Can Ferritin and Interleukin-6 Levels Prognosticate Patients with COVID-19

• Serial ferritin and IL-6 measurements can serve as prognostic indicators in COVID-19 patients.
• Findings suggest that ferritin may serve as a surrogate marker for IL-6, potentially offering an alternative for risk stratification.

Initially thought to be of zoonotic origin, SARS-CoV-2 was later found to be predominantly transmitted via respiratory droplets, aerosols, and contaminated surfaces [3]. Its high infectivity compared to SARS-CoV-1 is linked to structural differences in viral proteins and viral load kinetics [1,2]. The virus binds to the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in respiratory, intestinal, renal, and vascular endothelial cells, facilitating widespread infection [1,2,3]. Clinical manifestations vary from mild symptoms such as fever, cough, and anosmia to severe complications including acute respiratory distress syndrome (ARDS) and multi-organ failure, with higher mortality in older individuals, males, and those with comorbidities [2,4].

Table 4 & Figures 1 and 2 illustrate the temporal changes in ferritin and interleukin-6 (IL-6) levels from baseline to endpoint in both survivors and non-survivors. In the demised group, both ferritin and IL-6 levels increased significantly over time (p < 0.001), peaking at endpoint (ferritin: 10,020.2; IL-6: 821.03). Conversely, in the alivegroup, ferritin levels remained stable or declined (p < 0.001), while IL-6 levels significantly decreased over time (p < 0.001).

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has led to millions of deaths worldwide since its emergence in Wuhan, China, in December 2019 [9]. Several clinical and biochemical markers have been studied for their prognostic value in determining disease severity and outcomes [9,10,11,12,13]. This study specifically evaluated the association of ferritin and interleukin-6 (IL-6) levels with mortality risk in a South African cohort, while also considering key comorbidities such as hypertension, diabetes mellitus, and chronic kidney disease (CKD), along with other biochemical markers such as the neutrophil-to-lymphocyte ratio and HbA1C. While global studies have extensively investigated these factors, there remains limited data from African settings, necessitating further research to validate findings across different populations.

In this cohort of 125 patients, the median age was 45 years (IQR 32.0–56.0), and 64% were female. Neither age nor sex were significant predictors of mortality, which contrasts with studies from Europe and Asia, where older age and male sex were associated with poorer outcomes [9,12,14,15]. A South African study by Jalavu et al. reported similar findings, where more females than males were admitted with COVID-19, but higher mortality was observed in those older than 60 years [4].

Several studies have highlighted the role of comorbidities—including hypertension, diabetes mellitus, cardiovascular disease, and CKD—in worsening COVID-19 severity and outcomes [12,14,15]. In this study, BMI and CKD demonstrated strong associations with disease severity. Notably, for each unit increase in BMI, the odds of mortality increased by 8% (OR = 1.079). Li et al. previously reported that hypertension and diabetes contributed to increased COVID-19 severity [12,14,17]. However, in this cohort, hypertension (prevalence = 48.0%) was associated with reduced odds of mortality (OR = 0.228, p = 0.031), suggesting potential protective effects of antihypertensive treatments or other unmeasured confounding factors, particularly when considering interactions with CKD and ethnicity. Meanwhile, diabetes mellitus (23.2%) was associated with elevated odds of mortality (OR = 2.881), but this did not reach statistical significance (p = 0.086), indicating that the risk of death may be confounded by other factors.

Several biochemical markers have been used to guide ICU admission, risk of intubation, treatment decisions, and disease progression [13,16,18]. Hyperferritinemia, iron overload, and IL-6 have been implicated in the cytokine storm and macrophage activation syndrome, which are key drivers of severe COVID-19 [6,8,10,13,18]. Multiple studies have demonstrated that elevated ferritin and IL-6 levels predict both disease severity and mortality risk [9,10,12,14,15,16,19]. Ferritin levels above 400 ng/mL have been associated with severe disease, while values exceeding 3000 ng/mL are linked to higher mortality [16]. Cheng et al. found that baseline ferritin levels above 500 ng/mL predicted mortality in 58% of cases [9]. Similarly, IL-6 levels have been shown to correlate with disease progression and imaging severity on chest CT scans [18]. Luke et al. reported that IL-6 levels above 80 pg/mL significantly increased the risk of respiratory failure and mortality [6].

