key: cord-0895812-ihdvzayk
authors: Handayani, Dewi Ratih; Juliastuti, Henny; Nawangsih, Eka Noneng; Kusmala, Yudith Yunia; Rakhmat, Iis Inayati; Wibowo, Arief; Pranata, Raymond
title: Prognostic value of fasting hyperglycemia in patients with COVID-19 – Diagnostic test accuracy meta-analysis
date: 2021-04-04
journal: Obes Med
DOI: 10.1016/j.obmed.2021.100333
sha: cd51c96b1c1ce0f1ed89520e5e9967f2791d52c6
doc_id: 895812
cord_uid: ihdvzayk

AIMS: This meta-analysis aimed to assess the prognostic value of fasting hyperglycemia in patients with COVID-19. METHODS: A systematic literature search on PubMed, Embase, and Scopus were performed up until February 18, 2021. Fasting hyperglycemia was defined as fasting plasma glucose level above the reference value. The outcome of interest was poor outcome, which was a composite of mortality and severe COVID-19. The effect estimate was in odds ratio (OR). RESULTS: There were 9045 patients from 12 studies included in this systematic review and meta-analysis. The prevalence of fasting hyperglycemia was 29%. The incidence of poor outcome was 15%. Fasting hyperglycemia was associated with poor outcome in COVID-19 (OR 4.72 [3.32, 6.72], p < 0.001; I(2): 69.8%, p < 0.001). Subgroup analysis in patients without prior history of diabetes showed that fasting hyperglycemia was associated with poor outcome in COVID-19 (OR 3.387 [2.433, 4.714], p < 0.001; I(2): 0, p = 0.90). Fasting hyperglycemia has a sensitivity of 0.57 [0.45, 0.68], specificity of 0.78 [0.70, 0.84], PLR of 2.6 [2.0, 3.3], NLR of 0.55 [0.44, 0.69], DOR of 5 [3, 7], and AUC of 0.74 [0.70, 0.78] for predicting poor outcome. In this pooled analysis, fasting hyperglycemia has a 32% post-test probability for poor outcome, and absence of fasting hyperglycemia confers to a 9% post-test probability. Meta-regression and subgroup analysis showed that the sensitivity and specificity varies by chronic kidney disease but not by age, male (gender), hypertension, and chronic kidney disease. CONCLUSION: Fasting hyperglycemia was associated with mortality in COVID-19 patients, with or without diabetes. PROSPERO: CRD42021237997.

In patients with diabetes, hyperglycemia may also represent a glycemic poor control, in addition to the acute stress caused by infection. In this study, we aimed to quantity the association by pooling data from these studies using a meta-analysis approach.

Systematic Reviews and Meta-Analyses (PRISMA). This study is registered in PROSPERO (CRD42021237997).

We included studies that fulfill all of these criteria: 1) observational prospective and retrospective studies, 2) reporting patients with COVID-19, 3) fasting plasma glucose, 4) hyperglycemia versus without hyperglycemia, and 5) mortality/severe COVID-19.

We excluded the following studies: 1) conference abstracts, 2) preprints, 3) case reports, 4) review articles, and 5) non-English language studies were then removed after screening of the title/abstracts by two independent authors.

Discrepancies among the reviewers were resolved by discussion.

Two authors performed data extraction of the included studies independently. The data of interest includes the author, baseline characteristics, design of the study, cut-off points for fasting hyperglycemia, and the outcome of interest. Discrepancies among the reviewers were resolved by discussion.

Fasting hyperglycemia was defined as fasting plasma glucose level above the reference value defined by each studies. The outcome of interest was poor outcome, which was a composite of mortality and severe COVID-19. Severe COVID-19 was defined severe pneumonia or need for intensive unit care (ICU)/invasive mechanical ventilation (IMV). The pooled effect estimate in this study was in odds ratio (OR). Important diagnostic parameters 1) sensitivity, 2) specificity, 3) positive and negative likelihood ratio (PLR & NLR), 4) diagnostic odds ratio (DOR), and 5) area under the curve (AUC) were generated.

Two independent authors performed risk of bias assessment using the Newcastle-Ottawa Scale (NOS) . Discrepancies were resolved by discussion.

