Long-COVID Syndrome? A Study on the Persistence of Neurological, Psychological and Physiological Symptoms

1. Introduction

As of March 2021, it appears no longer necessary to repeat how and to what extent the COVID-19 pandemic has plagued humanity in the last year, being responsible for morbidity and mortality levels with few precedents in the recent history [1,2,3]. During the first weeks, in which we were all unprepared to face such a disaster, our attention had necessarily to be directed towards the negative and significant impact of the ongoing infection.

Although most individuals initially developed a mild COVID-19 infection that did not require hospitalization [4], countless individuals needed to be admitted to intensive care units, experiencing life-threatening symptoms. A growing number of studies have reported a set of neurological complications [5,6,7,8] associated with COVID-19 and significant psychopathological symptoms related to intense distress (i.e., post-traumatic stress disorder, secondary traumatic stress, complicated grief and anxiety, amongst others) in the general population and health-care workers [9,10,11,12,13,14,15]. This corollary of symptoms is particularly exacerbated within frontline health-care workers, a category of professionals who are at a significant risk of experiencing high levels of burnout and compassion fatigue compared to the general population [16,17,18] and are in contact with individuals at the final stage of life in their clinical practice [19].

Emerging aspects of COVID-19 clinical presentation are the long-term effects, which, in the absence of any formally agreed definitions, characterize the so-called “long-COVID” or “long-haul COVID” described in recent international journals [20,21,22].

As highlighted by Marshall [20] in Nature, “People with more severe infections might experience long-term damage not just in their lungs, but in their heart, immune system, brain and elsewhere”. In this context, several patients are experiencing a vast variety of symptoms that persist after recovery, despite a negativized pharyngeal swab [23,24,25].

In order to track possible long-term effects caused by COVID-19 with the aim to improve health outcomes, a new initiative has been established in the United Kingdom, called the Post-Hospitalisation COVID-19 Study (PHOSP-COVID) (https://www.phosp.org/, accessed date 2 April 2021). PHOSP-COVID is a consortium of leading researchers and clinicians which aims to recruit 10,000 patients for a year, with the aim to analyze clinical factors derived from clinical assessments and gain a comprehensive understanding of COVID-19 long-term effects along with the patients’ medical, psychological, and rehabilitation needs, enabling, in this way, their full recovery.

Long COVID may incorporate the following symptoms: (i) cardiovascular (i.e., chest tightness, chest pain, palpitations); (ii) respiratory (i.e., breathlessness, cough); (iii) neurological (i.e., stroke, encephalopathy, meningoencephalitis, seizures, cognitive impairment, headache, sleep disturbance, dizziness, delirium); (iv) gastrointestinal (i.e., abdominal pain, nausea, diarrhea, anorexia and reduced appetite); (v) musculoskeletal (i.e., joint pain, muscle pain); (vi) inflammatory (i.e., fatigue, fever, pain); (vii) generalized and aspecific (i.e., skin rashes, tinnitus, earache, sore throat, dizziness, loss of taste and/or smell) (NICE guideline, 2020). Moreover, a few studies also outlined how the sleep patterns change in patients with long COVID, with a drastic reduction in sleep quantity and quality [26,27,28]. In a clinical research conducted by Kokou-Kpolou and colleagues in 2020 [29], the authors analyzed the prevalence of insomnia in the general population and its contributing factors in a sample of French individuals. According to the aim of the study, participants underwent a qualitative sleep assessment based on the Insomnia Severity Index (ISI), and the study confirmed that COVID-19-related worries and loneliness may represent the major contributing factor to clinical insomnia. All these mentioned symptoms can cause a dramatic decrease of the quality of life [30,31].

In the recent literature, when symptoms persist beyond 3 or 12 weeks, the resulting pathological conditions have been defined as “long COVID/post-acute COVID” and “chronic post-COVID syndrome”, respectively. Both these conditions are characterized by a multisystem syndrome that requires an integrated multidisciplinary intervention capable of dealing with both the residual physical symptoms and the consequent social discomforts and mental disorders [32].

In Italy, most COVID-19 patients presented evident symptoms (71.4% of the 31,845 confirmed cases as of 3 June 2020) related to the long-COVID condition. However, there is still limited evidence of this as yet, indeed there are no precise data regarding the persistence of symptoms or its long-term consequences in the weeks and months following the remission period [33]. Consequently, little is known or published on the supposed long-COVID syndrome and its long-term consequences. Some studies have reported that fatigue and headache are the main symptoms displayed by these individuals [25,27,34]. Other clinical studies reported increased sleep-related issues, including insomnia, and a deterioration of the life quality [25,27].

Furthermore, it is also necessary to underline that lung diseases are an established and well-known causes of fatigue [35], and the central nervous origin of post-viral fatigue should also be considered (i.e., inflammatory-mediated and neurocognitive dysfunction) when we analyze long-COVID-related symptoms.

The purpose of the present study was to evaluate the physical and psychological health conditions of a representative sample of the Italian population suffering from symptoms related to long COVID. In particular, we focused our attention on the prevalence of physical, psychological, or neurological problems, insomnia, and the level of quality of life in the general population.

