Telepathology, or the practice of pathology at long distance that calls for viewing images on a monitor rather than directly through a light microscope, has advanced progressively since 1960. The progress of telepathology passed through four stages: Static, Dynamic, Hybrid & Whole Slide Imaging [WSI]. Both conventional and innovative surgical pathology diagnostic services are being designed and implemented as well. 

The trial for applying telepathology systems in the Middle East began in 1994 in the UAE and Saudi Arabia followed by another trial in Kuwait and Jordan in 1999 using the static telepathology technologies. However, both these trials were markedly limited. Egypt commenced its successful practical experiences in telepathology in 2002. The Egyptian trial applied the static and dynamic techniques in a pilot project between the Italian Hospital in Cairo (NPO) and the Civico Hospital in Palermo. This project began in 2003 and is continuing even now. 

In 2004, Ospedale S. Giovanni e Paolo Hospital in Venice, Charing Cross Hospital in London and University of Pittsburgh Medical Center Health System (UPMC) in the U.S. joined as active participants in the telepathology project. 

During the period from 2003 till 2008, we consulted on many problematic pathological cases with these different specialised pathological centres in Italy, UK and U.S. We concluded from our experience that telepathology is a very useful and applicable tool for additional consulting on difficult pathological cases especially for emerging countries with limited resources. In the light of this success, we established our Digital Pathology Unit (DPU) in the pathology department, Cairo University in 2010. The benefits we expected and have achieved from the introduction of this telepathology unit are clear: better medical service, more distributed specialisation, savings in time and money, increased knowledge exchange provides strong basis for improved teaching and learning practices.

The application of WSI technique in teaching [for under- and post-graduate candidates] was greatly successful and encouraged us to create a huge digital pathology library which will expand our Digital Pathology and E-learning programmes to cover our staff and students both in Egypt and in the longer term, in the wider Eastern Mediterranean. Furthermore, we successfully used the WSI technique in telepathology for consultation on several cases through a cooperation programme between the Histopathology Departments of Cairo University and St James University, Leeds, UK. 

Today, we are in the process of establishing a network between different cancer centres throughout Egypt with a central digital pathology lab - The Egyptian National Project of Digital Pathology. At this central lab, a large number of senior pathologists in different pathology subspecialties will be responsible for primary and secondary diagnosis for the cases sent from remote cancer centers. 

We are also trying to build an intranet between Egypt and other Arab countries to support their pathology units. We are in communication with pathology centres in the Middle East to create a digital pathology network for exchanging best practices in telepathology and also aiming to support the units that have an insufficient number of pathologists.

We have concluded from our experience that digital pathology is a very useful and applicable tool for additional consulting on difficult pathological cases especially for emerging countries. It has significantly increased knowledge exchange and thereby ensured our patients a better medical service, while simultaneously saving a lot of time and money over the previous practice. The application of WSI technique in teaching is highly successful and encouraging to create a digital pathology library. Digital pathology can be considered the golden solution to bridge the distance between pathologists worldwide.

References available on request.

Evolution of the Field of Medical Genetics
Over the past decade, remarkable progress has been made in the field of medical genetics. The development and integration of new testing technologies — whole exome sequencing (WES) and whole genome sequencing (WGS) — accelerated the discovery of genetic conditions and massively improved their diagnosis and management.

As a result, the role of the genetic counselor has also become increasingly pivotal as they provide guidance through the sometimes complex diagnosis and management process between the laboratory service, physician, and patient. They help patients better understand and adapt to the medical, psychological and familial implications of their genetic disorders; and, help facilitate informed decisions in a personalized manner. The Unified Healthcare Professional Qualification Requirements1 — issued by the UAE Ministry of Health and Prevention, the Department of Health Abu Dhabi, and the Dubai Health Authority — stipulate that in order to obtain a license to practice in the UAE, genetic counselors should hold a master’s degree in genetic counseling.

Rifaat Rawashdeh, a Licensed Certified Genetic Counselor with National Reference Laboratory (NRL) who has previously worked as a Molecular Laboratory Genetic Counselor at Emory Genetics Laboratory in Atlanta, USA, and as a Senior Genetic Counselor at the King Faisal Specialist Hospital & Research Centre in Riyadh, Saudi Arabia, explains: “With the significant increase in the number of genetic tests now available and requested, there has been a parallel increase in the complexity of test ordering. Consequently, there is a need to assist non-genetic providers – who may not be fully familiar yet with the latest technology innovations – with results interpretation. Genetic counseling has emerged as a discipline to bridge this gap, and genetic counselors are now an integral part of today’s healthcare system.” 

Genetic Disorders in the UAE 
As in most Arab countries, there is a high incidence of genetic disorders in the UAE. The database of the Center of Arab Genomic Studies reports approximately 360 different genetic disorders present within the UAE population.2 The most common are hemoglobinopathies such as β-thalassemia, α-thalassemia and sickle cell disease. Other common genetic disorders in the country include G6PD, metabolic disorders, hearing impairments, hereditary cancer syndrome, congenital abnormalities, intellectual disabilities and developmental delays, chromosomal syndromes and cystic fibrosis. 

Approximately 60 per cent of all genetic disorders in the UAE are autosomal recessive,3 meaning a child has inherited one copy of a defective recessive gene from each parent, which has resulted with development of the disorder.

This high frequency of autosomal recessive disorders is due to many factors including: consanguinity; large family sizes, which increase the chances of children inheriting a disorder or becoming carriers if the parents are carriers; gene pool homogeneity; lack of awareness of the importance of undergoing genetic counseling to better understand potential carrier risks; and, the prevalence of founder mutations, which is defined as a group of patients in a certain geographical area having a particular genetic disorder as a result of a common mutation inherited from a common ancestor.

Rawashdeh elaborates: “For example, the Sanjad-Sakati syndrome is a rare autosomal recessive disorder in the Middle East wherein people who have this disorder have two copies of the common founder mutation. It is believed to be an ancient mutation, inherited thousands of years ago. Features of this syndrome include severe challenges in growth and development, congenital hypoparathyroidism, dysmorphic features, and mild to severe intellectual disability.”

The Era of Personalized Genomic Medicine and Genetic Counseling 
Personalized genomic medicine, also referred to as precision medicine, is an emerging field where diagnosis and medical management is customised to each patient based on their genetic information, family history, and lifestyle. A patient’s unique genomic data combined with environmental factors, imaging, family history and other screening testing, yield a personalized insight into their susceptibility to disorders and response to treatment. 

With its increased affordability, whole genome sequencing is now an essential tool in precision medicine. It enables the detection of variations in the human genome that can signal the risk of acquiring certain disorders before clinical signs and symptoms appear. 

Examples of these include cancers, cardiovascular diseases, diabetes, chronic liver diseases, neurological and metabolic disorders. Early detection allows for planning strategies of prevention and early intervention for enhanced patient management. This is evident in women with germline mutations in BRCA1 & BRCA2 genes who have a 36 per cent to 85 per cent lifetime chance of developing breast cancer, and a 25 per cent to 60 per cent chance of developing ovarian cancer. Based on this genomic risk, intensive surveillance programs, such as increased frequency of mammograms or even prophylactic surgery including mastectomy and removal of the ovaries, are warranted.

Another application and major benefit of personalized genomic medicine is the field of pharmacogenomics. Pharmacogenomics is the science of examining specific genomic variations and their effect on an individual’s response to drugs, which provides physicians with a great advantage in selecting suitable therapies; this in turn improves outcomes while minimising side effects and toxicity in a personalized manner. Warfarin (Coumadin) — a well-known anticoagulant — is associated with a high incidence of over-anticoagulation with resultant bleeding, which limited its wide use for patients who can benefit from this therapy. It was found that genetic variants in two genes (CYP2C9 and VKORC1) are known to influence the appropriate warfarin dose for different patients.4 As a result, the U.S. Food and Drug Administration (FDA) has encouraged physicians to use genetic testing to recommend the appropriate warfarin dosing for their patients to increase drug efficacy and reduce undesirable side effects. 

Genetic counselors play a major role and are a key component of precision medicine, with their unique set of skills and expertise in genetics, genomics, risk assessment, and communication. 

Increased Demand for Genetic Counselors in the UAE
According to Rawashdeh, genetic counseling services are currently underserved in the UAE and should be expanded. “There are many reasons why a patient would be referred to a genetic counselor. Therefore, there is a high demand for medical professionals in this specialty who are trained to accurately order, interpret and communicate the results of genetic tests.”

