key: cord-1041932-bdwfyu59 authors: Moradi, Behnaz; Ghanaati, Hosein; Kazemi, Mohamad Ali; Gity, Masoumeh; Hashemi, Hassan; Davari-tanha, Fateme; Chavoshi, Mohammadreza; Rouzrokh, Pouria; Kolahdouzan, Kasra title: Implications of Sex Difference in CT Scan Findings and Outcome of Patients with COVID-19 Pneumonia date: 2020-07-16 journal: Radiol Cardiothorac Imaging DOI: 10.1148/ryct.2020200248 sha: 8380df0c3764e027cbcee15019e0497b35c3ce48 doc_id: 1041932 cord_uid: bdwfyu59 PURPOSE: The novel coronavirus pandemic has caused significant morbidity and mortality since December 2019. Although the role of chest CT for diagnosing COVID-19 pneumonia is still debatable, the modality has been used in scenarios of constrained real-time polymerase chain reaction (RT-PCR) testing. The epidemiologic reports indicate an unexplored difference between men and women in disease severity. We aimed to study the role of sex on disease severity and its correlation with CT-scan findings. METHODS: We retrospectively studied all confirmed cases of COVID-19 with thoracic CT-scans obtained at three hospitals from February 25, 2020 to March 15, 2020 in Tehran, Iran. CT involvement patterns of COVID-19 were analyzed based on sex and age of patients. RESULTS: One hundred and fifteen patients (64.3% [74/115] men) were enrolled with a median age of 57 (min:21, max:89). Thirty patients were admitted to the Intensive Care Unit (ICU), and thirty patients died during the hospital stay. Seventy-seven percent (37/48) of patients with unfavorable prognosis were males. Peripheral distribution of opacities was more common in males than females. When grouped by an age cut-off of 60 years, the females in the elder group had peribronchovascular distribution pattern, and younger males showed an anterior distribution of opacities. Females younger than 60 years had significantly lower CT-scores (7.5 ± 6.8). Receiver operating characteristic (ROC) curve analysis demonstrated a CT-score cut-off of 14.5 to have 100% sensitivity and 91.9% specificity for predicting poor prognosis in females younger than 60 years. CONCLUSION: Opacity patterns on chest CT in COVID-19 are different based on sex and age, and males are at higher risk of disease severity and death. The novel coronavirus disease 2019 (COVID-19) pandemic has infected more than 6 million people since December 2019. It has killed more than 371 thousand people in more than 210 countries and territories all over the world by June 1 (1) . Currently, Real-Time Polymerase Chain Reaction (RT-PCR) is the standard diagnostic test for detection of Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) infected patients; however, due to some limitations associated with this method (e.g., unavailability, inappropriate sampling method, and differences in manufacturer technology), computed tomography scanning (CTscan) is considered to be of ancillary value for patient management and diagnosis. Although debatable, I n P r e s s some studies have shown that chest CT could have higher sensitivity than RT-PCR (2, 3) . Some findings are commonly reported in COVID-19 chest CTs, including ground-glass opacities, consolidation, and crazy paving pattern (4) . Men and women have been reported to be equally infected, but different available epidemiologic analyses show sex-related differences in severity and mortality by the disease (5) . Only recently, a brief report on the gendered impact of the current pandemic discussed the different roles of genetic background and societal structure on the vulnerability of men and women (6) . Despite its importance, the role of sex difference in disease severity and mortality and its association with radiologic CT-scan findings has not been explored sufficiently. This study aimed to compare the demographic, clinical, and radiological findings of COVID-19 between men and women, and to assess whether the sex factor could have prognostic implications on the management of this devastating disease. From February 25, 2020 to March 15, 2020, the data of patients diagnosed with COVID-19 from three university hospitals of Imam Khomeini Hospital Complex, Amiralam Hospital, and Yas Women's Hospital were evaluated retrospectively in Tehran, Iran. This multicenter study was approved by the ethics committee (Protocol number: IR.TUMS.VCR.REC.1399.038), and informed consent was acquired from patients for using their admission data for research purposes. During the study period, all patients with a positive RT-PCR for COVID-19 who had undergone thoracic CT-scan examination on admission were consecutively included for the evaluation. Only the first CT scan of the referring patients was considered for evaluation. One hundred and fifteen patients were enrolled in the study, 67 of which did not need admission or were admitted, but not to the Intensive Care Unit (ICU). Thirty patients needed ICU care, and 12 of them died in the course of their disease. An additional 18 patients died before admission to ICU. Patients were categorized into two groups according to prognosis, defined as unfavorable (those who needed ICU admission or died) and favorable (those who recovered and did not need ICU admission). All I n P r e s s the discharged patients were checked for any disease-related health issue by telephone until March 20, 2020 , and none of them had died by that time. Two CT-scan systems (SOMATOM Emotion 16 scanner; Siemens, and SOMATOM Emotion 6 scanner; Siemens) were