2 N E W S & R E S E A RC H A united strategy counters COVID-19 spread Corona control in Taiwan Despite its proximity to China, Taiwan contained COVID-19 successfully, without a lockdown or move- ment restriction measures introduced elsewhere. With few new cases reported, life almost returned to normal. Behind the scenes, however, efforts have continued to maintain that positive situation. The medi- cal directors of Taipei Medical University Hospital (TMUH), a 727-bed facility in the Taiwanese capital, have explained how the coronavirus affects clinical workflows. Report: Wolfgang Behrends ‘In our hospital, COVID-19 has entire- ly upended daily routine,’ said hos- pital superintendent Dr Ray-Jade Chen. In fact, protection measures set in before you even enter the building: all visitors’ entrances – except one – are closed. Whoever wishes to enter the hospital has to undergo a multi-step control pro- cedure at the one remaining open door. Since fever is one of the major COVID-19 symptoms, body tem- perature is taken via infrared detec- tor; in addition, the so-called TOCC check collects information on travel, profession and contacts. Due to the sophisticated digital infrastructure in Taiwan’s health sys- tem, most of the necessary data is quickly scanned from the electronic patient card every citizen holds. With the exception of corona treatment, clinical procedures are reduced to a bare minimum. Elective interventions are currently not offered as distancing of patients is strictly enforced. To reduce waiting times inside the hospital, and thus the risk of hospital-acquired infec- tions, all patients are reminded of their appointments by push messag- ing on their smartphones. When in doubt, isolate The hospital aims to beat the infec- tion risk with strict prevention measures, Dr Chen explained. ‘Any patient who presents with fever or respiratory stress symptoms is con- To keep the COVID-19 pandemic in check, doctors and staff at TMUH face the challenges as an indivisible unit 6 0 3 n a m a k s e h t / k c o t s r e t t u h S © sidered a potential Covid-19 patient.’ This policy, according to the super- intendent, is key to Taiwan’s success in beating the virus. And indeed, the island has recorded very low case numbers and COVID fatality rate compared to its neighbours. As far as diagnosis is concerned, TMUH uses RT-PCR tests (reverse transcription polymerase chain reac- tion), said Dr Li-Yuan Chen, infec- tion expert at the hospital. ‘This technique offers high specificity and is thus well suited to distinguish COVID-19 infections from other pathologies with similar symptoms.’ When PCR test results are unclear, a CT scan is indicated. CT furthermore is used for follow-up. Patients with suspected infection are moved to a dedicated ward with the availability of quarantine beds being a major aspect of the anti- corona strategy, said TMUH head pulmonologist Dr Pai-Chien Chou. For additional hospital staff protec- tion, COVID-19 patients are separat- ed according to the disease severity. First line treatment is the malaria drug hydroxychloroquine, which has yielded promising results in var- ious studies due to its anti-inflam- matory properties and ability to reduce virus proliferation. In severe cases, treatment is supplemented by the HIV drug lopinavir, the mac- rolide antibiotic azithromycin und interferon beta. A strictly enforced strategy and diligence pay off To minimise infection risk, TMUH management designed an elaborate system of work areas and routes to avoid unnecessary contact: the paths of lab staff, radiologists and nurses do not cross and supplies marked for disposal or decontamination are beelined along dedicated corridors. Before staff are in contact with COVID-19 patients they undergo a minutely monitored procedure with more than a dozen steps. This dili- gence pays off. ‘To date, we have not seen a single infection among our staff,’ superintendent Chen proudly reported. ‘Should a member of our staff contract the virus despite the protection measures, we are well prepared to prevent the virus from spreading throughout the hospital,’ infection expert Dr Chen added. ‘Fortunately, the infection rate in Taiwan is very low,’ said Dr Po-Li Wei, deputy superintendent. ‘This is, to a large extent, due to our govern- ment taking containment measures very early.’ After the SARS epidemic in 2003, the Taiwanese government established the National Health Command Centre (NHCC), a central institution which has also led the efforts during the current pandemic. To avoid bottlenecks, the NHCC inter alia coordinates the produc- To ensure patient and staff safety, TMUH management implemented extensive measures for infection control * This year’s Medical Taiwan internat- ional medical, health and care expo (15-17 October) will follow a conspicuous theme – epidemic prevention – within which diagnosis, therapy and prevention of the COVID-19 will be a focus topic. tion and distribution of personal protective equipment. Digital track- ing allows quick identification and warning of contacted people before a spread of infection. In addition to diagnosis and ther- apy, the third pillar in the strategy against the virus, Dr Chen said, is information. ‘As a hospital, we carry an immense responsibility and we face the challenge as one indivisible unit. Thus, we not only train our clinical staff with regard to disin- fection best practices, donning or taking off protective equipment or handling patients. All our employ- ees, from technician to cleaning staff, receive in-depth training on protection measures.’ ‘Our employees are worried since many questions regarding the virus remain unanswered. We take these concerns seriously and ensure that all are up-to-date and feel well protected,’ he emphasised. ‘This is the only way for us to ensure that we can reliably perform our duties towards the people.’ Taiwan, he added, learnt many lessons from the SARS epidemic almost 20 years ago. ‘At this point, nobody can tell for how long this emergency situation will last,’ he pointed out. It is also important to look at other countries to gain a complete picture of devel- opments. ‘People around the globe are working hard to develop drugs or vaccines against coronavirus and COVID-19. This global sense of com- munity has triggered many research cooperation projects and a fruitful exchange of ideas across borders. We are convinced that this is the right approach. Together we will find a way out of this pandemic.’ Modernising healthcar Public acceptance of electronic health on the rise Focused on updating healthcare through digitisation, 41 experts and around 500 delegates gathered for the 4th ‘Digital Health Conference’ late in 2019. At the Berlin venue, they focused on solutions such as the potential lack of skilled staff, demo- graphic changes, urbanisation and multimorbidity. The organiser, Bitkom, the German digital association which represents more than 2,600 communications companies, had also organised a representative survey of the coun- try’s general public, with results that reflect the positive attitude towards digital offerings in healthcare across all age groups. Of the 1,005 people surveyed, 65% stated they would utilise the elec- tronic health file; 63% confirmed that they would use electronic prescrip- tions and 30% stated that they would be happy to discuss their symptoms with their family doctor during online appointments, instead of visiting the surgery. That level of acceptance is an important prerequisite for the mod- ernisation of the healthcare system. Digitisation as a political mandate In his keynote speech, Jens Spahn, Federal Minister of Health, stated that he was ‘accelerating digitisation’ to create ‘comprehensive and efficient healthcare’. It is hoped that digitisa- tion will also ‘maintain and win back the trust’ which the German public had lost over the debacle around the electronic health card, which the Federal Minister of Health referred to as the healthcare equivalent of the saga swirling around the new Berlin Airport’. Spahn also appealed to doctors to accept the need for obligatory con- nection to the telematics infrastruc- ture, which should make day-to-day communication with patients easier. Furthermore, the Minister urged for the utilisation of the innovation potential inherent in digitisation and not to limit discussions only to data protection and data sovereignty. To this extent, Spahn called for an active, balanced debate to ascertain exactly how technology can ben- efit medical staff as well as improve healthcare. Suggestions for the modernisation of the healthcare system Which solutions look particularly promising? Digitisation is a means to an end to achieve better medical care, confirmed Dr Barbara Holtz, Expert Business Consultant at Dassault Systèmes, but also queried ‘What does better look like?’ Some examples of successful digitally supported offer- ings were introduced at the confer- ence. Thomas Friese, SVP Digital Platform at Siemens Healthineers, explained the potential of clinical decision-mak- ing support systems when imaging procedures are needed for diagnoses. This is particularly important, given that a survey showed 26% of image studies in the USA do not correspond with the diagnosis because the doc- tors do not quite come to correct conclusions from the patients’ infor- mation. Holtz spoke of the development of personalised therapies, using the concept of a digital twin, and about apps for data acquisition. Using this data, the industry wants to model possible effects of, and reactions to, medication to help improve processes and exclude risks in advance. This concept is based on the automotive industry where the first five models of a production line are routinely crashed to achieve better products more quickly and to save costs. Holger Müller, Business Solutions Architect at Cisco Systems, explained EUROPEAN HOSPITAL Vol 29 Issue 2/20

