Symptoms of the Long COVID and Related Primary Health Care Implications: Systematic Literature Review

Kristina Ziuteliene, Erika Fabijonavice^*, Gabriele Bartkute and Ida Liseckiene
^*Correspondence: Erika Fabijonavice, Department of Family Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania, Email:

Keywords

COVID-19 • Long COVID • Family medicine • Primary health care • Post COVID-19 condition

Abbreviations

CDC: The Centers for Disease Control and Prevention; EC: European Commission; FP: Family Physician; ICU: Intensive Care Unit; LS: Long COVID; NICE: National Institute for Health and Care Excellence; PHC: Primary health care; PPCS: Persistent Post-COVID Syndrome; WHO: World Health Organization

Introduction

Coronavirus infection, commonly known as CoV-2, is a contagious viral disease caused by infection with the severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2) strain [1]. Clinical manifestation of the disease starts to appear after the incubation period and can range from mild symptoms such as cough, fever, fatigue, and sore throat to severe pneumonia and respiratory failure requiring mechanical ventilation. The treatment of the infection is usually supportive, however effective antiviral treatment that would change the course of the disease is not established yet [2]. Since scientists detected first cases of COVID-19 in December 2019 in Wuhan, China, SARSCoV- 2 has caused worldwide pandemic that resulted in high hospitalization and mortality rates [3]. There are 513 million confirmed cases of CoV-2, including 6.2 million deaths. The World Health Organization (WHO) stated that patients feel the impact of acute CoV-2 infection days and even months after being considered COVID-free [1,4]. CoV-2 may cause various ailments, unrelated and unexplained symptoms, and LC is one of them. 1 out of 10 people still have the remaining symptoms representing LC [1]. However, recent studies have shown that LC may be with much higher incidence. Studies in 2020 showed that LC incidence ranged 10-35% among the patients with acute CoV- 2 infection treated at home [5,6]. Among people hospitalized due to CoV-2, the incidence rate could be as high as 80% [5]. In reviewed literature, Huang C, et al. [7] study demonstrated that out of 1655 patients, 76% still had recurring symptoms. Carfi A, et al. [8] showed LC rate being 86.7% and Hermosillo JA, et al. [9] stated that after four weeks, 88.6% of patients experienced symptoms of LC. Townsend L [10] demonstrated that after 12 weeks of follow-up, only 42.2% of the study group felt completely healthy and with no COVID-19 related symptoms.

The early stages of CoV-2 enhanced health care system problems – faulty economic resources distribution, lack of human resources, and inability to cope with patient overload in all health care chains [4]. However, LC can become a new challenge in PHC due to its variability. Knowing the damage acute CoV-2 has caused worldwide, it is predicted that LC will have a massive impact on patient care, and the first responder and help provider to the patient will be a FP. It remains unknown how PHC should cope with such an upcoming burden.

The aim is to review studies exploring the most common symptoms as predictors of LC and potential syndrome management challenges in the PHC context.

Methods

The study undertook a systematic review using Cochrane methodology and PRISMA guidelines.

Search strategy and selection criteria

The literature review was conducted for publications in English indexed in MEDLINE, ScienceDirect, and ClinicalKey databases. Grey literature was searched but restricted to official the United States Centre for Disease Control (CDC) and World Health Organization (WHO) guidelines and presented data. Search terms included terms related to post-COVID condition, known as LC. Search terms were used: "post COVID-19 condition", "Long COVID-19", "syndrome", "symptoms", "long haulers". Subsequently, a search was conducted using "Long COVID" combined with "primary health care” and "general practice" to establish any recommendations and trials in PHC context, if possible. Based on lack of literature, all the available studies were included, not only based in PHC to achieve the objectives of this systematic review. Eligibility criteria are presented in Table 1. Reference lists in review articles were identified during this search and the final included articles were checked to identify additional potentially eligible studies. No restrictions were on the study publication date.

Study selection and data extraction

All titles and abstracts were initially screened manually by a single author, then two authors independently screened selected samples. If eligibility criteria were met – the full article was presented for the data extraction. When available, categories of data were extracted from each case study: population of the study and their characteristics (age, sex), symptoms the patients experienced for at least four weeks after considered "COVID-free" and their incidence, potential risk factors, follow up period.

