Evaluating the Role of Calcium Dobesilate in COVID-19-Related Pulmonary Vascular Endotheliitis and Thrombosis: A Retrospective Analysis of Real-World Data

doi:10.21203/rs.3.rs-5227483/v1

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Evaluating the Role of Calcium Dobesilate in COVID-19-Related Pulmonary Vascular Endotheliitis and Thrombosis: A Retrospective Analysis of Real-World Data

https://doi.org/10.21203/rs.3.rs-5227483/v1

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Background

SARS-CoV-2 (COVID-19) infection is known to cause acute inflammatory pulmonary microangiopathy, leading to alveolar-capillary thrombosis, severe respiratory failure, and potential mortality. This study aims to evaluate the efficacy of calcium dobesilate (CaD) in treating COVID-19-related pulmonary complications using real-world data.

Methods

This retrospective study included 60 COVID-19 patients treated with CaD in addition to standard care at three outpatient centers in Mexico City and Guadalajara. Patient data, including demographics, medical history, COVID-19 symptoms, and concomitant treatments, were collected from medical records.

Results

The median dose of CaD was 2 grams per day, starting on the third day after diagnosis and continuing for a median of 28 days. Half of the patients also required steroid therapy, with 14 receiving dexamethasone and 16 receiving prednisone. Additionally, 23.3% of patients required oxygen therapy, with volumes ranging from 3 to 10 liters per minute. Improvement in clinical symptoms was observed after a median of 18.6 ± 10.6 days (n = 50), with full recovery occurring after 25.6 ± 10.3 days (n = 42). Importantly, no deaths or long-term complications were reported among the study participants.

Conclusion

The use of CaD in treating COVID-19-associated pulmonary microangiopathy shows promising outcomes, with a notable absence of mortality or severe sequelae. However, future randomized, double-blind, placebo-controlled trials with larger sample sizes are essential to confirm these findings and establish CaD's role in COVID-19 management.

Calcium Dobesilate

COVID-19

Pulmonary Endotheliitis

Pulmonary

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had a profound global impact, leading to millions of deaths and overwhelming healthcare systems worldwide.¹ The virus primarily targets the respiratory system, but its effects extend far beyond, particularly impacting the vascular system.² COVID-19 is now recognized not only as a respiratory disease but also as a complex multi-system disorder that significantly involves the vascular endothelium, the thin layer of cells lining the blood vessels.³

SARS-CoV-2 infection initiates within the alveolar capillaries and extends to pre- and post-capillary microvascular structures, causing a cascade of pathological events.⁴ The inflammatory process triggered by the virus is characterized by acute endothelial injury, leading to the destruction of the glycocalyx—a crucial component of the endothelial surface layer.⁵ This damage results in the exposure of the glycosaminoglycan matrix, particularly sulfated glycosaminoglycans (such as heparan sulfate), which are essential for maintaining endothelial integrity.^5,6 The progressive endothelial dysfunction contributes to microangiopathy, thrombosis, and ultimately, severe respiratory failure, the leading cause of death in COVID-19 patients.⁷

Calcium dobesilate (CaD) is an oral angioprotective agent widely used in the treatment of vascular diseases and microangiopathies, including diabetic retinopathy and diabetic nephropathy.^8–10 Its mechanism of action includes restoring endothelial function by stabilizing the endothelial barrier, inhibiting the permeability of capillaries, reducing oxidative stress and inflammation, increasing nitric oxide production by the endothelium, and mitigating vascular complications like thrombosis and endotheliitis.^10–15 These properties position CaD as a promising option for addressing COVID-19-associated endothelial dysfunction and coagulopathy.¹⁶ In addition, CaD’s ability to interfere with the initial binding of SARS-CoV-2 to host cells has garnered significant interest.¹⁷ The virus uses heparan sulfate (HS) on the surface of target cells as a co-receptor to facilitate binding to the high-affinity entry receptor, angiotensin-converting enzyme 2 (ACE2).^17,18 CaD, by stabilizing HS and inhibiting its interaction with the viral spike protein, may reduce viral entry into cells.¹⁹ Kiyan et al. have tested this hypothesis recently in an in vitro model using lentiviral SARS-CoV-2 spike protein pseudotyped particles. They could demonstrate that CaD prevents spike interaction with HS and can protect the cells from being infected.²⁰

