key: cord-298881-u6uqroi0
authors: Huang, Ian; Lim, Michael Anthonius; Pranata, Raymond
title: Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia – A systematic review, meta-analysis, and meta-regression()
date: 2020-04-17
journal: Diabetes Metab Syndr
DOI: 10.1016/j.dsx.2020.04.018
sha: 
doc_id: 298881
cord_uid: u6uqroi0

BACKGROUND AND AIMS: Diabetes Mellitus (DM) is chronic conditions with devastating multi-systemic complication and may be associated with severe form of Coronavirus Disease 2019 (COVID-19). We conducted a systematic review and meta-analysis in order to investigate the association between DM and poor outcome in patients with COVID-19 pneumonia. METHODS: Systematic literature search was performed from several electronic databases on subjects that assess DM and outcome in COVID-19 pneumonia. The outcome of interest was composite poor outcome, including mortality, severe COVID-19, acute respiratory distress syndrome (ARDS), need for intensive care unit (ICU) care, and disease progression. RESULTS: There were a total of 6452 patients from 30 studies. Meta-analysis showed that DM was associated with composite poor outcome (RR 2.38 [1.88, 3.03], p < 0.001; I(2): 62%) and its subgroup which comprised of mortality (RR 2.12 [1.44, 3.11], p < 0.001; I(2): 72%), severe COVID-19 (RR 2.45 [1.79, 3.35], p < 0.001; I(2): 45%), ARDS (RR 4.64 [1.86, 11.58], p = 0.001; I(2): 9%), and disease progression (RR 3.31 [1.08, 10.14], p = 0.04; I(2): 0%). Meta-regression showed that the association with composite poor outcome was influenced by age (p = 0.003) and hypertension (p < 0.001). Subgroup analysis showed that the association was weaker in studies with median age ≥55 years-old (RR 1.92) compared to <55 years-old (RR 3.48), and in prevalence of hypertension ≥25% (RR 1.93) compared to <25% (RR 3.06). Subgroup analysis on median age <55 years-old and prevalence of hypertension <25% showed strong association (RR 3.33) CONCLUSION: DM was associated with mortality, severe COVID-19, ARDS, and disease progression in patients with COVID-19.

Coronavirus Disease 2019 (COVID -19) has been declared as a public health emergency by the World Health Organization (WHO) on 30 January 2020. At the time this paper is written, COVID-19 has inflicted more than 1.2 million people globally with overall mortality rate of 5.7%. [1] Although the majority of COVID-19 patients present with mild or no symptoms, some patients will develop severe pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, and death. Clinical predictors may provide vital clues regarding efficient resource planning and allocation during a pandemic.

Diabetes Mellitus (DM) is one of the most prevalent chronic conditions with devastating multi-systemic complication and was estimated to have inflicted 463 million people in 2019. [2] It is not yet known whether people with DM are more susceptible to COVID-19, but several studies have reported the association between severe COVID-19 infection with DM. [3, 4] It was postulated that the angiotensin converting enzyme 2 (ACE2) may be the plausible explanation of this association. [5] In this study, we aimed to perform a systematic review and meta-analysis in order to investigate the association between DM and poor outcome in patients with pneumonia. Our hypothesis is that DM is associated with poor outcome in patients with COVID-19 pneumonia. To the best of the authors knowledge, this is the first systematic review, meta-analysis, and meta-regression that comprehensively describe the association between DM and outcome in COVID-19.

Research articles that evaluate the association between COVID-19 and clinically validated definition of mortality, severe COVID-19, ARDS, ICU care, and disease progression.

We included all research articles in adult patients diagnosed with COVID-19 with information on DM and clinical grouping or outcome of the clinically validated definition of mortality, severe COVID-19, ARDS, ICU care, and disease progression. The following types of article were excluded: articles other than original research (e.g., review articles, letters, or commentaries); original research with samples below 20 or case reports and series; articles not in the English language; articles on research in pediatric populations (17 years of age or younger).

We performed systematic literature search from PubMed and EuropePMC with the search terms 1) "COVID-19" OR "SARS-CoV-2" AND "Characteristics", 2) "COVID-19" OR "SARS-CoV-2" AND "Diabetes", English, MEDLINE. Duplicate results were removed. The remaining articles were independently screened for relevance by its abstracts with two authors (MAL and IH). The full text of residual articles was assessed according to the inclusion and exclusion criteria. The search was finalized on April 8 th , 2020 The study was carried out per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline.

Data extraction was performed independently by two authors (IH and RP), we used standardized forms that include author, year, study design, age, gender, cardiovascular diseases, hypertension, DM, need for ICU care, and severe COVID-19.