Risk of bias

The study quality was assessed independently by three reviewers. The risk of bias was assessed with the Risk of Bias Assessment tool for Nonrandomized Studies (RoBANS) tool (Figure 1). One of the review authors undertook quality appraisal, and if any disagreement occurred, it was resolved through discussion.

Results

Our research strategy identified 5976 results. After further inspection, excluding duplicates (n=212), off-topic studies which did not meet inclusion criteria, and our research objectives (n=5680), only 49 were included for evaluation (Figure 2). After thorough full article reading and quality assessment, 15 publications fully met our literature review criteria and were included in the study (Table 2). The study population varies from 100 to 1265 patients, the largest one coming from the Huang C, et al. [7]. The total population sample of our study is 4420 patients. In the studies, the symptoms were considered LC if it occurred 4 weeks after the acute CoV-2 phase (confirmed with RT-PGR or IgG/IgM antibody testing). If possible, risk factors were evaluated [11,12].

LC is a syndrome characterized by the persistence of clinical symptoms beyond four weeks from the onset of acute symptoms [3,13]. The United States CDC has formulated "post COVID-19 condition" to describe health issues and to present their variability - Long COVID (which consists of a wide range of symptoms that can last weeks to months) or Persistent Post-COVID Syndrome (PPCS) [14]. It is unclear how long these symptoms may last. LC can be short-term- experienced for days or weeks, or long-term – persisting for months. Some studies divide post-acute symptoms at 1-month after acute COVID-19 (short term), persisting and new clinical manifestations between 2 and 5 months after infection (intermediate-term), and clinical manifestations that were present at least six months after COVID-19 (long term) [15]. LC would be defined as long term chronic disease if it would last for more than a year, according to CDC [16].

It seems that recent publications show that LC is ubiquitous among patients after acute SARS-CoV-2 infection. LC could emerge as a new hidden pandemic as many patients will seek professional help. The first responders – FP, will be put under pressure to diagnose and treat the LC patients.

Long COVID clinical manifestations

Individuals who have recovered from mild and moderate COVID-19 are also experiencing post COVID-19 symptoms, sometimes with disabling features and inability to return to their everyday life [6].

According to the publications, the most common symptom is chronic fatigue (34.8-68%) which lingers for up to 12-24 weeks after acute CoV-2 infection [6-15]. It can be experienced as exhaustion episodes, cognitive dysfunction, and depression [16]. Another common LC symptom is dyspnea, which occurs in 9.5 to 59.5% of the patients [6-8,11-13,15,17]. Dry cough occurs in 6.6- 35.1% of the cases. Worthy of mentioning that respiratory symptoms, such as dyspnea and chest pain, are more familiar to hospitalized patients diagnosed with moderate and severe acute infection [18]. Some patients diagnosed with LC noted muscle and joint pain (9-55%) [6,7,9-11,13-15,19-21].

Most LC patients experience some neurologic symptoms. According to the authors, the most common are anosmia or partial olfactory dysfunction (5- 59%), the headache was reported in 68% of patients [6,9,11,12,14,21]. Some even experience vertigos (up to 47%) (Table 3) [21]. These symptoms are usually negligible and related to indirect pathogenetic mechanisms, such as systemic inflammatory response and post-infectious immune response [22].

When a person experiences LC for months, it may manifest in psychiatric disorders-depression, anxiety disorder, mood changes, insomnia. Sleeping disorders were recurrent in LC patients who had comorbidities [10]. These psychologic after-effects were observed for more than 6 months after the SARS-CoV-2 infection [13,17,19]. Potentially, it could be caused by the virus itself, isolation that the infection causes, and stigma surrounding the infected [19]. These patients may demonstrate suicidal thoughts, so FP should take a thorough neurological and psychological exam to prevent potential harm [23]. LC symptoms incidence is presented in Figure 3. Most of the reviewed studies did not obtain a male to female ratio, so conclusions on symptom manifestation differences due to sex cannot be made. Further studies should investigate gender implications on LC as there are data that CoV-2 itself differs in males and females [24].

