key: cord-0942543-0hvgk95t authors: Kaya, Ahmet Turan; Akman, Burcu title: Mediastinal Lymph Node Enlargement in COVID-19: Relationships with Mortality and CT Findings date: 2022-03-10 journal: Heart Lung DOI: 10.1016/j.hrtlng.2022.03.006 sha: 490a93c2a2cff87507bfce87ea8131e37b2f5174 doc_id: 942543 cord_uid: 0hvgk95t BACKGROUND: The presence of mediastinal lymph node enlargement (MLNE) in computed tomography (CT) of Coronavirus disease 2019 (COVID-19) patients can be associated with disease severity. OBJECTIVES: To investigate the relationship between MLNE with intensive care unit admission (ICU), mortality rates, and CT findings, especially in early-stage COVID-19 patients. METHODS: This single-center retrospective case-control study, included aged ≥18 years, 250 COVID-19 patients with positive RT-PCR tests. We included two patient groups, 125/250 with and without MLNE. Demographic information of the patients, laboratory findings, length of stay in hospital or ICU, mortality rates, initial CT imaging findings and CT severity scores (CT-SS) were recorded and their relationship with MLNE was investigated. RESULTS: Patients with MLNE were older (69.61±11.16; p<0.001) and had a higher CT-SS (14.67±7.55; p<0.001). There was a significant difference between the presence of MLNE with mortality (58/77, 75.3%; p<0.001) and ICU admission (49/61, 80.3%; p<0.001). Also, a statistical association was found between MLNE with ICU admission (p=0.001) and (p<0.001) mortality rates in patients with CORADS≤2 CT findings. In multivariate logistic regression analysis, MLNE was 8.8-fold (95% CI: 1.62-47.86, p= 0.01) more correlated with linear opacity and 0.25-fold with bronchial wall thickening (95% CI: 0.07-0.92, p= 0.04). CONCLUSION: Mediastinal lymph node enlargement is an important CT finding that can predict the severe prognosis of COVID-19 patients. Even in patients without lung involvement on initial CT, the presence of MLNE should be carefully examined as it is associated with disease severity. COVID-19 is a progressive viral disease that can cause widespread morbidity and mortality worldwide 1 . This disease has typical pulmonary symptoms and can be severe, affecting many extrapulmonary systems 2 . For this reason, the patient should be diagnosed in the early phase and the imaging findings showing the progression of the disease should be known. Some of these factors are older age, male gender, and comorbidities [3] [4] [5] . A computed tomography (CT) performed in the first 4 days after the onset of symptoms may be negative 6 . This may make it difficult to predict the prognosis of patients with a positive reverse transcription-polymerase chain reaction (RT-PCR) test. The presence of typical thorax CT findings of COVID-19 pneumonia provides early diagnosis without waiting for RT-PCR test results. The typical CT findings are bilateral peripheral, multifocal ground-glass opacities (GGOs), consolidation, crazy paving pattern, halo and reverse halo signs. GGOs with or without consolidation is the most common CT finding of COVID-19 7 . Among the atypical features, the most common are mediastinal lymph node enlargement (MLNE), linear opacities, tree-in-bud sign, inter and intralobular septal thickening, cavitation and pleural effusion 8 . MLNE can occur as a result of infectious and non-infectious causes and is defined as enlargement of the lymph node short axis is ≥ 10 mm 9 . It is often associated with comorbidities such as heart failure, malignant diseases, and sarcoidosis. In addition, it has been found that the district where the person lives and smoking history are associated with the occurrence of MLNE. MLNE is not the typical chest CT finding in COVID-19 pneumonia 10 . However, atypical findings such as MLNE are associated with the prognosis of patients with COVID-19 11 . The incidence of MLNE in patients with COVID-19 pneumonia is 0%-66%, and the relationship between CT findings has not been demonstrated in the literature yet 10 . The higher mortality rate in hospitalized COVID-19 patients with MLNE than those without MLNE suggested that it should be investigated as a prognostic factor for serious disease 12 . The presence of MLNE in patients with idiopathic pulmonary fibrosis (IPF) is thought to be a result of a higher degree of chronic inflammation, and a correlation has been shown between disease severity of IPF and MLNE in the literature 13 . We aimed to investigate the relationship between MLNE with intensive care unit admission (ICU), mortality rates, and intraparenchymal CT findings, especially in early-stage COVID -19 patients. This study was approved by the Ethical Committee of Amasya University Faculty of Medicine and was conducted according to the Declaration of Helsinki and Good Clinical Practice (06 January 2022, number: 04). The study is retrospective, patient information was obtained from electronic records and censored. Since the study was retrospective, the ethics committee did not