Markers of coagulation dysfunction and inflammation in diabetic and non-diabetic COVID-19.

Coagulation dysfunction and inflammatory status were compared between diabetic and non-diabetic COVID-19 patients. The standardized mean difference (SMD) and its 95% confidence interval (CI) was computed for the difference of inflammatory and hypercoagulability markers. The levels of serum ferritin (standardized mean difference-SMD: 0.47, CI 0.17-0.77, p = 0.002), C-reactive protein (SMD = 0.53, CI 0.20-0.86, p = 0.002), interleukin-6 (SMD = 0.31, CI 0.09-0.52, p = 0.005), fibrinogen (SMD = 0.31, CI 0.09-0.54, p = 0.007) and D-dimers (SMD = 0.54, CI 0.16-0.91, p = 0.005) were significantly higher in diabetic COVID-19 cases as compared to non-diabetic COVID-19 patients, suggesting more susceptibility of diabetic COVID-19 patients to coagulation dysfunction and inflammatory storm.

Highlights

The markers of coagulation dysfunction and inflammation were studied between diabetic and non-diabetic COVID-19 patients by meta-analysis.

COVID-19 patients with diabetes have a significantly higher levels of coagulation dysfunction markers such as Fibrinogen (SMD = 0.31, CI 0.09–0.54, p =  0.007) and D-dimers (SMD = 0.54, CI 0.16–0.91, p = 0.005) than the non-diabetic COVID-19 cases.

COVID-19 patients with diabetes have a significantly higher inflammatory markers such as C-reactive protein (SMD = 0.53, CI 0.20–0.86, p = 0.002), Interleukin-6 (SMD =  0.31, CI 0.09–0.52, p = 0.005) than the non-diabetic COVID-19 cases.

These results indicate that diabetic COVID-19 patients are more susceptibility to coagulation dysfunction and inlammatory storm.

Introduction

The world is struggling in lockdown for months since December of 2019 due to novel coronavirus disease (COVID-19) outbreak, a pandemic declared by the World Health Organization [1]. Research evidence is growing on the role of several symptoms, comorbidities, inflammation and hypercoagulability markers in relation to disease progression and deaths in COVID-19 patients. The incidence of diabetes, one of the leading causes of morbidity has been shown to be high and is associated with disease progression in COVID-19 [2, 3].

Diabetic patients due to low pulmonary function have been reported to be more susceptible to intensive care admissions, mechanical ventilation and deaths due to COVID-19 than those without diabetes [4, 5]. Though several studies have reported various inflammatory and coagulability markers such as serum ferritin, C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen and D-dimers in relationship to disease severity and progression, much attention has to be paid to the comparisons between diabetic and non-diabetic COVID-19 cases [6-8].

Methods

In this pooled analysis, we aim to compare inflammatory storm and hypercoagulability status between diabetic and non-diabetic COVID-19 patients comprising a PROSPERO registered protocol (CRD42020186661). A total of 413 records were primarily identified. Of which, 39 relevant articles dealing with the inflammatory and hypercoagulation markers in COVID-19 patients were considered for full text evaluation. Out of these, 20 articles were excluded for not having relevant data, and 16 studies excluded for not comparing between diabetic and non-diabetic groups resulting in an inclusion of six observations from three studies for each of the variable between diabetic (n = 252) and non-diabetic (n = 497) COVID-19 cases [3-5]. These observations included for meta-analysis compared several markers between 252 diabetic and 497 non-diabetic cases. The study characteristics were presented in Table 1.

Table 1

The characteristics of included studies

Characteristic	Study
	Guo et al. [3]	Yan et al. [4]	Zhang et al. [5]
Country	China	China	China
Study type	Retrospective observational study	Retrospective observational study	Retrospective observational study
Criteria	WHO interim guidance	WHO interim guidance	Chinese National Health Committee (version 7)
RT-PCR	Yes	Yes	Yes
Outcomes	Comparisons between diabetic and non-diabetic cases	Comparisons between diabetic and non-diabetic cases	Comparisons between diabetic and non-diabetic cases

NA not available, No-CUD no other comorbidities

The standardized mean difference (SMD) with 95% confidence intervals (CI) were obtained for the difference of inflammatory and hypercoagulability markers between diabetic and non-diabetic COVID-19 cases. The between study heterogeneity was examined by the Cochrane’s Q statistic and expressed as the percentages of I2. A p value of < .05 was considered statistically significant. A one-study leave-out sensitivity analysis was performed to validate the results. All analyses were conducted using Review Manager Version 5.3.

