The recovery from COVID-19 should be more developed than checking for hospital discharge or testing negative for SARS-CoV-2 or positive for antibodies (13). This systematic review and meta-analysis shows that 80% (95% CI 65–92) of individuals with a confirmed COVID-19 diagnosis continue to have at least one overall effect beyond two weeks following acute infection. In total, 55 effects, including symptoms, signs, and laboratory parameters, were identified, with fatigue, anosmia, lung dysfunction, abnormal chest XRay/CT, and neurological disorders being the most common (Table 1, Fig. 2). Most of the symptoms were similar to the symptomatology developed during the acute phase of COVID-19. However, there is a possibility that there are other effects that have not yet been identified. In the following paragraphs, we will discuss the most common symptoms to illustrate how complex each one can be. However, further studies are needed to understand each symptom separately and in conjunction with the other symptoms. The five most common effects were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%).
Fatigue (58%) is the most common symptom of long and acute COVID-19(14). It is present even after 100 days of the first symptom of acute COVID-19(3, 14). There are syndromes such as acute respiratory distress syndrome (ARDS), in which it has been observed that after a year, more than two-thirds of patients reported clinically significant fatigue symptoms(15). The symptoms observed in post-COVID-19 patients, resemble in part the chronic fatigue syndrome (CFS), which includes the presence of severe incapacitating fatigue, pain, neurocognitive disability, compromised sleep, symptoms suggestive of autonomic dysfunction, and worsening of global symptoms following minor increases in physical and/or cognitive activity(16–20). Currently, myalgic encephalomyelitis (ME) or CFS is a complex and controversial clinical condition without established causative factors, and 90% of ME/CFS has not been diagnosed(21). Possible causes of CFS include viruses, immune dysfunction, endocrine-metabolic dysfunction, and neuropsychiatric factors. The infectious agents related to CFS have been Epstein-Barr virus, cytomegalovirus, enterovirus and herpesvirus (22). It is tempting to speculate that SARS-CoV-2 can be added to the viral agents' list causing ME/CFS.
Several neuropsychiatric symptoms have been reported, headache (44%), attention disorder (27%), and anosmia (21%). There are other symptoms reported, which were not included in the publications, including brain fog and neuropathy (23, 24). The etiology of neuropsychiatric symptoms in COVID-19 patients is complex and multifactorial. They could be related to the direct effect of the infection, cerebrovascular disease (including hypercoagulation)(25), physiological compromise (hypoxia), side effects of medications, and social aspects of having a potentially fatal illness(26). Adults have a double risk of being newly diagnosed with a psychiatric disorder after the COVID-19 diagnosis (26), and the most common psychiatric conditions presented were anxiety disorders, insomnia, and dementia. Sleep disturbances might contribute to the presentation of psychiatric disorders(27). Prompt diagnosis and intervention of any neuropsychiatric care is recommended for all patients recovering from COVID-19. An increase in mental health attention models in hospitals and communities is needed during and after the COVID-19 pandemic. Hair loss after COVID-19 could be considered as telogen effluvium, defined by diffuse hair loss after an important systemic stressor or infection, and it is caused because of premature follicular transitions from active growth phase (anagen) to resting phase (telogen). It is a self-limiting condition that lasts approximately 3 months, but it could cause emotional distress(28).
Dyspnea and cough were found in 24% and 19% of patients, respectively (Table 2, Fig. 2). In addition, abnormalities in CT lung scans persisted in 35% of patients even after 60–100 days from the initial presentation. In a follow-up study conducted in China among non-critical cases of hospitalized patients with COVID-19, radiographic changes persisted in nearly two-thirds of patients 90 days after discharge(29). Although most of the available studies do not include baseline pulmonary dysfunction or radiographic abnormalities, findings indicate improvement or resolution of abnormal CT findings. Previous data from recovered patients with other viral pneumonia(30, 31), also found residual radiographic changes. Abnormalities in pulmonary function, such as decreased diffusion capacity for carbon monoxide, were present among 10% of patients in this meta-analysis. Although these findings are not as high as compared to other available studies of survivors with COVID-19 or SARS, where the estimate of lung dysfunction is 53% and 28% respectively(32, 33), the reasons behind these differences could be distinct follow-up periods, definitions of pulmonary dysfunction, or characteristics of the patient population. Nevertheless, residual radiographic findings or lung function abnormalities require additional investigation on their clinical relevance and long-term consequences.
The immune-mediated tissue damage in COVID-19 involves cellular and humoral responses, but the immunity to SARS-CoV-2 and the protection to reinfection or a final viral (29, 34) clearance is unknown. Also, the reason why some patients experience long-term symptoms after COVID-19 is uncertain. This could be partially explained by host-controlled factors that influence the outcome of the viral infection, including genetic susceptibility, age of the host when infected, dose and route of infection, induction of anti-inflammatory cells and proteins, presence of concurrent infections, past exposure to cross-reactive agents, etc. Whether SARS-CoV-2 can cause substantial tissue damage leading to a chronic form of the disease such as the chronic lesions in convalescence observed in other viruses such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV), and some herpesviruses is still unknown.
The results assessed in the present study are in line with the current scientific knowledge on other coronaviruses, such as those producing SARS and MERS, both sharing clinical characteristics with COVID-19, including post symptoms. Studies on SARS survivors have shown lung abnormalities months after infection. After a one-year follow-up, a study showed that 28% of the survivors presented decreased lung function and pulmonary fibrosis signs (33, 35, 36). In addition, MERS survivors showed pulmonary fibrosis (33%) (37). Regarding psychiatric symptoms, a study reported high levels of depression, anxiety, and post-traumatic stress disorder (PTSD) (26) in the long term in patients previously infected with other coronaviruses.
To assure that future healthcare providers, researchers, and educators recognize the effects of long-term COVID19 that are sex- and age-specific related, it is of high importance to classify the groups according to such variables to make better decisions about prevention, diagnosis and disease management.
Limitations of this systematic review and meta-analyses include the small sample size for some outcomes, which makes it difficult to generalize these results to the general population. The variation in the definition of some outcomes and markers and the possibility of bias. For example, several studies that used a self-reported questionnaire could result in reporting bias. In addition, the studies were very heterogeneous, mainly due to the follow-up time references and the mixture of patients who had moderate and severe COVID-19. All of the studies assessed had performed their internal pre-definition of symptoms, and therefore there is the possibility that important outcomes were not reported. Another limitation is that, given that COVID-19 is a new disease, it is not possible to determine how long these effects will last. In order to decrease heterogeneity and have a better understanding of the long-term effects of COVID-19, there is a need for studies to stratify by age, previous comorbidities, the severity of COVID-19 (including asymptomatic), as well as the duration of each symptom. To determine whether these long-term effects either complicate previous diseases or are a continuation of COVID-19, there is a need for prospective cohort studies. The baseline characteristics should be well established.
There is a need to standardize biological measures such as peripheral blood markers of genetic, inflammatory, immune, and metabolic function to compare studies. Besides studying pre-defined symptoms and markers, an open question should be included. Proper documentation in medical charts by health care providers and the flexibility and collaboration from the patients to report their symptoms are of equal importance.