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Research Article
The challenges in symptomatic therapy of post-COVID-19: a Bulgarian cohort study
expand article infoEleonora Stamenova‡, Verginiya Ivanova§, Tsvetelina Velikova§
‡ University Hospital “St Anna”, Sofia, Bulgaria
§ Sofia University “St. Kliment Ohridski”, Sofia, Bulgaria

Corresponding author: Eleonora Stamenova ( stamenova.eleonora@gmail.com )

Academic editor: Georgi Momekov
© 2025 Eleonora Stamenova, Verginiya Ivanova, Tsvetelina Velikova.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation: Stamenova E, Ivanova V, Velikova T (2025) The challenges in symptomatic therapy of post-COVID-19: a Bulgarian cohort study. Pharmacia 72: 1-10. https://doi.org/10.3897/pharmacia.72.e166766
Open Access

Abstract

Background: Post-COVID syndrome encompasses a spectrum of persistent symptoms following acute SARS-CoV-2 infection. Fatigue, cognitive disturbances, and musculoskeletal complaints are among the most commonly reported symptoms. Emerging evidence suggests a role of immune dysregulation, autoantibody production, and micronutrient deficiencies in the pathogenesis of post-COVID.

Objective: To evaluate the clinical presentation, autoimmunity profile, vitamin D status, and response to targeted supplementation in a small cohort of patients with post-COVID syndrome.

Aim: Text.

Methods: Fourteen patients meeting clinical criteria for post-COVID syndrome (mean age 39.79 ± 5.49 years) were enrolled. ANA testing was performed in 13 patients, and serum vitamin D levels were assessed in 12. Eight patients received a supplementation protocol consisting of melatonin, N-acetylcysteine (NAC), 5-HTP, and vitamin D. Clinical improvement was evaluated at follow-up.

Results: The most common symptoms were fatigue (64.3%), blurred vision (57.1%), musculoskeletal pain (57.1%), brain fog (50.0%), and sleep disturbances (50.0%). ANA positivity was detected in 61.5% of the tested patients, although individuals with diagnosed autoimmune diseases were excluded after rheumatological consultation. Vitamin D deficiency or low levels were identified in 58.4% of patients. Among those who received supplementation and were available for follow-up (n = 5), 80% reported clinical improvement. The association between supplementation and symptom improvement did not reach statistical significance (p = 0.576), likely due to the small sample size.

Conclusion: Patients with post-COVID syndrome may exhibit signs of subclinical autoimmunity and vitamin D insufficiency. Supplementation with immunomodulatory and antioxidant agents may provide symptomatic benefit and warrants further investigation in larger, controlled studies.

Keywords

post-COVID syndrome, post-COVID, autoimmunity, vitamin D deficiency, immunomodulation, supplementation

Introduction

The COVID-19 pandemic has undoubtedly changed our perception of the world in just a few years. COVID-19 belongs to the category of particularly dangerous infections, characterized by high mortality rates. However, the progress is enormous, and this is related to experience from previous coronavirus epidemics, which underpins the work of implementing empirical protocols, planning, and conducting clinical trials (Baron et al. 2020; Li et al. 2020). In fact, the consequences of COVID-19, known as post-COVID, and the overlapping condition, long COVID, have turned out to be a bigger problem. Patients suffering from post-COVID syndrome experience a variety of symptoms on physical, psychological, and social levels. Previous psychiatric conditions, such as depression and anxiety, have been identified as separate risk factors for developing post-COVID syndrome. After the acute phase of SARS-CoV-2 infection, a proportion of those infected experience persistent somatic symptoms for weeks, months, and even years, including general tiredness, muscle pain, breathing difficulties, tingling extremities, and chest pain. The clinical picture is usually complex, lacking specific laboratory values, and leading to guidelines recommending an interdisciplinary approach that takes into account the whole person and continuity of treatment.

