The results of this study revealed that the prevalence of long COVID symptoms was higher among individuals with previous morbidities, with an emphasis on the significant association between depression, anxiety, respiratory diseases, previous rheumatic diseases, and long COVID symptoms. The presence of multimorbidity was associated with the occurrence of long COVID symptoms, in a dose-response manner.
Regarding the symptoms of long COVID, in a meta-analysis that covered 11,598 patients with persistent symptoms of COVID-19, it was highlighted that the prevalence of fatigue was 29.2% (95% CI 21.5–39.4); muscle pain was 13.3% (95% CI 7.4–23.6); joint pain was 28.2% (95% CI 14.7–54.0), loss of smell or taste and headaches were 14.7% and 10.4%, respectively, dyspnea was 21.4% (95% CI 14.3–21.2), cough was 17.8% (95% CI 13.3–23.8), and gastrointestinal problems was 6.2% (95% CI 4.6–8.3) over a period of four to eight months, which is in line with the results of our study [17].
Regarding mental health, several studies have pointed to a relationship between depression, anxiety, and stress and the number of symptoms of long COVID [18, 19]. In a study conducted in Mexico, the main symptoms were headache (62.1%); memory problems (58.6%); diarrhea (48.3%); mental confusion (48.3%); and dyspnea, arthralgia, and myalgia (41.4%) [18]. There is evidence of a range of long-term adverse effects of other viral infections, such as SARS-CoV-1 and MERS-CoV, and studies have verified the presence of chronic fatigue and long-term mental health changes 31 to 50 months after these infections [19–23].
Although the mechanisms of interaction between mental health morbidities and symptoms of long COVID are currently not well understood, there are some hypotheses on how COVID-19 may affect the nervous system, including neuroinflammation caused by the involvement of the respiratory system by the immune response to SARS-CoV-2 by increasing cytokines, chemokines, and immune cells in the brain, inducing reactive states in brain cells; an autoimmune response against the nervous system; the reactivation of viruses such as the Epstein-Barr virus, which can lead to neuropathology; ischemia of neural cells due to interruption of cerebral blood flow caused by cerebrovascular and thrombotic diseases; and lung and multi-organ dysfunction during the severe acute phase of the disease that can impair the functioning of neural cells [24].
Regarding respiratory morbidities, some studies corroborated our findings, finding an association between COPD/asthma and long COVID [25, 26, 27]. In one study [25], there was an association between COPD (RR = 1.55; 95% CI 1.47; 1.64), asthma (RR = 1.15; 95% CI 1.12; 1.18) and long COVID. In another study [26], there was an association between longer duration of long COVID symptoms lasting ≥ 28 days (15.8%) and ≥ 56 days (18.0%) and asthma [25].
In a survey conducted in Suriname, 26.4% of the respondents had SAH, 13.2% had a previous diagnosis of heart disease, 56.6% experienced mild COVID-19, and 39.6% experienced at least one persistent symptom after recovery from acute SARS-CoV-2 infection [28].
One of the most distinguished mechanisms in the literature for the emergence of long COVID is mitochondrial dysfunction, which can have cytopathic effects on the central nervous, respiratory, circulatory, immune, renal, and digestive systems [29]. After infection with SARS-CoV-2, the binding between a viral protein and mitochondrial complexes can lead to mitochondrial dysfunction, which in turn increases oxidative stress and causes immune cells to overreact, this exacerbated reaction leads to inflammation and potentially persistent symptoms of COVID-19 [5, 6].
Corroborating the results of the present study [30], was found an association between rheumatologic diseases and long COVID, wherein 74.0% had this outcome [30]. For musculoskeletal diseases such as osteoporosis, which was highlighted in our study, some suggestions for the involvement of the musculoskeletal system, COVID-19, and long COVID have been proposed, including the interaction of the SARS-CoV-2 spike protein with angiotensin-converting enzyme 2 (ACE2), which, in addition to being present in lung tissue, is present in other tissues such as smooth muscle, cartilage, and kidneys, which are also affected by the cytokine inflammation cascade, hypoxia, and muscle catabolism [31].
Some studies have demonstrated the impact of the coronavirus pandemic on the management of osteoporosis, both for the performance of control and diagnostic tests, as well as in drug therapy, including significant reductions in the performance of bone densitometry examinations (–49.0%) when compared to the first semesters of 2019 and 2020. There was also a reduction in the contact of health professionals for recommended treatment, with a range of only 29.0%, and 51.7% of professionals dealing with individuals with osteoporosis reported delays in starting treatment during the COVID-19 pandemic [32, 33, 34].
Regarding cancer [35], they found that 60.0% of people with neoplasms reported symptoms of long COVID, with an average duration of 7–14 months after infection; fatigue (82%), sleep disturbances (78%), myalgia (67%), and gastrointestinal symptoms (61%), followed by dyspnea (47%), and cough (46%) were the most reported symptoms [35].
Regarding multimorbidity, a study [8] conducted with older adults in Canada showed that having two or more morbidities had a 1.90 (95% CI 1.02–3.49) times higher risk of developing long COVID [8]. In a multicenter, population-based survey conducted in China with 2,712 patients with a history of mild-to-severe COVID-19, a relationship was found between the presence of three or more morbidities (odds ratio [OR] = 2.71, 95% CI 1.54–4.79) and long COVID [36].
Hypotheses point to the mechanism of long COVID through long-term tissue damage to organs such as the lungs, brain, and heart, and a pathological inflammation due to viral persistence, immune dysregulation, and autoimmunity, among others, which may likely contribute to the hyperactivation of monocyte-derived macrophages in the acute and post-acute phases of the disease [7, 37–44].
Finally, the present study had some limitations. The diagnoses of morbidities and symptoms of long COVID were self-reported, which may have underestimated the occurrence of data due to recall bias. The lack of inclusion of some important variables for adjustment, such as behavioral factors, generates residual confusion. Notably, 19 diseases included in the list of multimorbidities were not investigated; however, morbidities with the highest prevalence in the literature were investigated.
The strengths of the study include the fact that this is a population-based study with a representative sample that were mostly non-hospitalized, which reveals the relationship between morbidities and long COVID in individuals who did not develop the severe form of the disease, the mechanism of which is still poorly understood. Thus, the findings of this study reinforce the greater vulnerability of individuals with morbidities and multimorbidity to long COVID, and the importance of considering that morbidities and multimorbidity should be monitored and included in strategic health plans for the population, especially in those with COVID-19.
It is concluded that the existence of previous morbidities and infection by the SARS-CoV-2 virus, may predispose individuals to long-term symptoms of long COVID, and this experience is accentuated according to the number of preexisting morbidities. Thus, the interaction of long COVID with prior morbidities requires active investigation so that all individuals diagnosed with long COVID can access targeted health strategies. The data from this study can help us to understand the mechanisms that explain the strong relationship between morbidities/multimorbidity and long COVID.