key: cord-0774980-sig8w9d3 authors: Mazidimoradi, Afrooz; Hadavandsiri, Fatemeh; Momenimovahed, Zohre; Salehiniya, Hamid title: Impact of the COVID-19 Pandemic on Colorectal Cancer Diagnosis and Treatment: a Systematic Review date: 2021-11-29 journal: J Gastrointest Cancer DOI: 10.1007/s12029-021-00752-5 sha: 115b6a69e59b96937bed241d295a90e166366a84 doc_id: 774980 cord_uid: sig8w9d3 BACKGROUND: Following the official announcement of the COVID-19 pandemic by the World Health Organization (WHO) in March 2020 and decreased activity of healthcare systems, relocation of resources, and the possible reluctance of patients to seek medical help, colorectal cancer patients were exposed to significant risks. Given that colon cancer is the third most common cancer and the second deadliest cancer in the world, its timely diagnosis and treatment are necessary to reduce costs and improve quality of life and patient survival. The aim of this study was to investigate the effects of COVID-19 pandemic on the diagnosis and treatment of colorectal cancer. METHODS AND MATERIALS: A comprehensive search performed on June 2021 in various databases, including Medline, Web of Science, and Scopus. Keywords such as “diagnosis,” “treatment,” “coronavirus disease-19,” “COVID-19,” “coronavirus disease,” “SARS-CoV-2 infection,” “SARS-CoV-2,” “2019-nCoV,” “coronavirus, 2019 novel,” “SARS-CoV-2 virus,” severe acute respiratory syndrome coronavirus 2,” “COVID-19,” “COVID-19, coronavirus disease 19,” “SARS coronavirus 2,” “colorectal neoplasm,” and “colorectal cancer “ was used individually or a combination of these words. All retrieved articles were entered into a database on EndNote X7. Then, studies were first selected by title and then by abstract, and at the end, full texts were investigated. RESULTS: Of the 850 studies, 43 were identified as eligible. According to studies, the diagnosis of colorectal cancer and the number of diagnostic procedures have decreased. Emergency visits due to obstruction or perforation of the large intestine or in advanced stages of cancer have increased, and a delay in the diagnosis of colorectal cancer has reported from 5.4 to 26%. Treatment of colorectal cancer has also decreased significantly or has been delayed, interrupted, or stopped. This reduction and delay have been observed in all treatments, including surgery, chemotherapy, and long-term radiation therapy; only cases of emergency surgery and short-term radiotherapy has increased. The waiting time for hospitalization and the length of hospital stay after surgery has been reported to be higher. Changes in patients’ treatment plans and complete to partial cessation of hospitals activities—that provided treatment services—were reported. CONCLUSION: According to the reduction in the diagnosis and treatment of colorectal cancer due to the COVID-19 pandemic, compensating for the reduction and preventing the continuation of this declining trend, requires serious and effective interventions to prevent its subsequent consequences, including referrals of people with advanced stages and emergency conditions, increasing treatment costs and reducing the quality of life and patients survival. In late December 2019, a new strain of coronavirus was reported from China with symptoms such as acute respiratory disease that quickly spread to other parts of the world [1] . The virus, which was named the new coronavirus 2019 or SARS-CoV-2 [2] , was declared a public health emergency and international concern by the World Health Organization on January 30, 2020 [1, 3] . The impact of this virus on the function of healthcare systems and the allocation of resources to combat the disease caused by this virus, and also the reluctance of many patients to seek health care in crowded healthcare centers, led to the cessation of routine care in many care centers and subsequently, exposed vulnerable patients, including those with cancer, to significant risks [4, 5] . Colorectal cancer is also one of the cancers that diagnosis and treatment was faced with serious challenges during the COVID-19 crisis. According to GLOBOCAN 2020, colorectal cancer is the second deadliest and the third most common cancer in the world, accounting for 9.4% of all cancer deaths. Also, more than 1.9 million new cases and 935,000 deaths caused by this disease have occurred in 2020 [6] . Therefore, any delay in the diagnosis and treatment of this cancer can have irreparable consequences, as it is predicted that a delay of 3 months and only a change from stage I/T1 to stage II/T2 causes 88 additional deaths and is imposed $12 million additional costs on the healthcare system. Also, by 6-month delay in the diagnosis and treatment of