When clarifying the characteristics of post-COVID syndrome, it is necessary to keep in mind that the number of those who have undergone the infection is many times greater than those diagnosed. The majority of those infected have experienced a mild form of the infection and have stayed at home; however, all, regardless of the severity of the course, may exhibit symptoms, as well as functional and structural damage to various organs and systems, which can last weeks to months after the illness and require medical care. The changes that occur in the lung parenchyma and pulmonary vessels during COVID-19 can lead to permanent damage in the respiratory system and compromise gas exchange on a chronic basis (Mo et al. 2020). The underlying cause of these lung function abnormalities, however, remains unclear. Whether persistent microvascular damage, alveolar exudate retention, connective tissue formation and fibrosis, respiratory muscle weakness, or changes in lung compliance are responsible is still unknown (Frija-Masson et al. 2020). The assessment of patients suitable for therapy takes place no earlier than 1 month after discharge, and the therapeutic course follows the principles and protocol for the treatment of organizing pneumonia—the most common and characteristic structural manifestation of COVID-19 pneumonia, also encountered in other infectious and non-infectious causes.

Post-COVID is a significant global issue with profound medical, social, and economic implications. Prevalence estimates vary widely. One reason for this variation is the absence of a clear-cut diagnostic biomarker or other definitive diagnostic criterion that distinguishes those with post-COVID from those whose condition is due to other causes (Haslam et al. 2023). Defining the nature and characteristics of the post-COVID era is a challenging task. Patient groups, clinicians, researchers, government agencies, and international organizations have used different terms to name the condition and provided diverse descriptions to determine what fits the term (Sylvester et al. 2022). While most people infected with SARS-CoV-2 fully recover, tens of millions worldwide experience persistent symptoms and organ damage, as well as other consequences, for months to years after acute infection. According to WHO, post-COVID is a post-COVID-19 condition that occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from onset, with symptoms that persist for at least 2 months and cannot be explained by an alternative diagnosis (National Academies of Sciences, Engineering, and Medicine 2024).

The 2024 NASEM post-COVID-19 definition states that post-COVID-19 occurs after acute SARS-CoV-2 infection but does not require laboratory confirmation or other proof of initial infection. Epidemiologic estimates of post-COVID vary across variants, regions, and populations. Not all symptoms a person experiences following COVID-19 are causally related to the virus. Other conditions must be carefully ruled out (e.g., heart failure, cancer, and thyroid disease) (Baig 2021).

WHO has provided examples of how post-COVID could manifest, including symptoms and conditions, and how it may present as a new condition or as an exacerbation of pre-existing conditions. Studies estimate the prevalence of over 200 symptoms in multiple organ systems, and these symptoms can occur at varying frequencies (WHO 2023). Another notable feature of post-COVID is the variable temporal pattern and duration of symptoms. The severity of post-COVID symptoms can range from mild to severe. Various risk factors, such as underlying comorbid conditions, may influence the risk and presentation of COVID-19 and post-COVID in a particular individual and may be useful in assessing individual patients or populations at risk. Evidence supports several risk factors for post-COVID, including female sex, age above 40, obesity, smoking status, history of hospitalization or ICU admission during acute COVID-19, and several pre-existing conditions (anxiety and/or depression, asthma, chronic obstructive pulmonary disease, diabetes, immunosuppression, ischemic heart disease) (Mancini et al. 2021).

Many mechanisms of post-COVID have been proposed. To date, these have largely been studied and discussed in isolation. Individual publications often focus on providing evidence for or against a specific biological pathway or physiological abnormality (Mohandas et al. 2023). The biological drivers of post-COVID are upstream processes—perturbations of the immune system, coagulation system, and others—that in themselves do not cause disease. Instead, these processes may drive one another, as well as downstream physiologic changes that manifest as symptoms or syndromes in people with post-COVID. More virus replication is also associated with a more severe acute infection, and it is a consistent predictor of post-COVID outcomes. The best way to prevent post-COVID is to prevent the initial infection (Daina et al. 2017). Vaccination and natural immunity from prior infections may not completely prevent infection, but they could blunt the initial spread of the virus and hence limit both acute and chronic sequelae (Jangnin et al. 2024). Endothelitis, hypercoagulopathy, prolonged inflammation, and immune dysregulation are the most studied and established mechanisms.

