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      Faecal immunochemical test is superior to symptoms in predicting pathology in patients with suspected colorectal cancer symptoms referred on a 2WW pathway: a diagnostic accuracy study

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          Abstract

          Objective

          To assess whether a faecal immunochemical test (FIT) could be used to select patients with suspected colorectal cancer (CRC) symptoms for urgent investigation.

          Design

          Multicentre, double-blinded diagnostic accuracy study in 50 National Health Service (NHS) hospitals across England between October 2017 and December 2019. Patients referred to secondary care with suspected CRC symptoms meeting NHS England criteria for urgent 2 weeks wait referral and triaged to investigation with colonoscopy were invited to perform a quantitative FIT. The sensitivity of FIT for CRC, and effect of relevant variables on its diagnostic accuracy was assessed.

          Results

          9822 patients were included in the final analysis. The prevalence of CRC at colonoscopy was 3.3%. The FIT positivity decreased from 37.2% to 19.0% and 7.6%, respectively, at cut-offs of 2, 10 and 150 µg haemoglobin/g faeces (µg/g). The positive predictive values of FIT for CRC at these cut-offs were 8.7% (95% CI, 7.8% to 9.7%), 16.1% (95% CI 14.4% to 17.8%) and 31.1% (95% CI 27.8% to 34.6%), respectively, and the negative predictive values were 99.8% (95% CI 99.7% to 99.9%), 99.6% (95% CI 99.5% to 99.7%) and 98.9% (95% CI 98.7% to 99.1%), respectively. The sensitivity of FIT for CRC decreased at the same cut-offs from 97.0% (95% CI 94.5% to 98.5%) to 90.9% (95% CI 87.2% to 93.8%) and 70.8% (95% CI 65.6% to 75.7%), respectively, while the specificity increased from 64.9% (95% CI 63.9% to 65.8%) to 83.5% (95% CI 82.8% to 84.3%) and 94.6% (95% CI 94.1% to 95.0%), respectively. The area under the receiver operating characteristic curve was 0.93 (95% CI 0.92 to 0.95).

          Conclusion

          FIT sensitivity is maximised to 97.0% at the lowest cut-off (2 µg/g); a negative FIT result at this cut-off can effectively rule out CRC and a positive FIT result is better than symptoms to select patients for urgent investigations.

          Trial registration number

          ISRCTN49676259.

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          Most cited references37

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          Enteric involvement of coronaviruses: is faecal–oral transmission of SARS-CoV-2 possible?

