Long-term Impacts of Long COVID: Increased Incidence of Cardiomyopathies, Joint Diseases, and Psychoanxiety Disorders

Abstract

Background/Aim

The COVID-19 pandemic has intensified inquiries into the interplay between diabetes and disease severity, and the long-term impact of long-COVID. This study specifically explored the implications of different antithrombotic treatments on COVID-19 patients. It aimed to assess the long-term efficacy and safety of Vitamin K antagonists (VKA) and direct oral anticoagulants (DOACs) in mitigating thromboembolic complications in COVID-19 patients.

Patients and Methods

We conducted a study on 157 patients diagnosed with COVID-19 from August 2021 to August 2023. The study evaluated shifts in anticoagulant therapy recommendations, tracking the transition from VKA to DOACs, and analyzed associated health outcomes.

Results

A significant shift from VKA to DOACs prescriptions was observed, especially in high-risk patients. Despite the change in antithrombotic treatments, incidences of varices and varices with hemorrhoids increased by 2.6% and 3.2%, respectively. Long-COVID was also linked to higher occurrences of diabetes and gastrointestinal diseases. Joint diseases rose by 14%, indicating persistent inflammation. Cardiomyopathies increased by 3.9%, predominantly in high-risk groups, and psychoanxiety disorders surged by 39.5%, highlighting the need for further research. DOAC usage was more common in older age groups, with a 10.2% increase in recommendations among high-risk patients (p<0.05).

Conclusion

The study underscores the evolving landscape of antithrombotic therapy in managing COVID-19 complications. Despite the increased use of DOACs, the rise in various health conditions suggests the necessity for personalized treatment strategies tailored to patient risk profiles.

Varicose veins and hemorrhoids are well-documented to significantly impact individuals’ quality of life and pose risks of severe complications, including bleeding, ulceration, and phlebitis (1-3). The COVID-19 pandemic has shed light on the evolving landscape of chronic diseases, including varicose veins and hemorrhoids, and their broader implications for public health. Studies by Mahenthiran et al. (2021) have underscored the concerning delays in medical interventions for varicose diseases during the pandemic, leading to increased mortality rates (4-8).

Furthermore, the lingering effects of COVID-19, commonly referred to as “long-COVID”, have garnered considerable attention (9-12). Research indicates that individuals recovering from COVID-19 may experience persistent symptoms, such as extreme fatigue, shortness of breath, joint pain, brain fog, anxiety, and depression (13). These long-term consequences underscore the need for comprehensive management strategies to address the multifaceted health challenges posed by the pandemic. Notably, long-COVID has been associated with various complications, including the development or exacerbation of diabetes, gastrointestinal diseases, joint diseases, cardiomyopathies, and psychoanxiety disorders (14-17). Understanding the interplay between COVID-19 and these chronic conditions is crucial for informing effective treatment approaches and mitigating long-term health consequences.

In recent years, the concern has increased not only among doctors regarding the prevention of chronic diseases mediated by angiotensin-converting enzyme 2 (ACE2) (18), but also among public health agencies. These agencies have started evaluating the incidence of chronic diseases in the context of the pandemic, along with exploring preventive measures (19).

The objective of this study was to evaluate how improved antithrombotic treatment and long-COVID influence the incidence and severity of varicose veins, varicose veins with hemorrhoids, diabetes, gastrointestinal diseases, joint diseases, cardiomyopathies, and psychoanxiety disorders. We aimed to identify the effectiveness and associated risk factors of enhanced antithrombotic treatment, as well as the long-term impact of COVID-19 on multiple complications, to better inform the management and treatment of these conditions.

Patients and Methods

Data were collected from the family medicine practice. The patient sample size was increased to enhance the accuracy of the results, encompassing individuals with at least one of the chronic diseases under investigation, leading to a minimum age requirement of 53 years. The chronic diseases included in this study are varicose veins, diabetes, gastrointestinal diseases, joint diseases, cardiomyopathies (including hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, peripartum cardiomyopathy, Takotsubo cardiomyopathy, left ventricular noncompaction, tachycardia-induced cardiomyopathy, chest pain, syncope, feeling out of breath), and psychoanxiety disorders. Patients with these chronic conditions received established treatment from specialists and recommendations from their family doctors prior to the study period. Clinical data specific to the family practice, including blood pressure, body temperature, and weight, were periodically gathered for all patients. Bleeding/thrombotic complications were insignificant in patients with cardiomyopathies, who were being monitored and treated only in the family medicine office, not hospitalized.