In contrast, the dysregulation of RAAS, dysautonomia, and oxidative stress need further investigation to understand and establish their role in the pathogenesis of post-COVID-19 (Jangnin et al. 2024). In line with this, the treatment of post-COVID-19 remains primarily in outpatient care and is mostly symptomatic. It requires an experienced, multidisciplinary team and an individualized approach. Several nutraceuticals and bioactive compounds have shown potential in alleviating post-COVID-19 symptoms by targeting key mechanisms, including oxidative stress, neuroinflammation, and immune dysregulation. N-acetylcysteine (NAC) acts as a precursor to glutathione, restoring antioxidant defenses and supporting respiratory and neurological function. Melatonin, beyond regulating circadian rhythm, exerts potent anti-inflammatory and mitochondrial-stabilizing effects, which may aid in reducing brain fog, sleep disturbances, and fatigue. 5-hydroxytryptophan (5-HTP) supports serotonin synthesis and has been linked to improvements in mood, cognitive clarity, and sleep quality—common challenges following COVID-19 (Jarrott et al. 2022). Furthermore, vitamin D, known for its immunomodulatory role, may mitigate low-grade autoimmunity and enhance recovery by supporting T-regulatory cell activity and cytokine balance (Hikmet et al. 2023). Together, these agents offer a safe, multi-targeted approach to symptom relief in individuals struggling with prolonged post-viral sequelae.

This study aimed to evaluate the clinical characteristics, autoimmune profile, and vitamin D status of patients with post-COVID syndrome and to assess the potential symptomatic benefits of a targeted supplementation protocol—including melatonin, N-acetylcysteine (NAC), 5-hydroxytryptophan (5-HTP), and vitamin D—in alleviating persistent neurocognitive and systemic symptoms.

Methods

Subjects

We included 14 patients in our study who fulfilled the criteria for post-COVID-19, with a mean age of 39.79 ± 5.49 years (range: 31–48). Two patients were men, and 12 were women. The study was conducted in accordance with the Declaration of Helsinki, and all patients provided written informed consent to participate.

Therapeutic protocols

Vitamin D was administered individually, ranging from 3000 to 5000 IU daily. Melatonin was given according to the dosage of the selected product (1–3 mg), N-acetylcysteine (NAC) at 600 mg daily, and GNC 5-HTP (5-hydroxytryptophan) at 100 mg/day.

Statistical methods

Statistical analysis was conducted using IBM SPSS Statistics version 23. Descriptive statistics were used to summarize patient demographics, symptom prevalence, laboratory findings, and response to supplementation. Fisher’s exact test was applied to evaluate the association between targeted supplementation (melatonin, NAC, 5-HTP, and vitamin D) and reported clinical improvement at follow-up. A p-value < 0.05 was considered statistically significant.

Results

Demographic characteristics

The baseline clinical characteristics of the patients are presented in Table 1 and visually represented in Fig. 1.

Figure 1. 

Prevalence of post-COVID symptoms. A horizontal bar chart shows that fatigue, blurred vision, and musculoskeletal pain were the most common symptoms.

Table 1.
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The most common symptoms associated with post-COVID-19 in our cohort of patients.

Symptom Number %
Fatigue 9 64.3
Blurred vision 8 57.1
Pain in muscles, joints, and bones 8 57.1
Brain fog 7 50.0
Sleep disturbances 7 50.0
Vertigo 7 50.0
Loss of memory 6 42.9
Numbness in the limbs 6 42.9
Anxiety 5 35.7
Headache 3 21.4
Photo sensibility 2 14.3
Tinnitus 2 14.3
Extrasystoles, palpitations 2 14.3

Thirteen patients were tested for ANA using IIF. Five of them were ANA negative (<1:80), whereas eight were ANA positive (Table 2).

Table 2.
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Distribution of ANA titers. The presence of high titers (≥1:160) in several patients suggests the possibility of autoimmune activation.