The outcome of interest was composite poor outcome that comprised of mortality, severe COVID-19, ARDS, need for ICU care, and disease progression. ARDS was defined as per World Health Organization (WHO) interim guidance of Severe Acute Respiratory Infection (SARI) of COVID-19, including the acute onset, chest imaging, and origin of pulmonary infiltrates, and oxygenation impairment. [6] Severe COVID-19 was defined as patients who had any of the following features at the time of, or after, admission: (1) respiratory distress (≥30 breaths per min); (2) oxygen saturation at rest ≤93%; (3) ratio of partial pressure of arterial oxygen (PaO2) to fractional concentration of oxygen inspired air (fiO2) ≤300 mmHg; or (4) critical complication (respiratory failure, septic shock, and or multiple organ dysfunction/failure). [7] Statistical analysis Review Manager 5.3 (Cochrane Collaboration) and Stata version 16 were used for metaanalysis. Dichotomous variables were calculated using Mantel-Haenszel formula with random effects models regardless of heterogeneity. The effect estimate was reported as risk ratios (RRs) along with its 95% confidence intervals (CIs) for dichotomous variables, respectively. P-value was two-tailed, and the statistical significance set at ≤0.05. Random effects meta-regression was performed using restricted-maximum likelihood for prespecified variables including age, gender, hypertension, cardiovascular disease, and COPD.

Subgroup analysis was performed for each component of composite poor outcome. To assess the small-study effect, we performed regression-based Harbord's test for dichotomous outcome. Begg's funnel-plot analysis was performed to qualitatively assess the risk of publication bias.

Initial search yields 298 records, and 281 records remained after the removal of duplicates.

238 records were excluded after screening the title/abstracts. After evaluating 43 full-text for eligibility, 13 full-text articles were excluded because: no outcome of interest: severe, mortality, ARDS, disease progression. 30 studies were included in the qualitative synthesis and meta-analysis [ Figure 1 ]. [3, 8, [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] 9, [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [10] [11] [12] [13] [14] [15] [16] There were a total of 6452 patients from 30 studies.

This meta-analysis showed that DM was associated with composite poor outcome (RR 2.38 [1.88, 3 .03], p<0.001; I 2 : 62%, p<0.001) [ Figure 2 ]. Subgroup analysis showed that DM was associated with mortality (RR 2. 12 

Meta-regression showed that the association between DM and composite poor outcome was affected by age (p=0.003) [ Figure 3A ] and hypertension (p<0.001) [ Figure 3B ], but not gender (p=0.895), cardiovascular diseases (p=0.5) [ Figure 3C ], and COPD (p=0.47).

Multivariable meta-regression by including two covariates in single analysis showed age (p=0.334) and hypertension (p=0.107) effect is probably dependent on each other.

Subgroup analysis for studies with median age ≥55 years-old ( 

The funnel-plot analysis showed a qualitatively symmetrical inverted funnel-plot for the association between DM and composite poor outcome [ Figure 4A ]. Regression-based Harbord's test showed indication of small-study effects for DM and composite poor outcome (p=0.004) [ Figure 4B ].

This comprehensive meta-analysis of 30 studies showed that DM was associated with poor outcome that comprises of mortality, severe COVID-19, ARDS, and disease progression in patients with COVID-19. This association was influenced by age and hypertension. Further analysis based on meta-regression showed that magnitude of risk linked to DM as a single factor was greater in studies with younger and non-hypertensive patients, which is yet to be addressed by the existing literature.

Meta-regression showed that the association between DM and poor outcome was influenced by age and hypertension. Age and prevalence of hypertension was inversely proportional with the effect of DM on poor outcome. In other words, the effect estimate of DM was less in older and hypertensive patients. Subgroup analysis further demonstrates the vast difference in RR. Meta-regression also showed that age and prevalence of hypertension seemed to be dependent on one another, this is further demonstrated by subgroup analysis showing that the RR for age <55 years-old, prevalence of hypertension <25%, and both of them combined varies only slightly. The association between DM (as a single risk factor) with composite poor outcome in COVID-19 was greater in younger people and without hypertension). The presence of older age and hypertension may attenuate the association of DM with composite poor outcome. Hence, the total risk is expected to be higher in older patients with HT, but the magnitude of DM as a single risk factor is greater in younger people without hypertension.

