key: cord-0684762-vf1okih5 authors: Khalili, Shayesteh; Moradi, Omid; Kharazmi, Amir Behnam; Raoufi, Masoomeh; Sistanizad, Mohammad; Shariat, Masoud title: Comparison of Mortality Rate and Severity of Pulmonary Involvement in COVID-19 Patients with and without Diabetes: A Cohort Study date: 2020-11-01 journal: Can J Diabetes DOI: 10.1016/j.jcjd.2020.10.014 sha: 031e43519ee33cc8bf570e457ac81b9777a49863 doc_id: 684762 cord_uid: vf1okih5 Aims Patients with diabetes are potentially at higher risk of mortality due to COVID-19. We aimed to compare the outcomes and severity of pulmonary involvement in patients with and without diabetes. Methods In this cohort study, patients with diabetes, hospitalized due to COVID-19 from February 2020 to May 2020 were recruited. Hospitalized individuals without diabetes were enrolled as control subjects. All patients were followed for 90 days, and clinical findings and patients’ outcomes were reported. Results Over a period of four months, 127 patients with diabetes and 127 individuals without diabetes with a diagnosis of COVID-19 were recruited. The mean age was 65.70±12.51 years. Mortality was higher in population with diabetes (22.8% vs. 15.0%; P=0.109), although not significantly. More severe pulmonary involvement (P=0.015), extended hospital stay (P<0.001), and higher need for invasive ventilation (P=0.029) were reported in this population. Stepwise logistic regression revealed that diabetes was not independently associated with mortality (p=0.092). Older age (OR=1.054, p=0.003), aggravated pulmonary involvement on admission (OR=1.149, p=0.001), presence of comorbidities (OR=1.290, p=0.020) and hypothyroidism (OR=6.576, p=0.021) were associated with mortality. Diabetic foot infection had a strong positive correlation (OR=49.819, p=0.016), whereas insulin therapy had a negative correlation (OR=0.242, p=0.045) with mortality. Conclusions The mortality rate due to COVID-19 did not differ significantly between patients with or without diabetes. Older age, macrovascular complications, and the presence of comorbidities could increase mortality in people with diabetes. Insulin therapy during hospitalization could attenuate the detrimental effects of hyperglycemia and improve prognosis of patients with COVID-19 and diabetes. Coronavirus disease 2019 caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can lead to severe pneumonia and multiorgan failure, especially in older patients and those with comorbidities such as diabetes mellitus (DM), hypertension and cardiovascular disorders (1) . Diabetes has deleterious effects on the immune system and could lead to higher susceptibility to bacterial infections (2, 3) . In SARS-Cov-1 disease, it has been shown that individuals with preexisting DM are at increased risk of death (4) . Also, in previous retrospective studies, DM has been associated with an increased risk of mortality in SARS-Cov-2 infection (5, 6) . Until now, cohort studies regarding prognosis of patients with coexistent diabetes and COVID-19 with the same age and sex distribution have not been done. In this cohort study, performed on patients hospitalized for COVID-19, we aimed to investigate whether patients with diabetes had worse clinical outcomes and more severe radiological findings, compared with patients without diabetes. In this cohort study, 127 patients with diabetes hospitalized for COVID-19 and 127 control subjects without diabetes, also admitted due to COVID-19 were included. All participants were recruited from the Imam Hossein medical center, affiliated to Shahid Beheshti University of Medical Sciences, Tehran, Iran, from Feb 2020 to May 2020. The ethics committee of the Shahid Beheshti University of Medical Sciences approved the study and all patients signed the written informed consent before enrollment. Diagnosis of COVID-19 was confirmed for participants in the case and control groups by reverse transcription-polymerase chain reaction (rt-PCR) and/or Computed Tomography (7) scan findings. To control blood glucose levels during hospitalization, insulin intensification, basal-bolus insulin regimen, sliding scale, or insulin infusion protocols were considered for patients with diabetes mellitus to reach and maintain glucose level between 140 to 180 mg/dL (7.8-10 .0 mmol/L). Patients J o u r n a l P r e -p r o o f were visited daily during hospitalization and followed up for 90 days. All patients received COVID-19 treatment based on the latest interim national guideline for diagnosis and management of COVID-19 (8) . Patients underwent a chest CT examination after admission, and all CT-scans were reviewed and reported by the same experienced radiologist. The severity of pulmonary involvement was reported based on a quantitative scoring system (9) . A scoring scale from zero to five was considered for each of the lung