ANA titer Number %
<1:80 5 38.5
1:80 2 15.4
100 1 7.7
1:160 2 15.4
1:320 2 15.4
1:1280 1 7.7

Although eight out of thirteen tested patients (61.5%) were ANA positive, all individuals with known autoimmune diseases were excluded from the study. Prior to inclusion, each patient was clinically evaluated by a consulting rheumatologist to rule out systemic autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, or connective tissue diseases. Despite the exclusion of overt autoimmune conditions, the presence of low-to-mid-level ANA titers in some participants may reflect subclinical immune dysregulation or a post-infectious autoantibody response. These findings underscore the importance of long-term immunological follow-up, as some individuals might be at risk of developing autoimmune features later in the post-COVID course.

Twelve patients were tested for vitamin D levels, and the majority exhibited deficiency or insufficiency (Table 3).

Table 3.
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Vitamin D status of the subjects. The majority of patients had insufficient or deficient vitamin D levels, supporting a rationale for supplementation.

Vitamin D levels Number %
Deficiency 2 16.7
Low levels 5 41.7
Levels within the ref. range 5 41.7

Eight patients (57.1%) received supplementation for post-COVID symptoms along with their main treatment. Follow-up feedback was obtained from five individuals: four reported improvement (80%), and one reported no improvement or worsening of symptoms. Patients who did not receive supplementation did not provide feedback (Fig. 2).

Figure 2. 

Patient response to supplementation therapy. A grouped bar chart shows that 80% of patients who received supplementation improved, while none of those who did not receive supplementation showed improvement, although the sample size is small.

The subjective improvement in specific symptoms was reported by the five post-COVID patients who received supplementation. The most significant improvements were observed in blurred vision (in four out of five patients) and brain fog (in four out of five patients) (Fig. 3). Additionally, regarding brain fog and improvement (n = 5), a correlation analysis revealed r = –0.408, indicating a negative correlation between improvement and brain fog severity (although not statistically significant, the trend suggests better outcomes with lower severity). A strong inverse correlation was observed for headaches—patients with headaches were least likely to report improvement (r = –1.000, p < 0.001).

Figure 3. 

Most improved symptoms following supplementation.

A strong positive correlation was observed between blurred vision and memory loss (r = 0.75, p = 0.002), as well as between blurred vision and brain fog (r = 0.866, p < 0.001). These findings suggest that these cognitive-visual symptoms frequently co-occur in patients with post-COVID syndrome and may share common underlying mechanisms, such as neuroinflammation or neurovascular dysfunction. In addition, sleep disturbances were significantly correlated with both brain fog (r = 0.714, p = 0.004) and fatigue (r = 0.745, p = 0.002), highlighting the central role of disordered sleep in contributing to the cognitive and physical symptoms reported in post-COVID. These associations underscore the importance of assessing and managing sleep quality in individuals affected by these conditions. A moderate but statistically significant inverse correlation was identified between vitamin D levels and sleep disturbances (r = –0.577, p = 0.049), suggesting that better vitamin D status may be associated with fewer sleep-related complaints. This supports the potential benefit of vitamin D supplementation in mitigating certain symptoms of post-COVID syndrome.

Finally, a significant correlation was found between antinuclear antibody (ANA) positivity and reported extrasystoles (r = 0.574, p = 0.040). This association may indicate a link between autoimmunity and cardiac manifestations in post-COVID patients and warrants further investigation in larger studies.

Although not reaching statistical significance (p > 0.05), several trends were observed that may offer clinically relevant insights. Reported clinical improvement showed a moderate negative correlation with blurred vision (r = –0.408) and a stronger negative correlation with muscle and joint pain (r = –0.612), suggesting that patients experiencing persistent musculoskeletal symptoms may be less responsive to the applied intervention. Notably, an inverse perfect correlation was observed between photosensitivity and improvement (r = –1.000); however, this result is based on only five patients and should be interpreted with caution. These patterns support the hypothesis that neurocognitive symptoms (e.g., blurred vision, brain fog) tend to improve more readily with targeted therapy compared to systemic or autoimmune-related symptoms such as musculoskeletal pain and photosensitivity. Further research with larger cohorts is necessary to validate these findings.

