key: cord-0695548-d2haan6b
authors: Nafakhi, Hussein; Alareedh, Mohammed; Al-Buthabhak, Karrar; Shaghee, Foaad; Nafakhi, Ahmed; Kasim, Samet
title: Predictors of adverse in-hospital outcome and recovery in patients with diabetes mellitus and COVID-19 pneumonia in Iraq
date: 2020-12-05
journal: Diabetes Metab Syndr
DOI: 10.1016/j.dsx.2020.12.014
sha: 719ea98479918744bb645440dad6d27e94966301
doc_id: 695548
cord_uid: d2haan6b

BACKGROUND AND AIMS: There is limited data about the prognosis and impact of COVID-19 pneumonia on patients with diabetes mellitus (DM). We aimed to assess blood indices, ECG markers of sudden death and malignant arrhythmias on admission, and diabetes lowering drugs as possible predictors of adverse in-hospital outcome and COVID-19 pneumonia recovery status. METHODS: A retrospective study included patients with newly diagnosed COVID-19 pneumonia from August 20, to October 5, 2020. RESULTS: A total of 192 patients with COVID-19 pneumonia were included in the present study, of whom 67 patients had DM. Low lymphocytes % [0.4(0.1–0.9), P = .011] and QTc interval prolongation [0.4(0.1–0.8), P = .022] were associated with increased length of ICU stay. On the other hand, metformin use [0.3(0.2–4), P = .032] and DPP-4 inhibitors use [0.3(0.2–3), P = .040] were associated with decreased length of ICU stay. QTc interval prolongation [0.4(0.1–0.9), P = .017] was associated with increased length of hospital stay, while using metformin [0.4(0.2–3), P = .022] was associated with decreased length of hospital stay. Low lymphocytes % [0.5(0.4–1.6), P = .001], insulin use [0.4(0.3–5), P = .003], and old age [0.5(0.1–2.3), P = .025] were associated with extensive lung injury. The risk for in-hospital death was associated with high neutrophil% [1(1–1.4), P = .045], while metformin use was associated with decreased risk for in-hospital death [0.1(0.1–0.6), P = .025]. Insulin use [0.3(0.2–4), P = .013] was associated with partial recovery following acute COVID pneumonia. CONCLUSIONS: Metformin and DPP-4 inhibitors use were associated with favorable in-hospital outcomes, while insulin use was associated with extensive lung injury and post-acute COVID-19 pneumonia partial recovery.

Coronavirus disease 2019 is caused by infection from highly contagious coronavirus termed as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) [1] . COVID-19 infection has a heterogeneous presentation and the clinical spectrum of infection ranges from asymptomatic infection to life-threatening and even death [2e4] .

Patients with pre-existing chronic medical conditions, such as diabetes mellitus(DM), are considered as the high-risk group for adverse morbidity and death related to COVID-19 pneumonia [5] . DM has been identified as a risk factor for adverse outcomes from various types of infections, including those caused by respiratory viruses [6] . Increased susceptibility to respiratory infections may be related to inflammatory and immune imbalances associated with chronic hyperglycemia, which may aggravate viral infection, such as COVD-19 infection [7] .

The initial studies from China reported a higher prevalence of diabetes among patients with severe COVID-19 disease requiring hospital or intensive care unit (ICU) admission. However, the mechanisms underlying adverse outcomes related to infection remain undefined and there is limited data about the prognosis and impact of COVID-19 pneumonia on patients with DM in the literature [1, 6] .

The main aim of the present study was to assess baseline blood indices, ECG markers of sudden death and malignant arrhythmias on admission, and diabetes lowering drugs as possible predictors of adverse in-hospital outcome and post-acute COVID-19 pneumonia recovery status in patients with DM and COVID-19 pneumonia.