find it necessary to obtain written informed consent from the patients. Our study is a single-center, retrospective, case-control study. Our study analyzed the data of 250 patients who applied to our hospital's Emergency Service and COVID-19 polyclinic between January 2021 and May 2021. Patients over the age of 18 with at least one positive RT-PCR test were included in our study. Patients with negative RT-PCR test, with lung and other malignancies, under 18 years of age, pregnant women and patients who had image artifacts on their CT scans were excluded from the study. Demographic information, laboratory findings, length of stay in hospital or ICU, mortality rates, first CT imaging findings and CT-SS were recorded. The study sample was determined as a total of 228 patients, with at least 114 in both groups, with an effect size of 0.40, α=0.05, and power (1-β)=0.85 using the G-power program. Two groups were performed, 125 patients with MLNE and 125 without MLNE (control). The laboratory results obtained within 1 day from the initial chest CT date and comorbidities such as diabetes, chronic lung and cardiovascular diseases, admission to the hospital and/or ICU, and the dates of death were scanned from our hospital's electronic medical records. The patient's length of stay in the service and ICU and their survival were recorded. The non-contrast chest CT scans were performed using the multidetector CT (MDCT) scanners 128-slice GE Healthcare Revolution EVO CT (GE Medical Systems; Milwaukee, WI). Tube voltage, 120 kV; tube current, 100-450 mA; beam collimation, 64 mm × 0.625 mm; beam pitch, 1.375; gantry rotation, 0.4 seconds; acquisition direction, craniocaudal; reconstruction kernel, standard; slice thickness, 0.625 mm; and section overlap, 0.625 mm. All chest CT scans were assessed at lung window of 1500 WW and −450 WL and mediastinal window of 400 WW and 40 WL. The non-contrast chest CT is acquired during a single breath-hold. Craniocaudal axial images were obtained from the beginning of the thorax to the abdomen (middle part of the kidneys) with the patient in deep inspiration and supine position. The chest CT scan at admission to the hospital was evaluated for the presence of COVID-19 pneumonia and MLNE by a radiologist with 8 years of experience. Initial CTs were reported using the Coronavirus disease 2019 Reporting and Data System (CO-RADS) based on suspicions of COVID-19 lung involvement, 1 to 5 (1 = very low, 2 = low, 3 = uncertain, 4 = high, and 5 = very high, i.e. typical findings). GGOs, which are the typical finding of COVID-19 pneumonia, were present in CORADS≥ 3 14 . The CT-SS was calculated visually using a previously defined semi-quantitative CT severity scoring system ranging from 0-25. Scoring was done in the range of 0 -5 according to the percentage of involvement of each lobe (0=0%, 1=1-5%, 2=6-25%, 3= 26-50%, 4=51-75% and 5= >75%), and the scores of the 5 lobes were summed to obtain a total CT-SS [15] [16] [17] . The mediastinal lymph node short axis was measured on routine axial CT images. If the short axis was ≥ 10 mm, it was accepted as MLNE ( Fig. 1) The mean age of the total 250 patients included in the study was 64.84±13 years, and the mean age was 69.61±11. 16 (Fig. 2) (Table 6 ). In our study, we evaluated the prognostic role of the presence of MLNE and its relationship with CT findings in patients with COVID-19. In addition, we evaluated the frequency of MLNE in patients with COVID-19, its relationship with the length of stay in the service and ICU, and its association with comorbidities. Our results showed an association between the presence of MLNE with older age, increased inflammatory markers, high CT-SS, increased death and ICU hospitalization rates. The presence of MLNE was found to be associated with the prognosis of early-stage COVID-19 patients without CT imaging findings of COVID-19 pneumonia (CT-SS=0, CORADS 1 or 2). There was no difference between MLNE and gender. Parenchymal chest CT findings were more common in the group with MLNE. In multivariate analysis, linear opacity and increased bronchial wall thickness on CT scans and a history of chronic lung disease were associated with a higher frequency of MLNE. In addition, older age, MLNE, interlobular septal thickening and hyperlipidaemia were riskier in multivariate logistic regression analysis for mortality. There was no significant difference in terms of the presence of MLNE in the -fold between hospitalization (service or ICU) and death. During the peak of the COVID-19 pandemic, the most important problem in many health institutions was the lack of ICU and service beds. Especially at the beginning of the pandemic when PCR testing was not common, CT was more important in the diagnosis of COVID-19. It was reported that the typical CT findings are less common in the early period (0-4 days) and the CT-SS is mostly calculated as 0 6 . Therefore, we do not have enough information about the prognosis of