Exploring the Complexities of Long COVID

Abstract

Since the emergence of the SARS-CoV-2 virus in 2019, nearly 700 million COVID-19 cases and 7 million deaths have been reported globally. Despite most individuals recovering within four weeks, the Center for Disease Control (CDC) estimates that 7.5% to 41% develop post-acute infection syndrome (PAIS), known as 'Long COVID'. This review provides current statistics on Long COVID's prevalence, explores hypotheses concerning epidemiological factors, such as age, gender, comorbidities, initial COVID-19 severity, and vaccine interactions, and delves into potential mechanisms, including immune responses, viral persistence, and gut dysbiosis. Moreover, we conclude that women, advanced age, comorbidities, non-vaccination, and low socioeconomic status all appear to be risk factors. The reasons for these differences are still not fully understood and likely involve a complex relationship between social, genetic, hormonal, and other factors. Furthermore, individuals with Long COVID-19 seem more likely to endure economic hardship due to persistent symptoms. In summary, our findings further illustrate the multifaceted nature of Long COVID and underscore the importance of understanding the epidemiological factors and potential mechanisms needed to develop effective therapeutic strategies and interventions.

Keywords: Long COVID; SARS-CoV-2; post COVID-19 condition.

Figure 1

Major milestones in the evolution of Long COVID. A representative timeline for major events, including the emergence of COVID-19, lockdowns, initial reports of Long COVID, and recognition by major organizations, including the WHO and CDC. The attention gained aimed to establish a comprehensive definition, funding, and future allocations, engaging the United States Congress.

Figure 2

Long COVID symptoms. A representative diagram of Long COVID symptoms. All organ systems appear to be affected, including the heart, mouth/nose, muscle, head, gastrointestinal tract, brain, skin, lungs, kidneys, abdomen, and joints.

Figure 3

Most prevalent Long COVID symptoms. A pie chart representing the most prevalent five symptoms of Long COVID.

Figure 4

Gender disparities of Long COVID in the US. A bar graph depicting the gender of Long COVID adult patients. Compared to males, the number of Long COVID patients was significantly higher in females (21.2% vs. 14.7%, * p < 0.05). Additionally, more females (7.2% vs. 4.7%, * p < 0.05)) currently have Long COVID compared to males.

Figure 5

Direct viral invasion through the olfactory bulb. A schematic diagram demonstrating the proposed viral entry through the olfactory bulb. Alongside the ACE-2 receptor, NRP1 stands as an alternative entry point for the virus. SARS-CoV-2 may engage either NRP1 or ACE-2, infiltrating olfactory neurons and utilizing them as a pathway for direct access to the brain.

Figure 6

Direct viral invasion across the blood–brain barrier. A schematic diagram demonstrating the proposed pathogenesis across the blood–brain barrier. 1. Viral proteases induce endothelial damage. 2. SARS-CoV-2 binds to ACE-2 receptors. 3. The virus traverses the blood–brain barrier via the transcellular pathway. 4. Astrocytes and microglia undergo direct infection, triggering activation. 5. Activated astrocytes and microglia secrete cytokines, initiating a cascade that further activates the immune cells.