lobes, based on visual inspection (zero for no involvement in a particular lobe, and five for over 75 percent involvement); a score of 1 was considered for less than 5%, 2 for 5-25%, 3 for 26-49% and 4 for 50-75% of each lobe involvement. The maximum score of 25 was considered for the involvement of more than 75 percent in all five lobes of the lung. The predominant patterns on chest CT imaging were classified into three groups: Ground-glass opacity (GGO), consolidation, and GGO/consolidation (mixed). Other secondary CT findings such as pleural effusion, pericardial effusion, cardiomegaly and lymphadenopathy (10) >10mm were also recorded. Distribution of lung lesions was grouped into three categories: Subpleural, peribronchovascular and perihilar. The attending physician collected demographic data for all recruited patients. Primary clinical and laboratory data, including glycemic control profile, inflammatory marker panel, complete blood count with differentiation, renal and hepatic function profiles, electrolytes, blood pressure, ventilation and O 2 saturation status were documented. All patients were assessed with regards to comorbidities, underlying diseases and drug history. The data for type of hypoglycemic agents (i.e., insulin therapy or oral hypoglycemic agents) given to patients with diabetes were also compiled. Mortality rate was assessed during hospitalization and for up to 90-days after the disease onset. J o u r n a l P r e -p r o o f Oxygen requirement, mechanical ventilation, duration of hospital stay, acute respiratory distress syndrome (11) occurrence (11, 12) , shock and multiorgan failure were all considered as secondary outcomes (13) . Charlson index was utilized to assess the prognostic effects of comorbidities (14) . Statistical analysis was performed by STATA version 14 (Stata Corp, Texan, USA) and the R Project for statistical computing version 3.6.2 (R Foundation for Statistical Computing, Vienna, Austria). Data were assessed for parametric and non-parametric distribution by the Kolmogorov-Smirnov test. For data description, quantitative variables with normal distribution were reported as means ± standard deviations and with non-normal distribution reported as median (Interquartile range=IQR). For qualitative variables, frequency and percentage were used. Categorical data were analyzed by Chi-square or Fisher's exact test (if over 25% of the categories had frequencies below five). Differences in continuous data were compared by t-test or Mann-Whitney U in the bivariant situation. A P-value of less than 0.05 was considered significant. In the current study, multivariable logistic regression was used to evaluate the association between covariates and outcomes among the studied patients. AIC stepwise selection methods were used (backward and forward) to select a set of candidate predictors for inclusion in the multivariate model. The overall performance of models was evaluated using the Brier score, and Nagelkerke's R2 and area under the curve (AUC) calculated for discrimination and Hosmer-Lemeshow test were used for evaluation of calibration. The odds ratio and 95% confidence interval were reported. P-values of less than 0.05 were considered significant in univariant and multivariant regression analysis, respectively. By the end of the study period, 127 patients with diabetes (case group) and 127 patients without diabetes (control group) had been enrolled and followed up for 90 days. Mean age of the participants was 65.70±12.51 years. Baseline demographics and on admission laboratory and physical findings are represented in Table 1 . All patients in the case group had type 2 diabetes. A total of 10 patients were diagnosed to have type 2 diabetes during hospitalization for COVID-19. Twenty-three patients had a J o u r n a l P r e -p r o o f history of type 2 diabetes of five years or less. Thirty-eight, 24, and 32 patients had a history of type 2 diabetes for 5 to 10 years, 10 to 15 years and over 15 years, respectively. No correlation was found between the duration of diabetes and mortality (p=0.317). Mean hemoglobin A1C (HbA1C) level for patients with diabetes was 9.15±2.21 percent. According to the latest American Diabetes Association and Diabetes Canada guidelines for glycemic control (15, 16) , 97 patients (76%) had uncontrolled DM at the time of admission based on their initial HbA1C level of over 7%. Diabetes mellitus was treated with insulin in 39 patients. In 78 and 10 patients, oral hypoglycemic agents and nutritional diet intervention were utilized, respectively. During hospitalization, basal-bolus regimen, sliding scale and insulin infusion were considered for 55, 10, and 4 patients with poorly-controlled diabetes, respectively. Furthermore, 28 patients received insulin intensification for uncontrolled blood glucose. Eventually, blood