Meta-analysis overview

This comprehensive meta-analysis investigates the prognostic potency of VEGF-A in patients with COVID-19, involving a diverse sample of 1119 participants across multiple studies. The findings consistently indicate a significant elevation in serum VEGF-A levels in patients with severe COVID-19 outcomes compared to those with milder symptoms. The implications of these results are profound, suggesting that VEGF-A could serve as a potential biomarker for COVID-19 prognosis and severity. This discussion elucidates the underlying biological mechanisms, interprets the primary findings, and explores their implications for clinical practice and future research.

Interpretation of main findings

Our meta-analysis highlights a significant correlation between higher serum VEGF-A levels and poor outcomes in COVID-19 patients, with a standardized mean difference of 0.525. This suggests that VEGF-A may play a role in the pathogenesis or progression of severe COVID-19. The substantial heterogeneity observed (I2 = 90.44%) could be indicative of variability in the disease's impact based on demographic and clinical factors. Moreover, the prediction interval (− 1.23 to 2.28) underscores the variability in effect size, suggesting that while VEGF-A is generally predictive of poor outcomes, its specific utility might vary widely across different populations and clinical settings.

Deciphering study outcome patterns: meta-regression insights

Meta-regression analysis explored various factors influencing VEGF-A levels, including publication year, region, and total sample size. While these factors showed a positive correlation, they were not statistically significant, indicating potential trends over time and geographical variations in VEGF-A expression possibly due to evolving laboratory techniques or regional differences in COVID-19 strain virulence [34, 35]. Notably, a significant positive correlation was found with BMI and test method. Higher BMI, associated with an inflammatory state, showed increased VEGF-A levels. This suggests that obesity-related inflammation might amplify the severity of COVID-19 via enhanced VEGF-A pathways, exacerbating the immune response [27, 36]. Additionally, more sensitive test methods were correlated with higher detected levels of VEGF-A, emphasizing the critical role of assay sensitivity in capturing disease severity markers effectively. Conversely, study design and NOS score displayed a negative correlation with VEGF-A levels. This finding suggests that higher-quality studies or specific designs, which likely incorporate more stringent controls and sampling protocols, tend to report lower VEGF-A levels. This could reduce potential biases and variability in VEGF-A measurement, leading to more accurate assessments of its role in COVID-19 prognosis [37, 38]. These findings are consistent with prior research on other biomarkers, reinforcing the broader applicability of such associations in disease prognosis and highlighting the necessity of rigorous methods and study quality for reliable biomarker analysis in disease prognosis [39,40,41].

Prior research and contextualization

The current meta-analysis builds on a foundation of existing literature exploring the role of VEGF-A as a biomarker in various diseases, particularly in its well-established role in promoting angiogenesis and vascular permeability. Prior studies have also linked elevated VEGF-A levels with worse outcomes in respiratory diseases, such as ARDS, which shares some pathophysiological features with severe COVID-19, including hypoxia-induced vascular leakage and inflammation [42, 43]. Historically, research on VEGF-A in the context of infectious diseases has suggested that VEGF-A plays a significant role in the vascular and inflammatory responses to infections. For instance, increased VEGF-A levels have been observed in patients with H1N1 influenza and SARS, correlating with disease severity and outcomes [44, 45]. These precedents support the hypothesis that VEGF-A could be a critical mediator in the progression of COVID-19, particularly in its severe forms, where inflammatory and vascular complications dominate.

In the specific context of COVID-19, early studies have demonstrated that patients with severe outcomes exhibit significantly higher levels of VEGF-A compared to those with milder disease [23]. This correlation is thought to stem from role of VEGF-A in enhancing vascular permeability, thereby potentially exacerbating the pulmonary edema seen in severe COVID-19 cases [46]. VEGF-A interaction with immune modulation, specifically its effects on macrophage function and cytokine production, provides a plausible link to the cytokine storm syndrome frequently observed in severe COVID-19 patients [47].

Recent systematic reviews and meta-analyses prior to ours have provided mixed insights, with some studies indicating a strong prognostic value of elevated VEGF-A levels, while others pointed to a more nuanced role influenced by patient demographics, comorbidities, and disease severity. For example, a meta-analysis involving 7668 COVID-19 patients reported that while elevated VEGF-A levels were generally predictive of poor outcomes, significant heterogeneity across studies suggested that the prognostic utility of VEGF-A may depend on the population and local clinical practices [48]. This underscores the importance of context in interpreting VEGF-A levels, which our current analysis seeks to clarify further by including a more extensive and diverse dataset. These findings have profound implications, suggesting that VEGF-A holds promise as a potential target for therapeutic intervention. VEGF-A inhibitors, traditionally employed in oncology to impede tumor vasculature, could be repurposed to regulate the acute inflammatory response in COVID-19. Previous research has demonstrated their efficacy in mitigating the incidence or severity of complications such as ARDS and multiple organ failure [49,50,51]. However, given the pivotal role of VEGF-A in normal vascular function and wound healing, any therapeutic manipulation of its activity warrants cautious consideration.

