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Point-of-care tests for diagnosing infections in the developing world

      Abstract

      Infectious diseases continue to cause an enormous burden of death and disability in developing countries. Increasing access to appropriate treatment for infectious diseases could have a major impact on disease burden. Some common infections can be managed syndromically without the need for diagnostic tests, but this is not appropriate for many infectious diseases, in which a positive diagnostic test is needed before treatment can be given. Since many people in developing countries do not have access to laboratory services, diagnosis depends on the availability of point of care (POC) tests. Historically there has been little investment in POC tests for diseases that are common in developing countries, but that is now changing. Lack of regulation of diagnostic tests in many countries has resulted in the widespread use of sub-standard POC tests, especially for malaria, making it difficult for manufacturers of reliable POC tests to compete. In recent years increased investment, technological advances, and greater awareness about the importance of reliable diagnostic tests has resulted in rapid progress. Rapid, reliable and affordable POC tests, requiring no equipment and minimal training, are now available for HIV infection, syphilis and malaria, but POC tests for other infections are urgently needed. Many countries do not have established criteria for licensing and introducing new diagnostic tests, and many clinicians in developing countries have become disillusioned with diagnostic tests and prefer to rely on clinical judgment. Continuing advocacy and training in the use of POC tests are needed, and systems for quality control of POC tests need to be developed if they are to achieve their maximum potential.

      Keywords

      Introduction

      Infectious diseases continue to cause millions of deaths every year, the vast majority of them in developing countries, and a huge burden of disability. Because many of the deaths caused by infection are in young children, the burden of disease attributable to infectious diseases, in terms of healthy life-years lost, is high [
      • Bryce J
      • Boschi-Pinto C
      • Shibuya K
      • Black RE
      WHO estimates of the causes of death in children.
      ]. Strategies for reducing the burden of disease caused by infectious diseases include: vaccination programmes, which are now being expanded to cover Streptocccus pneumoniae and Haemophilus influenzae type b infections, in addition to the traditional vaccine-preventable childhood diseases; health education, to promote breastfeeding, hand-washing, and safe sex; the use of insecticide-impregnated bed-nets in malaria-endemic communities; improved provision of clean water and sanitation; and mass drug administration for certain neglected tropical diseases. However, appropriate clinical management of sick patients presenting to health facilities continues to be of paramount importance, and represents a tremendous challenge in global health.
      Most patients in developing countries are treated at health facilities that do not have access to laboratory tests. Patients in rural areas may have to walk for hours to reach a clinic where laboratory services are available. If they are asked to come back for their results the following day or week, many will fail to do so. The 2004 World Development Report cites lack of accessibility as one of the major reasons why health services fail [
      • World Bank
      ].
      In many cases, patients can be effectively treated by following WHO guidelines for syndromic management. For example, children with fever, cough and rapid breathing are treated for bacterial pneumonia according to guidelines for the Integrated Management of Childhood Illness (IMCI), using an antibiotic that covers the common causes; and patients presenting with symptoms of sexually transmitted infection (STI), such as urethral discharge or genital ulcer, are treated for the common causes of those syndromes [
      • World Health Organization
      ,
      • World Health Organization
      ]. Syndromic management can be highly effective, but inevitably results in overtreatment, resulting in wasted resources and, potentially, increased antimicrobial resistance. In other cases, e.g. where asymptomatic infection is common, clinical features are nonspecific, or treatment is potentially toxic and/or difficult to administer, diagnostic tests are needed. Ideally, the diagnosis should be made at the point of care, so that treatment can be started without delay, and should not depend on the availability of a laboratory or of highly trained staff. This review will focus on point-of-care (POC) tests for infectious diseases that could be used to improve clinical management in resource-limited settings.