glucose levels in 78% of patients with diabetes were controlled during hospitalization. Six patients experienced at least one episode of hypoglycemia (defined as blood glucose levels below 70 mg/dL (<3.9 mmol/L)) (17, 18). No significant differences were observed in the frequency of steroid utilization in the two groups (p=0.197); steroids were used in 7 (5%) and 3 (2%) individuals in the case and control groups, respectively. Four patients in the case group were hospitalized due to the recent cerebrovascular accidents (CVA), after which they were diagnosed with COVID-19. Significantly higher respiratory rate (p=0.017) and lower O 2 saturation (p<0.001) were recorded in patients with diabetes on admission; these patients also had more severe pulmonary involvement and higher CT scan severity indices (p=0.0015). At baseline, there was no significant difference in the development of ARDS between the two groups (p=0.841). As shown in Table 2 , GGO was the most common pattern on CT scans of all patients. Compared to patients without diabetes, consolidation was more frequently observed in patients with diabetes (p=0.01). The right and left lower lobes were the lobes with the highest percentage of involvement in all patients (85.4% and 85.5%, respectively). The left upper and lower lobes were more likely to be involved in patients with diabetes compared to their counterparts without diabetes (p=0.07 and p=0.06, respectively). Lung lesions were mostly distributed J o u r n a l P r e -p r o o f in the subpleural area (68.1%), a distribution type that was significantly more common among patients without diabetes (p=0.01). After the 90-day period of follow up, of 254 subjects, forty-eight (18.9%) had passed away during the treatment or follow up period. Ten patients were re-hospitalized after discharge. The mortality rate was higher amongst the population with diabetes mellitus compared to control group (22.8% to 15 .0%), a difference however not statistically significant (p=0.109). Furthermore, a statistically significant longer hospital stay was recorded in patients with diabetes (7 vs. 5 days, p<0.001). ARDS, septic shock and multiorgan failure were observed in 40, 21 and 25 patients during hospitalization, respectively. No statistically significant differences were observed between the two groups of patients with regards to secondary outcomes (Table 3 ). Our cohort study demonstrates that diabetes per se is not associated with a statistically significant increase in mortality due to COVID-19. However, patients with diabetes experienced more severe pneumonia and suffered a more severe course of illness; these patients had lower O 2 saturation and higher respiratory rate on admission compared to the control group. We observed a significantly greater extent of pulmonary involvement in patients with diabetes by evaluating and scoring the chest CT scans in our population, with the involvement of subpleural area mostly in the lower lobes. This group of the patients also had higher rates of intubation, the need for mechanical ventilation support and extended hospitalization. Our study differs significantly from previous studies, which considered diabetes and uncontrolled blood glucose level as independent risk factors for mortality in COVID-19 (19) . In those retrospective studies, patients with diabetes had different age distributions, and the patients were not age and sexmatched with a control group of patients without diabetes. Also, the sample sizes in the two groups were considerably different (5, 6, 19, 20) . In two large scale retrospective population based studies conducted in England, patients with diabetes were shown to be at increased risk for mortality due to COVID-19 (21, 22) . Subgroup analysis of the HbA1c levels in those studied demonstrated that patients with type 2 uncontrolled diabetes are at increased risk of death. In our study, we included individuals with or without diabetes in a 1:1 ratio, with no differences in age and sex distributions as remarkable confounding factors in the mortality of patients with COVID-19. A notable finding in our study is that duration of diabetes, and previous long-term hyperglycemia (evaluated by HbA1C measurement at admission) did not show any association with mortality. Recently, in the CORONADO study, Cariou et al. reported that in patients with coexistent COVID-19 and diabetes, HbA1C level, representative of long-term glucose control, was not associated with tracheal intubation and/or death, a finding similar to our study (7) . It has previously been reported that there are no significant differences between the severity of pulmonary involvement and mortality in patients with well-controlled and poorly-controlled diabetes and COVID-19 based on HbA1C levels (23) . In individuals with diabetes, acute hyperglycemia during the hospital