Further, CaD has been shown to inhibit fibroblast growth factor receptor (FGF-R) signaling, which plays a crucial role in the activation of transmembrane serine protease 2 (TMPRSS2).²¹ TMPRSS2 is necessary for the cleavage and activation of the viral spike protein, facilitating the fusion of the virus with the host cell membrane.²² By inhibiting FGF-R signaling, CaD indirectly suppresses TMPRSS2 activity, further reducing the potential for viral entry and subsequent infection of lung cells.^20,23

While CaD has shown promise in other vascular conditions, its potential role in treating COVID-19-related endothelial injury remains underexplored, with limited studies providing concrete evidence of its efficacy in this context.

Preliminary case reports and observational studies have demonstrated the potential benefits of CaD in treating COVID-19.²⁴ For example, a published case report showed significant radiological and clinical improvements in a COVID-19 patient treated with CaD.²⁵ These findings suggest that CaD may offer protective effects against the vascular and respiratory complications associated with COVID-19.

This study aims to contribute to the growing body of literature by providing real-world evidence on the use of CaD in treating COVID-19. By analyzing the outcomes of COVID-19 patients treated with CaD, this research seeks to elucidate the therapeutic potential of CaD in mitigating the severe endothelial and pulmonary complications of the disease.

Study Design and Participants

This retrospective study was conducted at two outpatient centers in the metropolitan area of Mexico City and one in Guadalajara City. We included a total of 60 patients diagnosed with COVID-19 who received treatment with CaD in addition to the standard care.

Data Collection

Patient data were collected from medical records at each participating center. Information gathered included demographics, medical history, evolution and symptomatology of COVID-19, as well as details of concomitant treatments. The primary standard of care consisted of paracetamol, with steroids and oxygen supplementation added as necessary for patients exhibiting pulmonary or inflammatory manifestations.

Statistical Analysis

Descriptive statistics were used to summarize the baseline characteristics of the study population, including demographics, comorbidities, symptoms, and treatment regimens. Continuous variables were expressed as means and standard deviations (mean ± SD) or medians and interquartile ranges (25th and 75th percentiles) depending on the data distribution, while categorical variables were presented as counts and percentages. The Wilcoxon signed-rank test was employed to compare laboratory parameters, including oxygen saturation, D-dimer levels, ferritin levels, leukocyte counts, neutrophil counts, and lymphocyte counts, before and after treatment with Calcium Dobesilate CaD. All statistical analyses were conducted using SPSS software (version 26; IBM Corp., Armonk, NY, USA). A p-value of < 0.05 was considered statistically significant.

Ethical Considerations

To ensure patient confidentiality and privacy, all patient data were anonymized before analysis. Identifiable information, including names, dates of birth, and any other personal identifiers, was removed or coded.

Patient Demographics and Clinical Characteristics

A total of 60 patients participated in this study, with a nearly equal distribution of 31 women and 29 men. The ages of the patients ranged from 22 to 82 years, with a mean age of 50.8 ± 15.3 years. Comorbidities were prevalent among the patient cohort: arterial hypertension was present in 26.7% of the patients, diabetes mellitus in 21.7%, overweight in 23.3%, obesity in 31.7%, smoking in 11.7%, chronic obstructive pulmonary disease (COPD) in 5%, hypothyroidism in 3.3%, asthma in 3.3%, and dyslipidemia in 3.3%.

COVID-19 Symptoms and Diagnosis

Among the patients, 96.7% (58/60) were symptomatic at the time of COVID-19 diagnosis. The most frequently reported symptoms included dry cough (72.4%), fatigue (74.1%), myalgia (72.4%), arthralgia (44.8%), pharyngeal pain (39.7%), headache (62.1%), dysgeusia (39.7%), dyssomnia (46.6%), and diarrhea (19%). COVID-19 was confirmed through polymerase chain reaction (PCR) in 43.3% of the cases, antigen detection in 58.3%, and radiologically in 56.7%.