used to obtain the images. The images were obtained in the supine position and during full inspiratory pause. The range of volume CT dose index (CTDI vol) was 2.3-8.4 mGy. Radiation exposure was minimized by setting the acquisition parameters as: tube voltage = 80-110 kVp, effective current 60-80 mA, pitch = 1-1.5, matrix = 512 × 512, slice thickness = 5 mm (reconstructed slice thickness= 1.5 mm), and pulmonary U90S kernel. Intravenous contrast material was not used. Both lung (width, 1500 HU; level, −700 HU) and mediastinal (width, 350 HU; level, 40 HU) settings were used to interpret the CT-scan images. Two radiologists experienced in the field of cardiothoracic imaging, with 5 and 10 years of experience respectively, reviewed each CT-scan at the same time. No information about patients' outcomes or their clinical condition was available for them. The checklist was filled after a final agreement between them and conflicts were resolved by mutual discussion. If an agreement was not reached, a third radiologist experienced in interpretation of chest CT scans helped to resolve the disagreement. Opacities were categorized into four groups according to density, including ground-glass opacity (GGO), consolidation, mixed type opacity with >50% GGO, mixed type opacity with >50% consolidation. Reverse halo sign, nodular pattern, intralesional bronchial distortion, and linear opacity were also evaluated (7) . Distribution of the lesions was recorded as peripheral (outer 1/3 of the lungs), axial (the patchy opacities that extend to lung hila and show lobar bronchial contact), peribronchovascular I n P r e s s (opacities that occur along the peribronchovascular bundle), and diffuse. Paracardiac (more than 2 cm in contact with pericardium at lingula and right middle lobe (RML)) and anterior (the involvement of anterior one-fourth of lung periphery in both upper and lower areas) areas were evaluated additionally. A severity score (CT-score) was calculated for all lobes separately, according to the extension of the pulmonary opacities. The scores ranged 0 to 5 based on the lobes' percentile involvement, using 0 for lack of involvement, 1 for less than 5% involvement, 2 for 5-24% involvement, 3 for 25-49% involvement, 4 for 50-74% involvement and, 5 for 75-100% involvement (8) . The total CT-score ranged from 0 to 25. Underlying emphysema, bronchiectasis, fibrosis, or masses were also recorded. Reactive lymphadenopathy (short axis diameter >10 mm), pulmonary artery enlargement (as >30 mm), and pleural effusion were evaluated in the mediastinal window. Statistical analysis was done using IBM SPSS Statistics Ver.26. Descriptive statistics were reported by frequency and mean ± std for qualitative and quantitative data, respectively. Pearson's chi-squared and Mann-Whitney U tests were used to check the significant relationship between study variables. Spearman's Rank order correlation test was used to assess the correlation of total CT-score and patient age. Receiver operating characteristic (ROC) curves were plotted to assess the performance of the total CT-score in predicting the patients who died or who were admitted to the ICU (unfavorable outcome). Cut-offs with the best trade-off for sensitivity and specificity (based on "closest top left" method) were also reported. A logistic regression analysis with backward stepwise Wald methodology was performed to ascertain the effects of age, sex, underlying comorbidities, different symptoms, and the total CT-score on the likelihood of patients' prognosis. One hundred and fifteen patients [74(64.3%) men and 41(35.7%) women] with a median age of 57 (min:21, max:89) were enrolled in the study. Thirty patients were admitted to the ICU from which 12 patients died. A total of 30 patients (23 men) died during their disease at the hospital. Based on the plot and the median age of patients (i.e., 57 years), we further categorized the study population into two groups: younger than 60 years, n=63/115 (54.8%), and older than 60 years, n=50/115 (43.5%). Table 1 summarizes the clinical and CT-scan findings for the study participants based on their sex and age. Seventy-seven percent (37/48) of patients with unfavorable prognosis and 55.2% (37/67) of patients with favorable prognosis were male. This difference was statistically significant (χ²=5.82, p=0.016, Phi=0.22), indicating that patients with unfavorable prognosis are more likely to be males. None of the CT-scan findings were significantly different between men and women, except for the peripheral distribution of opacities, which was more common in men (χ²=4.15, p=0.04, Phi=0.19). Sixtysix percent (69/104) of patients with peripheral involvement were men, while 63.6% (7/11) of cases with no peripheral involvement were women. Besides, bilateral CT-scan involvement had a marginally significant difference between men and women (χ²=3.43, p=0.064, Phi=0.17). Ninety-one percent (67/71) of men and 78.0% (32/41) of women had bilateral CT-scan involvement. (Figs. 1-3) Age and total CT-scores were linearly correlated (Spearman's rank order correlation test rho=0.27, p=0.003). In the elderly group, the two parameters were significantly or marginally significantly different between men and women; the peripheral opacity distribution was more common among the men I n P r e s s (p=0.03), while the peribronchovascular distribution was more common among women (p=0.08). In the other group (<60 