The cohort was stratified into three groups based on associated disease presence, indicating varying health risk levels. The “Control” group comprised 43 patients, 27.4% of the total sample (fewer than three chronic diseases). The “Reduced-Risk” group had 67 patients (three to four chronic diseases), 42.7% of the total. The “High-Risk” group included 47 patients, 29.9% of the total (five to six chronic diseases). Thus, a total of 157 patients, aged 53 to 87 years, were selected and observed over a 2-year period from August 2021 to August 2023, in accordance with the Declaration of the World Medical Association of Helsinki. The study included patients who had experienced mild-moderate or asymptomatic SARS-CoV-2 infection. All patients had varicose and/or hemorrhoidal thromboembolism of varying stages and were receiving stable allopathic treatment. Exclusion criteria included history of malignant tumors, organ failure, autoimmune pathologies, and severe forms of COVID-19.

Statistical analysis. The data obtained were analyzed using the statistical program SPSS 20 (IBM SPSS, Armonk NY, USA) employing statistical methods, such as analysis of variance (ANOVA), post hoc analysis, Chi-square test, and inferential statistics (Student’s t-test). The Bonferroni test was used for comparison among the three research groups. Correlations between parameters were examined using the Bravais-Pearson tests and paired sample correlation. The sample size of subjects included in the study was calculated based on the total number of patients attending the family medicine practice during the study period. The sample size calculation considered variables, such as p (probability of occurrence of the phenomenon, 0≤p≤1), q (counterprobability, q=1-p), t (probability factor), ∆x (permissible error limit), and N (community volume).

Results

Demographic and paraclinical data. The cohort, comprising 157 patients, was predominantly from an urban environment (61.8%), as depicted in Table I, without significant differences in the distribution between men and women (p=0.358). The distribution of the study cohort by sex was as follows: urban men accounted for 43.3%, a higher proportion compared to men from rural areas, who represented only 12.7%. Women from urban areas comprised 18.5%, whereas those from rural areas accounted for 25.5%.

Table I. Demographic description.

N: Number of patients; SD: standard deviation.

The mean age was 70.91±9.69 years in the control group, 72.40±9.16 years in the reduced-risk group, and 70.68±9.42 years in the high-risk group. These differences were not statistically significant (p=0.564).

C-reactive protein levels were elevated across all study groups without significant differences between them, suggesting a systemic inflammatory response associated with COVID-19. To determine whether there were significant differences in means between the control, reduced-risk, and high-risk groups, we conducted a Tukey’s HSD test. Figure 1 displays the pairwise comparisons of group means, including the difference between each pair and the corresponding p-values (all p=1.000). For example, comparing the control group with the reduced-risk group, the mean difference is -0.00555 with a p-value of 0.998, indicating no statistically significant difference between these groups. Similarly, comparing the Control group with the high-risk group shows a mean difference of -0.05096 with a p-value of 0.867, also not statistically significant. When comparing the reduced-risk group with the high-risk group, the mean difference is 0.04541 with a p-value of 0.870, suggesting no significant difference between these risk groups. The results indicate that the cytokine-mediated proinflammatory process is directly correlated with COVID-19 infection, without being significantly influenced by the presence of associated diseases.

Figure 1.

Graphical representation of the increased incidence of C-reactive protein (CRP) using the error bar technique. Average CRP values are high in all three research groups, and the standard deviation indicated no significant differences between groups. This suggests an inflammatory process was present in the context of COVID.

Clinical data specific to COVID. The effects of long-COVID on the peripheral vasculature were examined through the presence of peripheral vascular disease (varicose veins). Anal thrombosis or hemorrhoidal thrombophlebitis was monitored in the context of long-COVID, either alone or in association with varicose veins. No significant changes in varicose veins were observed in either the control or low-risk groups. However, a statistically significant increase in varicose veins was observed in the high-risk group, as shown in Table II. There was an increase of 2.6% for varicose veins and 3.2% for varicose veins with hemorrhoids. Conversely, a 5.7% decrease in hemorrhoidal disease was recorded. These percentages can be attributed to medication adjustments tailored to the progression of the existing pathology. The effects of prolonged COVID-19 are clearly evident in the high-risk group, as the ANOVA test indicated an increased incidence of varicose veins. However, the threshold for statistical significance was not reached.

Table II. Descriptive statistics of varicose diseases (varicose veins, hemorrhoids or both).