In this study, baseline ferritin levels were significantly higher in the demised group (mean = 2127.32, p < 0.001) compared to the alive group (mean = 563.96). Interestingly, baseline ferritin levels in the alive group were higher than those reported in other international studies but were consistent with findings from Jalavu et al. in Cape Town. Ferritin levels in the demised group increased markedly at the endpoint (mean = 10,020.2), while in the alive group, levels peaked and subsequently declined (mean = 336.29). Similarly, IL-6 levels were significantly elevated in the demised group at baseline (mean = 443.26, p < 0.001) and continued to rise at the endpoint (mean = 821.03). In contrast, IL-6 levels in the alive group declined significantly from baseline (97.24) to endpoint (18.1). These findings corroborate previous studies by Tau et al., demonstrating that elevated IL-6 levels correlate with poor outcomes. However, it is notable that baseline IL-6 levels in the live group were higher than those reported in other global studies, yet did not predict poor outcomes in this cohort.

While both ferritin and IL-6 levels have been validated globally as biomarkers of COVID-19 severity and mortality, an important unresolved question is whether ferritin levels can serve as a surrogate marker for IL-6. Given the strong correlation between these two inflammatory markers, further research is warranted to explore their interdependence and predictive accuracy in guiding the clinical management of COVID-19.

Study strengths and limitations

One of the primary limitations of this study is its small sample size, which may impact the generalizability of the findings. Additionally, the sample does not fully represent the ethnic diversity of South Africa, limiting its applicability to the broader population.

However, the study has several notable strengths. The setting in a quaternary hospital, which serves patients from various geographical areas across KwaZulu-Natal, enhances the diversity of clinical presentations and disease severity observed in the cohort. Furthermore, the inclusion of both admitted patients and previously healthy healthcare workers ensures a more unbiased sample, allowing for a comprehensive assessment of the impact of premorbid functioning and comorbidities on COVID-19 outcomes.

Another strength is the exclusion of ICU patients transferred directly from other facilities, which minimizes potential selection bias. This prevents the dataset from being skewed towards severe disease and poor outcomes, thereby ensuring a more balanced representation of disease progression and prognostic factors.

Despite its limitations, the study provides valuable insights into the prognostic role of ferritin and IL-6 in COVID-19 and highlights the need for larger, more representative studies to confirm these findings in diverse populations.

CONCLUSION

This study demonstrated that serial measurement of ferritin and interleukin-6 (IL-6) levels can serve as valuable prognostic markers in COVID-19 disease, with both biomarkers showing a strong correlation with disease severity and clinical outcomes. Elevated levels of ferritin and IL-6 at baseline were associated with increased mortality risk, and their progressive rise in non-survivors further emphasized their role in disease progression. These findings suggest that early identification of high-risk patients using these markers could facilitate timely therapeutic interventions, potentially altering clinical outcomes.

Moreover, this study found that ferritin levels are comparable to IL-6 in predicting disease severity and mortality, raising the question of whether ferritin could serve as a surrogate marker for IL-6 in inflammatory-driven disease states. Given ferritin's ease of measurement and accessibility, its potential role as an alternative biomarker for guiding risk stratification and treatment escalation warrants further investigation.

Future research should explore the generalizability of these findings to other inflammatory and infectious diseases, including their role in cytokine storm syndromes and hyperinflammatory states beyond COVID-19. Additionally, understanding the mechanistic link between ferritin, IL-6, and immune dysregulation could further optimize biomarker-driven therapeutic strategies. Ultimately, integrating these markers into clinical decision-making algorithms may improve early risk assessment, resource allocation, and patient outcomes in both pandemic and non-pandemic settings.

Ethical considerations: This study was conducted following ethical approval from the University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC) and the Provincial Health Research and Ethics Committee (PHREC), under project number KZ202412003.

Funding: No Funding was required

No Financial support was received from any organization for the work submitted.

Conflicts of interest: The Authors declare no conflict of interest

No other relationships or activities that could appear to have influenced the submitted work

Acknowledgment: Mr Deepak Singh, statistician