Prevalence of hyperglycemia and poor outcome was synthesized using the meta-analysis of proportion method. The pooled effect estimate was generated using the DerSimonian-Laird random-effects model. P-values <0.05 were considered statistically significant. The heterogeneity of the included studies was assessed using the I-squared (I 2 ) and Cochran Q test, value of <50% or p < 0.10 indicates heterogeneity. To evaluate the prognostic value of hyperglycemia, sensitivity, specificity, PLR, NLR, DOR, and AUC were calculated. Funnel-plot analysis and Egger's test were performed to evaluate the presence of small-study effects and publication bias. The association between hyperglycemia and poor outcome was then assessed using Restricted-maximum likelihood (REML) meta-regression, using baseline characteristics as covariates. Subgroup analysis was performed in patients without history of diabetes. STATA 16 (Stata Corp) was used to perform the analyses.

There were 9,045 patients from 12 studies included in this systematic review and metaanalysis [ Figure 1 ] (Cai et al., 2020; Chen et al., 2021; Coppelli et al., 2020; Deng et al., 2020; Gastélum-Cano et al., 2021; Huh et al., 2020; Liu et al., 2020; Sardu et al., 2020; Sun et al., 2020; Wang et al., 2020; Zhang et al., 2020) . Baseline characteristics of the J o u r n a l P r e -p r o o f included studies are presented in Table 1 . The prevalence of fasting hyperglycemia was 29%

[23% -35%]. The incidence of poor outcome was 15% [11% -20%].

Fasting hyperglycemia was associated with poor outcome in 6 .72], p<0.001; I 2 : 69.8%, p<0.001) [ Figure 2 ]. The funnel-plot was symmetrical [ Figure 3 ], and there is no indication of significant small-study effects (p=0.419). The association between fasting hyperglycemia and poor outcome was affected by chronic kidney disease ( Figure 4 ]. In this pooled analysis, fasting hyperglycemia has a 32% post-test probability for poor outcome, and absence of fasting hyperglycemia confers to a 9% post-test probability [ Figure 5 ]. Meta-regression and subgroup analysis showed that the sensitivity and specificity varies by chronic kidney disease but not by age, male (gender), and hypertension.

Subgroup analysis in patients without prior history of diabetes showed that fasting hyperglycemia was associated with poor outcome in 4.714 

This meta-analysis showed that fasting hyperglycemia was associated with poor outcome in patients with COVID-19, with a 57% sensitivity, 78% specificity, and AUC of 0.74. Our metaanalysis indicates that fasting hyperglycemia increases the risk of poor outcome in patients with and without diabetes.

Inflammation triggered by COVID-19 infection may impair insulin signaling which causes reduced glycogen synthesis, glucose uptake, and lipogenesis; thereby causing hyperglycemia and insulin resistance, which may manifest as new-onset diabetes (Sathish et al., 2021b ). An observational study on patients without diabetes indicates a significantly higher glycemic fluctuation in previously normoglycemic patients with COVID-19, compared to controlled match (Shen et al., 2021) .

Increased severity in diabetic patients with COVID-19 has been described previously, in which one of them is due to dysfunctional pro-inflammatory cytokine responses (Maddaloni and Buzzetti, 2020; Pal and Bhansali, 2020) . Higher pro-inflammatory cytokines are observed in diabetic patients. Inflammatory markers such as C-reactive protein and D-dimer are more pronounced in diabetic COVID-19 patients (Maddaloni and Buzzetti, 2020) . These factors are associated with severity and mortality in COVID-19 patients (Huang et al., 2020b) .

These may further aggravate COVID-19 induced cytokine storms, causing more severe disease (Mehta et al., 2020; Pal and Bhansali, 2020) .

The proportion of patients with diabetes might cause heterogeneity. In the subgroup analysis of patients without diabetes, the heterogeneity was 0%. In patients without diabetes, the increased mortality due to hyperglycemia might indicate acute blood-glucose disorder due to stress hyperglycemia (Bar-Or et al., 2019) . Critically ill patients are also likely to develop acute insulin resistance, which manifests as hyperglycemia and J o u r n a l P r e -p r o o f hyperinsulinaemia; this can be found in sepsis and other pathologies, irrespective of diabetes (Bar-Or et al., 2019; McAlister et al., 2005) . These mechanisms may also exacerbate hyperglycemia in diabetic patients.