N: Number of patients; p: value according to Chi-Square test. *Correlation is significant at the 0.05 level (2-tailed); **Correlation is significant at the 0.01 level (2-tailed).

Immediate complications. An elevated blood glucose level is associated with the exacerbated inflammatory response observed in COVID-19 (Table III). Given the pivotal role of monocytes and macrophages in the immune response, and considering the virus’s propensity to infect these cells, the association between elevated blood glucose levels and worsened prognosis in COVID-19 may reflect the virus’s detrimental impact on immune cell function, potentially contributing to dysregulated glucose metabolism (20). The current study noted an 8.3% cohort-wide increase in diabetes incidence. Notably, this increase was particularly prominent in the high-risk group, underscoring the detrimental impact of long-COVID. The ANOVA statistical test revealed a significant difference between the initial and final diabetes cases (p=0.009).

Table III. Descriptive statistics of immediate complications.

N: Number of patients, p: value according to Chi-Square test. *Correlation is significant at the 0.05 level (2-tailed); **Correlation is significant at the 0.01 level (2-tailed).

Regarding gastrointestinal diseases, the incidence increased by 5.8% in the low-risk group and 9.6% in the high-risk group by the end of the observation period. This finding underscores the direct impact of long-COVID not only on diabetes development but also on gastrointestinal diseases. The ANOVA test indicated a significant difference between the number of the initial and final cases of gastrointestinal diseases (p=0.001).

Long-term complications. The pro-inflammatory process induced by SARS-CoV-2 infection detrimentally impacted joint diseases. This inflammatory state manifests as an increase in the incidence of joint diseases, observed both at the cohort level (by 14%) and within each group, with the highest increase recorded in the low-risk group (6.4%), as presented in Table IV.

Table IV. Descriptive statistics of long-term complications.

N: Number of patients; p: value according to Chi-Square test. *Correlation is significant at the 0.05 level (2-tailed); **Correlation is significant at the 0.01 level (2-tailed).

Studies in the literature suggest that spike protein-mediated downregulation of ACE2, which could elevate Ang II levels, contributes to the pathogenesis of cardiovascular disease (21). The current study underscores an increase in the incidence of cardiomyopathies, evident at both the cohort level (by 3.9%) and within each group, with the largest increase observed in the high-risk group (1.9%).

The consistent increase in cases with anxiety disorders was unprecedented among patients with viral infection. A clear upward trend in psychoanxiety disorders was evident at the cohort level (by 39.5%), with the most significant increase observed in the reduced-risk group (20.4%).

At the end of the study period, cardiomyopathy and psychoanxiety disorders did not differ significantly among the three research groups. This can be explained by the fact that while a risk factor influences the incidence of these conditions, the effect of long-COVID is also a contributing factor. In the case of joint diseases, a significant increase was registered at the cohort level, with notable differences between the study groups. This could be attributed to the fact that risk factors associated with long COVID have a significant impact on the incidence of joint diseases. This significant increase indicates that associated diseases are not responsible for triggering psychoanxiety disorders; they can only increase the incidence. The significant rise in cases is correlated with a common factor among patients: infection with the SARS-CoV-2 virus, through mechanisms that are still incompletely understood.

Antithrombotic treatment. By the end of the research period, there was a notable decrease of 33.9% in monotherapy involving pentoxifylline (800 mg per day in two doses), diosmin with hesperidin (1,000 mg per day), and sulodexide (500 mg per day in two doses). Conversely, there was a marked increase of 51% in the recommendation for combined treatments. There was also a 4.5% increase in the combination treatment involving all three substances. Particularly noteworthy was the increase in the recommendation of sulodexide to counteract the negative thromboembolic effects associated with COVID-19. Notably, 15.3% of patients undergoing pentoxifylline monotherapy also received sulodexide, as detailed in Table V.

Table V. Antithrombotic treatment at the beginning and end of the study period.

N: Number of patients; p: value according to Chi-Square test. **Correlation is significant at the 0.01 level (2-tailed).

Figure 2 shows that most patients received combination therapy of pentoxifylline with sulodexide by the end of the research period. Patients with younger ages (66.91±10.9 years) received monotherapy with pentoxifylline, while those with the higher average age (74.30±7.76 years) received diosminum with hesperidinum. Triple therapy was recommended for patients with a mean age of 68.88±12.18 years. There was an increasing trend in recommending combination treatments for older patients. This trend indicates that age is a risk factor for long-COVID thromboembolic complications, necessitating the combination of multiple medicinal substances (Figure 3).