Biological mechanisms underlying roles of VEGF-A in COVID-19 severity

The underlying mechanisms connecting VEGF levels to the severity of COVID-19 involve both the factors that contribute to the elevation of VEGF in patients with COVID-19 and the subsequent impacts of heightened VEGF levels on the progression of the disease (Fig. 9).

Fig. 9

Graphical abstract illustrating the differential impact of VEGF-A on COVID-19 severity based on biological mechanisms

VEGF-A is known to be upregulated in response to hypoxia, inflammation, and endothelial dysfunction, which are prominent features of severe COVID-19. Hypoxia, which results from impaired gas exchange in the lung due to viral-induced pneumonia, triggers the activation of hypoxia-inducible factor 1-alpha (HIF-1α) [52]. This transcription factor, in turn, stimulates the expression of VEGF-A to promote angiogenesis and improve tissue oxygenation [53]. In addition, the cytokine storms observed in severe COVID-19, characterized by elevated levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), directly stimulate VEGF-A secretion from activated endothelial and immune cells [54, 55]. Furthermore, the direct impact of the virus on endothelial cells in blood vessels can also increase VEGF-A expression. Endothelial dysfunction and injury trigger a compensatory response involving VEGF-A to promote angiogenesis and repair processes [56, 57].

On the other hand, the consequences of elevated VEGF-A levels in COVID-19 patients are multifaceted and can significantly influence disease severity and outcomes. In this context, one of the key mechanisms is promoting vascular permeability. Elevated VEGF-A levels disrupt endothelial cell junctions and increase fluid leakage into surrounding tissues [58, 59]. In patients with COVID-19, this vascular leakage leads to the development of pulmonary edema and ARDS, which are critical factors in disease progression toward severe respiratory failure [60]. Moreover, VEGF-A may exacerbate the hyperinflammatory response in COVID-19 patients by promoting immune cell recruitment and stimulating pro-inflammatory cytokine production [61,62,63]. This sustained inflammatory milieu contributes to the cytokine storm and multi-organ dysfunction observed in severe COVID-19 cases. Concurrently, VEGF-A can modulate adaptive immune responses in ways that impact viral clearance and disease resolution. Studies have shown elevated VEGF-A signaling is associated with T-cell exhaustion and dysfunction [64, 65]. This dysregulated immune response can worsen disease severity and increase susceptibility to secondary infections. VEGF-A is also implicated in regulating coagulation pathways. It is established that high VEGF-A levels can result in a hypercoagulable state by increasing the expression of tissue factor and the release of von Willebrand factor in endothelial cells [66, 67]. This effect can contribute to microvascular thrombosis and systemic coagulopathy, hallmarks of severe COVID-19. In addition, VEGF-A is a potent inducer of angiogenesis, the formation of new blood vessels. While this process is critical for tissue repair, excessive VEGF-A signaling can lead to aberrant angiogenesis and abnormal vascular remodeling. This may contribute to fibrotic changes in the lungs, potentially affecting long-term respiratory function in survivors [68]. In summary, elevated VEGF-A levels in COVID-19 patients reflect a complex interplay between viral infection, inflammation, hypoxia, and vascular dysfunction. This elevation contributes to the pathogenesis of severe disease manifestations, including ARDS, thrombosis, and immune dysregulation.

Clinical implications and future directions

The significant correlation between elevated VEGF-A levels and worse COVID-19 outcomes suggests that VEGF-A could serve as a valuable prognostic biomarker for identifying patients at risk of developing severe disease. This could facilitate earlier, more targeted therapeutic interventions, potentially improving patient outcomes. Furthermore, understanding the mechanistic role of VEGF-A in COVID-19 could open new avenues for therapeutic strategies aimed at modulating this growth factor to mitigate disease severity.

Future research should focus on longitudinal studies to track VEGF-A levels over the course of COVID-19, from initial infection through recovery or progression to severe disease. Such studies could clarify the temporal dynamics of VEGF-A expression and its prognostic utility. Additionally, interventional studies examining the effects of therapies targeting VEGF-A pathways could provide insights into their potential benefits or risks in managing COVID-19.

Strengths and limitations

This study boasts several strengths, including a meticulous search methodology, a substantial sample size drawn from multiple studies, and consistent findings that underscore the prognostic significance of VEGF-A within the COVID-19 landscape. The utilization of subgroup analyses and meta-regression techniques has enhanced the interpretation of results, thereby augmenting the relevance and generalizability of our findings.

However, several limitations warrant acknowledgment. Foremost among these is the variability in detection methods employed across the included studies, which may introduce discrepancies in reported VEGF-A levels. Despite efforts to standardize our analysis, variations in assay sensitivity, specificity, and calibration standards could potentially influence result consistency. Additionally, the evolving landscape of COVID-19 treatment modalities during the pandemic imposes further constraints on our analysis. Moreover, the influence of genetic factors, ethnicity, and geographical location on disease severity emerges as a significant area for future investigation. Furthermore, inconsistent reporting of therapeutic interventions, such as anticoagulants, steroids, and antiplatelets, is a significant limitation in our understanding of the impact of endothelial and angiogenesis biomarkers on COVID-19 prognosis. The potential effect of these medications on the observed associations between VEGF-A and COVID-19 prognosis is unclear, and further research is needed in this area.