years), anterior distribution of opacities was significantly more common among men. Besides, almost all CT-scores were higher in men compared to women. Table 3 summarizes the significant and marginally significant differences in CT-scan findings between men and women. The best logistic regression model (χ2(6) = 76.592, p < .001) was developed by entering sex, age, underlying pulmonary disease, fever, dyspnea, and the total CT-score as input variables. The model Sex, as an essential contributing factor to the prognosis of COVID-19 patients, has been understudied, and several genetic as well as societal factors need more attention in this regard. So far, different reports have indicated equal numbers of men and women with COVID-19 (5, 9, 10) ; however, in contrast to the expected vulnerability of women in outbreaks, the death toll has impacted men more frequently (11) . The primary reasons for this observed fact seem to stem from genetic, immunologic, and also social differences between men and women (6) . It has been proposed that due to the location of the angiotensin-converting enzyme 2 (ACE2) gene on the X chromosome, and subsequent higher expression I n P r e s s of this gene in men, they are more susceptible to virus SARS-CoV-2 infection (12) . Moreover, smoking is also associated with higher ACE2 receptor expression, and considering the sex-related patterns of smoking, males are again more susceptible to the virus entry (13) . In a retrospective study on critically ill COVID-19 patients in Wuhan, China, the number of admitted men to the intensive care setting was twice the women (10) . Besides, in the pediatric population, the few studies surveying epidemiologic features indicate a male to female ratio of about 1.3 (14) (15) (16) . In a recent study by Jin et al, male sex was reported to be more susceptible to higher severity and mortality independent of age in SARS-CoV and SARS-CoV-2 (12) . Another study on clinical manifestations of refractory COVID-19 patients indicated that male sex and an in initial presentation with anorexia and no fever predicted a poorer prognosis (17) . Men constituted the majority of this study's population (74 men vs. 41 women). The participants were enrolled consecutively, so the higher frequency of men with COVID-19 in this study could be due to the fact that they are more symptomatic or susceptible to COVID-19 pneumonia, and as a result, they look for treatment and hospital care more frequently. The limited number of cases during the short period of the study could be another reason for this disparity. Furthermore, our study results showed a statistically significant male preponderance in the unfavorable prognosis group. Different studies have validated the role of chest CT-scan in COVID-19 management. CT-scan has been proposed as a remarkable method for diagnosis and determining disease severity besides other clinical and laboratory findings (18) (19) (20) . In the present study, multiple CT-scan patterns and specific characteristics of COVID-19 pneumonia lesions were analyzed. None of the CT-scan findings were significantly different between the two sexes, except for the peripheral distribution of opacities, which was more common in males. However, when we adjusted the data considering an age cut-off of 60 years, notable differences were observed. In patients younger than 60 years, men had a higher overall CT-score and more commonly showed anterior distribution of pulmonary opacities in comparison with women. In patients older than I n P r e s s 60 years, men showed a significantly more frequent number of peripherally distributed lesions, while women showed a tendency to have peribronchovascular lesions more frequently. As it is apparent in Table 2 , women younger than 60 years of age have a significantly lower CT-score (7.5 ± 6.8) compared to the mean CT-score of all the participants (i.e., 11 ± 6). An explanation for the lower CT-scores in women younger than 60 years might reside in the previously reported immunoprotected mechanisms of estrogen (21) through activation of estrogen receptor α and subsequent decrease in viral genome transcription and increased immune clearance, versus the opposite effect of androgens via androgen receptor signaling in viral infections (22) . Moreover, our study has shown that the use of severity CT-scores could predict short-term prognosis in both men and women younger than 60 years, especially in the latter group, with high sensitivity and specificity. This study is not without limitations. First, this is a relatively small convenience sample with limited representation of the four subgroups of patients based on age and sex. Second, the follow-up time was relatively short and the imaging assessment was solely based on the CT scan obtained on presentation. Third, some laboratory and clinical data (e.g. smoking history and treatment regimens) could not be reliably retrieved from the medical chart. Overall, we found no significant differences in chest CT-scan involvement patterns between men and women. Our results showed that men with COVID-19 more frequently had unfavorable prognosis compared to women, and that women younger than 60 years had a significantly lower CT-score. However, a CT-score of 14.5 or more in women younger than 60 could indicate an unfavorable prognosis (ICU admission or death) with high sensitivity and specificity. 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