2. Materials and Methods

3. Results

Table 1 shows descriptive statistics for socio-demographic characteristics and participants’ status (COVID-19-positive or not). Descriptive data are presented as number (N) and percentage (%) of subjects belonging to the group.

4. Discussion

Our results remark that the long-COVID-19 syndrome encompasses a rather heterogeneous set of symptoms (including headache, fatigue, muscle aches/myalgia, articular pains, cognitive impairment and loss of concentration, and loss of smell) that, however, appear to recede over time. In addition, when taking into account sleep disturbances, our results highlight that patients with COVID-19 and persistent symptoms associated with the long-COVID-19 condition showed a significantly higher rate of insomnia than subjects who never had COVID-19 (p < 0.05).

As for the psychological characteristics, higher levels of pain and discomfort, anxiety, and/or depression were observed in patients with long COVID-19 than in those who never had COVID-19. On the other hand, patients currently positive for COVID-19 and with long-COVID-19 symptoms reported lower quality of life compared to subjects who had never tested positive for COVID-19.

Such findings appear in line with those reported by other studies and therefore seem to confirm the results currently available in the scientific literature [25,27,34]. In the recent study conducted by Carfì and colleagues [25], 143 subjects were evaluated after 60 days from the onset of COVID-19. Of these, only 18 (12.6%) appeared completely asymptomatic, while 32% presented one or two symptoms, and 55% presented three or more. More specifically, 53.1% of participants reported fatigue, 43.4% dyspnea, 27.3% joint pain, and 21.7% chest pain. Such results appear substantially in line with those observed by Mandal and colleagues [34], indicating that subjects reported a persistence of fatigue (69%), dyspnea (53%), and cough (34%) after 54 days from their negative swab. Finally, a sample of 1733 subjects who had COVID-19 was re-evaluated on average 186 days after the negative swab, and muscle fatigue or weakness was observed in 63% of them.

As initially hypothesized, our results confirmed that patients with COVID-19 or long-COVID-19 syndrome had significantly higher rates of insomnia than subjects who never had COVID-19. Interestingly, such findings are very much similar to those reported in a recent study, in which 26% of participants with long-COVID-19 syndrome showed sleep disturbances [27]. It could also be speculated that the quality of sleep might be negatively affected by the overall pandemic distressful situation as well as by the national security measures applied to contain the spread of the infection. However, our control group (namely, respondents who never tested positive for COVID-19) was exposed to the same containment strategies and social situations, somehow ruling out this alternative explanation. Crucially, our results pointing toward increased sleep disturbance and increased level of mental distress (i.e., anxiety) converge with those of a recent investigation by Alaly and Bowe [39], which documented increased hazard ratio for those disturbances. (HR_{sleep-disorders} = 14.53, HR_anxiety = 5.42) and for death (HR_death = 1.59) after 6 months from the infection.

Finally, subjects with COVID-19 and long-COVID-19 showed a self-reported level of quality of life that was 14.64 points lower (19.5% less) than that of subjects who never had COVID-19. These results are consistent with the outcomes reported in recent investigations that revealed a reduction in the quality of life of subjects with COVID-19 or long-COVID syndrome [25,27].

This study suffers from a number of limitations: (1) the COVID-19 groups were not homogeneous; therefore, future works will have to investigate larger samples and provide statistically homogeneous data; (2) it is advisable to investigate other types of physical and psychological symptoms and to explore whether these are specifically related to COVID-19 or long-COVID-19 syndrome or if this symptomatology is present in other clinical populations; (3) the recruitment channels used could have led us to bias; therefore, future studies will need to expand and balance the recruitment channels; (4) at the time of the survey, the Italian regions were classified according to the level of infection and subjected to different containment measures, put in place by the Italian legislation; unfortunately, this study did not investigate the impact of the different measures of containment, and future studies should take in account such differences; (4) given the nature of this investigation, the study did not explore premorbid conditions of the sample.

As suggested by different empirical studies, there is a great utility in focusing on prediction, rather than explanation, during data analysis, both in the clinical and in the social sciences settings [37,40,41].

In conclusion, the present study highlights that the main symptoms associated with the so-called long-COVID-19 syndrome are the following: headache, fatigue, muscle aches/myalgia, articular pains, cognitive impairment and loss of concentration, and loss of smell. Additionally, in the analyzed sample, insomnia and a reduced quality of life were detected. Due to the limitations of the present investigation, the challenges encountered, and the limited number of studies available so far, robust conclusions are precluded. Further studies are needed to better define the clinical presentation of the long-COVID condition and consequently related tailored treatments.

Author Contributions

Conceptualization, G.O.; methodology, G.O., D.B., F.D.; validation, G.O., D.B., F.D.; formal analysis, G.O., D.B., F.D. and F.M.; investigation, G.O., D.B., F.D.; resources, G.O., D.B., F.D., and F.M.; data curation, G.O., D.B., F.D. and F.M.; writing—original draft preparation, G.O., D.B., F.D.; writing—review and editing, G.O., M.D.G., M.B., C.C., R.C.; supervision, G.O., C.C. and A.G.; All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional (University of Pisa n. 0036344/2020).) and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent Statement

Consent was obtained from all participants included in the study.

Data Availability Statement

The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy issue.

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.