Rawashdeh continues: “Also, there are social factors that occur where patients may be in denial, or they do not wish to be referred to a genetic counselor to avoid stigma. Although this is gradually changing, collectively we need to do more to educate patients and increase their awareness of the benefits of genetic counseling. This will encourage potential carriers and their families to visit a genetic counselor for support and guidance to make informed decisions regarding testing options, interpretation of test results, prevention, and life planning. Counselors not only offer guidance, but they also refer patients and their families to other medical specialties, advocacy, and support groups to help them effectively manage their condition.” 

As personalized medicine continues to evolve, the role of the genetic counselor will become increasingly important, and the field of genomic counseling will become even more pivotal to improving health outcomes.

“In the UAE, significant progress has been made in the application of advanced genetic testing in an effort to ensure patients receive the highest standards of care across every medical specialty. I would be glad to see the creation of an internationally accredited genetic counseling training program in the UAE, to complement these efforts and increase the number of licensed and certified genetic counselors in the country,” concludes Rawashdeh. 
 
References
1) Department of Health Abu Dhabi. (2017). Unified Healthcare Professional Qualification Requirements. [online] Available at: https://www.haad.ae/HAAD/LinkClick.aspx?fileticket=2K19llpB6jc%3D&tabid=927 [Accessed 12 July 2018].
2) Center for Arab Genomic Studies. (2018). CTGA Database Listing. [online] Available at: http://www.cags.org.ae/ctga/listing.aspx?sid=78e1abf42e1b4dd
4ac82aba309c79ee7 [Accessed 10 May 2018].
3) Teebi A, Farag T (eds), Genetic Disorders among Arab Populations, New York, Oxford University Press, 1997, pg341–372
4) Sconce, EA at al. (2005) The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 1;106(7), p. 2329-33. Epub

Point of Care Tests (POCT) refers to rapid diagnostic tests performed at or near the consultation of patients to make early decisions about patient management; but this definition continues to evolve. These tests are typically easy to perform and interpret by trained users. POCTs are widely used in the provision of healthcare services in a variety of settings such as general practitioner clinics, hospital clinics and wards, emergency departments, pharmacies etc. Nowadays, some tests can even be performed in the comfort of a patient’s own home.

POCT is well established in some specialities such as clinical chemistry and haematology but historically microbiology tends to lag behind in implementation of POCT. Some of the reasons for this include poor performance of assays, reluctance of physicians to accept POCT results, lack of cost effectiveness and clinical outcome studies, quality control and quality assurance concerns, staff training and interface issues with existing laboratory information systems.

POCT is not new to microbiology. One of the earliest known microbiology POCTs is gram stain for gonorrhoea in sexual health clinics. Due to recent advances in technology the landscape of POCT in microbiology is rapidly evolving. Other factors such as increasing pressure to reduce inappropriate antimicrobial prescribing to tackle antimicrobial resistance, and challenges associated with centralisation of laboratories, for example, increased turn-around time are driving laboratories towards implementation of POCTs. These tests can be broadly divided into tests that detect one or more pathogens and those that do not detect any specific pathogen but provide indirect evidence of infection such as urinary dipstick, C-reactive protein and procalcitonin.

The main benefits of POCT in microbiology are antimicrobial stewardship, infection prevention and control and public health. Other potential benefits include efficient patient flows, reduced length of stay, improved patient satisfaction, and avoidance of unnecessary investigations thus reducing overall healthcare costs. 

Antimicrobial Stewardship
Antimicrobial resistance (AMR) is a huge concern and tackling AMR is a priority globally. According to an independent antimicrobial resistance review led by economist Jim O’Neill, more than 700,000 people across the globe die every year due to infections caused by resistant microorganisms and this figure is likely to reach 10 million per year by 2050. 
Among the many strategies to tackle AMR, antimicrobial stewardship plays a crucial role. In simple terms, antimicrobial stewardship is about giving the right antibiotic to the right patient at the right dose and right route for the right duration whilst minimising adverse events such as Clostridium difficile and emergence of AMR, thus improving clinical outcomes and reducing healthcare costs. POCTs enable rapid and early diagnosis of infections, which has a significant impact on early and appropriate management of infections. 

Until recently, the most commonly used POCTs with impact on improving antibiotic prescribing were those that detected Influenza virus and Group A Streptococcus. These used to be predominantly immunochromatographic tests with variable sensitivities and were popular due to the speed of results, lack of instrumentation/maintenance, and ease of transport/storage making these tests low cost. 

In a randomised trial of children presenting with pharyngitis, rapid antigen detection test for Group A Streptococcus was found to decrease the rate of antibiotic prescriptions. Another randomised trial of influenza rapid test in a paediatric emergency department was found to significantly reduce the number of laboratory tests and radiographs ordered and their associated charges, decreased antibiotic use, increased antiviral use, and decreased length of time to discharge.

Lately, technological advances have revolutionised POCTs with adoption of molecular technology with superior sensitivities. In addition, there are now multiplex panels which can detect a large number of viral and bacterial pathogens from respiratory tract specimens. Other POCTs that could potentially impact antimicrobial prescribing include Legionella/Pneumococcal urinary antigen for pneumonia, Chlamydia/Neisseria gonorrhoeae in sexual health clinics and Mycobacterium tuberculosis. 

Infection Prevention and Control
Outbreaks caused by dissemination of transmissible infectious agents can be very costly and damage the reputation of an organisation. Microbiology POCTs allow rapid identification of transmissible agents which will enable infection control teams to implement appropriate control measures earlier to prevent further dissemination. POCTs that detect meticillin resistant Staphylococcus aureus (MRSA), Influenza/RSV, Carbapenemase producing enterobacteriaceae are some examples of tests that have the potential to aid infection control teams to prevent outbreaks.

POCTs in MRSA appears to be the most commonly studied but almost all the studies performed rapid MRSA test in the microbiology laboratory rather than on wards or in clinics.  Hence, results were not available within 1-2 hours of specimen collection and unsurprisingly some studies did not demonstrate a reduction in transmission or acquisition rates of MRSA. A cluster-randomised cross-over trial in a London hospital where MRSA POCT was performed on four admission wards found no effect on MRSA acquisition rates. They concluded that where compliance with infection prevention and control is high and MRSA carriage is low, POCT has no additional impact on MRSA acquisition rates.

Rapid results alone are not sufficient to prevent dissemination unless preventative measures such as isolation and other infection control measures are in place. Therefore, many factors need to be considered prior to implementing POCTs for infection control purposes. In this article I have not discussed infection control risks related to non-adherence of safe practices in the use of POCTs. Outbreaks of blood borne viruses such as Hepatitis B have been reported due to failures in safe practices such as poor hand hygiene, not wearing gloves, failure to disinfect instruments between patients and sharing of single use equipment.

Public Health
There are many infectious diseases of public health importance. Currently available POCTs for detection of infections such as tuberculosis, Chlamydia/gonorrhoea and HIV can have a significant impact on the control of these diseases. In addition to early diagnosis and treatment, surveillance of these infections play a crucial role in public health management. There is a danger that with POCTs being done in a variety of settings, it can affect public health surveillance, which could lead to failure to recognise outbreaks/epidemics. Thus, it is important that measures are in place to ensure continued surveillance of infectious diseases of public health significance irrespective of where the test is performed. Technology such as smartphone apps and cloud-based data sharing can help achieve this objective. 

Future
There remain significant challenges to more widespread use of these tests such as quality control, laboratory oversight, training, competency, interface and data sharing, accreditation clinical outcome and cost effectiveness etc. In 2017, The American Academy of Microbiology published a report that highlighted a number of recommendations in the implementation of POCTs in microbiology.  Despite operational challenges, the field of microbiology POCT has made huge strides over the last five years. Future of POCT in microbiology looks very exciting – further innovations and advances in technology will continue to expand repertoire of tests. This can radically change how microbiology services are delivered. Microbiologists should get involved at the earliest opportunity to be a part of this revolution.  

References available on request.

According to recent reports, the European medical laboratory market is expected to reach U.S. $15.5 billion by 2024 and the laboratory market industry is projected to show annual growth rates averaging approximately two per cent for laboratory services up to 2020. This assessment is based on analyses for countries such as Germany, France, Italy, Spain, Switzerland, Sweden, Norway and Portugal, which show that the European laboratory market trends display a constant growth.