This was an observational retrospective study that included Iraqi patients with newly diagnosed COVID-19 infection who presented to the outpatient clinic or admitted to the Al-Sader teaching hospital in Al-Najaf governorate from August 20, to October 5, 2020. All patients were presented with features consistent with OCVID-19 pneumonia based on clinical symptoms (fever, cough, sputum, or shortness of breath) and radiological findings. Patients diagnosed with COVID-19 according to positive nasopharyngeal swab by real time polymerase chain reaction (PCR). At hospital admission, the baseline clinical characteristics, complete blood count, ECGs were recorded using medical records and collected by physicians at research site elevel at the hospital. At outpatient clinic, the evaluation of patients was performed by physicians through the clinical interview with the patient during the outpatient clinic visit. The baseline clinical characteristics included age, sex, hypertension, DM, diabetes lowering drugs or insulin, smoking, body mass index (BMI), previous coronary artery disease, and in-hospital clinical outcome. DM type II was defined as glycated haemoglobin (HbA1c) 6.5% or any established diagnosis prior to admission. Complete blood indices included white blood cell count (WBC), lymphocyte count and %, neutrophil count and %, red blood cell count (RBC), hemoglobin (Hb), red blood cell mean volume (MCV), red blood cell width distribution (RDW), platelet count, platelet distribution width (PDW), and platelet mean volume (PMV). ECG markers of malignant arrhythmias and sudden cardiac death included QTc, T from peak to end interval (Tp-e), and QTc/Tp-e ratio which represents transmural dispersion of repolarization (TDR). The severity of lung injury by COVID-19 pneumonia was assessed by CT scan score at the time of hospital admission or outpatient clinic. According to pneumonia severity and radiological features of lung injury, patients with mild-moderate pneumonia were treated at home and patients with severe pneumonia were admitted to the hospital and followed up until discharge or death. All patients, whether admitted to the hospital or treated at home, must have a second visit to outpatient clinic after 14 day from the resolution of fever related to COVID-19 pneumonia or discharge from the hospital to assess recovery status and post-recovery persistent. Post-acute COVID-19 recovery status included complete recovery after 14 day from the resolution of the fever without persistent symptoms and partial recovery with persistent symptoms after 14 day from the resolution of fever, including persistent shortness of breath, cough, fatigue, smell, and taste loss. Patients with incomplete data or discharge on their responsibility before completion of treatment or not attended 14-day post-discharge or recovery visit were excluded. The main outcome was defined as the length of ICU stay, duration of hospital admission, degree of lung injury according to CT score, in-hospital death, complete recovery, and partial recovery with persistent symptoms. Approval of this study was provided by our medicine College Board.

The 12-lead ECGs were obtained for all patients at the time of outpatient clinic visit or within 24 h of hospital admission with a paper speed of 25 mm/s and voltage of 10 mm/mV by using a standard ECG system (Marquette Electronics, WI, USA) while the patient was resting in the supine position. ECG readings were measured manually by two cardiologists blinded to the patient's status, using calipers and a magnifying glass. Any disagreement in ECG interpretations between cardiologists was resolved by consensus. Tp-e interval was measured from the peak of the T wave to the end of the T wave in the precordial leads. The mean value of the measurements was used in the analysis. The QT interval was measured from the beginning of the QRS complex to the end of the T. Measured QT intervals were corrected by Bazett's formula (QT/ (RR interval)1/2) and defined as corrected QT interval (QTc). The Tpe/QTc ratio was calculated from these measurements [8] .

Statistical analysis was performed using SPSS ver. 23.0 (SPSS Inc., Chicago, IL, USA). P-value of < .05 was chosen for statistical significance. Baseline clinical data of the patients and clinical outcomes were expressed as mean ± standard deviation for continuous variables or as numbers with percentages for categorical data. Blood indices and ECG markers were expressed as mean ± SD. Univariate and multivariate logistic regression analyses were used to calculate the odds ratio and confidence intervals [OR (CI)] and assess the association of complete blood indices, ECG markers, and baseline characteristics with in-hospital outcomes, including the length of hospital and ICU stay, degree of lung injury according to CT score, and in-hospital death and post-acute COVID-19 pneumonia recovery status. Baseline clinical characteristics, including age, sex, hypertension, diabetes lowering drugs, smoking, BMI, previous coronary artery disease, ECG markers, and complete blood indices underwent univariable logistic regression to the in-hospital outcomes and post-recovery status. Those with a P value of < .05 were candidates for inclusion in the final multivariable logistic regression analysis.

A total of 192 patients with COVID-19 pneumonia were included in the present study. The patients were categorized into DM group [67 patients with age (years) 60 ± 10, 29(43%) were males] and without DM group [125 patients with age (years) 45 ± 15, 62(49%) were males). Fever (81%) was the most common clinical symptom among patients with DM followed by dry cough(76%), shortness of breath(63%), gastrointestinal tract (GIT) symptoms (46%), fatigue(45%), taste loss (27%), productive cough (25%), and smell loss(22%). Among patients with DM, metformin was the most commonly used diabetes lowering drug (52%) followed by sulfonylurea (36%), insulin (22%), and dipeptidyl peptidase-4(DPP-4) inhibitors (21%). Patients , characteristics are shown in Table 1 .