stay due to stressful J o u r n a l P r e -p r o o f conditions such as hypoxia, fever, medication side effects, cytokine storm and disease severity could cause insulin resistance (24, 25) . Furthermore, it has been speculated that SARS coronavirus, via binding angiotensin-converting enzyme 2 (ACE2) to the pancreas can destruct β-cells and induce acute hyperglycemia (26) . All these factors could weaken the value of HbA1C as a good predictor for the prognosis of patients with COVID-19. In the study conducted by Zhu L et al., it was demonstrated that even though type 2 diabetes correlated with a higher mortality rate in patients with COVID-19, well-controlled blood glucose (upper limit < 180 mg/dl/ 10 mmol/L) during hospitalization was associated with significantly lower mortality compared to individuals with uncontrolled blood glucose (20) . In our study, insulin therapy was considered for all patients in the case group with uncontrolled blood glucose levels to achieve a blood glucose level of 140-180 mg/dL (7.8-10.0 mmol/L), and the statistical analysis showed a significant negative association between insulin therapy and COVID-19 mortality. Initially, it was hypothesized that patients receiving insulin are at higher risk of COVID-19 mortality due to uncontrolled and more likely longer durations of diabetes. However, in subgroup analysis, we observed that patients who received insulin therapy had a decreased risk of mortality by about 75 percent, a finding that could be attributed to optimal blood glucose control during hospitalization, and is in line with the previously mentioned study (20) . We do not have data on treatment strategies from studies which concluded that patients with uncontrolled diabetes based on HbA1C levels have higher mortality rates compared to those with controlled diabetes (21, 22) . It is expected that patients with uncontrolled diabetes experienced more frequent episodes of hyperglycemia during hospital stay but it is not clear what glucose control strategies were implemented and how effective these strategies were. In a retrospective study conducted in United States in 88 hospitals, amongst 1122 patients, individuals with uncontrolled hyperglycemia (defined as ≥2 blood glucoses levels >180 mg/dL within 24-hour period during hospitalization) were shown to have noticeably higher mortality rates (27) . In our experience, Insulin therapy and good control of blood glucose levels could ameliorate the negative effects of hyperglycemia on patients' outcomes. Another factor could be the effects of insulin on the immune system with some immunomodulatory characteristics (28) . Given the hyperinflammatory state and cytokine storm that happens during SARS-Cov-2 infection, these characteristics may play an important role and insulin administration in patients with diabetes and COVID-19 may attenuate the magnitude of the inflammatory response (29) . Obesity is another major factor for severe infections due to an impaired immune system and could also cause a restrictive pattern in pulmonary function studies (30, 31) . The CORONADO study showed that BMI was associated with tracheal intubation rate rather than mortality; however, the association was less prominent in patients with morbid obesity (7) . Another study by Simmonet et al. revealed an association between obesity and mechanical ventilation requirement (32); however, our study did not show a significant association between BMI and mortality. It needs to be mentioned that in our study, the median BMI in the case group was 26.7 kg/m2 compared to 28.4kg/m2 in the CORONADO study and 29.6 kg/m2 in the study by Simonnet et al. (7, 32) . The difference between the findings of our study and the two previously mentioned studies could be due to ethnical and geographical variations. Ischemic heart disease, chronic kidney disease, diabetic foot infection (DFI), and CVA were more prevalent in our patients with diabetes. An unexpected vascular event such as ischemic stroke occurred in 4 patients in the DM population but none in the control group. Controlled diabetes without vascular complications or even short term uncomplicated uncontrolled diabetes were not found to be associated with increased mortality due to COVID-19. Patients with confirmed microvascular complications such as DFI, which occur in patients with long-lasting uncontrolled diabetes (33) , are at significantly higher risk of death (7, 34) . In our subgroup analysis, in individuals with diabetes, there was a significant association between DFI and mortality with a 50-fold increase in the rate of mortality. Low-grade inflammation induced by DM causes damage to the vascular system, and diabetes is a major risk factor of cardiovascular events (35) . Death due to cardiovascular events has been shown to be more prevalent in COVID-19 patients (36) . However, it