Placing the spotlight on this rapidly expanding and evolving market is the second edition of MEDLAB Europe 2018 that is set to take place from October 2 to 4 at the Fira Barcelona-Gran Via, Barcelona, Spain. The platform will present a unique opportunity for global laboratory industry leaders, including manufacturers, dealers and distributors, to make their presence felt in the European market. 

The show brings leading international exhibitors under one roof, covers 2,000 sqm of exhibition space, and provides visitors an opportunity to access cutting-edge medical laboratory products, next-generation technology, innovative services and world-class educational content. More than 3,000 industry professionals and over 120 exhibiting companies are expected to attend the second edition of one of Europe’s leading events for laboratory management and diagnosis.

Both exhibitors and visitors can look forward to a complete range of products, services and solutions for the medical laboratory industry, at the show. It is a central meeting point to witness the latest innovations and learn about the current and future industry trends in the laboratory sector.

Furthermore, the show acts as a marketplace where interested parties can place orders to equip their medical facilities with the latest products available on the market. Visitors can also gain valuable insights by attending one of the scientific conferences and hear from renowned scientists and clinicians from around the globe.

European Lab-testing Ecosystem
Keeping up-to-date with the latest industry trends emerging from within the medical laboratory industry is critical to the lab professional, particularly in Europe, where the In-Vitro Diagnostics (IVD), clinical laboratory, molecular diagnostics and Point-of-Care Testing (POCT) markets are some of the fastest growing in the world. 

The regulations around medical and IVD devices in Europe are also evolving, which involves important improvements to modernise the current system including risk-classification, improved transparency and new rules on clinical evidence. Under these new regulations, the classification of devices is based on risk and manufacturers need to demonstrate that their medical device meets the requirements by carrying out a conformity assessment. 

Plus, thanks to the latest advancements in health tech, the European medical laboratory-testing ecosystem has become safer, faster and more efficient, and technology and regulations are evolving to put patient safety and care at the heart of healthcare delivery.
Keeping these factors in mind, MEDLAB Europe is offering carefully tailored networking opportunities to all visitors, including medical laboratory and healthcare professionals, an insight into the latest information on instrumentation, applications and techniques used in laboratories and their management.

Multi-disciplinary Clinical Lab Conferences
Right from new methods of effective lab management to the development of techniques in detecting diseases, the MEDLAB Europe Congress 2018 will cover an extensive range of topics guaranteed to educate and enlighten all. The aim of the conferences at this edition is to discuss new methods of effective laboratory management to the development of techniques in detecting diseases, among other topical themes. These conferences are designed to cover an extensive range of topics guaranteed to educate and enlighten all.
 
The different conference tracks include: POCT, Immunology, Laboratory Management, Anatomic Pathology, Clinical Microbiology and Haematology. These have been accredited by the European Accreditation Council for Continuing Medical Education (EACCME) with 15 European CME credits (ECMECs). Furthermore, the Advisory Board & Scientific Committee of the conferences comprises a team of renowned names from the industry, who have set forth an interesting agenda for the conferences. 

These medical conferences will expose attendees to new ideas, discoveries, and regulations because medicine and methods are continuously developing. By learning current breakthroughs, doctors and even laboratory technicians can improve their practice and cure patients with recent technology, which can cure an illness efficiently. Also, healthcare providers can practice what they learn at the conferences and allows them to make the most of their newly acquired skills.

For instance, at the POCT conference, Dr. JL Bedini, Core Laboratory Head, at Hospital Clínic, Barcelona, will discuss key topics such as connectivity requirements and utility of POCT in the emergency department. This will help develop an understanding of rapid laboratory operations, instrumentation and test availability, and provide laboratory professionals the latest updates for better quality and turnaround time and POCT technology usage.

The Immunology conference, on the other hand, will aim to identify new discoveries in fundamental immunology, diagnostic and therapeutic options and will tackle challenges that arise from connecting fundamental and translational science. While at the Laboratory Management conference Dr. Ernesto Casis Sáenz, Director Clínic, Laboratoris Clínics, Hospital Universitari Vall d´Hebron, Barcelona, will address the new challenges in the management of the lab and how to encourage leadership for the future of the laboratory while also covering key challenges surrounding quality and reliability of test results.

The Anatomic Pathology conference will examine how to effectively facilitate and improve the rapid examination of surgical specimens and biopsies to deliver diagnoses allowing for immediate decisions regarding intraoperative and postoperative patient management. While the Clinical Microbiology conference will focus on the most current research related to the laboratory diagnosis of human infections, the role of the laboratory in both the management of infectious diseases and epidemiology of infections and the latest developments. Also, the Haematology Conference will discuss the role of laboratory testing and interpretations to aid in the diagnosis, staging, and prognosis of patients with haematologic malignancies and solid tumours.

The Automation Movement
The role of central labs has increasingly become quite critical to managing patients efficiently and allows labs to deliver quality data, speed and flexibility to complete projects on time and on budget. Laboratory automation is a multi-disciplinary strategy to research, develop, optimise and capitalise on technologies in the laboratory that enable new and improved processes. 

Central laboratory testing offers ‘combinable data’, generated from the same analytic method platform to correlate and standardise results. The end product will, therefore, be similar regardless of the facility it came from.

Most of the tasks executed in a clinical lab today, from microplate handling to liquid handling, are achieved through lab automation and these processes handle routine tasks that were once performed by pathologists and lab technicians and help in achieving a fully traceable and standardised sample processing. Further, the convergence of the different disciplines of laboratory medicine is driving the movement forward and will allow lab automation to expand as well as connect to all the parts of the lab.

Automation has a number of benefits as it reduces the workload and turnaround time, increases the total number of tests done in less time, eliminates repetition and monotony from human life, thereby decreasing human error, improving accuracy and reproducibility, and uses a minimum amount of sample. Furthermore, automation solutions have now started to extend their footprints into other areas of the lab such as microbiology and molecular diagnostics.

Considering the increasing importance of lab automation, the Congress will hold a dedicated workshop on automation, along with topics such as next-generation sequencing and mass spectrometry. These three-hour workshops will be conducted in Spanish and have been carefully designed for laboratory technicians.

Accreditation is the official process of recognising an establishment as having the status and the qualifications to perform a particular activity. It gives you an independent assurance that your business is capable of delivering outstanding patient care. It also ensures that your standards for quality are maintained and will continue to improve regardless of changes in personnel. 

Some laboratories consider accreditation as an expensive burden that requires time and resources, whereas others see the lack of accreditation as an example of poor quality of standards and an inability to produce accurate results. With accreditation, laboratories are more likely to work through a quality management system and produce better quality of work. They have a higher chance of performing better on proficiency tests and appealing to highly qualified employees. Moreover, their patients become well-informed customers of medicine and public reporting of quality indicators. After taking into consideration cost and determining the right accreditation for your laboratory, accreditation can become tremendously valuable because of its long-term benefits. 

There are currently several laboratory accrediting agencies, the most notable of which include:

1) ISO: 15189: Medical laboratories - Requirements for Quality and Competence
2) CAP: Laboratory Accreditation Program (LAP)
3) AABB: AABB Accreditation Program: Blood Banks and Transfusion Services
4) JCI: Joint Commission International Accreditation Standards for Laboratories

ISO: International Organization for Standardization
The International Organization for Standardization (ISO) is an independent, non-governmental organisation headquartered in Geneva, Switzerland. In 1926, it began as the International Federation of the National Standardizing Associations (ISA) and continued onwards until October 1946, when ISA and UNSCC (United Nations Standards Coordinating Committee) delegates from 25 countries met in London and agreed to join forces to create the new International Organization for Standardization (ISO). It officially began its operations in February, 1947. Since then, the ISO has produced over 21,000 International Standards, ranging from industrial and commercial standards to standards of Information Technologies (IT), graphical symbols, conformity assessment, metrology, manufactures, and consumers. It has become one of the largest developers of voluntary international standards in the world and by far, its most popular standards are the ISO 9000 Quality Management, ISO 14001 Environmental Management Systems Standard and ISO/IEC 27001 Information Security Management.
At one point in time, every country in Europe had its own accreditation system. Medical laboratories were becoming more sophisticated and this brought about the need to create a new quality standard for medical laboratories. In 1994, the ISO TC212 met in Philadelphia with 33 countries to start this process. It took seven years to develop the ISO 15189: Medical laboratories - Requirements for Quality and Competence.
Standard is based on two well known ISO Standards:  ISO/IEC 17025 (General Requirements for the Competence of Testing and Calibration Laboratories) and ISO 9001(Quality Management System Requirements). Once a laboratory is accredited, it follows a three-year re-accreditation cycle; in the first and second years of the programme, two surveillance assessments are scheduled and during the third year, a re-accreditation onsite assessment takes place.

