key: cord-0966528-iatxqr5m
authors: Rizza, Stefano; Nucera, Alessandro; Chiocchi, Marcello; Bellia, Alfonso; Mereu, Daniele; Ferrazza, Gianluigi; Ballanti, Marta; Davato, Francesca; Di Cola, Giovanni; Buonomo, Claudio Oreste; Coppeta, Luca; Vanni, Gianluca; Gervasi, Romualdo; Cardellini, Marina; Lauro, Davide; Federici, Massimo
title: Metabolic characteristics in patients with COVID-19 and no-COVID-19 interstitial pneumonia with mild-to-moderate symptoms and similar radiological severity
date: 2021-08-18
journal: Nutr Metab Cardiovasc Dis
DOI: 10.1016/j.numecd.2021.08.035
sha: b1967216bf6fde5142d069b33a407c7ce7a4bfe2
doc_id: 966528
cord_uid: iatxqr5m

Background and Aims It is known that the highest COVID-19 mortality rates are among patients who develop severe COVID-19 pneumonia. However, despite the high sensitivity of chest CT scans for diagnosing COVID-19 in a screening population, the appearance of a chest CT is thought to have low diagnostic specificity. The aim of this retrospective case-control study is based on evaluation of clinical and radiological characteristics in patients with COVID-19 (n=41) and no-COVID-19 interstitial pneumonia (n=48) with mild-to-moderate symptoms. Methods and Results To this purpose we compared radiological, clinical, biochemical, inflammatory, and metabolic characteristics, as well as clinical outcomes, between the two groups. Notably, we found similar radiological severity of pneumonia, which we quantified using a disease score based on a high-resolution computed tomography scan (COVID-19=18.6±14.5 vs n-COVID-19=23.2±15.2, p=0.289), and comparable biochemical and inflammatory characteristics. However, among patients without diabetes, we observed that COVID-19 patients had significantly higher levels of HbA1c than n-COVID-19 patients (COVID-19=41.5±2.6 vs n-COVID-19=38.4±5.1, p=0.012). After adjusting for age, sex, and BMI, we found that HbA1c levels were significantly associated with the risk of COVID-19 pneumonia (odds ratio=1.234 [95%CI=1.051-1.449], p=0.010). Conclusions In this retrospective case-control study, we found similar radiological and clinical characteristics in patients with COVID-19 and n-COVID-19 pneumonia with mild-to-moderate symptoms. However, among patients without diabetes HbA1c levels were higher in COVID-19 patients than in no-COVID-19 individuals. Future studies should assess whether reducing transient hyperglycemia in individuals without overt diabetes may lower the risk of SARS‐CoV-2 infection.

2 Abstract: 34 Background and Aims: It is known that the highest COVID-19 mortality rates are among patients 35 who develop severe COVID-19 pneumonia. However, despite the high sensitivity of chest CT scans 36 for diagnosing COVID-19 in a screening population, the appearance of a chest CT is thought to 37 have low diagnostic specificity. The aim of this retrospective case-control study is based on 38 evaluation of clinical and radiological characteristics in patients with COVID-19 (n=41) and no-39 COVID-19 interstitial pneumonia (n=48) with mild-to-moderate symptoms. 40 Methods and Results: To this purpose we compared radiological, clinical, biochemical, 41 inflammatory, and metabolic characteristics, as well as clinical outcomes, between the two 42 groups. Notably, we found similar radiological severity of pneumonia, which we quantified using a 43 disease score based on a high-resolution computed tomography scan (COVID-19=18.6±14.5 vs n-44 COVID-19=23.2±15.2, p=0.289), and comparable biochemical and inflammatory characteristics. 45 However, among patients without diabetes, we observed that COVID-19 patients had significantly 46 higher levels of HbA1c than n-COVID-19 patients (COVID-19=41.5±2.6 vs n-COVID-19=38.4±5.1, 47 p=0.012). After adjusting for age, sex, and BMI, we found that HbA1c levels were significantly (1, 2) . 69 The symptoms of COVID-19 range in severity from very mild to critical; severe cases of viral 70 infection can rapidly progress to acute respiratory distress syndrome, septic shock, and multiple 71 organ dysfunction syndrome (3). Elderly individuals and individuals with pre-existing conditions, 72 including hypertension, cancer, cardiovascular diseases, severe renal impairment, obesity and 73 diabetes, have a demonstrated higher risk for developing more severe cases of COVID-19 and for 74 COVID-19-associated mortality (4-7). 75 Although the interaction between the SARS-CoV-2 virus and the immune system of an 76 individual may result in a diverse, multi-organ, potentially lethal disease, the main manifestation 77 of COVID-19 is an interstitial pneumonia, called novel coronavirus-infected pneumonia ( distribution) and with symptoms that were clinically classifiable as mild to moderate (e.g., patients 113 had no need for mechanical ventilation during hospitalization and required only passive oxygen 114 therapy). This study was approved by the local ethics committee, and all patients provided written 115 informed consent before their enrollment. All data was collected anonymously, and the study 116 Figure 1 provides a flowchart overviewing the study approach. (Thoracic VCAR   155 v13.1, GE Medical Systems). Each lung was automatically divided into three zones for analysis: 156 upper, which included the parenchyma above the carina; middle, which included the parenchyma 6 below the carina and above the inferior pulmonary vein; and lower, which included the 158 parenchyma below the inferior pulmonary vein. 159 The volumetric and densitometric parenchymal analysis software that we used allowed us 160 to automatically calculate the volume of each lung and of each of the six lung zones (upper, 161 middle, and lower zones in each of the two lungs). We also used the color-coded ranges of 162 parenchymal density to calculate the percentages of each zone (by volume) that were occupied by distribution of ground-glass opacities or consolidation (0 for none, 1 for <25%, 2 for 25-50%, 3 for 176 50-75%, and 4 for >75%). The final scores for each zone were calculated by multiplying the two 177 scores, and then a total score for each patient was calculated by summing the scores for each 178 zone. Total scores ranged from 0 (absence of pathology) to 72 (maximum severity). In cases of a 179 discrepancy between the two radiologists, final scores were determined by consensus. 