colorectal cancer, 349 additional deaths per month and $46 million additional costs over 5 years can be expected [7] . It is also predicted that a 2-month delay in surgery will reduce patient survival by more than 9% and a 6-month delay by more than 29% [8] . During the COVID-19 pandemic, the diagnosis and treatment of other diseases have also been challenging, so knowing the effect of COVID-19 on the diagnosis and treatment of cancer is essential for healthcare systems for better planning. Therefore, the present study was conducted to investigate the effects of COVID-19 pandemic on the diagnosis and treatment of colorectal cancer. This systematic review was conducted in accordance with the PRISMA checklist. A comprehensive search was conducted in three databases including PubMed/MEDLINE, Scopus, and Web of Science, using the following keywords from 2020 to 2021: "early diagnosis," "treatment,"" "COVID-19," "coronavirus disease," "SARS-CoV-2 infection," "SARS-CoV-2," "2019-nCoV," "coronavirus, 2019 novel," "SARS CoV-2 virus," "severe acute respiratory syndrome coronavirus 2," "COVID-19," "COVID-19, coronavirus disease 19," "SARS coronavirus 2," "colorectal neoplasm," and "colorectal cancer." AND, OR and mesh term operators were also used to improve the search result. Also, a manual search was performed in reputable scientific journals to find articles related to the full text. All types of observational studies, addressing the impact of COVID-19 pandemic on colorectal cancer diagnosis and treatment, published in the English language were included in the review. Review studies, case reports, letters to editors, commentaries and reports were also excluded. All retrieved articles were entered into EndNote X7 software. After removing duplicates, studies were first selected by title and then by abstract. Then, their eligibility was verified by reviewing the full text. Articles that evaluated every aspect of colorectal cancer diagnosis and treatment during the COVID-19 epidemic were included in the analysis. To extract the data, the prepared checklist was used and the following information was extracted from each study: surname of the first author, year of publication, country of study, type of study, sample size, age and sex of the target group, period of evaluation and the main findings. "Adapted Newcastle-Ottawa Quality Assessment Scales" checklist was used to evaluate the quality of the articles in this review [9] . This tool consists of 3 separate sections: selection, comparison and conclusion. Studies were scored based on overall scores and divided into 3 categories: good, moderate and poor. The search result in the databases based on the intended keywords included 850 articles, which after deleting duplicates (398 articles), according to the title and abstract of the remaining articles, 350 articles were deleted. Afterward, a thorough review of the remaining articles was performed; then, 36 other articles were excluded due to publication in a language other than English [5 articles], a letter to the editor [9 articles], etc. Subsequently, the full text of the articles was reviewed, 22 articles were deleted due to lack of access to the full text or inconsistency with the objectives of the study, and finally, 43 articles were analyzed in this systematic review (Fig. 1 ). According to the goals of this study, included articles were divided in two groups: the effect of COVID-19 pandemic on the diagnosis of colorectal cancer and the effect of COVID-19 pandemic on the treatment of colorectal cancer. Subgroups in diagnosis group were general diagnosis [8, [10] [11] [12] [13] [14] [15] [16] [17] , emergency diagnosis and in advanced stages [8, [18] [19] [20] , diagnosis with usual visits [19] , diagnosis in screening program [8, 10, 17, 18, [21] [22] [23] [24] , delay in diagnosis [14, 25] and a number of diagnoses per number of diagnostic methods [16, 24] . Subgroups in treatment group were treatment in general [21, [26] [27] [28] , surgical treatment [15, 26, 27, [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [26, 30, 36, 39, [41] [42] [43] [44] , radiation therapy [26, 30, 37] , the treatment cost [45] , waiting time for hospitalization [8, 27, 45] , duration of hospitalization [41, 45, 46] , changes in patients' treatment plan [8, 27, 36, 39, 44] , changes in the activity of hospitals providing medical services [19, 39, 47] and follow-up of the suspicious screening cases [26, 45] . Based on the review using the checklist, 22 articles/studies were of good quality, and 16 articles/studies were of medium quality, and 5 articles/studies were of poor quality. The results are summarized in Tables 1 and 2 . General Diagnosis Decreased