LAP: Laboratory Accreditation Program
In the majority of countries, especially the U.S., laboratories are accredited by the College of American Pathologists (CAP). The CAP offers the Laboratory Accreditation Program (LAP), which has been around for over 50 years.  The LAP is a voluntary peer review process in which an on-site inspection is performed by practicing laboratory technicians. These volunteers use checklists appropriate for various laboratory disciplines and each laboratory has a minimum of three checklists:  a general checklist (for the whole lab), an ALL common checklist (one per section), and a section-specific checklist (can be one or more depending on the section’s scope of tests). A CAP Accreditation cycle spans two years and accredited laboratories are required to perform self-inspection 12 months after their initial accreditation.
Before choosing an accreditation, the laboratory needs to decide which one appeals to their particular blend of tests and technologists by taking into consideration their scope of service, workload, staffing, facility and most importantly, financial ability. u
Gap analysis is an important tool to use when aiming to obtain a different accreditation. It works by determining the differences and similarities between all types of laboratory accreditations. For example, CAP and ISO-15189 are two different accreditations. If you are CAP accredited and want to go for ISO accreditation, or vice versa, you would find it useful to know that these accreditations both have quality management,  personnel requirements, and identical analytical processing schemes; pre examination, examination, and post-examination. In addition, these accreditations also share laboratory information management, resolution of complaints, non-conformities, reporting of results, laboratory equipment, reagents, and consumables. On the other hand, we can also discover differences and deficits between both of these accreditations when analysing them. However, we will not be going into these details as they are beyond the scope of this article.   

The College of American Pathologist: ISO-15189 Accreditation Program
In 2008, CAP launched its CAP-ISO 15189 Accreditation Program. This programme is based on the ISO 15189:2007. To be eligible for this accreditation, the laboratory must be CAP accredited first. The laboratory fills out the application form and sends it to the CAP, alongside the requested documentation. 

Criteria and Requirements
Our laboratory has been CAP-accredited for the last several years. When management sought to attain ISO-15189, we observed the following differences: 

Management Review: As per ISO-15189, each laboratory is required to review its quality management system at least once a year. The review should have input data of your QMS (internal and external assessments, audits, risk management, KPIs, complaints monitoring and the resolution of, suppliers and vendors’ evaluation, and changes in scope of service).  The purpose behind the review of data is to identify causes of nonconformities, observe trends and patterns that indicate process problems, and to establish the actions required for the upcoming year following the outcome of the review. 

Uncertainty of Measurements: Medical pathology laboratories are required to determine or estimate the measurement of uncertainty for all quantitative results; as per ISO-15189. Studies have shown that all laboratory activities may be subject to variation and that these variations can occur during all the phases of diagnostic procedures (pre-analytical; analytical and post analytical processes). All these variations can be sources of uncertainty of measurement. Effect of these sources are combined and used to calculate an estimate of the uncertainty of a result. There are several ways to calculate uncertainty. One method includes the total imprecision of a quantitative method as reflected by routine QC (IQC data). When using this method, it is important to collect data over a long period of time to encompass as many routine changes as possible (maintenance, calibration, lot change, etc.).

Quality Manager (QM): QM is a member of staff who is responsible for quality management and reports directly to the laboratory leader on a regular basis (at least twice a month and more often if necessary). According to WHO, a quality manager monitors the laboratory QMS and ensures that policies are implemented on a continuous basis, and monitors all IQC procedures, ensuring that the laboratory participates in appropriate EQA schemes and that corrective action is taken on the results, as appropriate.

Service Agreements: SLA occurs on managerial level; staff and supervisors are usually not involved. However, supervisors can request modifications for SLA if they see that it is negatively impacting their section. Laboratories are required to have records of regular reviews of agreements and all changes to an agreement shall be documented and communicated to all affected parties.

Traceability: Traceability refers to tracing your results to a stated reference, usually national or international, through an unbroken chain. SI units of measurements are the most common recommended measuring scales.

Auditors Training: Audits shall be conducted by personnel trained to assess the performance of managerial and technical processes of the quality management system. This may entail additional costs for certain laboratories.

POCT (Point of Care Testing): POCT is not part of ISO-15189 but it is similar in structure to ISO-15189 standards. Its accreditation is ISO 22870. It has both Management Requirements (which is less detailed in comparison to 15189) and Technical Requirements (which lacks 5.9 and 5.10: Release of Results and Laboratory Information Management).

Safety: Safety is very limited in ISO-15189. It is mentioned in only one section: 5.2: Accommodation and Environmental Conditions. It has a separate accreditation-ISO 15190: Requirements for Safety in a Medical Laboratory-which was published in 2003. 
Whether you go for CAP, ISO, AABB, JCI, or any other accreditation, remember that inspection is an open-book exam, which requires beforehand preparation. Get staff involved, make sure the leaders are committed to the process, inspect yourself and, if possible, have another laboratory do your mock inspection.  

References available on request.

Haemovigilance is now an internationally established part of the safe management of blood process for patients. However, the part played by the Transfusion Practitioner within haemovigilance is less well known. The aim of this article is to outline the pivotal role that the Transfusion Practitioner plays within the haemovigilance process in the hospital setting.

Haemovigilance is a tool to improve the quality of the blood transfusion chain, primarily focusing on safety and can be defined as a set of surveillance procedures covering the whole transfusion chain from the collection of blood and its components to the follow-up of its recipients, intended to collect and assess information on unexpected or undesirable effects resulting from the therapeutic use of labile blood products and to prevent their occurrence and recurrence.

Within the UK, the haemovigilance scheme known as Serious Hazards of Transfusion (SHOT) has been in place for 20 years and it is now an integral part of the transfusion landscape, both clinically and within the laboratory. SHOT reporting encompasses both transfusion reactions and adverse events, with the latter from both the clinical and laboratory areas.

There is a great deal of emphasis within haemovigilance on the errors that are preventable and identifying points within the transfusion process where mistakes might happen. SHOT have identified nine critical steps (see 2016 SHOT report www.shotuk.org/shot-reports) where errors may occur and these steps encompass all parts of the transfusion process within the hospital setting, and to manage them requires team effort. An essential member of that team is the Transfusion Practitioner who is involved in the pre and post laboratory steps, and understands the laboratory processes.

The Transfusion Practitioner

Transfusion Practitioner (TP) is an umbrella term used to encompass the many different roles that exist in transfusion medicine. These roles include but are not limited to Transfusion Nurses, Transfusion Safety Officers, Haemovigilance Officers or Patient Blood Management Coordinators, and it can be undertaken by a Registered Nurse, Registered Midwife, Healthcare Scientist, Medical Practitioner or Operating Department Practitioner. One of the key aspects of the TP role is bridging the clinical-laboratory gap. In the laboratory there are rules and regulations that must be followed; “transfusion” is the main job whether grouping, cross matching or issuing components. The laboratory staff are the scientific experts in transfusion. In the clinical area, transfusion is one part of the patient journey contributing to the bigger overall picture. The clinical experts are not necessarily transfusion experts but understand where transfusion fits in their plans for the patient. The TP role helps to bridge that gap.

One summary of the TP role was in the 2014 UK Patient Blood Management (PBM) launch document:
Transfusion nurse/practitioner 

• Provide and/or facilitate transfusion-related education including for PBM throughout the hospital  
• Ensure clinical transfusion incidents, transfusion reactions, specimen labelling errors are investigated  
• Submit data to haemovigilance programmes  
• Develop constructive working relationships with the many clinical users of blood products, and assist with the implementation of PBM programme  
• Support local, regional and national transfusion audits by involving appropriate stakeholders to undertake data collection and implement quality improvements arising from audits.

So what role does the TP play in haemovigilance?

The TP involvement in haemovigilance includes the investigation and reporting of transfusion reactions/adverse events internally and externally to national haemovigilance schemes. By conducting process reviews and communicating directly with clinical/laboratory staff or patients, the TP can provide additional details that are needed to complete investigations. Often this extra information assists the determination of the type of transfusion reaction/adverse event and provide valuable input to future transfusion plans and management of the patient.