PCR positive COVID-19 patients without lung involvement in the early period (CORADS 1 or 2). Satıcı et al. investigated the relationship between MLNE and mortality in their study. They reported that patients with MLNE were older, had at least one comorbidity, and were associated with increased mortality 20 . In our study, the presence of MLNE was associated with higher mortality rates and worse prognosis in COVID-19 patients with CORADS≤2 CT findings in the early period. In Satıcı et al.'s study, 60/650 patients (9.2%) had MLNE, which was less than our study. In addition, the mean age was lower than in our study. In In our study, there was no significant relationship between the presence of consolidation and the prognosis of the patients. This may be due to the inclusion of chest CT at admission to our study. Consolidation is often seen in the mid-late stage of the disease. Satıcı et al. found that only the crazy-paving pattern was significantly higher in the group with MLNE in the study 20 . In our study, the incidence of all CT parenchymal findings (typical and atypical) except the treein-bud was high in the patient group with MLNE. We found that linear opacities and bronchial wall thickening are riskier for the presence of MLNE. Linear opacities often observed on follow-up chest CT scans, indicate lower segment atelectasis or pneumonia and are indicative of fibrosis. This may be related to the increase in the severity of the disease 29, 30 . Bronchial wall thickening due to increased vascular endothelial growth factor (VEGF) in severe disease is thought to increase the severity of the disease and airflow resistance 31, 32 . Consistent with the literature, linear opacities and bronchial wall thickness was associated with an increased frequency of MLNE in our study. In the literature, two studies except Sardanelli F. et al.'s study reported a relationship between older age and MLNE 12, 20, 33 . Angiotensin-converting enzyme 2 (ACE-2) is important in the entry of the virus into the cell, and its expression increases with age, so there is a higher risk for Covid-19 mortality in the elderly 34 . Consistent with the literature, the presence of MLNE was also associated with higher age in our study. In addition, in older patients, the possibility of comorbidities increases and immunity weakens. In Meyer et al.'s meta-analysis of the effect of their extrapulmonary findings on mortality, they reported that MLNE increased the risk of mortality approximately two-fold 11 . Consistent with the literature, in our study, we think that the relationship between chronic lung disease and cardiovascular diseases with the presence of MLNE is an important factor in the exacerbation of the infection 24 . Like other studies in the literature, there was no relationship between gender and MLNE in our study 12, 25 . This shows that gender is not a risk factor for the presence of MLNE. Satıcı et al. reported that there was no significant difference between MLNE and gender, as in our study 20 . In addition, while comorbidities and MLNE were unrelated in their study, the frequency of MLNE was significantly higher in patients with chronic lung diseases and cardiovascular diseases in our study. To our knowledge, our study is the first to examine the association between the presence of MLNE with mortality and ICU hospitalization in early-period COVID-19 patients with CORADS≤2 CT findings. A significant relationship was found between MLNE and ICU hospitalization and mortality. Our results suggested that we can have information about the prognosis of patients with COVID-19 by evaluating the presence of MLNE when the CT-SS is zero. In addition, we found that linear opacities and increased bronchial wall thickness, which is seen in severe disease, are common in patients with MLNE, consistent with the literature. There were some limitations in our study. First of all, our study was a single-center retrospective study. No classification was made according to mediastinal lymph node stations. The smoking of the patients was not questioned in terms of pack/year. CTs at the time of admission were used, and some of our patients did not have follow-up CT. Therefore, the mediastinal lymph node size of the patients could not be evaluated after treatment. In conclusion, the presence of mediastinal lymph node enlargement is associated with linear opacity and increased bronchial wall thickness, which are CT findings of severe disease. MLNE is a predictive factor of increased CT severity score and mortality risk in COVID-19. Therefore, evaluation of the mediastinum for the presence of MLNE on CT may be useful for prognosis. 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This study was approved by the Ethical Committee of Amasya University Faculty of Clinical Practice (06 January 2022, number: 04) and the requirement for informed consent was waived. In this study, there were no competing interests or financial benefits to the authors.