The clinical protocol for this study is presented as a flowchart in Figure 1 . In this retrospective case-control study, we found that COVID-19 and non-COVID-19 in-242 patients with pneumonia clinically classifiable as mild to moderate and similar HRCT image 243 severity, as determined by HRCT scan score, had similar metabolic and clinical characteristics. 244 There were also no differences in inflammatory burden or clinical outcomes between COVID-19 245 and non-COVID-19 individuals, though patients with non-COVID-19 pneumonia had higher 246 leukocytes counts possibly due to bacterial infection. These results are particularly unexpected. 247 One possible explanation is that it remains difficult to distinguish COVID-19 from other causes of 248 viral pneumonia. Although chest HRCT has been reported to have a high sensitivity for COVID-19 249 diagnosis, this method still has low specificity. For example, influenza and COVID-19 both present 250 J o u r n a l P r e -p r o o f 9 with ground glass opacities and consolidation on a chest CT (16), making it complicated to perform 251 a differential diagnosis. 252 Notably, pneumonia patients with and without COVID-19 also had similar circulating levels 253 of IL-6. The induction of IL-6 production by interleukin-1, the primordial proinflammatory cytokine, 254 instigates the well-known amplification loop that contributes to the cascade of cytokine 255 overproduction that characterizes a "cytokine storm" (22). However, even though IL-6 overload is 256 a fundamental part of the cytokine storm and plays a crucial role in the pathophysiology of severe 257 COVID-19, cytokine storm remains ill-defined, particularly when compared to cytokine levels in 258 patients with bacterial sepsis or other critical illnesses (23). Overall, our findings are surprising 259 given that the COVID-19 pandemic is a public health emergency of global concern, has generated 260 considerable public awareness, and has caused a major worldwide sanitary crisis (24). Our work has several limitations. First, our study mainly used a cross-sectional approach, 308 has an exploratory nature, and no prospective analysis has been performed to date. Second, 309 although the number of participants was balanced between the two study groups, the overall 310 sample size was relatively small and some results may be related to this point. Third, we were not 311 able to determine an alternative diagnosis for pneumonia patients who tested negative for SARS-312 J o u r n a l P r e -p r o o f 11 CoV-2 via nasopharyngeal swabs, though each patient was tested for SARS-CoV-2 up to four times. 313 Moreover, we did not provide clinical data regarding vital signs and blood gas analysis because 314 uncompleted collected and we did not perform a survival analysis, because information about the 315 occurrence of events has been acquired by telephone contacts and our knowledge on the exact 316 timing of events such as deaths or mechanical ventilation was limited. Finally, even if steroid 317 treatment was started in hospital's Emergency Department, where appropriate, we did not have 318 specific data to report. However, although the effect of hyperglycemia on COVID-19 outcome may 319 be confounded by glucocorticoid therapy being used in patients with more severe forms of disease 320 (40), in our opinion the risk that few days of steroid therapy may influence the stability of HbA1c is 321 very low. 

Rationale for 444 targeting complement in COVID-19

Hyperglycemia, hydroxychloroquine, and the COVID-19 pandemic

Binding of SARS coronavirus to its receptor damages islets 450 and causes acute diabetes

MERS-CoV spike protein: a key target for antivirals

Dipeptidyl peptidase 4 is 456 a functional receptor for the emerging human coronavirus-EMC

Glycated haemoglobin A1c as a risk factor of cardiovascular outcomes and all-cause mortality in 460 diabetic and non-diabetic populations: a systematic review and meta-analysis

Independently Associated with the Risk of Coronary Atherosclerotic Plaques in Patients without 464 Diabetes: A Cross-Sectional Study

Does cancer risk increase with HbA1c, independent of diabetes

The associations between fasting 470 plasma glucose levels and mortality of COVID-19 in patients without diabetes

The inflammatory status score including 475

MCP-1 and adiponectin underlies whole-body insulin 476 resistance and hyperglycemia in type 2 diabetes mellitus

Opposing Effects of Fasting 479

Metabolism on Tissue Tolerance in Bacterial and Viral Inflammation

482 glucocorticoid therapy, and outcome of COVID-19

Acronym definitions are the same as in Table 1 J o u r n a l P r e -p r o o f