For adverse events, TPs are often the drivers of the root-cause analysis process, and in collaboration with others, work on corrective and preventative measures. Surveillance is often achieved through audits which help to identify current clinical practice, understanding of transfusion processes, and any gaps or potential risks that may be present. Part of this may include a review of staff knowledge to guide education requirements, which all contribute to quality improvement.

As previously mentioned, the TP acts as a liaison between the clinical and laboratory settings improving communication and understanding. They also liaise between the hospital, the blood supplier and the national haemovigilance agency. To this end, an essential part of the TP role is excellent communication and collaboration skills as they interact with staff on different levels, in multiple settings.
TPs promote safe transfusion practice by sharing their excellent knowledge in this field to support changes and quality improvement in transfusion policies, procedures, reference guides, digital systems, and educational resources. They also participate in the development and delivery of staff education, for instance pre-transfusion sample collection or the management of transfusion reactions. Staff education by a TP may be formal in the form of lectures, or informal when staff can discuss a case or seek advice and ask questions. By maintaining a visible presence in the clinical setting, the TP ensures that staff have access to information and so support improved transfusion outcomes.

TP’s participate in transfusion committees and other professional groups that strive to improve practice on regional and national levels. TPs also collaborate nationally and internationally to develop the role and learn from each other. In most countries this is the only way to share knowledge, best practice and enhance quality because no specialised training for TPs is available.

Do TPs make a difference?

Although there is much published on the role of haemovigilance in safe transfusion practice, there is considerably less on the role of the Transfusion Practitioner in haemovigilance. There are some papers on the role of the Transfusion Practitioner and within the ISBT Transfusion Today member’s publication, the TP role has been highlighted but more peer reviewed papers are required to demonstrate their impact. However, in practice, most clinical audits related to blood management/transfusion rely on the TP to collect and submit the data, many SHOT report vignettes highlight the TP as part of the corrective and preventative actions or give a lack of TP as contributing factor, and the TP can also be pivotal in implementing patient blood management (PBM) strategies and acting as a central point for the different elements of PBM being undertaken.

Conclusion

The TP is uniquely placed to work with all teams bridging the transfusion gap and ensuring the patient remains at the centre of the transfusion process. They are seen as an expert practitioner in transfusion field with knowledge including appropriate blood management, use administration, and a good understanding of laboratory practices. They ensure clinical staff have access to the most up to date transfusion training and policies, and as a result patients and families are given the right transfusion information.

The TP role, which unfortunately is not yet established in all countries, can help to enhance transfusion and patient safety. Unfortunately, in many jurisdictions, they have limited formal status. There is wide variation in working hours, allocated tasks, payment, and training.  It is hoped that these issues are addressed over time. To promote this role internationally, International Society for Blood Transfusion (ISBT) recently established a TP forum. Part of this forum includes an online discussion forum for TPs or those interested in the role to have discussions, share ideas or pose questions. To further promote the role   there have been designated TP sessions at the ISBT Congress since 2016, and TPs are able to become a member of ISBT at a reduced rate (www.isbtweb.org). All this will contribute to the TP role being more widely recognised internationally as an essential part of the haemovigilance system.

The author would like to thank the ISBT Transfusion Practitioner Forum Steering Group for their contribution to this work.
Linley Bielby, Blood Matters Program Manager, Australia
Rozemarijn Deelen, Haemovigilance Officer , Netherlands                                     
Clare O' Reilly, Transfusion Safety Nurse, Canada
Aman Dhesi, Development Manager - Patient Blood Management Team, UK

Cardiac markers are small molecules inside the cardiac cell. Usually, there is a minimal or absence of these markers in the circulating blood in normal condition. However, if the muscle cell of the heart gets damaged because of lack of oxygen (ischemia) or strained (heart failure), some of these molecules will be released and diffused to the circulating blood. So, elevation of the level of these molecules (cardiac markers) will give us the indication of the presence and the extent of the damage of the heart muscles.

Under what conditions will these cardiac markers be helpful?

Acute coronary syndrome happens when there is a sudden decrease of blood supply to the myocardial cells. These cells will suffer from suffocation which will progress to irreversible damage of the cells unless urgent treatment of restoration of the blood supply has taken place. In the first hour or so of the ischemia, the myoglobin (MB) will be released first. After that, the creatine kinase (CK) and its MB isoenzyme (CK-MB), and subsequently, troponin T will be released.

The CK-MB usually gets elevated in 3-6 hours. The first test may be negative after acute myocardial infarction (MI), so the test needs to be repeated in 6-12 hours to rule out the MI. Usually the CK-MB peaks in the initial 12-24 hours and then goes down usually after 48 hours. On the other hand, troponin T takes 3-6 hours to get elevated, but it can last in the blood for 2 weeks. Troponin is the most specific cardiac marker for myocardial injury. Of late, new high sensitivity cardiac troponin assays are used which can detect circulating troponin 
within 1 hour and if the test is negative in 3 hours, we may safely rule out cardiac injury.

The benefits of these cardiac markers are that it confirms the diagnosis of the myocardial injury, gives the extension of the myocardial damage, and also gives a risk stratification to somebody who is presented with chest pain to the Emergency Room. If the chest pain is associated with elevated troponin T, that patient will be considered high risk and will require further urgent evaluation.

The other cardiac marker that is used for myocardial stretching in a patient with heart failure is called BNP (Brain Natriuretic Peptide). This marker can be very helpful to diagnose a patient who comes in to the Emergency Room with a complaint of shortness of breath. A normal level may make a heart failure as the cause of shortness of breath very unlikely. On the other hand, a severe significant elevated level makes the heart failure diagnosis very likely. The BNP is also very helpful in following up patients with heart failure to evaluate the efficacy of the treatment and to detect early decompensation.

Another cardiac marker is called High-Sensitivity C-reactive protein (CRP) which is an indicator of inflammatory process in the coronary atheroma. Patients with elevated High-Sensitivity CRP are at a high risk of having a cardiac event. On the other hand, there is a recent study to show that specific anti-inflammatory medications which is “Anti-Interleukin-1 Antibody” may decrease the cardiac event in patients who have coronary artery disease and High-Sensitivity CRP.

Cardiac markers not only help in confirming the diagnosis of myocardial injury and heart failure, and in following up with patients and their prognosis, but they also help in reducing medical costs by avoiding unnecessary admissions for patients with chest pain.                                                                                                     

Laboratory diagnosis of Ebola virus disease (EVD) plays a critical role in outbreak response efforts; however, establishing testing strategies for this high-biosafety-level pathogen in resource-poor environments remains extremely challenging. Since the discovery of Ebola virus in 1976 via traditional viral culture techniques and electron microscopy, diagnostic methodologies have trended toward faster, more accurate molecular assays. The unparalleled scope of the 2014-2015 West Africa Ebola epidemic spurred remarkable innovation in the field.

In this article, we describe the evolution of Ebola virus disease diagnostic testing in relation to its past, present and future. As new diagnostic technologies become available, it will be increasingly important for clinicians to understand both the analytic and practical strengths and limitations of these tools. Ultimately, the optimal diagnostic approach for a particular setting will depend upon multiple factors, including population characteristics and disease prevalence, the healthcare setting type, training requirements, regional laboratory capacity, regulatory status, and cost.

Methods for detecting Ebola Virus infection

Testing tools for Ebola virus fall into three basic categories: (i) serologic tests that detect host antibodies generated against the virus, (ii) antigen tests that detect viral proteins, and (iii) molecular tests that detect viral Ribonucleic acid (RNA) sequences. Specific antiviral antibodies can persist for years but the variable onset of antibody responses during acute illness makes serology a minimally useful diagnostic tool. On the contrary, antigen detection and molecular tests have proven very effective for acute diagnosis, as virus levels in the blood typically rise to high levels within the first few days of symptoms.

The incubation period following Ebola virus infection typically ranges between 3 and 13 days, no tests have yet demonstrated the ability to detect Ebola virus prior to the onset of symptoms. Some diagnostic tests have been designed to broadly detect Ebola virus infection, while others distinguish among the five known Ebola virus species (Zaire/Ebola [EBOV], Sudan [SUDV], Tai Forest [TAFV], Reston [RESTV], and Bundibugyo [BDBV]). Major outbreaks of Ebola virus disease in humans have been attributable to EBOV, SUDV, and BDBV; prior to the 2014-2015 epidemic, the origins of EVD outbreaks were restricted to five African countries: Democratic Republic of Congo (formerly Zaire), Sudan, Gabon, Uganda, and Republic of Congo.