Figure 2.

The graphic representation of allopathic treatments, using the combined multivariable method, at the end of the study period within the study cohort demonstrates that older participants are more likely to receive pentroxifylline and sulodexide.

Figure 3.

The graphic representation of allopathic treatments, using the clustered bloxplot method, at the end of the study period within the study groups.

Anticoagulant-specific initial – final treatment. Regarding anticoagulant treatment, two classes of anticoagulants were administered: Vitamin K antagonists (VKAs) represented by acenocoumarol (2 mg and 4 mg) and warfarin, and Direct oral anticoagulants (DOACs) represented by rivaroxaban, apixaban and dabigatran.

At the beginning of the research period, there were no significant differences (p=0.073) between the low-risk group and the control group, or between the low-risk group and the high-risk group, regarding the type of anticoagulant used (Table VI). However, significant differences were noted at the end of the research period. Significant differences were specifically noted between the control group and the low-risk group (p=0.025), the control group and the high-risk group (p=0.006), as well as between the low-risk group and the high-risk group (p=0.001). Data analysis using the ANOVA test revealed significant differences among the three groups at the end of the research period (F=14.192, p=0.001).

Table VI. Anticoagulant treatment description.

N: Number of patients; VKA: vitamin K antagonists; DOACs: direct oral anticoagulants; p: value according to Chi-Square test. *Correlation is significant at the 0.05 level (2-tailed); **Correlation is significant at the 0.01 level (2-tailed).

At the end of the research period, age did not differ significantly (p=0.895) between patients receiving VKAs versus those receiving DOACs. However, significant differences emerged at the end of the research period regarding the number of patients who received a recommendation for VKAs compared to those who received DOACs (Figure 4). An increasing trend (p=0.031) in the number of patients receiving DOACs treatment was observed, accompanied by a significant decrease in a VKA usage.

Figure 4.

Graphical representation of the distribution of antithrombotic treatment at the cohort level. At the end of the study, more patients benefited from DOAC treatment, and there is no significant difference in the average age between the two research groups.

Figure 5 indicates a trend toward recommending DOACs for older patients, thereby frequently eliminating the necessity for International Normalized Ratio (INR) analysis. This trend explains the reduced number of patients for whom INR was evaluated.

Figure 5.

Graphic representation of antithrombotic treatment by age in each study group at the end of the study period. The boxplot graphic shows no significant age differences between the two study groups regarding antithrombotic treatment with VKAs and DOACs. The only difference is observed in the control group.

At the beginning of the study, VKAs were prescribed to 45.9% of all patients, but by the end of the study period, this decreased to 35.7% (comprising 26 people in the control group, 25 people in the low-risk group, and only 5 people in the high-risk group).

Insignificant differences were recorded at the end of the study period regarding anticoagulant treatment among the three study groups (p>0.05), considering the age of the patients. No significant differences were observed between the presence or absence of the associated diseases and the applied treatments (p=0.574 initially and p=0.690 at the end of the study).

Discussion

The inflammatory cascade initiated by COVID-19 shares commonalities with pathways targeted in the management of rheumatoid arthritis, prompting exploration into cytokine inhibition for COVID-19 therapy. Unlike rheumatoid arthritis, however, COVID-19 typically does not present as clinical arthritis, suggesting a localized inflammation in alveolar structures. Chronic bacterial infections further contribute to the inflammatory milieu, heightening susceptibility during the pandemic. This investigation documented a notable 14% increase in joint pain, indicating the intricate interplay between inflammation, infection, and COVID-19 (22,23).

Individuals with pre-existing heart conditions are at a substantially increased risk of death from COVID-19, with mortality rates reaching up to ten times that of the general population. This heightened vulnerability is especially pronounced among those requiring intensive care, as cardiovascular complications, including high blood pressure affecting both the heart and brain, are commonly observed in these severe cases (24-26).

Gao et al.’s large retrospective study revealed that hypertensive patients face a significant risk of COVID-19 mortality, regardless of their antihypertensive medication status. Furthermore, the coexistence of hypertension and diabetes amplifies the likelihood of adverse clinical outcomes, with hypertension being twice as prevalent in diabetic patients compared to non-diabetic individuals (27-29).