Results

The forest plots of this meta-analysis were shown in Fig. 1. With a significant between-study heterogeneity (I2 = 64%, p < 0.0001), the random-effects model showed significantly higher levels of inflammatory and hypercoagulability markers in diabetic COVID-19 group when compared to that of non-diabetic COVID-19 group (Fig. 1). The pooled SMD and 95% CI were 0.43 (0.30; 0.55). The overall effect size for SMD calculated as Z was 6.67 (p < 0.0001). The sub-group analysis showed that serum ferritin (SMD: 0.47 95% CI 0.17–0.77, p = 0.002), CRP (SMD: 0.53 95% CI 0.20–0.86, p = 0.002), IL-6 (SMD: 0.31 95% CI 0.09–0.52, p = 0.005), fibrinogen (SMD: 0.31 95% CI 0.09–0.54, p = 0.007), and D-dimer (SMD: 0.54 95% CI 0.16–0.91, p = 0.005) levels are significantly elevated in diabetic patients as compared to non-diabetic counterparts with COVID-19. The sensitivity analysis showed that no single study had significantly influenced the overall result, which remained to be stable and significant after leaving-out any particular study/observation.

Fig. 1

The forest plots comparing hypercoagulability and inflammatory status between diabetic and non-diabetic COVID-19 cases

Discussion

These results show that the inflammatory and hypercoagulability markers significantly increase in diabetic group of COVID-19 patients when compared to their non-diabetic counterparts. Various reports suggest that diabetes activate several pathways leading to T-cell differentiation, immune system imbalance, pro- and anti-inflammation imbalance [4, 9]. Diabetes has been reported to be associated with infection and disease progression [3, 10]. According to recent research, virus invasion results in induction of coagulation activation, inflammatory responses, hypercoagulability induction and cytokine storms which may eventually cause disease progression in COVID-19 patients [2, 3].

The significant rise in ferritin, CRP and IL-6 levels reflect monocyte-macrophage activation resulting in inflammatory storm and cytokine storm. With its expression time longer than others, the cytokine IL-6 levels have been reported to be better predictors of disease progression [11]. It is known that during inflammatory storm, as a result of plasmin activation, the significant rise in D-dimer level indicates hypercoagulability [5, 7]. The significant rise in fibrinogen and D-dimer indicate diabetic COVID-19 patients are more susceptible to hypercoagulable state/intravascular coagulation. It is noteworthy that the association of diabetes and hyperglycemia with disease progression has been linked to increased inflammation, hypercoagulability and lung dysfunction in COVID-19 [3, 12].

It is well documented in several studies [6, 13, 14] that inflammatory and hypercoagulation status increase in COVID-19 cases as compared to non-COVID-19 respiratory illness. And, the presence of diabetes could further influence the magnitude of inflammatory and coagulation dysfunction in COVID-19. Strikingly, a recent study showed a significant increase in these markers in diabetic group as compared to non-diabetic group of COVID-19 patients without other comorbidities, indicating the independent impact of diabetes [3]. Moreover, the presence of diabetes has been associated with the poorer survival of COVID-19 cases with a hazard ratio (HR) of 3.17 (95% CI 1.93–5.20). And, this association remained to be significant even after adjusting for age and other comorbidities like hypertension, cardiovascular and cerebrovascular diseases (HR = 1.53, 95% CI 1.02–2.30). In a study by Zhang et al. [5], after adjusting for confounders like; age, sex, BMI and other comorbidities, a significantly higher rate of composite outcomes (ICU admission/mechanical ventilation/deaths) in both hyperglycemia (odds ratio-OR = 5.47, 95% CI 1.51–19.82) and diabetic groups (OR = 2.61, 95% CI 0.86–7.88) than the non-diabetic COVID-19 group were reported.

Our pooled analysis shows that diabetic COVID-19 patients are more susceptible to coagulation dysfunction and inflammation than the non-diabetic COVID-19 cases. The sensitivity analysis indicated the robustness of overall result. Though, the included studies matched the diabetic and non-diabetic groups for overall comorbidities [4] and all comorbidities except for CVD [3] and hypertension [5], the results should be interpreted with a caution that diabetes may coexist with other conditions in COVID-19 patients. Therefore, further well controlled studies are needed in future to establish an independent role of diabetes in COVID-19.