Cell Culture

The traditional gold standard method to confirm the presence of Ebola virus is viral isolation in cell culture, by using Vero E6 African Green monkey kidney cells. While detection of Ebola virus by these methods is definitive, these methods require biosafety level 4 (BSL-4) containment  and are typically restricted to research and public health laboratories.

Antibody Detection

Serologic assays for the detection of specific antiviral antibodies have been used to demonstrate current or prior infection with Ebola virus since the first outbreak investigations of this virus in 1976. Indirect fluorescent antibody detection test (IFAT), considered to have suboptimal sensitivity and specificity, and the requirement for BSL-4 bio containment rendered this method unsuitable for large-scale diagnostic efforts.

The development of enzyme-linked immunosorbent assay (ELISA) tests for the detection of Ebola virus-specific IgM and IgG antibodies offered a faster, higher-throughput system for serologic testing. ELISAs that utilise recombinant viral proteins have also been developed, but to date they do not appear to have been validated for clinical use.  Limited data are available to assess the sensitivity or specificity of these ELISAs.

The detection of viral protein antigens circulating in blood provides a reliable method for diagnosing acute EVD in symptomatic patients. An ELISA for the detection of Ebola virus antigens was first developed at US Army Medical Research Institute of Infectious Diseases (USAMRIID). By this method, viral antigen can be detected in the serum as early as the first day of symptoms. ELISA antigen detection tests utilising monoclonal antibodies   has not been reported clinically, as real time reverse transcription-polymerase chain reaction (RT-PCR) techniques have now replaced these tests. During the recent outbreak, lateral flow immunoassays (LFIs) emerged as powerful tools at the point of care.

Conventional RT-PCR

These assays used polymerase chain reaction (PCR) to amplify the L polymerase, glycoprotein GP, and nucleoprotein NP genes. An important advantage of this method is that RT-PCR detected viral RNA in two specimens collected on the day of symptom onset were negative for antigen at this time point. Early application of conventional RT-PCR demonstrated that it also performed well for detection of virus in other body fluids, such as saliva and seminal fluid.

Real time RT-PCR

This was first developed and tested in early 2000s. It has been seen that lower threshold (Ct) values with higher viral copy numbers correlate with higher mortality. Because existing data indicate that detection of RNA by real-time RT-PCR is variable in the first 72 hours of illness, current guidelines recommend that suspected EVD patients who test negative in this period should be retested after 72 hours of symptoms. Compared to conventional RT-PCR, it yields more rapid results (typically 2 to 3 h); real-time RTPCR assays are now employed by public health reference laboratories.

Automated real time RT-PCR

Several fully automated PCR platforms have been developed in recent years that yields results in 90 minutes or less. The Xpert Ebola assay (Cepheid), is an automated, cartridge based system for RNA extraction and real-time RT-PCR detection of EBOV, NP and GP genes.

The BioFire Defense FilmArray assays (FilmArray Biothreat-Etest and FilmArray NGDS BT-E assay) are automated real-time RT-PCR tests for detection of the EBOV L gene. The Film Array Biothreat-E test, is for the approved use of whole blood and paired urine specimens, while the FilmArray NGDS BT-E test can be used with whole blood, plasma, and serum specimens.

Rapid antigen detection tests

Three EVD rapid diagnostic tests (RDTs) are lateral flow immunoassays (LFIs). ReEBOV (Corgenix, Inc) detects VP40 matrix protein (EBOV, SUDV, BDBV) and is 100% sensitive and 92% specific. Ora Quick Ebola Rapid Antigen Test (OraSure Technologies, Inc) can be done in cadaveric fluid in addition to whole blood while sensitivity is 84% and specificity is 98%. Another rapid antigen detection test is SD Q  (SD Biosensor) for which sensitivity is 84.9% and specificity 99.7%.

Viral Sequencing in the 2014-2015 Epidemic

Viral sequencing tools hold the potential to benefit diagnostic efforts in the setting of an emerging outbreak, identification of viral strains responsible for new transmission chains in an ongoing outbreak, estimation of viral mutation rate, and analysis of the impact of viral mutations on the performance of molecular diagnostic. During the 2014-2015 epidemic, next-generation sequencing (NGS) platforms enabled the characterisation of large numbers of viral genomes in a relatively short time frame.

Summary and future directions

Novel diagnostic platforms, such as automated NAATs and rapid antigen detection tests (RDT) that can be used to decentralised healthcare setting with minimal laboratory infrastructure will likely play a major role moving forward. WHO recommends RDT when RT-PCR testing is not immediately available. As more clinical validation data become available and practical experience is compiled, local regulatory agencies, in collaboration with the WHO, will be responsible for developing updated EVD testing algorithms specific for different healthcare settings in both high-prevalence outbreak and low prevalence surveillance scenarios.

Serological tests nowadays form the backbone of coeliac disease (CD) diagnostics, with biopsy increasingly relegated to a confirmatory role and used only to clarify difficult cases. Official diagnostic criteria are based primarily on the detection of CD-specific antibodies, in particular against endomysium (EmA) or tissue transglutaminase (tTG) and deamidated gliadin peptides (DGP). Analysis of the immunoglobulin class IgG in addition to IgA can secure diagnosis even in persons with an IgA deficiency, which occurs with above average frequency in CD. Antibody tests are also effective for monitoring a gluten-free diet. The genetic analysis of CD-associated alleles can aid exclusion diagnostics, especially in close relatives of CD patients and persons with related diseases.

Coeliac disease

CD is a systemic autoimmune disease with a pronounced genetic predisposition which may affect different organs. The prevalence of coeliac disease is estimated to be around 1% in Europe, although atypical or mild symptoms are suspected to result in a large number of cases remaining undiagnosed. In the Middle East and North Africa (MENA) region, CD appears to be as common as in Europe, with reported prevalences of 0.1% to 1.2% in low-risk populations. CD is triggered by consumption of gluten, which accounts for around 90% of the protein content of many grain seeds. The disease manifests primarily with severe inflammation and damage to the small intestinal mucous membrane (enteropathy). However, due to the disruption of nutrient absorption, a broad spectrum of gastrointestinal and non-gastrointestinal symptoms can develop, including chronic diarrhoea, vomiting, abdominal pain, cramps, growth disorders, weight loss, delayed puberty, miscarriages, anaemia and osteoporosis. Clinical manifestation of CD also includes the chronic skin condition dermatitis herpetiformis (Duhring’s disease).

Pathogenesis

CD is triggered by a combination of genetic and environmental factors. The typical enteropathy is caused by an overreaction of the immune system to components of gluten, especially gliadin. Gliadin is only partially digested in the small intestine, and in CD patients the residual gliadin fragments are able to pass the intestinal barrier into the underlying connective tissue. Here, the enzyme tTG modifies (deamidates) the gliadin peptides at particular positions by converting the amino acid glutamine into glutamate. The modified peptides trigger an immune reaction especially in persons with the genetic variants DQ2 and DQ8 of the human leukocyte antigen (HLA) system, resulting in production of antibodies against both DGP and the body’s own tTG and secretion of pro-inflammatory cytokines. The resulting inflammation of the small-intestinal epithelium leads to atrophy of the intestinal villi and broadening of the intestinal crypts (hyperplasia).

ESPGHAN diagnostic criteria

The current CD diagnostic guidelines of the European Society of Paediatric Gastroentereology, Hepatology and Nutrition (ESPGHAN) centre on the determination of CD-specific antibodies and genetic risk factors. The guidelines define two strategies for diagnosis of CD: one for patients presenting with symptoms of CD and one for asymptomatic individuals with a high risk of CD. The criteria enable high diagnostic accuracy and aim to reduce stress to the patient e.g. from biopsy. If the titer of anti-tTG IgA antibodies is over 10 times the upper limit of normal (>10x ULN) and further non-invasive confirmatory tests (e.g. EmA, HLA-DQ2/DQ8) are performed, intestinal biopsy can be omitted. Biopsy is now only necessary in patients with inconclusive results.

