with a lower risk of long COVID vs no vaccination (odds ratio [OR], 0.64; 95 percent confidence interval [CI], 0.45–0.92; moderate certainty) and one-dose vaccination (OR, 0.60; 95 percent CI, 0.43–0.83; moderate certainty). Of note, one vaccine dose was not significantly associated with a lower frequency of long COVID. Vaccines included in the meta-analysis were Ad26.COV2.S, AZD1222, BNT162b2, CZ02, and mRNA-1273. [Vaccine 2023;41:1783-1790]

Another recent population-based, multicentre study that surveyed 2,712 community-dwelling COVID-19 patients from four large Chinese cities found that vaccination with ≥2 doses of CZ02 (adjusted OR [aOR], 0.35; 95 percent CI, 0.14–0.90; p=0.03) or BNT162b2 (aOR, 0.22; 95 percent CI, 0.08–0.63; p=0.005) was associated with a lower risk of long COVID symptoms of moderate-to-high severity. (Table) [JMIR Public Health Surveill 2023;9:e42315] 

Key take-away

“We need to change our mindset on vaccination,” said Dbaibo. “Preventing SARS-CoV-2 infection should not be viewed as the sole purpose of vaccination. Instead, vaccine efficacy should be viewed in terms of preventing severe and long-term disease. Even halving the 10–30 percent proportion of [all COVID-19] patients who are experiencing PACS would make a huge difference globally.”