Meta-regression analysis showed that chronic kidney disease reduces the association between hyperglycemia and poor outcome. Sardu et al. demonstrate that patients with hyperglycemia receiving insulin during hospitalization have lower mortality (Sardu et al., 2020) , patients with chronic kidney disease are more likely to be given insulin because of its safety profile in renal insufficiency. Thus, chronic kidney disease may seem to reduce mortality. Sardu et al. study also provides evidence that optimal glycemic control during hospitalization is of paramount importance to ensure the best outcome. Another possibility is because of renal insufficiency association with mortality in COVID-19 patients Raymond Pranata et al., 2020c) , hyperglycemia as a factor for mortality in these patients might be weaker than chronic kidney disease itself.

There are several limitations in our meta-analysis, first is that all studies were retrospective.

Then other essential parameters such as HbA1C, specifics of antidiabetic medications (Lukito with diabetes and secondary hyperglycaemia with coronavirus disease 2019: A singlecentre, retrospective, observational study in Wuhan. Diabetes, Obes. Metab. 22, 1443 -1454 . https://doi.org/10.1111 J o u r n a l P r e -p r o o f 

Stress Hyperglycemia in Critically Ill Patients: Insight Into Possible Molecular Pathways

Fasting blood glucose level is a predictor of mortality in patients with COVID-19 independent of diabetes history

Association of Early-Phase In-Hospital Glycemic Fluctuation With Mortality in Adult Patients With Coronavirus Disease

Hyperglycemia at hospital admission is associated with severity of the prognosis in patients hospitalized for COVID-19: The pisa COVID-19 study

Obesity as a Potential Predictor of Disease Severity in Young COVID-19 Patients: A Retrospective

Multiorgan Failure With Emphasis on Acute Kidney Injury and Severity of COVID-19: Systematic Review and Meta-Analysis

Hyperglycemia is a strong predictor of poor prognosis in COVID-19

The Effect of Metformin Consumption on Mortality in Hospitalized COVID-19 patients: a systematic review and meta-analysis

Covid-19 and diabetes mellitus: unveiling the interaction of two pandemics

Prognostic value of elevated lactate dehydrogenase in patients with COVID-19: a systematic review and meta-analysis

The relation between hyperglycemia and outcomes in 2,471 patients admitted to the hospital with community-acquired pneumonia

COVID-19: consider cytokine storm syndromes and immunosuppression

COVID-19, diabetes mellitus and ACE2: The conundrum

Clinical frailty scale and mortality in COVID-19: A systematic review and dose-response meta-analysis: Clinical Frailty Scale in COVID-19

Impact of cerebrovascular and cardiovascular diseases on mortality and severity of COVID-19-systematic review, meta-analysis, and meta-regression

Hypertension is associated with increased mortality and severity of disease in COVID-19 pneumonia: A systematic review, meta-analysis and meta-regression

Thrombocytopenia as a prognostic marker in COVID-19 patients: diagnostic test accuracy meta-analysis

Body mass index and outcome in patients with COVID-19: A dose-response metaanalysis

The Association Between Chronic Kidney Disease and New Onset Renal Replacement Therapy on the Outcome of COVID-19 Patients: A Metaanalysis

Outcomes in Patients with Hyperglycemia Affected by COVID-19: Can We Do More on Glycemic Control?

Is newly diagnosed diabetes a stronger risk factor than pre-existing diabetes for COVID-19 severity?

Potential metabolic and inflammatory pathways between COVID-19 and new-onset diabetes

Glycemic fluctuations caused by COVID-19: Results from continuous glucose monitoring

Type 2 diabetes is associated with increased risk of critical respiratory illness in patients COVID-19 in a community hospital

Independent and combined effects of hypertension and diabetes on clinical outcomes in patients with COVID-19: A retrospective cohort study of Huoshen Mountain Hospital and Guanggu Fangcang Shelter Hospital

Charlson comorbidity index and a composite of poor outcomes in COVID-19 patients: A systematic review and meta-analysis

Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: a multi-centre retrospective study

World Health Organization, 2021. Weekly epidemiological update -9

The clinical characteristics and outcomes of patients