          The end of 2019 was marked by the emergence of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused an outbreak of viral pneumonia (COVID-19) in Wuhan, China. At the time of writing, SARS-CoV-2, previously known as 2019-nCoV, has spread to more than 26 countries around the world. According to the WHO COVID-19 situation report-28 released on Feb 17, 2020, more than 71 000 cases have been confirmed and at least 1770 deaths. Coronaviruses are a family of single-stranded enveloped RNA viruses that are divided into four major genera. The genome sequence of SARS-CoV-2 is 82% similar to severe acute respiratory syndrome coronavirus (SARS-CoV), 1 and both belong to the β-genus of the coronavirus family. 2 Human coronaviruses such as SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), are known to cause respiratory and enteric symptoms. In the SARS outbreak of 2002–03, 16–73% of patients with SARS had diarrhoea during the course of the disease, usually within the first week of illness. 3 SARS-CoV RNA was only detected in stools from the fifth day of illness onwards, and the proportion of stool specimens positive for viral RNA progressively increased and peaked at day 11 of the illness, with viral RNA still present in the faeces of a small proportion of patients even after 30 days of illness. 4 The mechanism for gastrointestinal tract infection of SARS-CoV is proposed to be the angiotensin-converting enzyme 2 (ACE2) cell receptor. 2 In the initial MERS-CoV outbreak in 2012, a quarter of patients with MERS-CoV reported gastrointestinal symptoms such as diarrhoea or abdominal pain at presentation. 5 Some patients initially presented with both fever and gastrointestinal symptoms before subsequent manifestation of more severe respiratory symptoms. 6 Corman and colleagues 7 found MERS-CoV RNA in 14·6% of stool samples from patients with MERS-CoV. In-vitro studies have shown that MERS-CoV can infect and replicate in human primary intestinal epithelial cells, potentially via the dipeptidyl peptidase 4 receptor. 8 In-vivo studies showed inflammation and epithelial degeneration in the small intestines, with subsequent development of pneumonia and brain infection. 8 These results suggest that MERS-CoV pulmonary infection was secondary to the intestinal infection. In early reports from Wuhan, 2–10% of patients with COVID-19 had gastrointestinal symptoms such as diarrhoea, abdominal pain, and vomiting.9, 10 Abdominal pain was reported more frequently in patients admitted to the intensive care unit than in individuals who did not require intensive care unit care, and 10% of patients presented with diarrhoea and nausea 1–2 days before the development of fever and respiratory symptoms. 9 SARS-CoV-2 RNA has been detected in the stool of a patient in the USA. 11 The binding affinity of ACE2 receptors is one of the most important determinants of infectivity, and structural analyses predict that SARS-CoV-2 not only uses ACE2 as its host receptor, but uses human ACE2 more efficiently than the 2003 strain of SARS-CoV (although less efficiently than the 2002 strain). 2 Data exist to support the notion that SARS-CoV and MERS-CoV are viable in environmental conditions that could facilitate faecal–oral transmission. SARS-CoV RNA was found in the sewage water of two hospitals in Beijing treating patients with SARS. 12 When SARS-CoV was seeded into sewage water obtained from the hospitals in a separate experiment, the virus was found to remain infectious for 14 days at 4°C, but for only 2 days at 20°C. 12 SARS-CoV can survive for up to 2 weeks after drying, remaining viable for up to 5 days at temperatures of 22–25°C and 40–50% relative humidity, with a gradual decline in virus infectivity thereafter. 13 Viability of the SARS-CoV virus decreased after 24 h at 38°C and 80–90% relative humidity. 13 MERS-CoV is viable in low temperature, low humidity conditions. The virus was viable on different surfaces for 48 h at 20°C and 40% relative humidity, although viability decreased to 8 h at 30°C and 80% relative humidity conditions. 14 At present, no viability data are available for SARS-CoV-2. The viability of SARS-CoV and MERS-CoV under various conditions and their prolonged presence in the environment suggest the potential for coronaviruses to be transmitted via contact or fomites. SARS-CoV and MERS-CoV are both viable in conditions with low temperatures and humidity.12, 13, 14 Although direct droplet transmission is an important route of transmission, faecal excretion, environmental contamination, and fomites might contribute to viral transmission. Considering the evidence of faecal excretion for both SARS-CoV and MERS-CoV, and their ability to remain viable in conditions that could facilitate faecal–oral transmission, it is possible that SARS-CoV-2 could also be transmitted via this route. The possibility of faecal–oral transmission of SARS-CoV-2 has implications, especially in areas with poor sanitation. Coronaviruses are susceptible to antiseptics containing ethanol, and disinfectants containing chlorine or bleach. 15 Strict precautions must be observed when handling the stools of patients infected with coronavirus, and sewage from hospitals should also be properly disinfected. The importance of frequent and proper hand hygiene should be emphasised. Future research on the possibility of faecal–oral transmission of SARS-CoV-2 should include environmental studies to determine whether the virus remains viable in conditions that would favour such transmission. Study of the enteric involvement and viral excretion of SARS-CoV-2 in faeces is required to investigate whether faecal concentrations of SARS-CoV-2 RNA correlate with the severity of the disease and presence or absence of gastrointestinal symptoms, and whether faecal SARS-CoV-2 RNA can also be detected in the incubation or convalescence phases of COVID-19. © 2020 NIAID-RML/National Institutes of Health/Science Photo Library 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
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            STARD 2015: An Updated List of Essential Items for Reporting Diagnostic Accuracy Studies.

            Incomplete reporting has been identified as a major source of avoidable waste in biomedical research. Essential information is often not provided in study reports, impeding the identification, critical appraisal, and replication of studies. To improve the quality of reporting of diagnostic accuracy studies, the Standards for Reporting of Diagnostic Accuracy Studies (STARD) statement was developed. Here we present STARD 2015, an updated list of 30 essential items that should be included in every report of a diagnostic accuracy study. This update incorporates recent evidence about sources of bias and variability in diagnostic accuracy and is intended to facilitate the use of STARD. As such, STARD 2015 may help to improve completeness and transparency in reporting of diagnostic accuracy studies.
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              Guidelines for the management of iron deficiency anaemia.

