Long COVID, a new clinical entity constantly evolving

By Tarun Sai LomteReviewed by Benedette Cuffari, M.Sc.Oct 27 2022

A recent Journal of Microbiology, Immunology, and Infection study discusses the epidemiology, diagnosis, pathogenesis, and treatment of long coronavirus disease 2019 (COVID-19).

Study: Long COVID: An inevitable sequela of SARS-CoV-2 infection. Image Credit: fizkes / Shutterstock.com

What is long COVID?

COVID-19 manifests as mild or asymptomatic illness in most patients; however, some patients develop severe disease or acute respiratory distress syndrome (ARDS), even following receipt of antiviral treatments and/or vaccines. Even after recovery from severe COVID-19, some patients have reported persistent symptoms that have been collectively referred to as long COVID, post-COVID-19, or post-acute sequelae of COVID-19 (PASC).

Long COVID may be defined in multiple ways, such as the presence of symptoms that have persisted beyond three weeks after initial symptom onset or the development of symptoms unexplained by an alternative diagnosis lasting for more than four weeks. The present study provides an overview of the current understanding of long COVID.

Epidemiology and risk factors of long COVID

A meta-analysis of 50 studies estimated the global prevalence of long COVID at 28 days or more to be 43%. Asia had the highest prevalence at 51%, followed by Europe and America.

Another meta-analysis reported that over 63% and 71% of patients had at least one post-COVID-19 symptom after 30 and 60 days post-onset/hospitalization, respectively. One study observed that the prevalence of long COVID among children and adolescents was 25.24%, whereas the rate of long COVID was 29.19% for hospitalized patients.

Furthermore, an Italian study revealed that long COVID prevalence in healthcare workers varied across COVID-19 pandemic waves. One United States study on veterans indicated that vaccine-breakthrough infections exhibited an elevated risk of post-acute sequelae, including gastrointestinal, cardiovascular, mental health, neurologic, and hematologic disorders. Another retrospective study identified age and severe disease as factors associated with a higher risk of experiencing at least three symptoms at one-year follow-up.

Clinical manifestations and mechanisms of long COVID

Long COVID can affect multiple organs, with one study concluding that respiratory, cardiovascular, and neuropsychological symptoms were most frequently reported in COVID-19 survivors. Numerous studies have identified fatigue as the most prevalent systemic symptom. Mood swings are most frequently reported in children and young adults.

Shortness of breath, post-activity polypnea, dyspnea, chest distress, pain while breathing, cough, and polypnea are common respiratory symptoms of long COVID. Common neurologic manifestations include brain fog, memory impairment, paresthesia, dysnomia, vertigo, headache, poor attention span, bradykinesia, anhedonia, and anguish.

In addition, psychosocial symptoms such as depression, anxiety, psychosis, post-traumatic stress disorder (PTSD), and behavioral disorder have also been reported. One meta-analysis observed anxiety and depression in 22% and 23% of long COVID patients, respectively. Memory loss/complaints, forgetfulness, and difficulty concentrating and sleeping were also prevalent in this study.

One study found elevated interleukin 2 (IL-2) and IL-17 levels, as well as reduced IL-4, IL-6, and IL-10 levels, in long COVID patients relative to those without any sequelae. Several biomarkers were found to be associated with neurologic sequelae, of which included angiotensin-converting enzyme 2 (ACE2), IL-17, transmembrane protease serine 2 (TMPRSS2), zonulin, and interferon (IFN)-γ.

The explicit mechanisms of long COVID remain poorly defined given its novelty. However, several mechanisms have been theorized, of which include damage to ACE2-expressing organs by SARS-CoV-2, inflammation due to persistent viral reservoir post-infection resolution, host responses such as over-production of cytokines, auto-immunity, and delayed inflammation resolution affecting homeostatic milieu of the organ(s), among others.

Vaccines, diagnosis, and potential treatment

One prospective case-control study reported that individuals were less likely to report persistent symptoms after receiving a second COVID-19 vaccine dose than non-vaccinated individuals. An Italian observational cohort study observed that BNT162b2 vaccination was associated with a lower prevalence of long COVID that decreased with the number of vaccine doses administered.

The appropriate diagnostic criteria for long COVID are unclear, as the condition can manifest with non-specific symptoms and involve multiple organ systems. Nevertheless, the diagnosis should be guided by the patient’s history, physical examination, and clinical manifestations. Functional status and quality of life can be assessed using a post-COVID-19 function status scale and patient-reported outcome measurement information system.

Montreal cognitive assessment, Compass 31, mini-mental status examination, and neurobehavioral system inventory may be used to evaluate neurologic conditions. Electrocardiograms, echocardiograms, pulmonary function tests, or chest radiography may be helpful for new cardiac or respiratory concerns.

Long COVID management warrants prompt a multi-disciplinary assessment that focuses on managing specific symptoms and supporting rehabilitation. Hyperbaric oxygen therapy (HBOT) is also a potential therapeutic modality.

Several trials are currently investigating the effects of physiotherapy, physical rehabilitation, neurorehabilitation, and cognitive interventions. These studies may provide more conclusive evidence in the future.

Concluding remarks

The number of long COVID cases may increase as the number of COVID-19 cases continues to rise worldwide. Based on currently available information, long COVID could develop in all COVID-19 patients, although severe patients are at an increased risk.

Furthermore, long COVID could present with heterogeneous clinical manifestations, with vaccination potentially being the only way to avert long COVID. Future studies are needed using established diagnostic and definition criteria to gain more insights into long COVID.