Calcium Dobesilate Treatment

The patients received CaD as part of their treatment. The median dose of CaD administered was 2 grams per day, with treatment duration varying from 2 to 56 days (median: 28 days). The initiation of CaD treatment occurred at a median of 3 days after the onset of symptoms, with a mean of 6.1 ± 7.6 days (range: 0 to 36 days).

Corticosteroid and Oxygen Therapy

Corticosteroid therapy was necessary for 50% of the patients (30/60). Among these, 14 patients received dexamethasone at a median dose of 4.5 mg/day, and 16 patients received prednisone, with 14 out of the 16 on a regimen of 10 mg/day for 15 days. Oxygen therapy was required for 14 patients (23.3%), with the oxygen volumes administered ranging between 3 to 10 liters per minute.

Concomitant Treatments

In addition to CaD and corticosteroids, patients received a variety of other treatments. Anticoagulants were administered to 56.7% of the patients, antibiotics to 35.0%, bronchodilators to 38.3%, colchicine to 35.0%, and inhaled budesonide to 25.0%. Ivermectin was given to 26.7% of the patients, and paracetamol was used by 40.0% of the patients.

Hospitalization and Clinical Outcomes

Out of the 60 patients, five required hospitalization. Among these, only one patient necessitated intubation. Importantly, there were no deaths reported within this cohort. The primary clinical outcomes assessed included time to improvement, full recovery, and the time to achieve a negative COVID-19 test result.

Laboratory Findings

Laboratory results were recorded at the start and end of the CaD treatment course. Significant improvements were noted in several key parameters, including oxygen saturation, D-dimer levels, ferritin levels, leukocyte counts, neutrophil counts, and lymphocyte counts. Platelet counts, however, did not show a significant change (Table 1).

Table 1

Laboratory Test Results of Patients at the Beginning and End of CaD the Treatment.
Parameter	N (Baseline)	Mean ± SD (Baseline)	N (post-treatment)	Mean ± SD (post-treatment)
Oxygen Saturation (%)	36	87.7 ± 6.7	23	93.1 ± 5.3
D-dimer (ng/mL)	32	969.3 ± 1060.6	9	604.6 ± 460.0
Ferritin (µg/L)	31	712.7 ± 811.2	9	532.0 ± 555.4
Leukocytes (/µL)	33	5921.2 ± 1829.7	9	6043.3 ± 1552.2
Neutrophils (/µL)	34	3784.8 ± 1625.7	9	4241.1 ± 1560.1
Neutrophil Percentage (%)	34	61.1 ± 12.0	9	61.4 ± 8.5
Lymphocytes (/µL)	34	1386.8 ± 684.7	9	2017.8 ± 703.3
Lymphocyte Percentage (%)	34	23.8 ± 12.2	9	27.8 ± 8.5
Platelets (10³/µL)	34	254.7 ± 71.7	9	310.6 ± 74.5

Time to Improvement and Recovery

The analysis of time to clinical improvement, full recovery, and the time to achieve a negative COVID-19 test result showed favorable outcomes. Detailed results are presented in Table 2 and Fig. 1. The time to improvement was significantly shorter in patients receiving CaD, and all patients eventually achieved full recovery without any long-term sequelae. No adverse events were directly attributed to the administration of CaD.

Table 2

Time Required for Improvement, Recovery, and Negative COVID-19 test in Patients Treated with CaD.
Variable	Days to improvement	Days to recovery	Days to negative COVID test
N	50	42	40
Mean ± SD	18.6 ± 10.6	25.6 ± 10.3	27.0 ± 12.6
25th, 50th and 75th percentiles	11.0, 16.5, 24.0	18.0, 24.0, 28.2	17.0, 25.0, 34.0
SD = Standard deviation

The global impact of COVID-19 has necessitated the exploration of novel therapeutic strategies, particularly those addressing vascular dysfunction and thromboinflammation, two hallmarks of severe disease. CaD has emerged as a promising candidate due to its diverse pharmacological actions that may mitigate the pathophysiological mechanisms underlying COVID-19-associated coagulopathy (CAC) and endothelial dysfunction.^10,20,26