diagnosis of new cases of colorectal cancer during COVID-19 pandemic is seen in most countries, as Spain has reported 48% reduction [8] and Brazil has reported 46.3% reduction in the diagnosis of colorectal cancer [10] . Numerous studies have been conducted in the UK and various studies have reported 54.2% [48] , 43.1% [25] , and 62% [11] reduction in the diagnosis of new cases of colorectal cancer. According to the results of other studies, the average number of cancer cases detected per week has decreased by 71.3%, and it seems that 71.7% (2828) of cases of colorectal cancer have not been diagnosed during this period [12] . Also, the average number of monthly diagnoses of cancer has decreased from 44 cases in the last 3 years (2017-2019) to 30 cases by February 2020 [13] . One study found that the diagnosis of colorectal cancer, after a 70% decrease in April 2020, has reached the expected level after 5 months with a gradual increase [14] . In Italy, the reduction in the diagnosis of colorectal cancer in 2020 was reported to be 11.9% [50] , 19.5% [15] , and 46.6% [49] . In Hong Kong, after the diagnosis of the first case of COVID-19, the mean number of colorectal cancer diagnosis decreased by 37%, from 91.8 to 58 cases per week (p < 0.001) [16] . In the Netherlands, the number of colorectal cancer diagnoses in people under 55 and over 75 in the first weeks of April was significantly lower than expected (45% decrease), but after that, it reached the expected level and remained constant since [17] . In Spain, it was observed that, in 2020, a higher rate of patients were diagnosed in emergency situations (12.1% vs. 3.6% in 2019; p = 0.048) [8] . In the UK, the number of emergency visits in 2020 was higher than in 2019 and 2018 (36.0% vs. 28.6%; p = 0.03), and the diagnosis of T4 stage cancer during 2020 was higher than in 2018-2019 (34.5% vs. 27.1%; P = 0.03). Colon obstruction also increased from 4.3% in 2019 and 2018 to 8.6% in 2020 (p = 0.01) and colonic rupture from 3.3% in 2018-2019 to 4.1% in 2020 (p = 0.01) [18] . In England and Wales, due to the prevalence of COVID-19, most hospitals experienced a significant reduction in the number of emergency visits with advanced stages of colorectal cancer [19] . In Japan, admission of emergency cases increased from 18.2 to 38.7% (p < 0.05) and partial or total obstruction of colon increased from 19-42 to 67% (p < 0.05) [20] . In England and Wales, due to the prevalence of COVID-19, only 6 hospitals (5%) out of 123 hospitals did not report a decrease in their number of patient visits due to colorectal cancer and stated that their number of patient visits was more than 90% of the usual number. Also, 12 hospitals (10%) saw a slight decrease (71 to 90% of the usual number) in the number of patient visits, 95 hospitals (77%) reported a large decrease (20 to 70% of the usual number), and 10 hospitals (8%) reported a significant decrease in their patient visits (0 to 19% of usual number), [19] . In Spain, the diagnosis of colorectal cancer in screening programs decreased from 33.3 to 5.2% (p = 0.000) [8] . In the Netherlands, the number of people diagnosed with colorectal cancer among people aged 55 to 75 (those in the target group of the 2-year FIT screening program) was 48.7% lower than the expected number since early May (6 weeks after the cessation of colorectal cancer screening), and from the end of June, the number of diagnoses reached the expected level [17] . There was also a relative increase in suspected cases of rectal cancer (0.6% [95% CI 0.4-0.7] vs. 0.3% [95% CI 0.2-0.4], P < 0.001), while the number of suspected cases of colon cancer and endoscopic cases of suspected rectal cancer decreased by 44% and 2%, respectively [23] . In Poland, the issuance of oncology diagnosis and treatment cards (ODaTCs) decreased by 3.8% [21] . This decrease was more evident in April, so that, in April 2020, 2063 cards were issued, and in the same month in 2019, this number was equal to 3980, and this represents a 51% decrease in referral cases [21] . In Italy, in the screening program that was carried out during the restriction period, the rate of "high-risk" adenomas was significantly higher (47% vs. 25%), (p = 0.001) and with fewer examinations during the restriction period, a significantly higher number of colon cancer was detected (5 cases, 8%, vs. 3 cases, 1%, p = 0.002) [22] . In the UK, the number of colon cancer diagnoses in endoscopic centers decreased from 4 cases per week to 1.8 cases [24] , and in Brazil, the number of referrals from the public health system to the hospital for a definitive diagnosis dropped from 21 to 14% [10] . [25] , and in another study, the delay in diagnosis of colorectal