Patients with DM were older (60 year versus 45 year, P < .000) and had a higher rate of hypertension (66% versus 33%, P < .000) and severe pneumonia requiring hospital admission (52% versus 14%, P < .000) than patients without DM. On the other hand, patients without DM had a higher rate of mild-moderate COVID-19 pneumonia treated at home and not requiring hospital admission(86% versus 48%,P < .000) compared to patients with DM. No significant difference in the distribution of BMI, previous coronary artery disease, and smoking pattern between DM and without DM groups. Regarding blood indices distribution, higher values of neutrophil % (78 vs 67, P ¼ .001), PDW (14 versus 12, P ¼ .002), PMV (9.5 versus 8.8, P ¼ .014), neutrophil/lymphocyte ratio (10 versus 6, P ¼ .035), and platelet/lymphocyte ratio(288 versus174, P ¼ .002) were observed among patients with DM compared to patients without DM. On the other hand, higher values of lymphocyte % (24 versus 15, P ¼ .001), lymphocyte count (2.1 versus 1.1, P ¼ .001), and RBC (4.6 versus 4.3, P ¼ .019) were observed in patients without DM compared to patients with DM. Patients with DM had significant prolongation in QTc interval (438 versus 423, P ¼ .023) compared to patients without DM while no significant differences in Tp-e interval and TDR were observed between groups. The prevalence of complete and partial recovery showed no significant difference between DM and without DM groups. The prevalence of adverse inhospital outcomes, including increased length of hospital and ICU stay, extensive lung injury, and death was higher among patients with DM than patients without DM (P < .05). (Table 1) . Table 2) . 

Female sex [0.2(0.1e0.4),P ¼ .009] and high PMV [0.2(0.1e0.9),P ¼ .045] were associated with complete recovery following acute COVID-19 pneumonia. On the other hand, insulin use [0.3(0.2e4), P ¼ .013] was associated with partial recovery associated with persistent symptoms following acute COVID-19 pneumonia (Table 3) .

Previously described, coronaviruses, including middle east respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), epidemics were associated with severe course and adverse outcome including higher deaths among patients with DM [7] . It has been suggested that diabetes might adversely impact the course of the coronaviruses infection through its effects on receptors that mediate virus entry into the cells including DPP-4, which is involved in the regulation of several physiological processes and is modulated by chronic hyperglycemia and diabetes lowering drugs commonly used in diabetic patients [6] .

In the setting of the COVID-19 pandemic, DM has been reported as frequent comorbidity of COVID-19 infection associated with a worse prognosis. The adverse outcome of patients with diabetes is the likely consequence of clustering of several comorbidities, including chronic hyperglycemia, older age, and hypertension, which all contribute to an increase in the risk of disease severity in these patients [9] . Also, DM can affect white blood cells function and response to viral infection via decreased mobilization of polymorphonuclear leukocytes, chemotaxis, phagocytic activity, and elevated pro-inflammatory cytokine levels which may exaggerate the cytokine storm seen in COVID-19 [5, 6] . Furthermore, patients with DM were noted to have more pronounced inflammatory and coagulation abnormalities than in non-diabetic patients, independently of other comorbidities [7, 10] .

A comprehensive meta-analysis of 30 studies showed that DM was associated with adverse outcomes in patients with COVID-19. This adverse association was influenced by age and hypertension. All these comorbidities are characterized by systemic inflammation and hypercoagulability that contribute to COVID-19 progression and eventually to a poor outcome [11] . Besides immune, inflammatory, and coagulation disturbances noted in DM, it has been found that patients with diabetes have a higher prevalence of prolonged QT and decreased repolarization reserve with a significant increase in the risk of arrhythmic death, make patients with diabetes particularly vulnerable to the proarrhythmic effects of QT prolongation [12] .

The relationship of anti-diabetes drugs with COVID-19 severity and prognosis is inconsistent among studies. Racial disparity, study design, number of enrolled patients, potential confounders inherently found in observational studies, and frequency of adverse events in some studies may be the possible causes for this inconsistency in the literature.

The available data from observational and retrospective studies showed controversial results regarding the association between metformin use and clinical adverse outcomes in patients with DM and COVID-19. Some studies showed no definite association between metformin use and clinical outcomes, including survival, and raised concerns about the possible risk of lactic acidosis in cases of multiple organ failure [13e15], while others reported that metformin use was associated with a higher risk of disease progression in patients with COVID-19 with DM during hospitalization [16] . However, five studies with a total of 6937 patients showed that metformin use was associated with reduction in mortality rate from COVID-19 infection [17] . The potential beneficial effect of metformin noted in COVID-19 infection might be attributed to its inherent anti-inflammatory properties beyond its glucoselowering action and independent of glucose control, which could positively influence the prognosis and disease course of patients with DM and COVID-19 [18, 19] .