The syndrome can have numerous manifestations, as seen before - mostly nonspecific. FP is challenged to differentiate whether the problems patients experience are related to the recent acute infection, presence of other diseases, or even reinfection of CoV-2. The National Institute for Health and Care Excellence (NICE) guidelines advice that assessment and management should be tailored to the individual's problems, after excluding any coexisting illness that may be giving rise to the symptoms reported. This would include chest radiography in those with respiratory symptoms, checking for a postural drop in blood pressure in those with dizziness. Red flag symptoms should be excluded by FP as they could indicate the need for emergency care for serious complications of COVID-19. Red flag symptoms include severe, newonset, or worsening breathlessness or hypoxia, syncope, unexplained chest pain, palpitations or arrhythmias, new delirium, or focal neurological signs or symptoms [1]. If any suspicions of LC occur, FP should consider identifying antibodies against CoV-2 [25-32].

The authors claim that LC incidence is higher in patients with comorbidities such as diabetes mellitus, hypertension, and ischemic coronary disease [19,33]. Moreno-Perez O, et al. [18] state that LC risk is higher among patients hospitalized in ICU, especially those who were intubated and received pulmonary ventilation. Links between lymphopenia, higher ferritin, D-dimer levels, and LC were also observed. Huang C, et al. [7] and Menges D, et al. [26] determined that severity of acute infection, female gender, and smoking are also significant risk factors [17,19]. González-Hermosillo JA [9] linked LCS to obesity [8]. Prolonged symptoms were primarily observed in this 40-60 years age group [6]. According to literature, most of the patients experiencing LC were 50 years old on average and the incidence of LC was much higher when compared to, for example, the patient group under 18 years, where LC rate was observed <1% [34].

Since many authors agree that LC has a cyclical and not progressive course, the patient potentially will come for many appointments, and it could put PHC into an overload if no actions are taken [24,29,35]. There are no predictors which would let a FP predict LC course, severity, and how long it will take the patient to get to total health.

Discussion

More than 513 million CoV-2 infection cases have been diagnosed worldwide up to this day, and the numbers are still growing. According to the available literature, LC incidence may be up to 80%, so it can be assumed that there could be more than 410 million people suffering from LC. However, no clinical trials or statistical data was collected and presented globally about LC prevalence so far.

As established before, LC symptoms are very unspecific and rely primarily on anamnesis. Symptoms such as fatigue, dyspnea, chest, head, and body aches, sleep difficulties, and cognitive disorders may signal many diseases. As this is becoming a challenge for FB, new guidelines and recommendations emerge daily. Some studies suggest approaching diagnosis by ruling out processes unrelated to CoV-2 infection. It may include identifying each and individual system’s pre-existing pathologies. If required, follow ups with complimentary testing for other etiologies, may be scheduled, so a FP could identify whether it is persisting post COVID-19 manifestations or not [36]. Delphi study (2021) suggests that the general approach in someone with suspected LC, symptoms of possible non-COVID-19-related issues should be investigated and referred as per local guidelines. Most specialists agreed that carry out a face-to-face assessment including a thorough anamnesis, examination, and tests such as full blood count, C-reactive protein, renal, liver, and thyroid function markers, glycated hemoglobin, vitamins D and B12, folate, ferritin, magnesium, and bone studies should be included [37].

It is important to notice that the symptoms may be debilitating to some individuals and impact their daily life and workability heavily. The prolonged symptoms can make a person unable to work full-time and take sick leaves. Average sick leave length, when diagnosed with LC, remains undetermined. However, in 2021, Sweden's National cohort (n = 11966) presented that more than 13% of the LC patients were forced to take sick leaves, which had a significant economic impact [38]. Some studies show that 84.1% of the patients experienced activity limitation and restrictions in daily life and their workability was heavily impacted [39]. In addition, a recent study, spanning 56 countries, has demonstrated that 45.0% of people who had been sick for over 28 days with cases of COVID-19 reported a reduced work schedule due to ongoing symptoms, and 22.0% not working more than six months after falling sick [40]. Withal, the exact duration of LC is unknown, and people could be disabled from working for extended periods and this could cause major economic implications worldwide. In some countries, PHC specialists are also responsible for issuing sick leave notices both short and long term, which creates an additional administrative and time-consuming challenge for the PHC sector.