cancer increased by 5.4% (74.0% vs. 68.6%), and as a result, the early diagnosis of cancer decreased from 31.4 to 26% [14] . In the UK, the endoscopic procedures required to diagnose one case of colorectal cancer have been reduced from 47 to 12 cases per week [24] . In Hong Kong, the rate of positive colorectal cancer cases per 1000 endoscopies increased from 75.6 to 118.2 over the entire period (p < 0.001) [16] . The results of various studies show that the treatment of colorectal cancer has decreased significantly during the COVID-19 pandemic. In India, for example, the number of patients referred for treatment or under treatment decreased by 65% [26] . In Spain, the number of referrals for treatment in 2020 decreased by 48% [8] , and in Poland, the number of colorectal cancer treatments decreased by 51% from January to April 2020 [21] . The results of an international survey in 84 countries also showed that treatment has been delayed in 70.9% of colorectal cancer cases during the COVID-19 pandemic [27] . In the UK, the treatment of 23.4% of colorectal cancer patients was delayed, interrupted, or stopped [28] . The results of various studies show that colorectal cancer surgery has significantly decreased during the COVID-19 pandemic. The rate of this decrease was 34% in Germany [29] , 19.5% in Portugal [15] , 14.5% in New Zealand [30] , and 60% in Australia [31] . In India, colorectal cancer surgery has generally decreased by 40%, including upfront/ post-neoadjuvant surgery by 78%, palliative care by 80%, and stoma closure by 83% [26] . In China, elective colon surgery showed a 35% reduction. Also, the duration of surgery in 2020 (245.22 ± 88.94) compared to 2019 (206.21 ± 63.6) showed an increase (p = 0.002), [32] . In the UK, 79.3% of surgeons delayed their surgeries, and 10.3% stopped their surgeries. Also, 69% of them performed their surgery in places free of COVID-19, and 11.5% transferred their cancer surgery to a private hospital or a separate place, while only 11.5% continued to perform their surgery in previous places [33] . In Italy, despite the similar number of colorectal resection surgeries in 2019 and 2020 (75 in 2019 and 74 in 2020), the percentage of colorectal resection due to cancer has increased (32 cases or 42.6% in 2019 vs. 44 cases or 59.5% in 2020; p = 0.049). Also, the *NTG normal-time group, **STG special-time group (based on hospitalization date), ***ODaTCs Oncology Diagnosis and Treatment Cards surgery of patients whose tests were positive for COVID-19 was delayed by 15 days until they receive two negative results [34] . In UK, with the onset of COVID-19 pandemic, robotic surgery was delayed for 60% of colorectal cancer patients, increasing the time of diagnosis to treatment from 62 to 94 days [35] . Colorectal resection surgery generally increased by 30% and fluctuated in the long run, so that it decreased in May, June, and July, and then increased, and the number of open surgeries increased in 2020, from 26 to 48% (p = 0.03) [36] . Also, in England, the number of surgeries for referred patients decreased by 31% (95% CI: with less laparoscopic procedures, and stomaforming procedures accounting for a larger share [37] . The results of an international survey in 84 countries showed that during the COVID-19 crisis, 70.9% of colorectal cancer cases were delayed, and in 90.1% of cases, the delay was 5 to 8 weeks longer than usual and in 9.9% of cases, the delay was more than 8 weeks [27] . In Romania, emergency colorectal cancer surgery increased due to obstruction or perforation (32 vs. 6.97%; P = 0.0039), [38] . In Spain, 27% of colorectal cancer surgeries were performed with a delay of more than 30 days, and more than 3% of patients refused to undergo the surgery [39] . In Austria, in the first public restrictions, colon cancer surgery decreased by 71.4% (p = 0.02) and emergency surgery cases increased by 25% (p = 0.03) [40] . In China, the number of outpatient stoma closures per month decreased by 35.6% and in patients with nonlocal perforation, it decreased by 41.7%. Also, palliative surgeries decreased in February 2020 and multidisciplinary surgery decreased from late January to early March, mainly for the elderly and patients with liver metastases. Curative resection showed a 42.4% decrease from late January to late March. The proportion of patients undergoing laparoscopic surgery was 49.4, which was significantly higher than 39.5 in the same period in 2019 [41] . The results of various studies show that colorectal cancer chemotherapy during COVID-19 pandemic has declined in some countries, including India by 70% [26] , Scotland by 43.4% [42] , and the UK where chemotherapy cases have declined from 30 