Regarding DPP-4 inhibitors and COVID-19 prognosis and severity, it has been reported that DPP-4 plays a role in various physiological processes, including the immune responses. DPP-4 inhibitors may exert immune regulatory functions, that are potentially beneficial in autoimmune and inflammatory diseases, such as rheumatoid arthritis. [ 5] An upregulation of DPP-4 in patients with DM remains a plausible explanation for the greater severity of COVID-19 in patients with DM [20] . A recent metaanalysis (n ¼ 1607 patients with DM; 16 trials) found a significant reduction in inflammatory markers following DPP-4 inhibitors use compared with placebo [18, 21] . In our study, insulin use was associated with extensive lung injury as evident on CT examination of the chest and partial recovery with persistent symptoms following acute COVID-19 infection. Insulin inhibit the action of A Disintegrin And Metalloprotease (ADAM)17 in an experimental study conducted on mice [22] . ADAM-17 is involved in the shedding of several transmembrane proteins, including angiotensin-converting enzyme 2(ACE2),which may suggest that insulin increases the activity of ACE2 and subsequently increases the infectivity of SARS-CoV-2 [23] .According to Chen et al. study, patients with COVID-19 infection using insulin for treatment of DM were associated with poor prognosis compared to non-insulin users. [24] Consistent with our results, a recent study conducted in Lombardo found that treatment with insulin and lower lymphocyte count were associated with higher mortality, even after adjustment for sex and age, whereas the use of metformin or DPP-4 inhibitors were associated with a lower mortality rate [25] .

The present study has several limitations. This was a retrospective study including relatively a small number of patients with DM, and the data of patients were extracted from medical patient history or records. The specific rhythm type that occurred in those who died of COVID-19 was not reported in medical records because of a lack of telemetry information or serial ECGs. Therefore, we cannot verify the specific type of cardiac rhythm or arrhythmic events that occurred during ICU staying or prior to death. It is not possible to eliminate the potential effects of unmeasured confounders as with every observational study. A randomized controlled trial is required to confirm the potential favorable effects of metformin and DPP-4 inhibitors or the unfavorable effects of insulin use in the setting of COVID-19 infection.

Metformin and DPP-4 inhibitors use were associated with favorable in-hospital outcomes, while insulin use was associated with extensive lung injury and partial recovery following acute COVID-19 pneumonia. Low lymphocyte %, high neutrophil %, old age, prolongation of QTc interval, and high RDW were predictors for adverse outcomes in diabetic patients with COVID-19 pneumonia.

There were no external funding sources for this study.

The authors declare that they have no conflict of interest. 

Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes

The expression level of angiotensin-converting enzyme 2 determines the severity of COVID-19: lung and heart tissue as targets

The new challenge of geriatrics: saving frail older people from the SARS-COV-2 pandemic infection

A new coronavirus associated with human respiratory disease in China

Diabetes and COVID-19: a systematic review on the current evidences

Is diabetes mellitus a risk factor for COronaVIrus Disease 19 (COVID-19)?

Clinical characteristics and outcomes of COVID-19 hospitalized patients with diabetes in the United Kingdom: a retrospective single centre study

ECG markers of arrythmogenic risk relationships with pericardial fat volume and BMI in patients with coronary atherosclerosis

COVID-19 in people with diabetes: understanding the reasons for worse outcomes

Diabetes is a risk factor for the progression and prognosis of COVID-19

Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia -a systematic review, meta-analysis, and meta-regression

Effect of intensive glycemic and blood pressure control on QT prolongation in diabetes: the ACCORD trial

Metformin use IS associated with reduced mortality IN a diverse population with COVID-19 and diabetes

Metformin use amid coronavirus disease 2019 pandemic

COVID-19 and diabetes: is metformin a friend or foe?

Risk of metformin in patients with type 2 diabetes with COVID-19: a preliminary retrospective report

Metformin use is associated with reduced mortality rate from coronavirus disease 2019 (COVID-19) infection

Anti-inflammatory properties of antidiabetic drugs: a "promised land" in the COVID-19 era?

Metformin and COVID-19: from cellular mechanisms to reduced mortality

The clinical characteristics and outcomes of patients with moderate-to-severe coronavirus disease 2019 infection and diabetes in daegu, South Korea

Effect of dipeptidyl-peptidase-4 inhibitors on Creative protein in patients with type 2 diabetes: a systematic review and metaanalysis

Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice

SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2

Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication

Impact of comorbidities and glycemia at admission and dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes with COVID-19: a case series from an academic hospital in lombardy