Photosensitivity demonstrated the strongest negative correlation (r = –1.000), followed by muscle/joint pain and neurocognitive complaints such as brain fog and blurred vision. These findings align with clinical observations, suggesting that neurocognitive symptoms are more responsive to the applied supplementation protocol, whereas pain-related and systemic autoimmune manifestations show lower improvement. Although some of these associations did not reach statistical significance, they underscore important trends warranting further investigation in larger patient cohorts (Fig. 4).

Figure 4. 

Correlation between improvement and key symptoms. A bar plot visualization revealed notable inverse correlations between specific symptoms and reported clinical improvement.

These symptom clusters point toward a potential shared pathophysiological mechanism, likely involving neuroinflammation, neurovascular dysregulation, or neurotransmitter imbalance (Fig. 5). This pattern supports the hypothesis that central nervous system involvement is prominent in post-COVID syndrome and may be responsive to antioxidant and neuroprotective therapies. These findings provide a clinical rationale for targeted interventions that address cognitive and neurovascular symptoms in affected patients.

Figure 5. 

Symptom intercorrelations in post-COVID syndrome. The heatmap analysis revealed strong positive correlations among brain fog, memory loss, and blurred vision (r > 0.75), as well as significant associations with sleep disturbances.

Discussion

Growing evidence suggests that SARS-CoV-2 infection may trigger the development of autoantibodies, including antinuclear antibodies (ANA), antiphospholipid antibodies, and anti-interferon antibodies. Proposed mechanisms include molecular mimicry, bystander activation, and viral persistence, all of which can disrupt immune tolerance. Several studies have demonstrated ANA positivity in previously healthy individuals following COVID-19 infection, even in the absence of clinical autoimmune disease (Park et al. 2023). This transient or persistent autoantibody production may contribute to symptoms such as fatigue, brain fog, and joint pain—hallmarks of post-COVID syndrome. Thus, SARS-CoV-2 may act as an autoimmune trigger in susceptible individuals, warranting further study and post-recovery surveillance (Li et al. 2021).

This preliminary observational study describes the clinical characteristics and response to supplementation in a small cohort of patients with post-COVID syndrome (Augustin et al. 2021). The most common persistent symptoms were fatigue, neurocognitive disturbances (brain fog, memory loss), and musculoskeletal complaints, consistent with existing literature on post-COVID. The immunological findings are notable: over 60% of the tested patients were ANA positive, suggesting a potential autoimmune component in post-COVID symptomatology. While ANA positivity is not specific to COVID-19, its presence reinforces growing hypotheses that post-viral immune dysregulation may underlie many presentations of post-COVID (Kocivnik et al. 2022).

Vitamin D insufficiency or deficiency was present in the majority of patients (58.4%), consistent with studies that associate lower vitamin D levels with poorer outcomes in both the acute and long-term phases of COVID-19. The supplementation protocol appeared promising: among the patients who received it and were available for follow-up, 80% reported clinical improvement. Melatonin is known for its anti-inflammatory and neuroprotective effects, NAC for its antioxidant and mucolytic properties, and 5-HTP for improving mood and sleep, each addressing relevant symptoms of post-COVID. Vitamin D, beyond its role in bone health, has been recognized for its immunomodulatory properties, which may support recovery (Kim et al. 2020; Athanassiou et al. 2022).