CD-specific antibodies

Autoantibodies against tTG are a very sensitive and specific marker for CD. They can be determined by monospecific immunoassays, such as antigen-coated ELISA or immunoblot or indirect immunofluorescence test (IIFT) based on transfected cells expressing recombinant tTG. They can also be detected by IIFT using tissue sections of liver or oesophagus. In this method they are classified as EmA, whereby tTG is the actual target antigen of these antibodies.

Antibodies against deamidated epitopes of gliadin fragments (anti-DGP antibodies or anti-gliadin fragment antibodies, CD-AGFA) are specific for CD. Antibodies against native gliadin, on the other hand, are less specific and are no longer determined as they are frequently also found in healthy individuals. Anti-DGP antibodies can be determined by ELISA, immunoblot or monospecific IIFT, for example based on the specially designed gliadin analogous fusion peptide GAF-3X.

Anti-tTG and EmA of immunoglobulin class A (IgA) in particular are decisive for diagnosis. However, if a patient has a selective IgA deficiency (sIgAD), a condition which occurs with above average frequency in CD patients, anti-DGP of immunoglobulin class G (IgG) are an important, alternative indicator for CD.

Generally, the determination of CD-specific antibodies should be performed under a normal gluten-containing diet, since they disappear under a gluten-free diet.

Separate or multiplex antibody detection

Different antibody detection methods are available for different laboratory requirements. ELISAs are ideal for high-throughput quantitative analysis of large sample numbers, providing highly reliable diagnostic results. For example, in patients with biopsy-confirmed CD or dermatitis herpetiformis (n = 277) and control subjects (n = 1126), the Anti-tTG IgA ELISA yielded a very high sensitivity of 96% at a specificity of 98%. The Anti-Gliadin (GAF-3X) ELISA yielded sensitivities of 95% for IgG and 87% for IgA with specificities of 94% for IgG and 93% for IgA.

IIFT provides highly specific detection of EmA. The substrates liver and oesophagus are equally well suited for this application. For example, in CD patients (n = 298) and controls (n = 574) the liver substrate yielded a sensitivity of 96% and a specificity of 97% for EmA IgA, while for oesophagus, the sensitivity was 95% at a specificity of 98%. Liver offers the additional advantage that it allows immediate discrimination of EmA from anti-smooth muscle antibodies (ASMA), which occur relatively frequently in the general population. The EUROPLUS IIFT combines a tissue section for detection of EmA with GAF-3X antigen dots for parallel detection of anti-DGP antibodies (Figure 1). Automated evaluation of fluorescence results with EUROPattern software increases the efficiency of the IIFT analysis.

The line blot EUROLINE contains membrane chips coated with tTG and GAF-3X for parallel detection of the corresponding antibodies (Figure 2). In addition, an IgA control band allows simultaneous identification of an IgA deficiency. Automated evaluation of the blot with EUROLineScan software enables quantitative measurement with indication of titers of >10 ULN. The immunoblot demonstrates high specificity and sensitivity with respect to the corresponding ELISAs.

Secure diagnosis without biopsy

Recently published studies have confirmed the usefulness of antibody tests for diagnosis of CD without biopsy. In an international multicenter study of 707 paediatric patients, the value of the criterion anti-tTG IgA >10x ULN was confirmed and resulted in more than 50% of biopsies being avoided. Notably, in a comparative study of anti-tTG ELISAs from different manufacturers, the highest number of >10x ULN results in a panel of biopsy confirmed samples was obtained with the EUROIMMUN ELISA (range: 47% to 90% for the different assays).

In a further 1071 tested samples, the Anti-tTG ELISA (IgA) contributed to a clear diagnosis. The additional determination of anti-DGP antibodies using the Anti-Gliadin (GAF-3X) ELISA (IgG) further increased the statistical accuracy so that the share of tested persons requiring biopsies could be reduced to below 11%.

In the first international prospective study with 898 patients, a large number of biopsies could be avoided by combined testing using the Anti-tTG ELISA (IgA) and the Anti-Gliadin (GAF-3X) ELISA (IgG). This test combination yielded a positive predictive value of 99% and a negative predictive value of 96% and was superior to an approach based on testing total IgA together with anti-tTG IgA.

Reliable serology in patients with IgA deficiency

In patients with sIgAD, the detection of anti-DGP antibodies of class IgG is a useful alternative to IgA-specific tests. In a panel of 34 patients with sIgAD, the sensitivity of the Anti-Gliadin (GAF-3X) ELISA (IgG) exceeded that of both the EmA IIFT (IgG) and the Anti-tTG ELISA (IgG).

Effective monitoring of a gluten-free diet

A gluten-free diet (GFD) is essential for the health of patients with CD. A GFD can be easily monitored using the Anti-Gliadin (GAF-3X) ELISA and the Anti-tTG ELISA. Dietary adherence results in decreasing antibody concentrations (IgA, IgG). In an 18-month study, the majority of 78 tested patients adhering to a GFD showed a significant decrease in CD-associated IgA and IgG antibodies. Moreover, in a comparative study of tests from different manufacturers, the Anti-tTG ELISA (IgA) from EUROIMMUN reacted most sensitively to increasing titers if the dietary rules were not observed.

HLA variants

The determination of the coeliac disease-associated HLA variants DQ2 and DQ8 is recommended particularly in symptomatic patients with an unclear diagnosis and in asymptomatic risk patients, for example first-degree relatives of CD patients and persons with other autoimmune diseases, sIgAD or genetic syndromes. If neither HLA-DQ2 nor -DQ8 is present, CD can be as good as excluded (negative predictive value: at least 98%).

The HLA-DQ molecules are heterodimers composed of an α and a β subunit. The genes coding for the α and β subunits exist in many different forms in the human population. The allele combinations coding for HLA-DQ2.2, -DQ2.5 and -DQ8 are considered risk factors for CD.

All clinically important alleles of the relevant genes (HLA-DQA1 and –DQB1) can be determined using microarray systems such as the EUROArray (Figure 3). This test system, moreover, distinguishes between homo- and heterozygous presence of the alleles coding for the alpha and beta subunits of HLA-DQ2.2 and HLA-DQ2.5, allowing improved risk assessment. The genetic analysis can be performed on whole blood samples or isolated patient genomic DNA and includes fully automated data evaluation.

Perspectives

The increasing usage in clinical practice of the non-biopsy diagnostic strategy for CD has confirmed its high diagnostic accuracy. In particular, the combination of anti-tTG IgA and anti-DGP IgG provided the most reliable diagnosis/exclusion of CD. Performing both tests can strengthen diagnosis in cases with grey zone titers for one or other of the parameters. Based on an extrapolation model from a study of paediatric CD and non-CD patients, it was found that the predictive values for this test combination would remain above 95% even at a clinical prevalence as low as 4%. Therefore, this strategy is optimal even for low-prevalence patient populations. The test combination is, moreover, suitable for all age groups, as the antibody prevalences have been shown to be similar in adults and children. The possibility to obtain a CD diagnosis without invasive, costly and time-consuming biopsy is especially beneficial in paediatric patients.                          

ISO accreditation for laboratory services (ISO 15189) is gaining widespread acceptance and adoption internationally. Indeed, many jurisdictions are making ISO accreditation mandatory for their pathology services to ensure quality and competence.  

For example, Daman (Abu Dhabi Insurance Provider) has instructed that all medical laboratories in the Emirate of Abu Dhabi must have ISO 15189 accreditation status for laboratory test payments to occur. In the Irish Republic, all laboratory transfusion activities must be accredited to the standard. Many more are adopting it voluntarily as a sign of quality and commitment to the highest standards.
One pathology discipline that has been left behind in this accreditation renaissance is Point of Care Testing (POCT). The reasons for this are many, varied and complex. The challenges associated with POCT accreditation and potential solutions are the subject of this editorial piece. The attitudes towards POCT and its management need to change by all those involved, inside and outside the laboratory. Nowadays it would be unthinkable for a reputable laboratory not to undergo ISO 15189 accreditation, but yet for POCT, it is seen as “an impossible dream”. This viewpoint is held because the discipline falls between two stools (hospital and laboratory) making management difficult with no effective organisation/governance structure in place. Resources are typically ring fenced for the main laboratory with POCT usually at the end of the line.

Cleveland Clinic Abu Dhabi is the first hospital in the Middle East to gain accreditation status (ISO 22870) for its POCT services with the United Kingdom Accreditation Service (UKAS). ISO 22870 is an annex document to 15189 and both standards are assessed in parallel by the accreditation agency. Our experience shows that the obstacles facing POCT services to gain accreditation are not insurmountable if the commitment from laboratory and hospital leadership exists. Its benefits once implemented are obvious. Accreditation provides a framework to structure the service, establishes quality benchmarks in a challenging pathology discipline and gives independent and international recognition of competence. 