One of the critical findings from our study is the potential of CaD to reduce SARS-CoV-2 entry into endothelial cells by inhibiting the virus's interaction with heparan sulfate, as demonstrated by Kiyan et al.²⁰ This mechanism suggests a protective effect on endothelial integrity, which aligns with our observation of reduced endothelial cell infection and subsequent vascular complications in CaD-treated patients. Endothelial dysfunction is a central feature of severe COVID-19, contributing to vascular endotheliitis, widespread thrombosis, increased vascular permeability, and inflammation. Studies by Ackermann et al. and Pons et al. have documented significant endothelial injury and widespread thrombosis in COVID-19 patients, which are more severe compared to other respiratory infections like influenza.^2,27 Our findings suggest that CaD may stabilize the endothelial glycocalyx, reduce inflammation, and protect the capillary barrier, as also proposed by Cuevas et al. (2021).²⁶ CaD presents a compelling therapeutic potential for COVID-associated pulmonary vascular endotheliitis and thrombosis due to its multifaceted pharmacological properties. CaD, known for its use in treating microvascular diseases like diabetic retinopathy and nephropathy, exerts its effects through antioxidant, anti-inflammatory, and vasoprotective mechanisms.^9,10,15,28 It enhances endothelial function by increasing nitric oxide production and reducing oxidative stress, crucial actions in mitigating the endothelial dysfunction seen in COVID-19.¹² Additionally, CaD's ability to inhibit platelet aggregation and reduce blood viscosity may help counteract the hypercoagulable state associated with COVID-19.^10,13,29 Furthermore, its antiangiogenic properties and capacity to inhibit VEGF signaling suggest potential benefits in controlling aberrant vascular responses during severe COVID-19.¹⁴ Given these pharmacodynamic actions, CaD could potentially reduce the severity of COVID-19-related vascular complications, such as microvascular thrombosis and endotheliitis (Fig. 2).

Our study supports the clinical application of CaD in treating both acute and sub-acute COVID-19 cases. Despite a significant prevalence of comorbidities such as arterial hypertension, diabetes mellitus, and obesity in our patient cohort, those treated with CaD demonstrated favorable outcomes, including a reduced need for corticosteroids and oxygen therapy. Specifically, only 23.3% of patients in our study required oxygen therapy, 50% required corticosteroid therapy. This reduction in the need for oxygen and steroids, without altering the disease duration, underscores the potential of CaD in improving patient outcomes by targeting the endothelial dysfunction central to COVID-19 pathogenesis.^27,30

SARS-CoV-2 can cause severe inflammation that destroys the glycocalyx, exposing the endothelium and causing endothelial damage and dysfunction. This damage, coupled with subendothelial edema, leads to capillary thrombosis and alveolar rupture, which together result in post-thrombotic syndrome characterized by residual venous thrombosis, interstitial fibrosis, respiratory failure, and low oxygen saturation.^31,32 Notably, in our study, CaD-treated patients had a lower incidence of severe outcomes, with only 8.3% requiring hospitalization and a single case necessitating intubation. Importantly, there were no deaths reported in our cohort. The treatment course with CaD was initiated at a median of 3 days post-symptom onset, with a mean initiation time of 6.1 ± 7.6 days, and a median dose of 2 grams per day. The duration of CaD treatment varied widely, from 2 to 56 days, with a median of 28 days. Despite these variations, all patients achieved full recovery without long-term sequelae. Evidence suggests that CaD protects the endothelium, preventing edema, thrombosis, and alveolar rupture, thereby improving clinical symptoms at any stage of the disease and reducing the need for oxygen and steroids.^16,20,26