However, the small sample size and lack of a control group limit the ability to draw definitive conclusions. The absence of statistical significance (p = 0.576) in the therapy–outcome association likely reflects insufficient power rather than a lack of effect. Further controlled studies with larger cohorts are needed to evaluate the efficacy of such supplementation strategies. There is no specific drug treatment for post-COVID. Treatment involves addressing the symptoms the patient experiences, such as breathlessness, fatigue, weakness, or gastric issues. Emerging treatments for post-COVID aim to target chronic inflammation, immune dysregulation, and hormonal imbalances associated with the condition (Fernández-de-Las-Peñas et al. 2022). WHO notes that post-COVID can significantly reduce a patient’s ability to work or participate actively in society. Mental health issues can also develop from the distress this causes (Au et al. 2022). Rehabilitation and physiotherapy have helped alleviate symptoms such as headaches and musculoskeletal pain (Piquet et al. 2021). Given the evolving nature of the pandemic and the appearance of new viral strains, future research should also focus on the long-term health impacts of post-COVID and the effectiveness of therapies across different viral strains and patient demographics. This is particularly important for high-risk individuals, such as those who are immunocompromised and patients with pre-existing comorbidities, to ensure that treatment strategies can be adapted to their specific needs (Scott et al. 2024).

The marked improvement in cognitive symptoms (brain fog) and visual disturbances aligns with the known mechanisms of action of the administered supplements. NAC replenishes intracellular glutathione and combats oxidative stress in neuronal tissues; melatonin supports mitochondrial function and sleep regulation; and 5-HTP may alleviate serotonergic dysregulation associated with fatigue and mental fog. These agents are likely to act synergistically in reducing neuroinflammation, which is believed to underlie many post-COVID cognitive and sensory disturbances (Wong et al. 2023).

In contrast, musculoskeletal symptoms—such as joint, muscle, and bone pain—were less responsive to supplementation. These symptoms may not be solely attributable to post-viral fatigue but rather to latent or subclinical autoimmune activation (VanElzakker et al. 2013). This hypothesis is supported by the high rate of ANA positivity in the cohort, despite the absence of diagnosed autoimmune disease. Such findings suggest that for some individuals, post-COVID syndrome may unmask or initiate autoimmune pathways, particularly in those with a genetic predisposition or insufficient immunoregulation (e.g., due to vitamin D deficiency). These cases may require longer-term immunological follow-up and potentially different therapeutic strategies than those provided by general antioxidant or neuroprotective supplements (Anaya et al. 2022).

Among the patients who received supplementation and provided follow-up data (n = 5), the most notable symptomatic improvements were reported in visual clarity and a reduction in brain fog. Patients reported enhanced focus, improved cognitive performance, and resolution of visual disturbances, including blurred vision. These effects were particularly observed in individuals receiving the full supplementation protocol, including N-acetylcysteine (NAC), melatonin, and 5-hydroxytryptophan (5-HTP). The neuroprotective, antioxidant, and anti-inflammatory properties of these agents may have contributed to the observed improvements, particularly in symptoms associated with neuroinflammation and oxidative stress, processes that are increasingly implicated in the development of post-COVID (Rosenblum et al. 2015).

The most significant improvements were observed in blurred vision and brain fog. These improvements may reflect the neuroprotective and antioxidative effects of NAC, melatonin, and 5-HTP. Less notable improvements were observed in fatigue, sleep disturbances, and musculoskeletal pain, suggesting that some symptoms may have a different, possibly autoimmune, pathophysiological basis (Rus et al. 2023).

Other therapeutic options and future directions in post-COVID therapy

Antifibrinolytic agents

In a study following 55 patients with COVID-19 three months after hospital discharge, 71% still had radiological changes characterized by focal fibrosis and interstitial induration, which led to persistent symptoms and functional changes. To prevent the formation of fibrosis, various antifibrinolytic agents are increasingly used in clinical practice, which, thanks to their anti-inflammatory properties, significantly reduce the progression of fibrosis. In our clinical practice, we have experience with a combination of two proteases (the enzymes sericopeptidase and bromelain) and the bioflavonoid rutin. These are endopeptidases that hydrolyze peptide bonds at specific locations on peptide chains based on their affinity for specific amino acid residues. The source of sericopeptidase is non-pathogenic enterobacteria of the genus Serratia, species E-15. These microorganisms were first isolated in the 1960s from the silkworm Bombyx mori. The enzyme helps the butterfly escape from its cocoon by lysing it. Serratiopeptidase is a metalloproteinase containing a zinc atom, which plays a key role in its proteolytic activity. It is composed of 470 amino acids (Nakahama et al. 1986). After oral administration, serratiopeptidase is absorbed through the intestinal mucosa and enters the bloodstream directly. The peak plasma concentration of the enzyme is reached within 15–30 min after administration and remains relatively constant until the sixth hour. In the blood, it forms a complex in a 1:1 ratio with the plasma protease inhibitor alpha-2-macroglobulin, which masks the antigenicity of the enzyme, thereby preventing allergic or autoimmune reactions. Studies show that serratiopeptidase improves mucociliary transport and clearance by reducing neutrophils and modulating sputum viscoelasticity in patients with respiratory diseases (Lu et al. 2021).