The following impediments need to be addressed before a decision to undergo accreditation is made.

Commitment across the organisation

POCT involves stakeholders across the entire hospital organisation: nursing, perfusionist, physicians, and respiratory therapists amongst many others. The successful implementation of accreditation requires commitment from all of them. It also requires commitment from the highest level: hospital and nursing leadership. At the outset of our accreditation journey for POCT, meetings were held with the chief nursing officer of CCAD. Support and 100% assistance required was offered and given.   

Subsequent meetings were held with nursing management and floor staff across the hospital. The Chief Nursing Officer was present at some of these meetings seeking support from everyone. Without this public endorsement and engaged commitment from the top, the quality culture and accountability required for a successful POCT programme would not permeate through middle management and patient facing health personnel.

The engagement of busy nursing, physician and allied health personnel is a constant challenge. Staff are focused on the clinical management of patients and not the technical limitations of instrumentation and pre-analytical variables which can cause wrong results. It requires the “soft skills” to build good relations with our nursing colleagues, ensuring that quality outcomes are always assured. Without this collaboration and mutual respect, root causes of quality issues may not be identified to ensure corrective actions are put in place.

Governance and management

The governance and management of POCT in hospitals is frequently misunderstood, ineffective or not in place at all! When establishing a POCT programme it is important to identify and involve the key stakeholders and to initiate a well-defined organisational structure which includes a POCT Committee. Membership should include clinical engineering, hospital risk management, nursing leadership, Information Technology (IT), clinicians, POCT manager, pathologists, hospital quality, finance and nursing educators to ensure a multi-departmental approach is adopted.
Essential documents include the POCT Charter and POCT policy which are developed by the POCT committee and endorsed by the hospital executive.

Developing the POCT policy, which is a high-level document outlining the core principles and rules applicable to the discipline, was the first step in clarifying the role of the POCT programme. It also defines what POCT is in CCAD. This provides clarity if questions are raised about certain testing or devices. Every hospital will have their own definition outlining the scope of testing in their local institution.

The charter details the committee membership, rules and procedures governing the group. It also highlights the reporting relationships with other committees in the hospital, in particular the Medical Executive Committee (MEC) or governing committee of the hospital.  The POCT committee reports directly to the MEC, the management committee of the hospital. The strategic role of the POCT committee is described in the POCT committee charter signed by the Chief Executive Officer (CEO) of the hospital. This endorsement is very important as it gives legitimacy and recognises the central role the POCT committee plays as the gatekeepers of POCT in the organisation.

How the service is managed on a day to day level is another key challenge. POCT is often a sub-discipline of clinical chemistry. However, POCT incorporates other disciplines such as haematology, coagulation, microbiology and molecular biology. Technologies involve a wide variety of different analytic principles: reflectance, lateral flow, electrochemistry and multi wavelength spectrophotometry amongst others. Hospitals with a large POCT programme in place, may decide not to subsume it under another discipline where it might not receive the attention or resources it deserves.

CCAD took the view that POCT is a unique pathology discipline and it should be treated as such. A separate POCT department was established, led by a POCT medical director and POCT manager with dedicated staff. The POCT Medical Director is responsible for the overall operation and administration of the POCT programme whilst the POCT manager is responsible for the technical and scientific oversight, training and competence assessment of testing personnel. The manager also plays a key role in selecting the testing methodologies appropriate for the clinical demand and verifying its performance. This is not the only model for POCT management. Other approaches can be taken (such as that outlined above) and responsibilities can be shared, but adequate resources to provide quality oversight and control must be given!

IT Connectivity

Managing hundreds of devices and 1,000s of operators effectively whilst ensuring quality on a daily basis is beyond the means of any POCT Coordinator or management team. We cannot be everywhere all the time, over everyone’s shoulder. IT management solutions are vital for enabling the oversight and day to day control needed to ensure patient safety and meaningful quality oversight. An integrated system allows for electronic patient identification, operator traceability, reporting of results to the patient’s permanent medical record, real time device monitoring, remote maintenance and that all-important day to day management!
There are many solutions available now from vendors with frequently no cost associated with the software itself. Resources are needed to integrate it with the hospital IT system and ideally patient results flowing to the Electronic Medical Record (EMR). Frequently the best devices come from different vendors. With this in mind, it’s better to procure vendor neutral software that does good things for all devices rather than vendor support software which frequently have limitations with connecting other vendor device types to it.
Training and competency
Most errors relating to POCT are usually not related to the analytical performance of the instrument itself but occur during the pre-analytical phase, i.e. operator associated. The cause of these errors typically includes inadequate training, miscommunication and misunderstanding. An effective well-structured and standardised training and competency programme is vital to ensure quality and patient safety. In a large organisation, this challenge is magnified due to the variety of staff, different mind sets, different skill sets and experiences. 
The volume of caregivers requiring training is frequently beyond the capability of POCT coordinators. Support is needed from nursing administration and education to assist and complete these important tasks. Having this kind of multidisciplinary support and collaboration is key to successfully training significant numbers of staff. It is extremely important that laboratory and nursing leadership have a mutual understanding and appreciation of one another’s departmental operations and requirements to ensure cooperation and success.
Documentation of training is another challenge. A paper-based system detailing all the concomitant requirements such as patient sampling, QC and exams, posed significant administrative demands. 
Tracking and monitoring competency records for many of our devices is performed manually which is very challenging, particularly when competency periods expire. Paperwork is kept centrally and all details recorded and tracked on a spreadsheet.
Software solutions are available now that can automate the process, capturing all the requirements as they are done, simplifying the process. This can transform the management of this perennial problem but requires financial resources which are not always available.  CCAD has procured software to manage our glucometer and coagulation instruments. This has ensured we are able to provide all training and competency requirements for these devices more efficiently. Such a system is known as auto certification. More software has now been recently procured and CCAD intends to implement a similar auto certification system to the glucometers, for as many other instruments as possible in the future
Continual Improvement
One of the most challenging aspects of introducing any quality management system, is establishing an effective system of identifying, reporting and managing non-conformities. This is very challenging with hundreds of devices and thousands of operators.
CCAD uses an online incident reporting and risk management system for our nursing and allied health colleagues. Intuitive software with different icons direct hospital staff to the appropriate drop down menu with specific fields to record the event information. Instructions on how to report any events are included in an online mandatory POCT course for staff when they begin working at CCAD. This course includes how POCT is governed, managed and expectations of responsibilities from clinical staff. As part of this hospital wide event reporting system, a specific POCT option was created as part of the menu to allow hospital staff to report events. This is directed to the POCT manager and the department for follow up.
The POCT department also has its own internal event reporting system, which is part of the quality department system in the laboratory. A dedicated person in the POCT department manages this day to day. This generates a lot of information which gives meaningful data by location, caregiver type, instrument type and testing phase: pre-examination, examination, post examination. We also have a comprehensive audit schedule in place covering all our devices, locations and instrument operator types. This satisfies our ISO obligations. The object of performing audits is to identify non-conformities and address them. The POCT department also wants to identify potential non-conformities-situations identified that may cause future issues. Non-conformities are written up with a close out target of 30 working days. The audit cycle is completed annually.
The POCT department constantly strives to improve our service to the end users and so a POCT email address was created to allow the end users an easier and more convenient way of communicating with the team. The department also periodically seeks input from hospital staff as to how the POCT service and training can be improved. For example, suggestions from our nursing educators and POCT users have led to a simpler and shorter knowledge test for POCT glucose. We have an annual online survey where we seek feedback from our colleagues working on the floors. This generates a lot of feedback on valuable information which we follow up on.
Addressing the myriad of challenges that POCT typically suffer from require resources.   Without adequate financial and human capital resources, best practice, quality and competence cannot be assured and remains an impossible dream. With widespread acceptance of ISO 15189 in the main laboratories, attention will inevitably fall on POCT.  Health authorities will seek the same standards to be applied to POCT. So, change is coming sooner or later. Let the renaissance of POCT accreditation begin! More importantly, accreditation ensures the goals of best practice and patient safety are realised for the discipline of POCT. The impossible dream will become a reality. Let’s get to work!