4 N E W S & R E S E A RC H Catching up with COVID-19 Rapid response test kits – the race is fierce To develop and manufacture COVID-19 test kits in massive quantities was not part of their 2020 business plans. Yet, as the epidemic evolved into a global pandemic, the urgent need for diagnostic and antibody SARS-CoV-19 test kits triggered an unprecedented scramble among medical manufacturers. Report: Cynthia E Keen That urgency in most countries pre- cluded the established procedures required for regulatory approval for their use. When those developed by the U.S. Centers for Disease Control and Prevention (CDC) proved unre- liable, the USA’s FDA invoked emer- gency use authorisation (EUA) to allow the use of COVID-19 test kits. The World Health Organisation (WHO), the European Centre for Disease Prevention and Control (ECDC), and the CDC recommend use of molecular tests, the reverse transcription polymerase chain reac- tion (RT-PCR) tests, which detect the SARS-CoV-2 virus ribonucle- ic acid (RNA). These tests need well-equipped laboratories, highly skilled technologists, and multiple reagents. At best, results take about four hours to come and results can take days, if samples are sent to offsite labs. Reliable rapid diagnostic tests that are relatively simple to perform and interpret and provide results in less than an hour, are vital. The two types of COVID-19 rapid tests include direct SARS-CoV-2 antigen detec- tion and indirect antibody detection. Linda Carter PhD, an information scientist at the American Chemical Society CAS division, explains, in her article in ACS Central Science, that these assays detect viral anti- gens and are complimentary to molecular genetic assays. The serol- ogy tests detect antibodies to the virus in the bloodstream. Clinical testing and quantified benefits of rapid COVID-19 diagnostic tests On 1st April, ECDC, in a technical report, warned that even for com- pliant CE-marked rapid diagnostic tests, performance may vary in the routine testing laboratory compared with a manufacturer’s performance study done for CE-marking purpos- es. ECDC cautioned: ‘rapid tests may be less accurate and less sensitive than laboratory-performed diagnos- tic tests’ and that clinical validation of the diagnostic performance of rapid tests for COVID-19 in real life should be carried out by comparing them with standard RT-PCR labora- tory tests. Example: In the UK, in one rapid turnaround laboratory testing device, the SAMBA II, a compact, portable machine developed by Cambridge Uni spin-off Diagnostics for the Real World, after swabs with samples are loaded, the device searches for tiny traces of virus genetic code. Addenbrooke’s Hospital of the Cambridge University Hospitals NHS Foundation Trust, was the first to use the device in a clinical set- ting. The results of a clinical study of 149 symptomatic individuals showed that SAMBA II had a 96.9% sensitivity and a 99.1% specificity, compared to the standard RT-PCR lab tests. A subsequent hospital-based implementation study included an analysis of 992 tests of 913 symp- tomatic individuals over a 10-day period. Professor Ravi Gupta and researchers at the Cambridge Institute of Therapeutic Immunology and Infectious Diseases, reported in medRxiv that the tests were used mainly for emergency department patients, as well as those in the acute admission ward, presurgical patients, and the elderly being dis- charged to nursing homes. The median time to a result was 3.6 hours compared to over 21 hours for the standard lab RT-PCR test. The average time that patients had to spend in a COVID-19 ‘hold- ing ward’ before discharge or pro- gress with treatment dropped from 58.5 hours to 30 hours. Use of sin- gle-occupancy isolation rooms also Linda Carter PhD, is an information scientist at the American Chemical Society CAS division. decreased, from 30.8% to 21.2%. The research team advised that the switch by Addenbrooke’s to rapid testing kept more surgical bays open for uninfected patients and prevented 11 ward closures for these patients in the 10 days after hospital-wide implementation. Rapid result COVID-19 antibody tests Companies responded in droves to develop rapid response antibody detection tests. Roche, for example, worked 24/7 in late March and April to develop one. In early May, the company announced that its new Elecys Anti- SARS-CoV-2 antibody, approved for EUA use by the FDA and with CE-IVD marking, started shipping worldwide. Roche reports ramping up pro- duction capacity to high double- digit millions per month. The serology test has a 99.81% specificity and 100% sensitivity in detecting antibodies in blood sam- ples taken 14 days after a PCR- confirmed coronavirus infection, according to results of nearly 5,300 samples. When processed on Roche’s Cobas e analysers, results come in 18 minutes, with a test Professor Ravi Gupta is a researcher t the Cambridge Institute of Therapeutic Immunology and Infectious Diseases throughput of up to 300 tests/hour. Siemens Healthineers rapidly developed a molecular PCR Fast- Track Diagnostics SARS-CoV-2 Assay test kit to identify antibodies. This molecular test analyses nasal/throat swabs, detects antibodies believed to neutralise the COVID-19 virus, specifically targeting antibodies that attach to a spike protein on the sur- face of the virus (* CE Mark received April; FDA EUA approval, May). Rapid results take up to 10 min- utes when used with Siemens high throughput immunoassay analysers, which can deliver up to 440 tests/ hour, and in 18 minutes with other Siemens analysers that test up to 240 samples/hour. Tests conducted on over 1,850 samples demonstrat- ed a 100% sensitivity and 99.8% specificity. Siemens is ramping up produc- tion to a capacity exceeding 50 million tests per month, starting in June. Beckman Coulter expects to report the availability of its Access SARS-CoV-2 IgG serology test in June, and plans to produce 30 mil- lion tests per month. Hospitals using the company’s highest performance immunoassay analysers will pro- cess up to 200 results per analyser per hour. Abbott, Cellex, Chembio Diagnostics, and Ortho Clinical Diagnostics have also developed tests. i o d u t s _ K P P / k c o t s r e t t u h S © Potential and perils in home test kits Home testing kits for initial risk assessment of diabetes, high choles- terol, and colon cancer offer a more affordable and convenient option than on-site diagnostic laboratory testing. Inexpensive, patient-admin- istered COVID-19 testing kits to diagnose coronavirus, or identify the presence of antibodies, could significantly expand population test- ing. Need for hundreds of millions of such kits results in academic researchers and companies scram- bling to develop them. RUCDR Infinite Biologics, part of the Rutgers University Human Genetics Institute of New Jersey, developed the first saliva self-col- lection test to receive a FDA EUA. Everlywell also received an EUA for a self-collection test that utilises nasal swabs to collect a sample. With both, samples go to a lab for processing. These tests are not without risk. In early April, The Guardian report- ed that 17.5 million coronavirus antibody detection home test kits purchased by the British govern- ment had a low sensitivity and accu- racy level, according to an unnamed testing expert. The New York Times reported that the test kits pur- chased from two Chinese compa- nies, Hangishou AllTest Biotech and Wondfo Biotech, had been found ‘insufficiently accurate by an Oxford University laboratory’. The test kits are not used. Dr Carter warns that users of home COVID-19 test kits could incorrectly collect a sample, or not place a sample properly in its collec- tion medium, or return the sample late, or the manufacturer has not ensured test results will be reliable under a wide variety of conditions, or that all recipient labs can process samples accurately. Research continues to develop robust, easy to use, inexpensive tests. With her team, Marit Nilsen- Hamilton PhD, a professor of bio- chemistry, biophysics, and molecu- lar biology at Iowa State University, is aiming to develop a smartphone size viral testing platform, to iden- tify a DNA aptamer, a nucleic acid that behaves like antibodies in the immune system, which could recog- nise the viral cause of COVID-19, for diagnosis and antibody recognition. Nilsen-Hamilton told European Hospital that at least a year of research is needed. ‘Our long-term vision is to develop a small/portable point-of-care unit that can simulta- neously detect several viruses. The unit would accept a range of chips, each chip containing aptam- ers that recognise a series of viruses that present clinically with similar symptoms. With this kind of inexpensive, easy-to-use device, we hope that individuals who are infected with a virus and need isolation, can be rapidly identified, and that a future pandemic such as COVID-19 could be rapidly suppressed.’ EUROPEAN HOSPITAL Vol 29 Issue 2/20

6 H YG I E N E Is home sanitisation vital? How long can a virus survive? COVID-19: Lifespan and disinfection – the reality Surface disinfection has proved an effective method to control COVID- 19 infection, as virologists from the Ruhr University Bochum (RUB) have shown. However, an effective disin- fection strategy against Coronavirus must consider various factors, says Professor Eike Steinmann. The head of the Department of Molecular and Medical Virology at the RUB explained when disinfection is an effective procedure against SARS- CoV-2, which agents are suitable to inactivate the virus and why private individuals should not reach for the ‘strong stuff’ without good reason. Whether or not a disinfectant is effective against a certain type of virus depends, among other rea- sons, on the structure of the virus, Steinmann explains: ‘Coronavirus is covered by a lipid membrane which stores proteins. This makes it susceptible to alcohol-based dis- infectants because they destroy the membrane and inactivate the virus.’ If this membrane is missing, as, for instance, is the case with norovirus, other agents need to be used for disinfection. The use of UV radiation has proved effective against such non- enveloped types of virus because it attacks the nucleic acids (RNA) of the virus. In concrete terms, this means that agents classed as hav- ing a limited virucidal effect are perfectly adequate for the inactiva- tion of Coronavirus SARS-CoV-2. However, as more resistant agents, such as the aforementioned noro- virus, are also present in a clinical environment, the use of more potent agents (classed as ‘virucidal’ or ‘lim- ited virucidal plus’) may also be of benefit. Effective disinfection should be carried out on all surfaces which have potential contact with the virus: work surfaces and surfaces close to patients, beds, and medi- cal equipment. Current studies on SARS-CoV-2 confirm the presence of the virus – or at least its RNA – in many locations in a room where an infected patient had been accom- modated: the edges of the bed, light switches, door handles, but also toilet seats, remote controls and pillows. ‘This shows that the virus is spread almost everywhere in the room via contact with hands as well as through the smallest droplets,’ Steinmann says. ‘However, thorough cleaning and disinfection can reli- ably deactivate the virus.’ Laboratory lifespan of SARS- CoV-2 gives indications One of the central issues which researchers worldwide are examin- ing concerns the lifespan of the new coronavirus on surfaces. Whilst initial calculations are mainly based on experience with the related virus types SARS-CoV and MERS- CoV, newer studies provide reli- able figures on COVID-19 pathogen v a d i r a M / k c o t s r e t t u h S © SARS-CoV-2: ‘One study, published in the New England Journal of Medicine, is of particular interest,’ says Steinmann. ‘US researchers examined for how long the virus survived on different materials, including copper, carton, steel and plastic surfaces. The results showed that in some cases, the virus is still present and active after several days. Everyday items such as banknotes, handkerchiefs and masks were test- ed in another study published in the Lancet Microbe: ‘The virus was still present on the inside of masks after 7 days,’ says the virologist and adds: ‘Although these measurements were taken under laboratory conditions, they give us a pretty good idea of how long the virus can remain sta- ble in everyday conditions.’ What role does temperature play? Currently, researchers at the RUB under Junior Professor Dr Stephanie Pfänder are examining the effect of changes in room temperature on the lifespan of the virus. Scientists compared the surface stability of the virus at room temperatures of 4°C and 30°C. They found that the virus remains infectious on surfaces for roughly the same length of time in both hot and cold conditions. ‘The assumption had been that higher temperatures would lead to a lower transmission rate of SARS-CoV-2 in summer,’ says Pfänder.’ However, it appears that the stability of the virus on surfaces is not impacted by changes in temperature.’ A poten- tially lower rate of infection in sum- mer could be due to other factors such as UV radiation and humidity though, says the virologist. Less is more in private households Professor Eike Steinmann has been head of the Department of Molecular & Medical Virology at the Ruhr University Bochum since 2018. After completing his degree in biology at Hanover University and Northeastern University, Boston, USA, he completed his doctorate at the Institute of Molecular Virology at Heidelberg University. Steinmann then became a research associate and junior group lead- er in the Department of Experimental Virology at TWINCORE - the Centre for Experimental and Clinical Infection Research in Hanover. In 2012, he wrote his habilitation in Experimental Virology at Hanover Medical School, and from 2014 he managed the working group on ‘Virus Transmission’ at TWINCORE. In 2016, he was appointed ’Adjunct Professor’ at Hanover Medical School. Steinmann emphasises that there should be different criteria for pri- vate households as opposed to hos- pitals: ‘In everyday life, normal hand washing – combined with social distancing and following the correct etiquette when coughing – is usually completely sufficient. Disinfection is only required once there has actually been contact with an infect- ed person.’ Steinmann explains, in terms of the explosive demand for disinfectants amongst private indi- viduals as follows: ‘In many cases, this will have been impacted by a psychological effect: If you have a disinfectant at home, it makes you feel safe just in case. The actual use is then not actually that important.’ If private households reach for the ‘strong stuff’, i.e. a disinfectant – they may not be doing themselves a favour, warns the expert: ‘These agents are aggressive and can attack the skin if used regularly.’ Without comprehensive care, this can easily result in skin injuries. (WB) Confirmed: Steam sterilisation is gold standard Study puts cleansing meth A new study from the USA highlights how low temperature sterilisation can jeopardise effective cleans- ing of medical tools and lead to transmission of dangerous bacteria to patients. Steam sterilisation was shown to be the most effective and robust sterilisation technology. Dr Bill Rutala is the Director and co- founder of the Statewide Program for Infection Control and Epidemiology and a Professor for the Division of Infectious Diseases at the University of North Carolina’s School of Medicine. He directed the Hospital Epidemiology, Occupational Health and Safety Program at the University of North Carolina Hospitals for 38 years, retiring in 2017. Also a retired Colonel with the US Army Reserve, and certified in infection con- trol, Rutala is a member of various com- mittees on the local, state, national and international level, plus professional societies that include the American Society for Microbiology, Association for Professionals in Infection Control and Epidemiology and the Society of Healthcare Epidemiology of America. Report: Mark Nicholls However, the researchers, working at the University of North Carolina, also showed that vaporised hydro- gen peroxide (VHP) failed to com- pletely sterilise surgical tools 76% of the time. Led by Dr Bill Rutala, Director and co-founder of the Statewide Program for Infection Control and Epidemiology, the team simulated the impact of proteins and salts left on surgical tools prior to steri- lisation to test the effectiveness of three low-temperature technologies, increasingly required for plastic tools, compared to steam sterilisa- tion. cal instruments are equal,’ Rutala pointed out. ‘While sterilisation technology is intended to kill a very large number of microorganisms on instruments, healthcare person- nel can unintentionally impede the effectiveness of sterilisation technol- ogy by improper cleaning of the instruments prior to sterilisation.’ Cleaning, or the removal of vis- ible soil and microbial contaminants from objects, must precede sterilisa- tion: ‘If instruments are not properly cleaned prior to sterilisation and then placed in a low-temperature sterilisation technology such as VHP, there is a possibility of failure,’ Rutala added. ‘Not all sterilisation technologies used in healthcare to sterilise surgi- He stressed, however, that the technology, such robustness of as steam sterilisation, makes it extremely unlikely that a sterilised instrument will be the source of infection and that most medical and surgical devices used in healthcare facilities are made of heat stable materials and thus are sterilised by heat, primarily steam sterilisation. Comparison of the microbiocidal activity of FDA-cleared technologies In their experiments to compare the microbicidal activity of FDA-cleared, low-temperature sterilisation tech- nologies to steam sterilisation in the presence of salt and serum – simu- lating inadequate cleaning of instru- ments prior to sterilisation – the equipment was then sterilised with VHP, ethylene oxide (EO), hydrogen peroxide gas plasma (HPGP), or steam. ‘This study evaluates the “robust- ness” of sterilisation technology that is used by hospitals throughout the United States,’ Rutala poinred out. ‘Robustness is defined as the ability to withstand and overcome adverse conditions or rigorous testing.’ He emphasised that the inten- tion was not to compare the fac- tors that affect sterilisation, such as temperature, duration of cycle, concentration of gas/vapour, but to simply determine whether FDA- cleared sterilisation technologies have the same robustness or “mar- gin of safety”. ‘Using the methodology defined, we found some sterilisation tech- nologies were more robust than others,’ he added. Steam, EO and HPGP sterilisation techniques were capable of inacti- vating the test organisms on stain- EUROPEAN HOSPITAL Vol 29 Issue 2/20

8 L A B O R AT O RY Economic aspects and COVID-19 Increased lab quality – because of, or despite automation? The academic teaching Karlsruhe Hospital, at the University of Freiburg, is the largest hospital providing tertiary care in the Middle Upper Rhine Valley. Every year, 63,000 in-patients and 180,000 out-patients are treated in the 1,500-bed facility with 50 departments and 30 out-patient clinics. Inevitably, a hospital of this size has a central lab. EH correspondent Walter Depner spoke with Dr Horst Mayer, managing sen- ior physician of the Department of Clinical Diagnostics, about the lab and particularly automation, intro- duced there over recent years. The effects on the lab of COVID-19 were also explored. Currently, the hospital has 38 full- time employees and 12 full-time support staff – mainly students. The trauma and emergency department admits about 35,000 adult patients per annum. ‘Each day, we process on average 4,000 samples, of which approximately 1,500 are serum, 500 are coagulation and 800 are blood tests,’ explained Mayer, speaking of the lab’s involvement. ‘The remainder is made up of all other materials. In toto, this amounts to 16,000 analyses per day. Peak times are between 7-9 am. In that window, we receive 800 samples; the rest is spread more or less evenly over the day.’ EH: A hospital lab usually pro- cesses more pathology samples than non-hospital labs. Is this the case in Karlsruhe? Mayer: ‘Indeed. Here about 30 per- cent of the individual samples are pathology samples; in a non-hospital lab group this would be about five percent.’ Over recent years, hospital length of stay has been shrinking, while patient throughput has increased significantly, thus also increasing the number of samples arriving in the lab and thus encouraging lab automation. Does that mean there is less time for analytics? ‘Definitely. We started automation more than ten years ago with a Siemens Flexlab. This automated lab system generated major benefits, because it could be operated even with a very small team. It ran 24/7 and made a marked improvement because length of stay decreased and throughput increased. The new lab system, which has been installed since, offers even shorter turn- around times as well as significant quality improvements. In fact, at this point we are not running to capacity.’ Not all areas present themselves for the same degree of automa- tion; take mass spectrometry, special microtiter serology or pathology. What is the situation in Karlsruhe? Where did you start automation and where could the most significant effects be real- ised? ‘Obviously, there are limits to what is feasible. In terms of technology we could link a Sciex 5600 mass spec- trometer to the lab system. However, I don’t consider this particularly useful at this point. Assays, which are currently performed as ELISA on MT, that is microtiter plate basis, but which can be done in an immunoas- say analyser linked to the system, are all transferred.’ If you rank clinical disciplines by degree of automation, where would you place clinical chemis- try? ‘Indeed we do old-school clinical chemistry, around the clock – tumour markers, hormones and infection serology. Currently, I still consider conventional clinical chemistry rel- evant. Going forward, however, I u y o a i x / k c o t s r e t t u h S © think this will change over the next 10 to 15 years. Current resource- intensive methods will be replaced by molecular biology analyses, in particular their miniaturisation will be influential. In a nutshell: tradi- tional clinical chemistry in its current form will have become obsolete.’ How did your staff structure change over recent years due to automation? Did you have to or were you able to switch staff? Did you ease the burden in labour- Rapidly meeting a surging demand The science behind 3-D printed nasal swabs design team tested the prototypes on themselves to identify the most com- fortable designs. the performance of the 3-D-printed swab with a traditional one. The 3-D printed swab performed as hoped, but to make sure, the clinical trial expanded to include 35 hospitals nationwide. Report: Cynthia E. Keen A nasal swab may seem rudimentary, but is essential for testing COVID-19 diagnostic test kits and components – nasal swabs, collection vials, and chemical reagents – have been in short supply worldwide, especially in March. Ironically, nasopharyngeal swabs are predominantly manufac- tured in northern Italy and China, two countries first impacted by coro- navirus. Concerned by diminishing supplies and near impossibility to restock, the dean of the University South Florida (USF) Morsani College of Medicine, wondered if the radiology department’s 3-D Clinical Application Division could produce swabs. 3-D Clinical Applications director and imaging scientist Summer Decker PhD, with Jonathan Ford PhD, bio- medical engineer and fellow medical printing expert model, create vir- tual analyses for simulations of injury mechanics and blood flow, for exam- ple, as well as 3-D prints of anatomi- cal models of organs and regions of the body. In two decades of research they produced trailblazing work and numerous publications. Worldwide, their lab, located at USF Health and Tampa General Hospital, is one in about two dozen renowned for this expertise. Immediately investigating the idea, they started to develop nasopharyn- geal swab prototypes that would use materials cleared by the USA’s FDA as patient-safe. They received one representative standard-of-care naso- pharyngeal swab to examine before creating a new design for a 3-D printer. ‘On the surface, creating a naso- pharyngeal swab doesn’t seem that complicated a design,’ Decker observed. ‘But it’s more complicated than it looks. We knew we couldn’t replicate components of the tradi- tional swab, such as the flocking on the tip which collects the sample. We needed a device that could be printed as one unit, collect a suffi- cient mucosal and epithelial sample for viral testing, and be safe and comfortable during the collection pro- cess. Additionally, the material could not interfere with the actual testing machines.’ Decker and Ford sought ideas and advice from colleagues. They also invited 3-D medical printing expert Todd Goldstein PhD, director of Northwell Health and 3-D Design and Innovation Center, in Manhasset, NY. The final design team included the 3-D medical printing experts, infec- tious disease physicians, otolaryngol- ogists, a virologist, and a pulmonary radiologist who suggested rounded ‘nubs’ on the tip of the swab to max- imise surface area to collect a sample. Ultimately, 12 designs were inves- tigated and prototypes printed. The prototypes were given to the design team physicians for feedback and consensus. Hospital residents and the The final design was a standard- length swab with a tip that has a smooth cap on the top to protect the tissue as it goes through the nasal passage. Nubs or ridges in a stag- gered pattern around the sides collect the sample as it goes into the nose. An expert virologist performed robust bench lab testing to verify that the swab design would grab enough sample and met viral load detec- tion requirements. The length of time the swab could hold a sample was measured. The swab also underwent rigorous compatibility testing for the collection media and the virus testing machines. The team contacted Formlabs, a digital fabrication company and licensed medical device manufacturer based in Somerville, MA, which man- ufactures professional 3-D printers. The company worked with USF to optimise the design and production of the prototype swabs. ‘Swab sticks have an intention- ally weak point 7-8 cm from the tip, which allows the stick to be broken to the correct length so that the vial can be capped before transportation to a laboratory for testing,’ explained Stephan Hollaender, Formlabs’ man- aging director EMEA. ‘The most dif- ficult part of designing these swabs to be 3-D printed was ensuring the material was strong enough to be used in a patient’s nose without fear of it breaking, and weak enough that it can be easily snapped and put in a vail.’ USF and Northwell rapidly con- ducted a 120-person trial comparing Goldstein’s team is conducting the 3-D printing work for all of Northwell Health, which is a 23-hospital health- care provider in New York state, the epicentre of the crisis in the USA. ‘We have eight Formlabs’ 3-D print- ers with the capacity to print about 4,000 swabs a day. By the end of May, the lab had printed over 90,000 swabs which were distributed among Northwell Health hospitals and out- patient facilities,’ Goldstein said. ‘In our efforts to bring nasopharyn- geal swabs into production in record time, we helped supply the Northwell Health system with a critical diagnos- tic tool needed to combat this disease. In a time of crisis, it is ingenuity and innovation that helped keep everyone motivated to help our community as best we can.’ Formlabs is manufacturing the nasophangeal swabs in its 200 3-D printer manufacturing facility in Ohio, and has the capacity to produce up to 100,000 swabs a day when printing capabilities are fully ramped up. ‘We are pricing the swabs to cover their production cost and the investment we made to ramp up production,’ Hollaender explained. ‘We do not intend to produce these swabs long term.’ The USF 3-D Imaging Lab holds a provision patent for the swab with Northwell Health. USF made a deci- sion to share the files with any hospital that has a Formlabs printer through April 2021, Decker explained. EUROPEAN HOSPITAL Vol 29 Issue 2/20 Medical device approved 3-D printers are producing clinically safe and effective nasopharynge- al swabs for COVID-19 testing. Jonathan Ford PhD, is a biomedical engineer and fellow medical printing expert model Summer Decker, PhD, is a 3-D Clinical Applications director and imaging scientist

1 0 M E D I C I N E Abbott: Creating Life Changing Technology An increasingly dynamic cardiovascular presence In the world of laboratory diagnostics, ‘Abbott’ is a household name. Few people however are aware of the fact that the company, headquartered in Illinois, USA, is also leading in other fields. A number of innovations in cardiac and vascular diagnostics and therapy might soon put Abbott in the limelight. Dr Angela Germer, Regional Director DACH, and Volker Keller, Head of Marketing DACH, Vascular at Abbott, updated Daniela Zimmermann on the company’s most recent developments and the plans for the future. Abbott’s German cardiovascular busi- ness area operates from Wetzlar and Eschborn, in the Frankfurt/Main region, with Vascular und Structural Heart managed in Wetzlar. Whilst the Structural Heart team focuses on the treatment of structural heart disease (SDH), the Vascular team’s exper- tise lies in diagnosis and treatment of vascular conditions with systems to assess vascular physiology, guide wires, and drug-eluting, as well as non-drug eluting, balloons and stents. OCT and FFR to avoid unnecessary stents Today, some patients receive stents without proven ischaemia, on suspi- cion so to speak. Usually, two tech- niques are used to assess ischaemia: either fractional flow reserve (FFR) or resting full-cycle ratio (RFR). A spe- cially designed pressure wire looks for drops in pressure caused by a stenosis. If the pressure drops signifi- cantly, the oxygen supply to the heart is impeded, says Dr. Angela Germer. firstly, Abbott uses a two-pronged approach to ensure that stents are implanted when and where clini- cally needed and to improve patient outcomes: the guidewire PressureWire™ X uses wireless data transmission, thus facilitating ischae- mia assessment by FFR; secondly, the Abbott-developed imaging solution OCT (optical coherence tomography) which allows precise measurement of vessels. ‘With this approach, we aim to optimise percutaneous coro- nary interventions, PCI for short, and to increase the likelihood that the right stent is placed at the right location,’ Dr Angela Germer explains. OCT delivers high-resolution colour images to monitor vessels prior to the intervention as well as in the follow- up when the stent is checked for correct placement and functionality. Abbott supports physician training From left: Volker Keller, Head of Marketing for DACH, Vascular at Abbott, Dr Angela Germer, Regional Director DACH and Astrid Tinnemans, who heads Public Affairs in Germany, updated Daniela Zimmermann on the company’s most recent developments and its plans for the future. with modern technologies, such as virtual reality (VR). In cooperation with several hospitals, the company recorded catheter-based procedures, such as FFR und OCT, and turned them into 3-D simulations to be used with VR headsets. ‘Thus, inter- ventions can be practised virtually, which increases patient safety during the actual procedure,’ Volker Keller points out. Abbott and the interna- tional cardiologist working group (AGIK) jointly organise workshops at trade fairs and congresses, and in hospitals, to provide in-depth training for clinical staff. The pressure wire is also used to diagnose microvascular heart disease which, in Germany alone, affects 175,000 people, Dr. Germer says: ‘This condition is rather frequent among cardiac patients, but difficult to diagnose. Many patients present OCT delivers high-resolution images of vessels several times without the cardiologist being able to detect the root cause. Our PressureWire X, combined with a dedicated software solution, can help detect minute deposits in the vessels and thus identify the disease.’ The highly specialised Abbott stent portfolio covers the many require- ments the tiny support structures have to fulfil in the different anato- mies. Stents for the femoral artery, for example, must be able to with- stand enormous biomechanical forc- es, such as torsion. ‘The nitinol wires in our Supera stent are not lasered but woven,’ Germer explains. ‘This unique technology makes Supera much sturdier than conventional stents, whilst maintaining its flexibility.’ Closure system accelerates patient mobility Perclose ProGlide, the tried and test- ed closure system that deploys suture after endovascular procedures with a femoral puncture larger than 5F without the use of collagen, is now also indicated for the femoral vein. ‘A suture is placed right at the ves- sel wall and the edges are joined again initiating primary healing. The closure can be tested right after the intervention. Unlike conventional sutures, Perclose ProGlide allows the patient to get up and move around quickly,’ explains Dr. Germer. Thus, hospital length of stay is reduced and accompanying procedures, such as a bladder catheter, can be avoided. Another advantage: If re-access is necessary, which is, in fact, the case with several conditions, the very same site can be used, even right after the initial procedure. Today, patients benefit hugely from implantable cardiac support systems, such as LVAD (left ventricular assist device). Abbott is currently devel- oping the next-generation of such When classic ventilation therapy fails in COVID-19 cases a device: FILVAS, fully implantable left ventricular assist system. It has no external components, such as battery packs or charging ports, which patients have to carry 24/7. FILVAS was recently designated a Breakthrough Device by the USA’s FDA. ‘Obviously, the new implant has to be charged regularly as well,’ Keller explains, ‘but FILVAS does this by induction via an implanted coil.’ Since energy sup- ply does not require opening the abdomen, patients can bathe, swim, enjoy the sauna – these are activi- ties that are almost, or even entirely, impossible with LVAD. Not to men- tion the fact that in conventional systems the external energy supply opening is a potential door for infec- tions to enter the body. AI algorithm calculates infarction risk Abbott not only uses diagnostic and treatment devices to improve cardiac patient care but also designs solu- tions based on artificial intelligence (AI). A recently developed AI-based algorithm to assess infarction risk is about to be used in clinical settings. The Abbott R&D team benefited from the in-house lab medical expertise: ‘Our algorithm correlates troponin values with other patient data, such as age, gender or prior disease,’ Keller points out. ‘This allows a detailed assessment of individual infarction risk.’ Prior to the commercial launch of the algorithm, clinical tests need to be concluded but, so far, the studies have yielded very promising results [Circulation: https://doi.org/10.1161/ CIRCULATIONAHA.119.041980]. With these ambitious projects in the wings, Abbott is well positioned to expand its reputation beyond the lab and have a strong impact in car- diovascular medicine. Extracorporeal therapy use rises ‘As the coronavirus spreads and infec- tions with COVID-19 further increase throughout Europe, Extracorporeal Membrane Oxygenation (ECMO) therapy turns out to be a neces- sary option for patients with severe courses,’ Xenios AG reports. The company’s ECMO consoles can pro- vide support in cases of severe pneumonia and ARDS with lung failure. ‘However,’ the company points out, ‘in contrast to the venti- lation methods usually used in these cases, the extracorporeal method is usually only used if the classic venti- lation therapy is not effective or not effective enough. ‘For critically ill COVID-19 patients with acute lung failure and refrac- tory hypoxemia, despite use of all standard therapy related measures, our treatment often remains the last therapeutic option and, in the best case, is a lifesaver for these patients,’ adds Dr Jürgen Böhm, Chief Medical Officer of Xenios. Bypassing lung function, the sys- tem clears the patient’s blood of carbon dioxide outside the body and enriches it with oxygen, giving lungs time to heal. ‘Because of the increase of critically ill COVID-19 patients, more physicians will opt for ECMO therapy.’ The company reports significantly higher demand for the devices and patient kits and has increased production of ECMO consoles. The devices are already in use in many COVID-19 hot spots such as in Italy, Spain and France, and beyond Europe. China’s most affected region Wuhan received a delivery of ECMO consoles and patient kits in February. ‘Our biggest challenge now is availability of specific components for our products,’ said Dr Andreas Terpin, Chief Executive Manager of Xenios, who also underlined the need to meet various standards, for example, the CE mark and FDA clearance (approved by the USA’s FDA through Fresenius Medical Care North America earlier in 2020). The system is available in more than 50 markets worldwide. Training intensity has been ramped up to ensure safety and straightforward use of the devices and is provided internationally via video transmission. EUROPEAN HOSPITAL Vol 29 Issue 2/20

1 2 R A D I O LO G Y SPECIAL REPORT: The long-term impact of COVID-19 On the rise: Internal and external radiology The coronavirus pandemic – an international tragedy – created unprecedented upheaval and challenges within health systems, economies, and society. In hospitals, new ways of working had to evolve. Social distancing led to virtual consultations and teleradiology has found an added dimension, with its success, practicality, and effectiveness likely to see more widespread future use. Mark Nicholls asked three radi- ologists about the relevance of teleradiology during the epidemic, and what the future holds. Evidence collected during the SARS- CoV-2 pandemic by a team from the University of Tennessee, USA, clear- ly showed changing patterns in the use of teleradiology. Dr Mohammed Quraishi, Assistant Professor of Radiology, Section Chief of Body Imaging and Informatics Director at the University of Tennessee Medical Center, believes the term “teleradiol- ogy” needs disambiguation. ‘Often it brings to mind a radiologist far removed geographically, perhaps in a different country, reading for multiple hospitals with limited rap- port with any specific hospital,’ he said. ‘I would term this “external teleradiology”, because the radiolo- gist is external to the local group. It’s important to differentiate this from “internal teleradiology” where a radiologist, employed by the prac- tice, reads remotely.’ In the USA, practices during the pandemic increased internal telera- diology, and significantly decreased external teleradiology. ‘The reason seems two-fold,’ Quraishi surmised. ‘First, removing radiologists from the hospital makes sense when try- ing to mitigate the risk of contract- ing SARS-CoV-2 and, second, the increase in internal teleradiology – as opposed to external teleradiol- ogy – was almost certainly due to the drastic decrease in case volume.’ Whilst, traditionally, internal and external teleradiology have been used for on-call and overnight shifts for emergency radiology cases, day- time shifts during the pandemic were transferred to internal telera- diology – bringing off-site reading into the daily fold to help decrease radiologist exposure to potential SARS-CoV-2 infection, and allowing radiologists to work at home. The increased use of internal tel- eradiology was seen throughout the USA – particularly in the northeast, where the pandemic had preva- lence. To gauge changing teleradiology use, the group queried 290 loca- tions, representing a geographically diverse cross section of institutions. They found an overall jump in the proportion of sites installing home workstations (65.2%) and switching normal daytime shifts to internal tel- eradiology (73.6%). Around 56% of respondents said they saw enough benefit from the experience that they plan to continue similar work- flows post-COVID. 64.8% Specifically, reported decreased stress levels, and 96% found improved or no change in turnaround times, a position Quraishi echoed from his personal experience. ‘I found internal tel- eradiology less stressful, with an overall increase in productivity,’ he said. ‘Radiologists also reported less interruptions at home allowing them to focus on interpreting studies.’ He believes the pandemic will see a change of emphasis in the use of teleradiology, with practices re- evaluating teleradiology with new business models, services and work- flows, such as second opinion reads or even practices sending out stud- ies for subspecialty interpretations. Teleradiology to fight burnout problems Given increased evidence of radiolo- gist burnout and demands for bet- ter work/life balance, teleradiology might offer a solution. ‘According to our survey, the majority of groups plan to incorporate internal teleradi- ology into the post-pandemic work- flow. I predict internal teleradiology will rise across the country and, as groups get comfortable with that, there will likely be spill over into No compression. No superimposition. JUST GREAT IMAGING Visit us @ECR Virtual or www.ab-ct.com external teleradiology.’ Former NHS consultant Dr Stephen Davies, now Medical Director of the Medica Group, a business providing teleradiology services to the NHS, said: ‘Working from home using teleradiology has allowed radiology teams to work “in hospital” and out of hospital on rotation and increase opportunity for social distancing.’ Medica has facilitated “pass through” home reporting for radi- ologists to undertake their NHS ses- sional work using Medica’s existing image transmission and reporting. ‘The culture shift towards using technology to enable high-quality home working has risen during the COVID-19 crisis,’ he pointed out. Teleradiology has been used across the scope of diagnostic imag- ing, from emergency reporting – stroke and COVID chest X-rays – to elective imaging, and geographically this has been ‘without boundaries and is widespread’. Foreseeing a long-term growth ‘Teleradiology has been on a long- term growth trajectory and this will continue,’ Davies predicted. ‘COVID has increased the understanding of working from home. Teleradiology providers deliver a scalable, flexible quality assured reporting service which can respond to geography, reporting demand, time constraints and subspecialty constraints.’ He believes post-crisis teleradiolo- gy will become a bigger part of daily work routine with radiology servic- es finding a new balance between “in house” face-to-face radiology and protected and uninterrupted tel- eradiology home working. However, Davies has noted a downturn in vol- umes for all teleradiology services during the crisis, primarily due to a fall in elective work and emergency cases during lockdown, although, as restrictions ease, elective imaging services are increasing. Yet over the last decade, Dr Davies said teleradiology has been growing and is part of service provision for more than 90% of the NHS, with the delivery technology becoming ever-more sophisticated. That now sees the Medica Group offering a round-the-clock service across 90 UK hospitals. ‘The more experienced users of teleradiology have integrated the provision into their service in a seamless fashion. I expect this trend to continue and increase,’ he added. Key lessons have been learned in teleradiology use during the epi- demic, primarily from the NHS, rather than teleradiology companies – particularly ‘successful teleradiol- ogy replicating NHS office radiology requires more than simple deploy- ment of a workstation over simple domestic broadband. ‘Teleradiology,’ he predicts, ‘will continue to become more sophis- ticated with increasingly advanced operational delivery and image review, both supported by artifi- cial intelligence. Its penetration will increase into the provision of radiol- ogy reporting both emergency and elective work and will also use its platform and operational expertise to deliver emerging digital telepa- thology.’ With the Basel area a COVID- 19 hotspot in Switzerland, the Department of Radiology at the University Hospital Basel provided support via its teleradiology capa- bility. As cases rose in March, the unit – which delivers regular teleradiol- ogy services to local and regional hospitals at night and weekends – introduced a structured CT report- ing template for COVID-19 cases that included quantification of lung opacifications. ‘Around the peak of new infections in Switzerland at the end of March,’ said Dr Thomas Weikert, resident at the department, ‘we saw increasing numbers of CTs performed with the question of COVID-19 associated pulmonary infiltrates rising by +17% a day. ‘If that continued, we would have been in serious trouble very quickly. Luckily, the curve flattened during April as rigid public health meas- ures taken by the Swiss authorities brought the number of new infec- tions down. We were also develop- ing automated quantification pipe- lines to prepare for the situation where it was not possible to con- duct all the analyses manually.’ For COVID cases, lung segmenta- tion was conducted and via density thresholding, the percentage of lung tissue affected by infiltrates was established. ‘This is very useful for clinicians especially when it comes to follow-up. It is about quantifying COVID-related changes.’ The unit (which also runs an inter- national expert teleradiology read- ing program to provide structured reporting on Idiopathic Pulmonary Fibrosis (IPF) cases, which allows hospitals in Central Eastern Europe and Asia to send high-resolution chest CTs of suspected IPF to the university hospital), has continued to provide structured COVID-19 reports to local/regional partner hospitals via teleradiology. The value of teleradiology during the pandemic has been apparent and the Basel department moni- tored its growth during this period Dr Mohammed I Quraishi is Assistant Professor of Radiology, Section Chief of Body Imaging and Informatics Director at the University of Tennessee. He research- es data analytics and medicine, working towards ultimately improving patient care through advancing healthcare effi- ciency, diagnostic accuracy, cost-savings, and mitigation of physician burn-out. Dr Stephen Davies is Medical Director of the Medica Group and Fulltime Executive Director. A former NHS radiolo- gist, with more than 25 years’ experience as a consultant radiologist within the NHS, he is also a Past President of the British Institute of Radiology. Dr Thomas Weikert is a resident in the Department of Radiology at University Hospital Basel, Switzerland, where he researches translation of digital solutions in medicine and is involved in an evalua- tion of the IPF teleradiology program. with an internal RIS/PACS crawling tool, allowing them to identify all exams with COVID-19 related clini- cal questions. in ‘Teleradiology for COVID-19 cases can prove beneficial in three respects. First,’ Weikert continued, ‘by promoting structured report- ing, including quantification of pul- monary changes; second, should regional hotspots arise the future, overwhelming capacities of the regional health service provid- ers, teleradiology could share the diagnostic workload with radiology departments in less affected areas; third, by automatically analysing cases from many regions, it could be part of a regional outbreak early warning system. If many exams are diagnosed with COVID-19-suspected pulmonary changes, a warning sig- nal could be sent to the authorities. ‘I think, in a broader way, tel- emedicine, which includes teleradi- ology and provision of services of other specialties, will get a profound boost by this, because there are many people who used telemedi- cine for the first time and I think they will continue to use that.’ Consequently, Weikert expects the role of telemedicine and teleradiol- ogy to rise independently of the current public health crisis. EUROPEAN HOSPITAL Vol 29 Issue 2/20

1 4 R A D I O LO G Y Epidemic: POCUS hailed as the initial screening tool Ultrasound confirms frontline value Ultrasound could become the prime modality in emergency set- tings for tracking disease progression in Covid-19 patients, Mark Nicholls reports. sound fellowship director for the Department of Emergency Medicine and the Director of Point-of-Care Ultrasound Education for Yale School of Medicine, said the key seasons ultrasound has emerged as a first liner in emergency settings to diagnose Covid-19 is largely due to avoidance of exposure and trans- mission of virus particles; disinfec- tion; and preservation of PPE. ‘Emergency personnel are often the first to see, examine, and talk to a patient,’ she said. ‘As we need to see the patient anyway, it makes sense if we perform as complete an evaluation as possible to avoid others needing to come into con- tact with that patient. This includes obtaining swabs, lab work and imaging. If the emergency provider can perform diagnostic imaging at the same time as evaluating the patient, then this prevents others – transporters, cardiologists, radiolo- gists and technicians – from needing to come into close contact with the patient.’ Cleaning and disinfection A second critical area is cleaning and disinfection, particularly where CT suites are fixed spaces that would be shared by COVID and non-COVID patients. ‘Many hospitals do not have enough machines, or the infrastruc- ture to create cohorted radiology spaces. So, a CT performed on a Covid-positive patient would shut down that machine for up to an hour, so that it, and the surrounding Depicting fluid in the interstitial space that surrounds alveoli with severity causing confluent B lines We need a global view of Covid-19 influenza A virus, in which radiolo- gists see T2/FLAIR hyper intensity within bilateral thalami and temporal lobes, evidence of haemorrhage and enhancing lesions on post-gadolini- um sequences. Cytokine storms – ‘Acute haemor- rhagic necrotising encephalopathy has therefore been related to intra- cranial cytokine storms. This is inter- esting because cytokine storm syn- Continued from page 13 drome has been recently reported in COVID-19 patients and may play a role in the development of those types of encephalopathy,’ Edjlali- Goujon noted. Another example of the polymor- phism of the different secondary diseases related to COVID-19 is the aspect of the cytotoxic lesion of the corpus callosum (CLOCC) in a COVID-19-positive patient. There is a presence of an ovoid region of Patient with Covid-19 pneumonia: CT shows left lower lobe pulmonary emboli. Dependent dense opacification and anterior ground glass opacities are present in keeping with ARDS. Note also serpiginous dilated peripheral vessels that are frequently seen in patients with severe disease While chest CT has held a key diag- nostic role thus far, many experts now advocate the benefits of ultra- sound within the context of the coronavirus epidemic. Dr Rachel Liu, who recently led a high-profile panel discussion with experts from the USA and areas of Europe with high incidence of COVID-19, dis- cussed the advantages offered by ultrasound, and particularly point- of-care ultrasound (POCUS). Liu believes the role of POCUS and traditional ultrasound has changed with the length of the pan- demic, and will continue to evolve. ‘In the early stages of the crisis, lung ultrasound was used diagnostically in conjunction with COVID swab testing, because swab testing could be unreliable,’ she explained. ‘It may have also been used to aid physi- cians in selecting the patients most eligible for swab testing.’ However, as the pandemic evolved, and with better testing available, the value of ultrasound as a portable, flexible and time- efficient modality increased, with its value becoming more apparent in categorising mild, moderate or severe disease, discharge decision- making, and baseline monitoring of cardiac function and lung involve- ment for patients admitted to the hospital, for example. Liu, who is the emergency ultra- increased rates of ischaemic stroke, myocardial infarction, and aortic and cardiac thrombus, Devaraj explained. complications – Neurological COVID-19 can also be responsi- ble for neurological complications, according to Myriam Edjlali-Goujon, a neuroradiologist at Hôpital Raymond-Poincaré, Paris-Saclay University. ‘There are two physio- pathological mechanisms suggest- ed to explain these complications. The first is using the spread from mechanoreceptors in the lung via a synapse-connected route to the med- ullary cardiorespiratory centre; the second is entering the brain primar- ily via the olfactory bulb,’ she said. This second hypothesis has been validated on other types of SARS- CoV virus and was published more than ten years ago. The hypothesis is sustained by clinical symptoms, such as anosmia, which is present in more than 80% of patients with mild-to-moderate forms of COVID- 19. ‘Anosmia is becoming a very spe- cific symptom of COVID-19, espe- cially when reported without nasal obstruction or rhinorrhea. It is also sustained by imaging publications showing abnormal T2 signals of olfactory bulbs,’ she explained. One of the first articles on brain lesions, from March 2020, described acute haemorrhagic necrotising encephalopathy, a well-known post- viral complication, especially of the space, can be cleaned. Contrast that with a portable ultrasound machine which can be cleaned and disin- fected in a matter of minutes, with a dwell time of only 2-3 minutes between cleaning and use on the next patient. ‘Often, and particularly if a site also uses pocket or handheld devic- es, there is more than one machine in the emergency department. That means that there is a possibility of dedicating machines solely for use in COVID spaces, while also having machines available for non-COVID spaces.’ Thirdly, as fewer people need to come into contact with the patient, less PPE is used, which helps con- serve PPE in a time of worldwide shortage. Liu said ultrasound offers advan- tages over CT, and other modali- ties, in the coronavirus context and points to preliminary literature in the Covid time period, as well as previous imaging literature on Acute Respiratory Distress Syndrome (ARDS), suggesting that lung ultra- sound approaches share similar test characteristics with CT. With all the advantages of isola- tion from others, speed of operation and cleaning, Liu concluded POCUS to be overall ‘the most expedient modality’. Portable chest X-ray, she added, does not have test character- istics that match CT, and findings on both CT and lung ultrasound can be seen before they appear on X-ray, though she acknowledged that all imaging has limitations. Five reasons for diagnostic ultrasound The 10-strong expert panel’s discus- sion report highlighted five reasons why diagnostic ultrasound should be considered for imaging in suspected COVID infection cases: both a nor- mal and abnormal lung ultrasound may provide key clinical insights; lung ultrasound may help rule out other pulmonary diseases; cardiac ultrasound could detect heart prob- lems caused, or exacerbated, by COVID-19; ultrasound may benefit critically ill patients needing periph- eral or central venous access; POCUS can reduce numbers of healthcare workers exposed while supplying immediate diagnostic information. the splenium of the corpus callosum with increased T2/FLAIR signal, high DWI diffusion, with restricted ADC values and reduced T1 signal on post-gadolinium injection. CLOCC lesions are known to be secondary to an underlying evolving cause and the corpus callosum is very sensitive to markedly increased levels of cytokines. ‘Both acute haemorrhagic necrotising encepha- lopathy and CLOCC therefore sug- gest specific complications related to maladaptive cytokine profile,’ she explained. Different retrospective studies have been published reporting the preva- lence of neurological complications. One from Strasbourg and another from Wuhan show that neurological manifestations may occur in 40-70% of hospitalised COVID-19 patients. In terms of neurological signs, agi- tation was very frequent; and in terms of brain MRI, leptomeningeal enhancements, perfusion abnormali- ties and cerebral ischaemic stroke have been noticed. ‘Most frequently, when a lumbar puncture was done, the RT-PCR for SARS-CoV-2 in CSF was negative. Meanwhile, new reports of rarer complications are emerging, such as Guillain-Barré syndrome, Myelitis, Miller-Fisher syndrome and enceph- alitis,’ she added. Besides, a study published in the New England Journal of Medicine showed an association between COVID-19 and increased incidence of stroke, because of pro-inflam- matory and prothrombotic disease, with emergent large vessel occlusion detected as an early stage or even presenting symptom. However, the studies show that the number of stroke patients decreased within the COVID-19 pandemic, Edjlali-Goujon pointed out. ‘In France, there is a 21% decrease of mechanical thrombec- tomy during the quarantine. But this could be questioned too, because of the significant increase in care delays,’ she said. Anosmia and other abnormalities of the olfactory bulb are usually linked to mild-to-moderate symp- toms, often isolated, without other neurological deficits and most often without any other abnormalities on MRI. Apart from anosmia, there are more severe complications, such as maladaptive cytokine profile, leptomeningitis and encephalitis, and hypoxic and thromboembolic lesions. In the second phase of the disease, inflammatory lesions can appear and radiologists have to watch for these very carefully. ‘There is a need for a global view on the disease,’ Edjlali-Goujon concluded, ‘and an epidemiological follow-up; and it is important for the physiopathological hypothesis to be validated on post-mortem studies.’ EUROPEAN HOSPITAL Vol 29 Issue 2/20

1 6 R A D I O LO G Y Radiographers on the front line Prioritising equipment hygiene The pandemic has put extra pressure on radiology services and radiographers are particularly at risk of catching and spreading the disease. Strict cleaning and disinfection protocols must be followed, accord- ing to Pablo Valdés Solís, President of the Spanish Society of Radiology (SERAM), who recently published new guidelines on how to protect staff and patients. Report: Mélisande Rouger Ever since the first COVID-19 cases were reported in January, radiology workflow changed entirely and the focus fell on an essential, yet not vis- ible, part of the department’s work: equipment hygiene. ‘Increasing awareness of how to clean and disinfect devices adequately is cru- cial not only to protect our staff, but also not to spread the disease to patients and colleagues during radiology examinations,’ cautioned radiologist and President of SERAM, Pablo Valdés Solis. A new resource to support radiographers: basic con- cepts of Covid-19 The SERAM published guidelines last April to help radiographers keep staff and patients safe during the pandemic, because the Spanish radiographer doesn’t include the necessary microbiology background to understand how the disease spreads. training ‘Radiographers don’t receive that much training in virology. But if you understand what the disease is and how it spreads, you will better understand what needs to be done,’ Valdés said. The document reviews basic con- cepts of COVID-19 and suggests a detailed list of measures that must be taken in radiology departments to prevent its spread during radio- logical examinations. It has been observed that the virus can survive as long as three days on stainless steel and plastic. Staff must therefore not only wash their hands before, during and after an examination, but also clean and disinfect all the equipment they have used with a patient. Keeping equipment intact means that all surfaces that will be in direct contact with a patient should be covered as much as possible with impermeable material that can be discarded after each examination. For example, in portable X-ray, radiographers should cover the shell with a plastic bag. In ultrasound, it is preferable to use a sleeve to cover the probe, but not absolutely neces- sary if the patient’s skin is clean. ‘If you have sleeves, you should cover the equipment and especially the console area, to facilitate poste- rior disinfection and minimise dam- age risk to the equipment,’ Valdés pointed out.. The equipment can be washed directly with soap and water or specific cleansers. Powerful cleansers, organic disinfectants, alcohol and dissolvent should never be used as they may damage the surface. Disinfection is another key step of the cleaning routine, especially during the pandemic. The aim is to diminish the microorganism load, assuming that some will remain in non-threatening levels. Disinfection can be classified into three levels. The so-called low level is the elimination of bacteria, fungus and some viruses by applying the product in the examination room and on the equipment surface for less than ten minutes. Intermediate-level disinfection consists of eliminating TB bacillus and most of the existing bacteria, viruses and fungus. High-level dis- infection is the complete elimina- tion of germs – except bacterial spores – and is traditionally used to decontaminate medical devices, such as endoscopes, anaesthetic material and other medical devices that have been in touch with a patient’s mucosa. Sterilisation will eliminate all microorganisms, including bacterial spores, from any surface in criti- cal material like endocavity probes, surgical material and non-reusable interventional material. The coronavirus is covered by a lipid layer and is therefore vulner- able to soap and traditional disin- fectants. For most medical equip- ment used in daily routine, low to intermediate disinfection is enough. Pablo Valdés Solís is Area Director of Costa del Sol Healthcare Agency in Marbella, Malaga, Spain, and the cur- rent President of the Spanish Society of Radiology (SERAM), and has over 25 years professional experience. His special interest lies in paediatric radiology and emergency radiology. For the past fifteen years, he has focused on management and quality. Special products are not neces- sary and the disinfectant solution can be applied for five minutes. For example, a solution made of 0.1% sodium hypochlorite (bleach), 62-71% ethanol or 0.5% hydrogene peroxyde can inactivate the virus in just a minute. The solution should not be applied directly though, but by using a gauze, compress or cloth that has been previously soaked. Different areas throughout the country need different protocols Hospitals across Spain are affected differently depending on the local incidence of the COVID-19 coro- navirus. Madrid has been the most impacted area, with 68,852 infected patients as of June 1, according to the Spanish Ministry of Health. The Spanish capital has derived COVID-19 patients to major insti- tutions like La Paz and Ramon y Cajal, and temporary structures like IFEMA, a conference centre that has become Spain’s largest hospital with 5,500 beds. By comparison, Andalusia has registered 12,679 infected patients, 134 of these in the past 14 days. Due to these differences, hospi- tals must themselves decide which hygiene protocols they need to fol- low. ‘We recommend establishing these rules together with the local preventive medicine experts. Taking care of the examination rooms and materials starts by adequate clean- ing, according to the hospital poli- cy,’ Valdés pointed out. Also important to bear in mind are the protocols recommended by equipment manufacturers, as some devices or components may be more sensitive, for instance ultra- sound probes and some areas in CT gantries. The unexpected positive consequences for simple X-ray exams Radiology is learning lessons from the pandemic, Valdés observed. ‘We’ve regained an excellent habit, which is to report on simple X-ray examinations. This is really some- thing we need to value more. Being able to study simple radiology is extremely important.’ Keeping equipment clean has also returned to centre stage. ‘Radiation and magnetic resonance safety have long been the focus of our preoc- cupations, but it’s very important to take care of the material as well,’ the SERAM President concluded. Infectious diseases are traditionally the concern of clinicians, but this pandemic has reminded us of how important hygiene is and that we all have a role to play.’ EUROPEAN HOSPITAL Vol 29 Issue 2/20