Effects of serratiopeptidase

Anti-inflammatory and anti-edematous effects: Seropeptidase reduces edema in several ways, including by inhibiting capillary permeability (through the reduction of histamine, bradykinin, and serotonin), decreasing fluid viscosity through the degradation of abnormal exudates and proteins (mucolysis), and facilitating fluid drainage. In addition, the enzyme activates the breakdown of necrotic tissue surrounding the focus of inflammation, thereby accelerating the recovery process (Klein and Kullich 2000). Analgesic effects: It inhibits the release of pain-inducing amines from inflamed tissues (bradykinin) (Mazzone et al. 1990). It reduces swelling and pain due to compression on sensory neurons. Fibrinolytic effects: Through proteolysis, it breaks down non-vital and damaged tissues without affecting healthy tissue—fibrin in thrombi, cysts, and necrotic tissues (Bhagat et al. 2013). Serratiopeptidase blocks plasmin inhibitors, thereby promoting the fibrinolytic activity of plasmin. Inhibits bacterial biofilm production: A study conducted in Italy in 2012 examined the action of various enzymatic proteases, such as proteinase K, trypsin, chymotrypsin, carboxypeptidase A, and serine carboxypeptidase, against bacterial biofilm formation (Arni et al. 2013). Serratiopeptidase is a potential anti-infective agent that can inhibit the entry of S. aureus into human tissues and disrupt the pathogen’s ability to attach to prostheses, catheters, and other medical devices (Papa et al. 2013). Serratiopeptidase has also shown efficacy against invasion and biofilm formation by Listeria monocytogenes (Longhi et al. 2008).

Essential oils

It has long been known that essential oils possess anti-inflammatory, immunomodulatory, bronchodilator, and antiviral properties and are effective in the symptomatic treatment of post-COVID. Essential oils contain numerous active phytochemicals that can act synergistically at many stages of viral replication and also induce positive effects on the host respiratory system, including bronchodilation and mucolysis. Due to their lipophilic nature, they have the potential to insert into the lipid bilayer of the viral envelope (Mediouni et al. 2020).

Eucalyptus oil

Various in vitro and ex vivo studies have been conducted on the effects of eucalyptus oil and eucalyptol treatment on monocyte and macrophage recruitment in response to pulmonary inflammation and infection. Data from these trials demonstrate marked immunomodulatory properties of both eucalyptus oil and its active ingredient, i.e., eucalyptol. Both treatments demonstrated a reduction in the release of pro-inflammatory cytokines from monocytes and macrophages while preserving their phagocytic properties. Eucalyptol is also known to have mucolytic and bronchodilator properties (Juergens et al. 2003). Our clinical observations suggest the potential of eucalyptus oil and its active ingredient, eucalyptol, in the prevention and treatment of post-COVID (Panikar et al. 2021).

Lavender oil

The essential oil is obtained by steam distillation from the flowering tops and stems of Lavandula latifolia. The main components of the essential oil are linalool (30–50%), 1,8-cineole (20–35%), and camphor (1–20%). These three main ingredients of broadleaf lavender oil have been proven to have anti-inflammatory, antibacterial, antiseptic, expectorant, and immunostimulating properties. This leads to an increase in mucociliary clearance by liquefying mucus without increasing its total volume (Li et al. 2017). This increases the frequency of ciliary movement in the bronchi. Thick mucus is liquefied and actively transported to the oral cavity and thus easier to expectorate (Begrow et al. 2012).