Studies show that chronic illnesses such as LC are associated with unemployment and a higher prevalence of psychological disorders, due to workability issues [41]. As the LC population consists primarily of middle-aged people, unemployment may increase, as studies show that as workers get older, the duration of their unemployment lengthens, and the chances of finding a job decline [42]. Rehabilitation and ensuring persons' workability should be a national priority. Furthermore, to help patients with mild to moderate symptoms of LC stay functionally engaged is appropriate workplace accommodations and an adjustment to a job or work environment that makes it possible for a person with a health-related disability to make a timely and safe return to work and to perform their job duties effectively. A FP should advise such accommodations and rehabilitation programs to the patient [43].

New strategies are being developed by the European Commission (EC) to treat LC. It is essential to lecture PHC specialists and provide them with up-todate information and guidelines about LC as this upcoming burden will become more and more frequent in the primary care chain. To this day, there are no unified guidelines worldwide on how to cope with LC in the PHC chain, only sporadic suggestions. According to some articles, EC will invest 5 million euros at clinical trial safety assessments, another 5 million to map treatments being developed and what supply chains they would need and provide 40 million euros to support the manufacture of remedies for LC. However, this remains uncertain. More and more countries took the matter into their own hands and established post COVID-19 care centers with specialists that help patients with LC. The United States has 44 centers, UK and Italy also have rehabilitation centers, and with certain decisions and guidelines, the centers could potentially help relieve the healthcare system and suffering patients [44,45]. It is crucial to give this upcoming hidden pandemic the attention and prioritize it as the extent of the disease and the damage it could bring devastating results in challenges for many FP as the burden of diagnosing and treating LC patients is entrusted to them.

Few studies explore LC challenges in PHC. Now the only resource of information is NICE guidelines and WHO recommendations, as not many literature reviews or guidelines explore LC in primary care context. A recently published study by Siso-Almirell, et al. suggested local clinical practice guidelines to identify patients with symptoms of LC in primary care through a protocolized diagnostic process and establish an accurate differential diagnosis [36]. In August 2020 first attempts to develop management strategies of LC in PHC occurred even though there was limited evidence, and it was suggested that there was no need to refer or investigate LC cases if the patient is otherwise well [6]. As more significant data about LC emerges, broad, multi-center studies should be initiated to develop diagnostic strategies and management guidelines specifically for FP to follow in the future.

Conclusion

The most common LC symptoms in the selected studies were chronic fatigue, dyspnea, chest pain, muscle and head pain, and neurological and psychological manifestations. Only a few clinical trials determined specific symptoms as possible risk factors for LC development, however, hospitalization in ICU, intubation, smoking, obesity and comorbidities are some of the few confirmed. Currently, there is a substantial lack of universal guidelines or diagnostic protocols that would allow a FP to differentiate LC symptoms from other pathologies. No factors which would help to predict the course and severity of the syndrome, and how long it will take for the patient to recover were defined so far. Further studies investigating LS predictors and PHC management strategies are necessary to correspond to a growing need to provide quality PHC for patients worldwide.

Limitations and Recommendations for Future Studies

There are few systematic literature reviews covering LC sequelae, however, to the authors' knowledge, this is one of the first systematic literature reviews discussing LC in the PHC and its possible impact on patients' workability, and the challenges that the syndrome brings for a FP to diagnose and treat a patient. It provides broad, up-to-date information from the researched literature and even though the topic of Long COVID symptoms has been covered, not many studies discuss the symptoms in on primary healthcare basis and what impact it may have to FP. Most of the studies had a low/moderate risk of bias. The studies identified were all from various countries and are therefore representative of many international contexts. However, more global studies are needed. Many of the included studies used qualitative methods, such as questionnaires, to explore participants' symptoms. Only studies in English were included, however there may be studies in other languages.

A key research priority understands the impact of LC. PHC specialists must become acquainted with LC manifestations and groups at risk to contain them. Evaluations and data should explicitly work towards unified global guidelines as many countries have solitary tries to overcome LC. Further research needs to explore relations between LC and gender, race, comorbidities. Data should be multi-centered. Further predictions can be made based on an unprecedented amount of data collection of this unique pandemic as it would assist unified guidelines and worldwide policies development of LC.

Acknowledgements

The authors would like to kindly thank colleagues at the Lithuanian University of Health Sciences for their consultations and insight on topics related to this study, and to the Head of the Family medicine Department - Professor Leonas Valius.

Conflict of Interest

The authors declare no conflict of interest.

Appendix

Supplementary materials.

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