The persistent symptoms experienced post-SARS-CoV-2 infection are primarily attributed to the immune response rather than the virus itself, suggesting sustained inflammation. Anxiety disorders, prevalent in post-COVID and long-COVID cases, may stem from acute phase hypoxia and the cytokine storm characteristic of SARS-CoV-2 infection. The prevalence of anxiety following COVID-19 is influenced by a combination of factors, including media coverage, everyday stressors, the evolving nature of the disease, and its impact on the central nervous system (30). Understanding the mechanisms underlying heightened anxiety levels in long-COVID patients is crucial. Additionally, research into the effectiveness of various anticoagulant therapies, including those used to manage diabetes, in addressing potential links between blood clotting and mental health conditions warrants further investigation (31).

Elderly patients, predisposed to falls, face heightened risks of bleeding and stroke compared to their counterparts. Bikdeli et al. (2020) highlighted COVID-19’s potential to increase thrombotic disease risk through inflammatory processes, platelet activation, and endothelial dysfunction (32). Managing thrombotic disease amidst the pandemic necessitates meticulous consideration of antithrombotic therapy, including drug selection, dosing, and monitoring. Prioritizing anticoagulation is imperative for ischemic stroke prevention, with DOACs emerging as alternatives to VKAs, particularly in high-risk patients. Fall prevention strategies, encompassing environmental modifications and balance training, are indispensable during anticoagulant therapy. Effective patient education is crucial for optimizing treatment outcomes in the post-COVID healthcare transition. Providing clear information about medication interactions and bleeding prevention strategies is essential to ensure patients adhere to their treatment plans (33,34). The transition from VKAs to DOACs, driven by safety and efficacy concerns, underscores the importance of patient education and adherence, especially in the post-COVID landscape.

Studies suggest that antiviral treatment for COVID-19 can significantly affect DOAC plasma concentrations, necessitating alternative antithrombotic strategies. DOACs offer advantages, such as fixed dosing, minimal monitoring, and reduced bleeding risk, particularly pertinent in resource-limited healthcare settings (35-38). Our study examined the favorable outcomes associated with DOACs in post- and long-COVID contexts, considering variables, such as age, comorbidities, and concurrent treatments (39-41).

One limitation of this study is its retrospective design, which may introduce inherent biases and limitations associated with relying on pre-existing data. Additionally, the study’s sample size and patient demographics may not be representative of the broader population, potentially limiting the generalizability of the findings. Furthermore, the study may be subject to confounding variables and unmeasured factors that could influence the observed outcomes. Moreover, the reliance on medical records and data collection methods may introduce inaccuracies or missing information, which could affect the validity of the results. Lastly, the study’s duration and follow-up period may be insufficient to capture long-term outcomes or fully assess the effects of certain interventions.

Conclusion

An increase of 2.6% in the incidence of varices and 3.2% of varices with hemorrhoids was observed, although specific antithrombotic treatment was changed. A direct effect of long-COVID was noted on the development of diabetes, as well as on gastrointestinal diseases. The increase in the incidence of joint diseases, both at the cohort level (by 14%) and within each group, underscores that cytokine-mediated inflammation persists beyond the acute phase of SARS-CoV-2 infection.

A significant increase in the incidence of cardiomyopathies, both at the cohort level (by 3.9%) and within each group, was observed, with the highest increase recorded in the high-risk group. This highlights the heightened cardiovascular risk not only during acute COVID-19 but also in the long-term.

We observed a clear upward trend in psychoanxiety disorders at the cohort level, with a concerning percentage increase of 39.5%. This aspect remains insufficiently studied and warrants increased attention due to its direct impact on quality of life. Treatment with DAACs was predominantly chosen for older age groups. There was a 10.2% increase in the recommendation of DOACs at the cohort level, predominantly among patients in the high-risk group.

Funding

The APC was funded by the University of Oradea, Oradea, Romania.

Conflicts of Interest

The Authors declare no conflicts of interest in relation to this study.

Authors’ Contributions

Conceptualization, A.F.M. and T.C.G.; methodology, T.C.G.; software, T.C.G.; validation, K.B., D.F.T. and F.M.; formal analysis, T.C.G.; investigation, T.C.G.; resources, T.C.G.; data curation, T.C.G.; writing—original draft preparation, T.C.G.; writing—review and editing, T.C.G.; visualization, T.C.G.; supervision, T.C.G.; project administration, T.C.G.; funding acquisition, T.C.G. All Authors have read and agreed to the published version of the manuscript.

Acknowledgements

The Authors would like to thank the University of Oradea for financial support.