It is not yet known whether people with DM are more susceptible to COVID-19, but several studies have reported a greater risk of severe COVID-19 in diabetic patients. [3, 4] Diabetic individuals have a greater risk of respiratory infections due to compromised immune system, especially the innate immunity. [5, 37] Even transient hyperglycaemia may temporarily affect innate immune responses to infection. [38] It was hypothesized that ACE2 may be the key pathfinder of COVID-19 severity in diabetic individuals. [5] ACE2 is a type 1 integral membrane glycoprotein expressed in the epithelial cells of cardiovascular, pulmonary, renal, brain and intestinal tissue, it acts by breaking down angiotensin II into angiotensin 1-7. [37, 39, 40] This enzyme acts by counteracting the inflammatory actions of angiotensin II, lowering the concentration of pro-inflammatory cytokine interleukin (IL)-6, increasing the anti-inflammatory, and increasing the antioxidant action of angiotensin 1-7, escalating the levels of surfactant protein D and promoting vasodilation. [41] The novel coronavirus responsible for COVID-19 is expected to act similary to Severe Acute Respiratory Syndrome (SARS-CoV). Both utilize ACE2 to bind and gain entry to the host pneumocytes. [39] Viral surface spike (S) protein of COVID-19 binds to ACE2 after spike protein activation by transmembrane protease serine 2 (TMPRSS2). [40] Routine use of ACEI and ARB as a medication for chronic conditions upregulates ACE2 expression, [5, 37] thereby facilitating entry of SARS-CoV-2 into the pneumocytes and consequently cause severe and fatal infection. [42] Among other diabetic medications, the use of liraglutide and pioglitazone have also been found to be related with increased ACE2 regulation in animal studies. [42, 43] The interconnection between ACE2, renin-angiotensin system (RAS) signalling, aging, DM, hypertension, and severity of COVID-19 may not be as simple as it may seem. As we described before, our meta-regression analysis showed that the association between DM and poor outcome was interdependent on age and hypertension. One of the possible rationale behind this finding is the use of medications, particularly ACEI or ARB in hypertensive individuals. The risks and benefits associated with ACEI/ARB use in COVID-19 patients remains controversial [44] , a specific type of ARB has been shown to ameliorate lung injury in SARS-CoV infection in animal model. [45] It is unfortunate that all of the included studies did not provide report on diabetic or hypertensive medications.

Furthermore, the link between those specific variables could be in line with the hypothesis of AlGhatrif et al. [46] Older hypertensive individuals have lower ACE2 levels but a higher RAS signalling, this difference is further expressed in COVID-19 patients in which ACE2 developed into a critically low levels and RAS signalling is exaggerated even more. Such disturbance result in a potentially decreased susceptibility to the disease, but a greater severity. In contrast, younger people without hypertension have higher ACE2 levels and lower RAS signalling, which transforms into a modestly low ACE2 levels and modestly increased RAS signalling due to COVID-19 infection. This results in a possibly increased susceptibility to the disease, but a lesser severity. Our meta-regression result may support the aforementioned hypothesis. The use of ACEI/ARB is expected in patients with both DM and HTN; and we observe that the age and HTN were in parallel, studies with older subjects having higher prevalence of hypertension. Hence, the clinical significance of DM in the older patients may be attenuated by the risk of hypertension and ACEI/ARB use (which was hypothesized to increase severity in older patients).

Dysfunctional pro-inflammatory cytokine responses in diabetic patients might also be the underlying cause of severe COVID-19. [37, 47, 48] Diabetic patients have been shown to have an elevated pro-inflammatory cytokine level, in particular IL-1, IL-6 and tumor necrosis factor (TNF)-α. [48] Different markers, including C-reactive protein, fibrinogen and D-dimer were also found to be elevated in diabetic patients who contracted COVID-19. [47] Thus, this condition may further exaggerate the cytokine storms in COVID-19 leading to a more severe disease. [37, 48, 49] 

DM was shown to be associated with poor outcome in patients with COVID-19 and was influenced by age and hypertension. The association was stronger in younger patients and should alert physician even though the patient only presented with one comorbidity. This indicates that DM is a potential prognostic marker that should be explored in triage. We encourage including DM in studies investigating prognostic model for patients with COVID-19. Moreover, this finding adds the needs of further studies concerning the use of ACEI/ARB in COVID-19.

Data on diabetic/hypertension medications were lacking in the included studies, hence, cannot be analysed. Since ACEI/ARB is often used in DM, it may have influence on prognosis.

Most of the articles included in this meta-analysis were preprints; nevertheless the authors have made exhaustive efforts to ensure that only sound studies were included. Most of the reports were from China, hence, the samples might overlap across the reports. The included studies were retrospective in design.

DM was associated with mortality, severe COVID-19, ARDS, and disease progression in patients with COVID-19. The association was weaker in the older and hypertensive patients.

The data used to support the findings of this study are included within the article

The authors declared no conflict of interest 

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≤40 (53%)

CAD: Coronary artery disease; COVID-19: Coronavirus disease 2019; CLD: Chronic Lung/Pulmonary Disease; CVD: Cardiovascular Disease; ICU: Intensive Care Unit

IH and RP conceived and designed the study. IH, RP, and MAL acquired the data. IH and MAL drafted the manuscript. IH and RP performed data extraction and interpreted the data. IH and MAL performed extensive research on the topic. RP reviewed and performed extensive editing of the manuscript. All authors contributed to the writing of the manuscript. IH and RP performed the statistical analysis.

None