The emergent virus SARS-CoV-2 is responsible for the actual pandemic of coronavirus disease 2019 (COVID-19) that has caused so far 394 million infections worldwide and more than 5.7 million deaths (WHO Coronavirus (COVID-19) Dashboard. https://covid19.who.int/. Access 8 February 2022). These numbers are rapidly increasing due to new emergent variants highly contagious such as Omicron. The clinical outcome of COVID-19 is very variable, ranging from asymptomatic or mild to a fatal disease, mostly dependent on how the immune system reacts during the primary infection. In fact, an exacerbated systemic inflammatory response has been described in the most severe and critical forms of the disease that may lead to multiple organ dysfunction syndrome.

Most individuals completely recover after mild COVID-19 and all signs and symptoms in those patients that do not require hospitalization usually disappear from 10 days to 4 weeks after diagnosis (Sudre CH, et al. Nat Med 2021). However, there is an increasing proportion of patients with mild COVID-19 (about 10%) in which the symptoms do not resolve completely after 4 weeks and may last up to 12 weeks after the clinical onset (World Health Organization. New policy brief calls on decision-makers to support patients as 1 in 10 report symptoms of “long COVID.” (2021)). This new syndrome has been termed Long COVID and is characterized by the persistence of the signs and symptoms developed during or following acute COVID-19 that may continue for more than 12 weeks and cannot be explained by an alternative diagnosis (NICE. COVID-19 rapid guideline: managing the long-term effects of COVID-19. (2021)).

 

Due to the essential role of the immune response in the duration and severity of COVID-19 presentations, several immunological differences may unlikely be observed among individuals with Long COVID and individuals who suffered from mild COVID-19 and completely recovered from the disease. In fact, when we analyzed the immune response developed by individuals with Long COVID or completely recovered from mild COVID-19, we observed a persistent cellular immune response based on memory CD8 and NK cells that were very responsive against SARS-CoV-2-infected cells. Conversely, the immune response was impaired in individuals with Long COVID, as the specific anti-SARS-CoV-2 IgG titers and their neutralizing capability were decreased in their plasma.

 

These data indicated that, despite the potent and sustained cellular response, the ability of the immune system to clear the infection might be ineffectual. This conclusion was supported by the fact that one individual from our cohort of Long COVID still had detectable RNA from SARS-CoV-2 in plasma and also that a significant proportion of individuals with Long COVID (33.3%) showed reactivation of Epstein-Barr virus (EBV) in plasma (Vigón et al., CROI 2022; Abstract 315).

 

In conclusion, Long COVID is a new syndrome developed by individuals in which the immune response is active more than 12 weeks after diagnosis but may be ineffectual to clear completely the virus from the organism. Besides, due to the sustained presence of effector cytotoxic cells long after the primary infection, Long COVID appears to share common characteristics with autoimmune diseases.

Lorena Vigón and Mayte Coiras

AIDS Immunopathology Unit

National Center of Microbiology

Instituto de Salud Carlos III

Madrid, Spain

Contact: lvhernandez@isciii.es, mcoiras@isciii.es

The Challenge of Understanding Long COVID