to 19% [36] , while in New Zealand, it has not decreased significantly [30] . In Turkey, the delay in chemotherapy increased from 7.6% in the pre-pandemic period to 50% in the post-pandemic period [43] , and in Spain, it was delayed in 1.7% of patients [39] . In China, outpatient chemotherapy decreased by 17.1% [41] , and 43.6% of patients experienced a delayed chemotherapy (50%) or had their treatment regimen changed (9.7%), [44] . Also, the rate of delay in hospitals to which patients were referred from the surgical wards was higher than in hospitals to which patients were referred directly from the oncology wards (82.5% vs. 18.5%; p < 0.001) [44] . In India, the percentage of patients receiving long-term radiation treatment (LCTR) has decreased by 45%, and the number of patients receiving short-term radiation treatment (SCTR) has increased by 200% [26] . In New Zealand, radiotherapy has dropped by 8% [30] . In England, neoadjuvant radiotherapy for rectal cancer increased by 44% (95% CI: , and the use of short-term treatment regimens decreased in June 2020 and then increased until October 2020 [37] . The Treatment Cost In China, treatment costs were higher in patients who attended after the COVID-19 pandemic than in those who attended before the pandemic (P < 0.05) [45] . In China, the waiting time for hospitalization in patients who attended after the COVID-19 pandemic (9.59 ± 14.19 days) was longer than in patients who attended before the pandemic (7.95 ± 13.97 days) [45] . In the UK, the mean time interval between colorectal cancer diagnosis and treatment during the pandemic (16) (17) (18) (19) (20) ) was longer than before pandemic (8 weeks (IQR 5-13)) (p = 0.001) [52] . In an international survey, it was shown that, in 90.1% of cases, the delay time was 5 to 8 weeks longer than usual, and in 9.9%, it was longer than 8 weeks [27] . In Spain, the time interval between diagnosis and treatment before and after COVID-19 pandemic showed no difference [8] . In China, the length of hospital stay after surgery was longer in patients who attended after the COVID-19 pandemic than in patients who attended before the pandemic (P < 0.05), [45] . Also, the average day of hospital stay for all surgical procedures during the pandemic was significantly higher than the average day in the same period in 2019. This figure for stoma closure surgery was 8.8 ± 3.1 vs. 6.8 ± 2.2, p < 0.001, for palliative surgery was 11.0 ± 4.3 vs. 9.1 ± 3.1, p = 0.002, and for multidisciplinary surgery was 14.3 ± 4.3 vs. 12.3 ± 3.3, p = 0.049 [41] . In the UK, average hospital stay (3.5 days) in the postpandemic period was lower in patients who had undergone surgery than in patients who had undergone sigmoidoscopy (5 days) prior to COVID-19 crisis [46] . In China, the treatment plans of 9.7% of patients undergoing chemotherapy were changed [44] . In the UK, changes were made to patients' treatment plans, and they used fewer short-term radiotherapy programs and preferred surgery to chemotherapy [36] . The results of an international survey showed that the delay in treatment was 48.9% due to a change in surgical program and 26.3% due to a change in elective surgery to emergency surgery [27] . In Spain, the treatment plan was changed in a number of patients who had been diagnosed before the COVID-19 pandemic and in 8% of newly diagnosed patients [8] . Another study also showed that 62% of patients' treatment plans have been changed [39] . Changes in the Activity of Hospitals Providing Medical Services In India, during the national quarantine period, more surgeons performed colorectal cancer surgery in specialized oncology hospitals and green areas in terms of COVID-19 prevalence compared to multidisciplinary hospitals and red areas in terms of COVID-19 prevalence (89.3% vs. 75.9%; P = 0.04) [47] . In England and Wales, 23% of hospitals reduced their activities to 0-10% of their normal capacity and 43% of hospitals reduced their activities to 11-70% of their normal capacity, only 34% of hospitals operated at 71-100% of their normal capacity [19] . Also, 56% of hospitals replaced the treatment plan for 50% of their patients, 47 hospitals (38%) reported changes in the length and type of chemotherapy treatment in more than 50% of their patients, and 23 hospitals (19%) reported the use of interim treatments in more than 50% of their patients, such as stent insertion for obstructive cancers and radiation therapy for rectal cancer with a "long waiting period" [19] . In Spain, 33.3% of hospitals performed only emergency surgery, 1.23% performed delayed or referral surgery, and 55.6% accepted asymptomatic colorectal cancer after chemotherapy [39] . In India, the follow-up of