              Iron deficiency anaemia (IDA) occurs in 2-5% of adult men and postmenopausal women in the developed world and is a common cause of referral to gastroenterologists. Gastrointestinal (GI) blood loss from colonic cancer or gastric cancer, and malabsorption in coeliac disease are the most important causes that need to be sought. DEFINING IRON DEFICIENCY ANAEMIA: The lower limit of the normal range for the laboratory performing the test should be used to define anaemia (B). Any level of anaemia should be investigated in the presence of iron deficiency (B). The lower the haemoglobin the more likely there is to be serious underlying pathology and the more urgent is the need for investigation (B). Red cell indices provide a sensitive indication of iron deficiency in the absence of chronic disease or haemoglobinopathy (A). Haemoglobin electrophoresis is recommended when microcytosis and hypochromia are present in patients of appropriate ethnic background to prevent unnecessary GI investigation (C). Serum ferritin is the most powerful test for iron deficiency (A). Upper and lower GI investigations should be considered in all postmenopausal female and all male patients where IDA has been confirmed unless there is a history of significant overt non-GI blood loss (A). All patients should be screened for coeliac disease (B). If oesophagogastroduodenoscopy (OGD) is performed as the initial GI investigation, only the presence of advanced gastric cancer or coeliac disease should deter lower GI investigation (B). In patients aged >50 or with marked anaemia or a significant family history of colorectal carcinoma, lower GI investigation should still be considered even if coeliac disease is found (B). Colonoscopy has advantages over CT colography for investigation of the lower GI tract in IDA, but either is acceptable (B). Either is preferable to barium enema, which is useful if they are not available. Further direct visualisation of the small bowel is not necessary unless there are symptoms suggestive of small bowel disease, or if the haemoglobin cannot be restored or maintained with iron therapy (B). In patients with recurrent IDA and normal OGD and colonoscopy results, Helicobacter pylori should be eradicated if present. (C). Faecal occult blood testing is of no benefit in the investigation of IDA (B). All premenopausal women with IDA should be screened for coeliac disease, but other upper and lower GI investigation should be reserved for those aged 50 years or older, those with symptoms suggesting gastrointestinal disease, and those with a strong family history of colorectal cancer (B). Upper and lower GI investigation of IDA in post-gastrectomy patients is recommended in those over 50 years of age (B). In patients with iron deficiency without anaemia, endoscopic investigation rarely detects malignancy. Such investigation should be considered in patients aged >50 after discussing the risk and potential benefit with them (C). Only postmenopausal women and men aged >50 years should have GI investigation of iron deficiency without anaemia (C). Rectal examination is seldom contributory, and, in the absence of symptoms such as rectal bleeding and tenesmus, may be postponed until colonoscopy. Urine testing for blood is important in the examination of patients with IDA (B). All patients should have iron supplementation both to correct anaemia and replenish body stores (B). Parenteral iron can be used when oral preparations are not tolerated (C). Blood transfusions should be reserved for patients with or at risk of cardiovascular instability due to the degree of their anaemia (C).
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                Author and article information

                Journal
                Gut
                Gut
                gutjnl
                gut
                Gut
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0017-5749
                1468-3288
                June 2021
                21 October 2020
                : 70
                : 6
                : 1130-1138
                Affiliations
                [1 ] departmentColorectal Surgery , Croydon University Hospital , Croydon, UK
                [2 ] departmentColorectal Surgery , Basingstoke and North Hampshire Hospital , Basingstoke, UK
                [3 ] departmentSurgery & Cancer , Imperial College London , London, UK
                [4 ] departmentResearch & Development , RM Partners , London, UK
                [5 ] departmentClinical Biochemistry , Royal Surrey County Hospital , Guildford, UK
                Author notes
                [Correspondence to ] Mr Muti Abulafi, Colorectal Surgery, Croydon University Hospital, Croydon CR7 7YE, UK; muti.abulafi@ 123456nhs.net
                Author information
                http://orcid.org/0000-0002-9614-6113
                http://orcid.org/0000-0001-7088-4292
                Article
                gutjnl-2020-321956
                10.1136/gutjnl-2020-321956
                8108285
                33087488
                63e1d093-73ef-47ed-ba11-53e8f9256747
                © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

                History
                : 24 May 2020
                : 06 August 2020
                : 09 August 2020
                Funding
                Funded by: NHS England;
                Award ID: Cancer Transformation Funding (no grant number)
                Funded by: FundRef http://dx.doi.org/10.13039/501100000272, National Institute for Health Research;
                Award ID: No grant/award number.
                Categories
                Bowel Cancer Screening
                1506
                2312
                Custom metadata
                unlocked

                Gastroenterology & Hepatology
                endoscopy,colonoscopy,colorectal cancer,stool markers,clinical decision making

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