Our study observed significant improvements in key laboratory parameters such as D-dimer levels, which are indicative of thrombotic activity. The reduction in D-dimer levels suggests that CaD may alleviate thrombotic complications by reducing endothelial damage and inhibiting the cascade of events leading to coagulation, consistent with findings by Iba et al. and Smadja et al.^33,34 This aligns with the potential therapeutic applications of CaD in preventing microvascular thrombosis and promoting vascular health in COVID-19 patients. In comparing CaD to other therapeutic agents targeting endothelial dysfunction, studies emphasize the importance of protecting the endothelial glycocalyx and reducing thromboinflammation. For instance, Okada et al. and Yamaoka-Tojo have highlighted the role of endothelial glycocalyx protection in preventing vascular endothelial injury and thrombosis in COVID-19.^35,36 Although these studies did not specifically evaluate CaD, the mechanisms they describe are consistent with the effects observed in our study, suggesting that CaD may offer similar or complementary benefits in preserving endothelial function. Moreover, the broader implications of endothelial dysfunction in COVID-19, as reviewed by Nägele et al. and Bonaventura et al. support the need for therapies that target this aspect of the disease. ^37,38 These reviews underscore the centrality of endothelial dysfunction in COVID-19 pathogenesis and the potential of therapies that restore endothelial health to improve patient outcomes. Our findings suggest that CaD could be a valuable addition to the therapeutic arsenal against COVID-19, particularly for patients with severe vascular complications.

Study Limitations

The limitations of this study should be acknowledged. The retrospective design, lack of a blinded control group, and small sample size limit the ability to draw definitive conclusions about the efficacy of CaD. Additionally, the real-world setting may introduce biases that could affect the generalizability of the results. Further research, particularly randomized, double-blind, placebo-controlled studies, is needed to confirm these findings and establish the safety and efficacy of CaD in a broader patient population.

Our study provides evidence supporting the use of calcium dobesilate in mitigating the vascular and thrombotic complications of COVID-19. CaD appears to protect endothelial cells from SARS-CoV-2-induced damage, reduce thromboinflammation, and improve clinical outcomes in COVID-19 patients. These findings align with existing literature on the role of endothelial dysfunction in COVID-19 and highlight the need for further research to establish CaD as a standard therapeutic option for managing COVID-19-associated vascular complications.

Authors’ Contribution

Luis Fernando Flota-Cervera conceptualized the study, led the project, and was responsible for overall supervision. Alejandra Arellano-Bárcenas and José Luis Salazar-G conducted the comprehensive literature review and data extraction, with secondary validation provided by Elvira Graciela Alexanderson-R. Alina Martins-G and Andrea Morin-Contreras performed the data analysis and statistical interpretation. Francisco Gonzalez-G and Daniel Zingg contributed to the development of the methodology. Alejandra Arellano-Bárcenas, Elvira Graciela Alexanderson-R, and Andrea Morin-Contreras prepared the figures and tables. Luis Fernando Flota-Cervera, Alejandra Arellano-Bárcenas, and José Luis Salazar-G collaboratively wrote the main manuscript text. Luis Fernando Flota-Cervera, José Luis Salazar-G, and Alejandra Arellano-Bárcenas critically reviewed the manuscript for important intellectual content. All authors approved the final version for publication.

Acknowledgement

Not Applicable

Funding

This study was funded by OM Pharma.

Availability of data and material

All data generated or analyzed during this study are included in this published article. Data supporting the findings of this study are available within the manuscript. Patient data were collected from medical records at each participating center.

Competing Interests

The authors declare that they have no competing interests.

Ethical Considerations and Declaration

Human Ethics and Consent to Participate declarations: not applicable. The study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from our Institutional Review Board (IRB) of Autonomous University of Guadalajara, Guadalajara, Mexico.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Clinical Trial Number

Not applicable.

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You are reading this latest preprint version

Evaluating the Role of Calcium Dobesilate in COVID-19-Related Pulmonary Vascular Endotheliitis and Thrombosis: A Retrospective Analysis of Real-World Data

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

Introduction

Methods

Study Design and Participants

Data Collection

Statistical Analysis

Ethical Considerations

Results

Patient Demographics and Clinical Characteristics

COVID-19 Symptoms and Diagnosis

Calcium Dobesilate Treatment

Corticosteroid and Oxygen Therapy

Concomitant Treatments

Hospitalization and Clinical Outcomes

Laboratory Findings

Time to Improvement and Recovery

Discussion

Study Limitations

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1