screening cases for sigmoidoscopy and colonoscopy reduced by 90% [26] . This study investigated the effect of COVID-19 pandemic on the diagnosis and treatment of colorectal cancer by systematic review approach and the final analysis was performed based on 43 articles related to the purpose of the study. Due to the high prevalence of colorectal cancer and its high mortality rate in European countries, the USA, and India and China in Asia [53] , most eligible studies have been conducted in European countries 38 articles as well as India and China (6 articles). As cancer-screening programs have been reduced or stopped following the outbreak of COVID-19 pandemic, the diagnosis of cancers, including colorectal cancer, has been facing with challenges. Most studies have reported that the diagnosis of colorectal cancer has been significantly reduced [8, 10-17, 25, 48-50] . This reduction included a reduction in the overall diagnosis of cancer, a reduction in routine referrals [19] , and a reduction in cancer detection through screening programs [8, 10, 17, [21] [22] [23] [24] . At least 2828 colorectal cancer cases have not been diagnosed in the UK [12] . Also, due to the decreased participation in screening programs and referrals of suspected people to diagnostic centers, the number of diagnostic methods required to identify cancer has decreased [16, 24] and the percentage of positive cases has increased [16] . Since the lack of early detection of cancer cases leads to consequences such as disease progression, delayed treatment, and increased mortality [54] , all studies conducted on colorectal cancer show an increase in urgent referrals or after the onset of consequences such as obstruction or rupture of the large intestine or in advanced stages of cancer [8, [18] [19] [20] . In general, during the COVID-19 crisis, the delay in diagnosis of colorectal cancer has been reported from 5.4 [14] to 26% [25] . Another effect of COVID-19 pandemic has been a delay in the treatment of colorectal cancer, which can have detrimental consequences for the overall and disease-free survival of patients [55] , so that, with the onset of COVID-19 pandemic, the number of referrals for colorectal cancer treatment has decreased significantly [8, 21, 26] or has been delayed, interrupted, or stopped [27, 28] . This reduction or delay is seen in all treatments including surgical treatment [15, 26, 27, 29-33, 35-37, 39-41] , chemotherapy [26, 36, 39, [42] [43] [44] , and long-term radiation therapy [26, 37] , only cases of emergency surgery [38, 40] and short-term radiotherapy [26, 37] show an increase. However, in Italy, the number of colorectal resection surgeries [34] and, in New Zealand, the cases of chemotherapy before and after COVID-19 pandemic have remained unchanged [30] . During COVID-19 pandemic, the waiting time for hospitalization and admission has also been increased [27, 45, 52] , and up to 16 weeks delay has been reported [52] , but only one study in Spain reported no difference in this regard before and after the COVID-19 crisis [8] . Also, the length of hospital stay after surgery has been reported to be higher in patients who have attended after the COVID-19 pandemic [41, 45] . In the UK, however, the average hospital stay was lower in patients who had undergone surgery during the COVID-19 pandemic than in patients who had undergone sigmoidoscopy prior to the COVID-19 crisis [46] . Some studies have also reported changes in patients' treatment plans, including changes from chemotherapy to surgery, changes from long-term to short-term radiation therapy, and from elective surgery to emergency surgery, and the main reason for these changes has been reported to be reducing the risk of developing COVID-19 in patients [8, 27, 36, 39, 44] . COVID-19 disease has affected the activities of hospitals that provide treatment services to patients with colorectal cancer, and given the prevalence of this cancer in their area of activity, this effect ranges from complete or partial cessation of activities or changing treatment plans to alternative methods of treatment or relocation of treatment center [19, 39, 47] . In general, the COVID-19 pandemic has posed serious challenges to all aspects of colorectal cancer diagnosis and treatment. As the results of this study show, the diagnosis and treatment of colorectal cancer during COVID-19 pandemic have faced serious challenges, which can be a wake-up call for diagnostic systems, especially healthcare systems in the post-COVID-19 crisis, because they will be faced with a large number of patients with advanced stages of the disease who may require emergency treatment. 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