Eugenol, menthol, and carvacrol

Plant extracts rich in menthol have been used for centuries in traditional Asian medicine to treat respiratory diseases. Menthol provides symptomatic relief from nasal congestion associated with rhinitis and the sensation of dyspnea through its specific interaction with a cold- and menthol-sensitive receptor located on the trigeminal nerve endings. Menthol treatment was found to significantly reduce the levels of pro-inflammatory cytokines, i.e., IL-1, IL-23, and TNF-α. Eugenol treatment inhibits leukocyte recruitment to the lung and reduces the expression of pro-inflammatory cytokines (IL-6 and TNF-α) (Tobaiqy et al. 2020).

In recent years, there has been no other disease with such “artistic” behavior, more talented even than tuberculosis, which we call “the great actress.” The good news is that most patients treated at home recover almost completely, with little residual damage and symptoms. Post-COVID therapy requires a multidisciplinary approach and is primarily aimed at residual symptoms, namely cough, shortness of breath, brain disorders, emotional consequences, etc.

Conclusion

This observational study highlights the complex interplay between persistent post-COVID symptoms, emerging autoimmunity, and nutritional status. ANA positivity was common even in patients without overt autoimmune disease, suggesting that SARS-CoV-2 may induce subclinical immune activation. Additionally, the high prevalence of vitamin D insufficiency supports its role as a modifiable factor in post-COVID recovery. Preliminary results indicate that targeted supplementation with melatonin, NAC, 5-HTP, and vitamin D may be beneficial in alleviating symptoms such as fatigue, cognitive dysfunction, and sleep disturbances. Although the small sample size limits statistical conclusions, the clinical trend toward improvement in the treated group is encouraging. Further longitudinal studies with larger cohorts are needed to better understand the autoimmune dynamics post-COVID and the therapeutic potential of supportive supplementation, particularly in patients with unresolved symptoms and signs of immune dysregulation. Among the patients who received supplementation and provided follow-up data (n = 5), the most notable symptomatic improvements were reported in visual clarity and reduction in brain fog. Patients reported enhanced focus, improved cognitive performance, and resolution of visual disturbances, including blurred vision. These effects were particularly observed in individuals receiving the full supplementation protocol, including N-acetylcysteine (NAC), melatonin, and 5-hydroxytryptophan (5-HTP). The neuroprotective, antioxidant, and anti-inflammatory properties of these agents may have contributed to the observed improvements, particularly in symptoms associated with neuroinflammation and oxidative stress—processes that are increasingly implicated in the development of post-COVID.

Acknowledgments

This study was financed by the European Union–Next Generation EU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project No. BG-RRP-2.004-0008.

Additional information

Conflict of interest

The authors have declared that no competing interests exist.

Ethical statements

The authors declared that no clinical trials were used in the present study.

The authors declared that no experiments on humans or human tissues were performed for the present study.

Informed consent from the humans, donors or donors’ representatives: The patients were administered to the treatment as a part of their ambulatory treatment and agreed their data to be analysed anonymously.

The authors declared that no experiments on animals were performed for the present study.

The authors declared that no commercially available immortalised human and animal cell lines were used in the present study.

Use of AI

No use of AI was reported.

Funding

This study is financed by the European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project No BG-RRP-2.004-0008.

Author contributions

Conceptualization, E.S. and T.V.; methodology, V.I.; software, T.V.; validation, E.S, V.I. and T.V.; formal analysis, T.V.; investigation, E.S.; resources, E.S; data curation, E.S.; writing—original draft preparation, E.S. and T.V.; writing—review and editing, V.I.; visualization, T.V.; supervision, T.V.; project administration, T.V.; funding acquisition, T.V. All authors have read and agreed to the published version of the manuscript.

Author ORCIDs

Eleonora Stamenova https://orcid.org/0000-0003-2323-0493

Verginiya Ivanova https://orcid.org/0009-0009-6874-8342

Tsvetelina Velikova https://orcid.org/0000-0002-0593-1272

Data availability

All of the data that support the findings of this study are available in the main text.

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