1 8 D I G I TA L PAT H O LO G Y D I G I TA L PAT H O LO G Y A more integrative approach The door to simple, cheap, reliable bio-stratification Bringing molecular and digital pathology closer together through a more integrative approach can lead to clear advantages for diagnostic and research workflows, Mark Nicholls reports During the recent Digital Pathology and AI Congress (London) and in his keynote presentation ‘Molecular and digital pathology - the value of an integrative approach’, Professor Viktor Koelzer explored the ben- efits and paid particular attention to colorectal cancer (CRC) during the event. ‘It’s an exciting time in pathology as we better connect tissue morphology and molecular changes using digital pathology and artificial intelligence,’ he told del- egates. Koelzer, who is Attending Pathologist and Assistant Professor at the Institute of Pathology and Molecular Pathology at University of Zurich and University Hospital Zurich, explored recent paradigm changes in clinical diagnostics and research workflows with the poten- tial of predicting molecular features from image data. ‘Information from surgical pathology feeds into molec- ular testing, but we rarely make the loop back. Today we are starting to close this gap,’ said Koelzer. Looking at tumour annotation for molecular analysis, he said chal- lenging areas include the limited reproducibility of visual pathology review, inconsistency with bioin- formatic prediction of tumour cell content using sequencing data and Image-based consensus molecular subtype classification (imCMS) and morphological interpretation with tissue level features the resulting limited correlation of standard pathology assessment with DNA and RNA yield from clinical samples. As the ability to detect somatic variants in cancer samples drives personalised therapy, better tissue classification strategies could help to improve clinical diagnostic workflows. ‘An area of development is tis- sue segmentation by supervised machine learning for the estimation of tumour cell percentage by digital pathology,’ he said. This approach allows correlation between different levels of information and provides accurate area information for each tissue component on a given histol- ogy slide. Excellent reproducibility ‘It allows us to look at the cell- level composition of histology slides at great detail and with excellent reproducibility,” he added, “we can thereby gain additional information from pathology review in an auto- mated fashion that would otherwise be very laborious to obtain.’ Indeed, initial data showed that tissue composition analysis with DNN (deep neural networks) allows analytical robustness, automatisa- tion and standardisation and pro- vides high reproducibility at single cell resolution. DNA-based tumour purity esti- mates are more accurate than vis- ual view or deconvolution from genome-wide omic platforms which, he said, tend to under- as well as over-estimate tumour purity respec- tively. Therefore, digital pathology review using DNN could be used to inform downstream molecular anal- yses better and investigate tissue- based metrics as potential biomark- ers in clinical trials. CRC has significant potential and is a current area of focus for his research team at USZ in collabora- tion with Professor Jens Rittscher and Professor Tim Maughan at the University of Oxford. As part of the CRUK and MRC Infrared spectroscopy as a diagnostic tool New techniques of infrared-based technology are showing strong potential for cost-effective tissue analysis, Mark Nicholls reports. Peter Gardner, Professor of Analytical and Biomedical Spectroscopy at the University of Manchester, outlined how hyperspectral imaging coupled with sophisticated computer algo- rithms can identify and grade can- cerous tissue, as well as offer an indication of prognosis. The technique, Gardner said, speaking at the 6th Digital Pathology Peter Gardner is Professor of Analytical and Biomedical Spectroscopy and a fel- low of the Royal Society of Chemistry at the University of Manchester. He heads a successful biomedical spectroscopy group that focuses on the development of vibrational spectroscopy methods for use in pathology and has demonstrated the utility of the technique for both prostate and breast cancer samples. and AI Congress in London last December, lends itself to automation and would be particularly useful to screen large numbers of biopsy samples for common cancers, such as prostate cancer. Posing the question ‘Infrared spectral pathology – an academ- ic exercise or a new diagnostic tool?’, he explained that infrared micro-spectroscopy uses an array detector with the image of the sample focused onto an array of MCT (Mercury Cadmium Telluride) detectors, so that spectra from each point on the sample can be obtained simultaneously. ‘All tissue contains molecules that vibrate, particularly if you shine infrared light through them,’ explained Gardner. The infrared light is absorbed and if we measure this, we obtain an absorption spec- trum. Because we have thousands of pixels in our image, we have thousands of spectra and this makes up our data.’ Reducing error rates Focusing on prostate cancer, the team liaised with pathologists over the technique with feedback sug- gesting that pre-screening with infrared micro-spectroscopy would help focus on the most important cases and that automated pre or post screening of biopsy samples could reduce error rates. However, Gardner stressed, ‘If looking at tissue with infrared spec- troscopy, we cannot pin down indi- vidual proteins – this is not mass spectrometry – but we can get a spectroscopic fingerprint that might be indicative of something in the tissue. because the wavelength of light is longer than visible light, but the research team believe this is still enough to obtain key spectroscopic information. With no need for stains or dyes, he said, grading for cancer can be shown as well as prognostic infor- mation. ‘For a two-band criterion looking at stages T1 and T2 against T3 and T4, we can obtain sensitivi- ‘The question is, is the fingerprint different enough to say something about that tissue? We can get spec- tral evidence of that tissue and the image has evidence of the peaks in that tissue – we can see the protein peak, for example.’ The professor acknowledged that spatial resolution is an issue – the best is about five microns – simply ties and specificities of 91% and 93% respectively,’ he added. He also outlined how spectral information reveals primary tumour behaviour and whether it is invad- ing surrounding tissue. Infrared identification of the tissue pathol- ogy highlighted the epithelium, smooth muscle, lymphocytes, blood, extracellular matrix, concretion and fibrous stroma. With 2.5 million spectra processed and classified in less than sixty sec- onds with no staining needed, or de-waxing of the sample, a draw- back is the requirement for infrared transparent substrates for pristine results. Despite this, the research team has shown that reasonable results and diagnostic information could be obtained using standard 1mm glass slides just from the region of spectrum using epithelial pix- els. Furthermore, the researchers showed that ‘reasonably good’ clas- sifications of stroma and epithelium could be obtained directly from heavily H&E stained tissue. Gardner – who believes the tech- EUROPEAN HOSPITAL Vol 29 Issue 2/20 Ki67, ER, PR, CD3 Imaging•Fully automatic•For WSI or microscope camera•LIMS IntegratedDigital Pathology Solutionswww.vmscope.de

2 0 D I G I TA L PAT H O LO G Y COVID-19 Fast detection of virus antibodies Researchers at Hokkaido University have succeeded in detecting anti-avian influenza virus antibody in blood serum within 20 minutes, using a portable analyser they have developed to conduct rapid on-site bio tests. The microfluidic device to which ~20 µL of samples containing 2 µL of serum will be applied IntelliSite More productive. Insightful decisions. Be more productive with solutions that help you to work smarter. Digital and computational pathology can streamline your workfl ow and add intelligence for insightful decision-making. Full digital case sign-out is possible with the Philips IntelliSite Pathology Solution today. Visit our website to learn how Philips supports the transformational change of digital pathology to empower your decision making and precision diagnostics. : B s r o t a u t c A d n a s r o s n e S , . l a t e . K a m a y i h s i N : e c r u o S 0 2 0 2 , 1 2 l i r p A . l a c i m e h C If a suitable reagent is developed, a new portable analyser could be used to detect antibodies against SARS- CoV-2, the causative virus of COVID- 19. Avian influenza is a poultry disease caused by influenza A virus infection. Rapid initial response for a suspected infection and continu- ous surveillance are essential to mitigate the damage from highly pathogenic, transmittable pathogens such as avian influenza viruses. The group, including Keine Nishiyama, a PhD student at Hokkaido University’s Graduate School of Chemical Science and Engineering, and Professor Manabu Tokeshi of the university’s Faculty of Engineering, conducted this study to develop a new method and analyser capable of rapid, facile and selec- tive detection of antibodies. The method is based on conventional fluorescence polarization immuno- assay (FPIA) but applies a different measurement mechanism to make the analyser much smaller and port- able. The analyaer weighs only 5.5 kilograms. Simultaneous examination of multiple samples The combined use of liquid crystal molecules, an image sensor and the microfluidic device makes it possible to simultaneously examine multiple samples and reduces the volume of each sample required. Liquid crystal molecules are capable of controlling the polarisation direc- tion of fluorescent light, while the microfluidic device has a number of microchannels as a measurement vessel. The group also developed a reagent to detect anti-H5 avian influenza virus antibody, a fluores- cein-labelled protein that binds only with the antibody. The reagent was made by reproducing hemaggluti- nin (HA) protein fragments, which are expressed on the surface of H5 avian influenza virus, through gene recombination and by labelling fluo- rescent molecules to the fragments. To make the measurement, serum collected from birds was mixed with the reagent and left for 15 min- utes. The mixture was injected into the microfluidic device and meas- ured with the portable fluorescence polarisation analyser. Molecular movements of the reagent bound with the antibody will be smaller in the liquid, producing a different degree of polarisation from the rea- gent not bound with the antibody. The system can detect anti-H5 avian influenza virus antibody with only two microlitres of serum sample and within 20 minutes. ‘Our analyser could be used to conduct other bio tests,’ Tokeshi said, ‘if suitable rea- gents are developed.’ EUROPEAN HOSPITAL Vol 29 Issue 2/20