Special Issue “Post-COVID-19 Symptoms in Long-Haulers: Definition, Identification, Mechanisms, and Management”

The worldwide spread of coronavirus disease 2019 (COVID-19), a condition caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen, led to the most unprecedented disease outbreak of this century, provoking around 770 million confirmed cases and nearly 7 million deaths globally [1]. The extensive literature about COVID-19 has concentrated on the disease and the management of acute cases [2]. With the development of COVID-19 vaccines, hundred of studies investigating their effects have been published [3].

Despite incommensurable efforts being exerted in fighting against SARS-CoV-2, the world is now faced with a post-COVID-19 pandemic, the “long-haulers”, individuals who recovered from COVID-19 but developed long-lasting symptomatologies or post-COVID-19 conditions [4]. Evidence describes the presence of up to 100 post-COVID-19 symptoms [5]. The Global Burden of Disease Long COVID study which included 1.2 million of subjects who had experienced an acute symptomatic SARS-CoV-2 infection, reported that up to 15.1% of COVID-19 survivors experienced long-lasting symptoms one year after infection [6]. Rahmati et al., reported that 41.7% of COVID-19 survivors still experienced post-COVID-19 symptoms two years after infection [7]. However, gaps exist in definitions, timeframe, identification, mechanisms, and treatment strategies for the management of these post-COVID-19 symptoms [8]. The aim of this Special Issue entitled “Post-COVID-19 Symptoms in Long-Haulers: Definition, Identification, Mechanisms, and Management” of the Journal of Clinical Medicine focuses on different aspects of post-COVID-19 symptoms, a topic of emerging relevance due to the expected presence of millions of “long-haulers”. Herein, an overview of all the papers included in this Special Issue is provided.

One study investigated sex differences in the development of COVID-19-associated onset symptoms and post-COVID-19 symptoms [9]. The authors found similar onset symptoms but a higher number of post-COVID-19 symptoms in females than in males [9]. Thus, female sex was associated with a higher presence of post-COVID-19 fatigue, dyspnea, pain, hair loss, and ocular problems, as well as higher depressive levels and worse sleep quality [9]. The fact that female sex is a risk factor associated with post-COVID-19 symptoms has been confirmed in two posterior meta-analyses [10,11]. Biological and psychological sex differences could explain the higher risk for females [12,13,14], which should be considered in future studies where post-COVID-19 treatment would be conducted from a sex perspective.

Fatigue, brain fog and pain are among the most prevalent post-COVID-19 symptoms [6,7]. Post-COVID-19 pain is experienced by 15–20% of subjects after an acute SARS-CoV-2 infection [15,16]. Two papers published in this Special Issue investigated different aspects of pain symptomatology, since the identification of potential risk factors associated with specific post-COVID-19 symptoms can help clinicians to better understand this condition. Both papers focused on the presence of sensitization-associated symptoms in people with post-COVID-19 pain. Several musculoskeletal chronic pain conditions are associated with sensitization [17]. In fact, the evidence supports the presence of sensitization symptoms in individuals with post-COVID-19 condition to a similar extent to in people with fibromyalgia syndrome [18]. Since one clinical manifestation of pain sensitization is the presence of larger areas of pain [19], its association with other measures of central sensitization could reveal potential mechanisms of post-COVID-19 pain. In individuals with post-COVID-19 pain, the pain extent was not associated either with psychophysical (e.g., pressure pain thresholds) or with psychological (anxiety, depression, or sleep quality) outcomes, suggesting that pain extent represents a different aspect of the pain spectrum [20]. Similarly, the presence of sensitization-associated symptoms was not associated with serological biomarkers at hospital admission in a cohort of previously hospitalized COVID-19 survivors [21]. These results suggest that sensitization-associated symptoms and their relevance in patients with post-COVID-19 pain need to be further investigated, since it would be possible that a group of individuals with post-COVID-19 pain exhibit a nociplastic phenotype [22] and, hence, require particular attention. In fact, current hypotheses suggest that post-COVID-19 conditions and fibromyalgia syndrome share common mechanisms [23].

The study by Matias-Guiu et al., tried to identify cognitive predictors of the most prevalent post-COVID-19 symptom, fatigue [24]. This study was not able to identify any neuropsychological predictor explaining the presence of post-COVID-19 fatigue, suggesting that these symptoms, i.e., fatigue and cognitive impairments [24]. This study suggests that physical and cognitive post-COVID-19 symptoms exhibit different underlying pathophysiological mechanisms [24].

The remaining papers included specific populations. For instance, Yamamoto et al., identified the presence of late-onset hypogonadism in almost 50% of individuals who had survived COVID-19 [25]. This study found that the association between the serum level of free testosterone and levels of blood hemoglobin and serum total protein and albumin observed in COVID-19 survivors was not identified in individuals developing late-onset hypogonadism [26]. Another study including kidney transplant recipients, a vulnerable population, identified that 70% developed post-COVID-19 symptoms, with fatigue, hair loss, memory impairment and pain being the most prevalent symptoms [26]. The development of post-COVID-19 symptoms in this population is highly relevant, since kidney transplant recipients show a deficient antibody immune response after the administration of an mRNA SARS-CoV-2 vaccine [27].

The last paper published aimed to identify the role of endothelial dysfunction and the reduced cardiopulmonary exercise performance exhibited by COVID-19 survivors [28]. This study found that alteration of the endothelial barrier properties in systemic and pulmonary circulation may represent a key mechanism of the reduced cardiopulmonary exercise performance identified in this population [28]. The identification of an alteration of endothelial barrier properties could lead to better rehabilitation strategies targeting this mechanism and could explain why some patients with a post-COVID-19 condition develop post-exertional malaise. Again, this endothelial dysfunction is also observed in individuals with myalgic encephalomyelitis/chronic fatigue syndrome [29,30], another entity showing common mechanisms with post-COVID-19 conditions [31].

As Guest Editors of this Special Issue, we would like to thank the reviewers for their insightful comments, all authors for their valuable contributions, and the JCM staff for their collective support and assistance during this process.