Post-COVID-19 syndrome: Knowledge gaps

Post-COVID-19 syndrome consists of the persistence of a set of symptoms derived from infection by the SARS-CoV-2 virus (COVID-19), which can last for several weeks or months, and therefore not only affect people’s ability to recover their health, but also their quality of life, mental health, and ability to carry out daily activities. Since this new condition began to be documented, various names and clinical definitions have been used.^1-3 However, in September 2020, the World Health Organization enabled classification codes for this disease and, in October 2021, proposed a clinical definition of the disease through expert consensus: “Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction, but also others, and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time. A separate definition may be applicable for children”.³
As can be seen, this is a rather tentative definition due to the state of knowledge thus far. The most common symptoms of the acute phase of COVID-19 disease have already been reported with sufficient clarity, but quite a few questions remain about the pathophysiology and the manner of persistence of many symptoms over time.^4-6 Other enigmas concern the different effects among patients and the more general consequences for health systems, the economy, and society.^7,8 According to different reviews and updates in the scientific literature, seven knowledge gaps about post-COVID-19 affectation are recognized (Table 1).

Conceptual Gap	Several equivalent terms have been used to define this new condition: ‘Long COVID’, ‘Post Acute COVID’, ‘Post COVID Syndrome’, etc.  This diversity in terms has produced a variety of definitions and also significant differences in literature.
Theoretical Gap	Theoretical definitions are imprecise with respect to certain populations and do not adequately cover mental health aspects.   There is no general agreement on the duration of persistent symptoms. Studies indicate disparate reports of continuity over time for the same symptom.   There are different hypotheses about the pathophysiological mechanisms involved for the persistence of certain symptoms, mainly for neurocognitive and psychiatric symptoms.
Empirical Gap	There is much heterogeneity in the manifestation and prevalence of symptoms among patients. The results of some studies are contradictory; therefore, the reported data are not easily comparable.   The exact duration of the sequelae or whether they will be permanent is unknown.  The evidence suggests that there is no great difference between hospitalized and non-hospitalized patients. There is conflicting information about the correlation between initial severity and persistence of symptoms over time.
Methodological Gap	There is great variability in the design of extant studies regarding the use of (PCR) tests for case confirmation, patient follow-up time, time considered for symptom duration, hospitalized patients and non-hospitalized patients. There is no standardized assessment: particularly for neurocognitive, psychological, and psychiatric symptoms.  Data are mostly self-reported and may contain errors of interpretation by patients.  Some symptoms are neither objectively measurable nor easy to operationalize; particularly psychological symptoms.  There is a lack of precision in the measurement of clinical data and adequate development of specific assessment instruments for post-COVID-19 syndrome.
Population Gap	There are underrepresented populations in the studies: children, older adults, pregnant women, people with disabilities, workers, vulnerable populations, racial and ethnic minorities, and others. The data come mainly from populations in Europe, Asia, and the United States, with very little representation from other regions, such as Latin American and Caribbean countries.
Practice Gaps	Due to the lack of theoretical, conceptual, and empirical information, the clinical diagnosis of this disease is very complex.  Pre-existing health conditions, the difficulty in accessing adequate health care and the conditions imposed by the context of the pandemic may complicate the correct professional diagnostic criteria. PCR tests, although useful for the diagnosis of infection, are not valid for monitoring the persistence of symptoms.  At present, there is no way to prevent this condition. Although vaccines may play an important role in reducing transmission, deaths, and incidence of the disease, it is unclear whether they are an effective barrier to the long-term effects of COVID-19.  While some guidelines and recommendations for management have been established, as well as protocols for care and some tools created specifically for the assessment and monitoring of post-COVID-19 symptoms, such resources are not widespread.  The focus has been on the description and pathophysiology of the disease, thereby neglecting resilience and social support factors. The multiprofessional approach to cases is not yet sufficiently widespread.  There is a need for better understanding and recognition by healthcare personnel of the symptoms reported by patients and their families.
Social Gap	As stated above, the implications for the burden on health systems, the family economy and society are not well known.   There is a lack of specific studies of post-COVID-19 involvement in the working population, and in particular, in healthcare workers.  Low- and middle-income countries may find it difficult to adequately recognize, monitor, and care for long-term COVID-19.
Table 1. Knowledge gaps about post COVID-19 syndrome. Tabella 1. Lacune conoscitive sulla sindrome post-COVID-19.

These knowledge gaps were independently identified by the authors from reading several previous papers,^4-12 which have not only provided insight into this new international public health concern, but also helped to recognize different aspects that have not been sufficiently addressed. The COVID-19 pandemic has opened up a set of questions and challenges for global public health, creating a new set of knowledge gaps about long-term effects are added.
Undoubtedly, more precision is still needed when approaching the study of this new post-COVID-19 condition, so that the results improve the understanding of the disease and its long-term effects, and at the same time allow an adequate clinical approach by health professionals and better planning of public policies. The set of knowledge gaps identified in this work should be part of the next global public health research agenda,^9-12 mainly in those regions and countries where this problem has not yet been properly addressed. This is important because of the inequalities between countries and regions of the world, where the neglect of a condition such as post-COVID-19 syndrome can affect the well-being of individuals, their communities and society. 

Conflicts of interest: none declared.

References

1. Fernández-de-Las-Peñas C. Long COVID: current definition. Infection 2022;50(1):285-86.
2. Yong SJ, Liu S. Proposed subtypes of post-COVID-19 syndrome (or long-COVID) and their respective potential therapies. Rev Med Virol 2021;32(4):e2315.
3. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV, WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis 2022;22(4):e102-7.
4. Asadi-Pooya AA, Akbari A, Emami A, et al. Long COVID syndrome-associated brain fog. J Med Virol 2021;94(3):979-84.
5. Choutka J, Jansari V, Hornig M, Iwasaki A. Unexplained post-acute infection syndromes. Nat Med 2022;28(5):911-23.
6. Gaffney AW. The long COVID Conundrum. Am J Med 2022;135(1):5-6.
7. Parums DV. Editorial: Long COVID, or post-COVID syndrome, and the global impact on health care. Med Sci Monit 2021;27:e933446.
8. Kwok CS, Muntean E, Mallen CD. The impact of COVID-19 on the patient, clinician, healthcare services and society: A patient pathway review. J Med Virol 2022;94(8):3634-41.
9. Adeloye D, Elneima O, Daines L, et al. The long-term sequelae of COVID-19: an international consensus on research priorities for patients with pre-existing and new-onset airways disease. Lancet Respir Med 2021;9(12):1467-78.
10. Munblit D, Nicholson TR, Needham DM, et al. Studying the post-COVID-19 condition: research challenges, strategies, and importance of Core Outcome Set development. BMC Med 2022;20(1):50.
11. Stefanou M, Palaiodimou L, Bakola E, et al. Neurological manifestations of long-COVID syndrome: a narrative review. Ther Adv Chronic Dis 2022;13:20406223221076890.
12. Gallegos M, Portillo N, Martino P, Cervigni M. Long COVID-19: Rethinking mental health. Clinics (Sao Paulo) 2022;77:100067.