is important to consider J o u r n a l P r e -p r o o f that DM per se, without vascular complications, may not be associated with increased mortality in COVID-19. Another important aspect that needs consideration is the presence of comorbidities in patients with or without diabetes. Different underlying conditions such as hypertension have previously been considered as risk factors for the severity of COVID-19 (7, 37) , and when it coexists with diabetes, more detrimental effects can be expected. In our study, comorbidities were associated with a significant increase in mortality in the total population, and the risk was even higher in patients with DM. We assessed the effect of underlying conditions via the Charlson comorbidity index; higher Charlson scores, i.e. a higher number of serious underlying diseases, were associated with an increased risk of mortality. Interestingly, hypothyroidism was shown to be an independent risk factor of mortality in the total population and could increase the mortality rate to 7-fold of COVID-19 patients without hypothyroidism. It has been demonstrated that hypothyroidism could be related to decrease in the Angiotensin-converting enzyme (ACE) serum level, and, in turn, this could lead to an increase in ACE receptor expression, which plays a fundamental role in the SARS-CoV-2 cell entry mechanism (38) (39) (40) . Thyroid dysfunction could be more prevalent in critically ill patients (41) , which could increase the mortality rate in these patients (42, 43) . Given the critical condition of many COVID-19 patients and the potential effects of hypothyroidism on mortality, it seems reasonable to investigate the status of thyroid function in all COVID-19 patients. Our study was done at a single center, and it lacks racial diversity, which is a limitation of this study even though the hospital was a referral center for COVID-19. Diabetes per se was not associated with a significant higher mortality rate due to COVID-19. Regardless of baseline HbA1C levels, insulin therapy and tight control of the blood glucose levels during hospitalization can improve the prognosis and decrease the mortality rate of individuals with coexistent COVID-19 and type 2 diabetes. These findings suggest that greater pulmonary involvement J o u r n a l P r e -p r o o f on CT scans of patients with diabetes is not necessarily associated with higher mortality rates and thus, physicians should be aware that appropriate blood glucose management of such patients with insulin therapy may be beneficial. Our findings showed that a history of hypothyroidism increased the risk of mortality. More studies with larger sample sizes are needed to assess the effects of metabolic and endocrine conditions on patients with COVID-19. The authors wish to acknowledge Ms. Niloofar Shiva for critical editing of English grammar and syntax of the manuscript. Data is presented as n (%). GGO, ground-glass opacity J o u r n a l P r e -p r o o f With the submission of this manuscript I would like to undertake that the above mentioned manuscript has not been published elsewhere, accepted for publication elsewhere or under editorial review for publication elsewhere. I understand that, as the Corresponding Author, I am responsible for completing the Authorship information on behalf of all authors listed on the manuscript. All contributing authors listed on the manuscript are aware of and agree to the submission of this manuscript. All authors have read and confirmed that they meet the ICMJE criteria for authorship. I confirm that the submitted manuscript cannot be withdrawn by author without agreement of the journal, and I am able to pay the publication fee of the article upon the acceptance of the manuscript and before publishing process. Potential reviewers for the manuscript: Covid-19: risk factors for severe disease and death Type 2 Diabetes and its Impact on the Immune System Diabetes and infection: is there a link?--A mini-review Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS Diabetes is a risk factor for the progression and prognosis of COVID-19 Patients with diabetes are at higher risk for severe illness from COVID-19 Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study Pulmonary sequelae in convalescent patients after severe acute respiratory syndrome: evaluation with thin-section CT Airway proteases: an emerging drug target for influenza and other respiratory virus infections Acute Respiratory Distress Syndrome: The Berlin Definition Nonlinear Imputation of PaO2/FIO2 From SpO2/FIO2 Among Mechanically Ventilated Patients in the ICU: A Prospective, Observational Study Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation Glycemic Targets: Standards of Medical Care in Diabetes-2020 Targets for Glycemic Control Glycemic Targets: Standards of Medical Care in Diabetes-2019