      Unmet Needs for POC Tests in the Developing World

      Although POC tests are commercially available for several infectious diseases of public health importance in the developing world, a large unmet need remains [
      • World Health Organization
      ] (Table 1).
      TABLE 1Unmet needs for point‐of‐care (POC) tests in the developing world
      Current diagnosisUnmet need for POC test
      Syndromes/conditions
       Acute lower respiratory infectionsSyndromic management using Integrated Management of Childhood Illness algorithmsTest/biomarker to distinguish between bacterial and viral pneumonia
       Febrile illness in childrenPresumptively treat for malaria in areas of high endemicityMultiplex POC test for common causes of fever
       Sexually transmitted infections, including HIVSyndromic management for patients presenting with symptoms; POC tests to screen for HIV and syphilisPOC test for genital chlamydial and gonococcal infections; POC test for paediatric diagnosis of HIV; POC test for CD4 and viral load
       Antenatal carePOC test for HIV; haemoglobin POC test for anaemiaMultiplex POC test for screening HIV, malaria, syphilis, and anaemia
      Diseases
       MalariaRapid antigen detection tests
       TuberculosisNoneTest for active tuberculosis and antimicrobial susceptibility
       Human African trypanosomiasisNone that works wellPOC test for staging disease; POC test of cure
       Visceral leishmaniasisPOC serological test works well in India but not in AfricaPOC test of cure
      HIV, human immunodeficiency virus.

       Fever in children

      Until 2009, the WHO recommended that all children presenting to health facilities with fever in malaria-endemic areas should be treated presumptively for malaria [
      • Mabey D
      • Peeling RW
      • Ustianowski A
      • Perkins M
      Diagnostics for the developing world.
      ]. Since 2009, as a result of the increased cost of artemisinin combination treatment and the availability of POC tests with acceptable performance, the WHO has recommended that malaria treatment should only be given to children in whom malaria parasites are detected in the blood [
      • World Health Organization
      ]. However, with the increasing use of malaria POC tests, it has become clear that the majority of children presenting to health services with fever in malaria-endemic areas do not have malaria [
      • World Health Organization
      ,
      • Reyburn H
      • Mbatia R
      • Drakeley C
      • et al.
      Overdiagnosis of malaria in patients with severe febrile illness in Tanzania: a prospective study.
      ,
      • Reyburn H
      • Mwakasungula E
      • Chonya S
      • et al.
      Clinical assessment and treatment in paediatric wards in the north-east of the United Republic of Tanzania.
      ]. Moreover, mortality is higher in the group without malaria, many of whom are suffering from other infections that are not adequately treated [
      • Reyburn H
      • Mbakilwa H
      • Mwangi R
      • et al.
      Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tanzania: randomised trial.
      ]. Hospital-based studies in Africa have found that a high proportion of children admitted with fever are suffering from serious bacterial infections [
      • Nadjm B
      • Amos B
      • Mtove G
      • et al.
      WHO guidelines for antimicrobial treatment in children admitted to hospital in an area of intense Plasmodium falciparum transmission: prospective study.
      ,
      • Brent AJ
      • Ahmed I
      • Ndiritu M
      • et al.
      Incidence of clinically significant bacteraemia in children who present to hospital in Kenya: community-based observational study.
      ]. In many cases, because of the spread of antimicrobial resistance, the treatment recommended in the IMCI guidelines may not be effective [
      • Reyburn H
      • Mbakilwa H
      • Mwangi R
      • et al.
      Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tanzania: randomised trial.
      ,
      • Berkley JA
      • Lowe BS
      • Mwangi I
      • et al.
      Bacteremia among children admitted to a rural hospital in Kenya.
      ,
      • Bejon P
      • Mwangi I
      • Ngetsa C
      • et al.
      Invasive Gram-negative bacilli are frequently resistant to standard antibiotics for children admitted to hospital in Kilifi, Kenya.
      ,
      • Gordon MA
      • Graham SM
      • Walsh AL
      • et al.
      Epidemics of invasive Salmonella enterica serovar enteritidis and S. enterica serovar typhimurium infection associated with multidrug resistance among adults and children in Malawi.
      ,
      • Blomberg B
      • Manji KP
      • Urassa WK
      • et al.
      Antimicrobial resistance predicts death in Tanzanian children with bloodstream infections: a prospective cohort study.
      ]. A POC test for the common causes of fever, which will be different in different geographical areas, could have a major impact on the management of life-threatening infections. It is also important to know the local antimicrobial susceptibility of the major bacterial pathogens, which may change rapidly, although POC tests are not necessarily needed to determine this.

       Acute lower respiratory infections

      Acute lower respiratory infections are estimated to cause 1 million deaths annually in children aged <5 years [
      • Bryce J
      • Boschi-Pinto C
      • Shibuya K
      • Black RE
      WHO estimates of the causes of death in children.
      ]. The WHO IMCI guidelines suggest simple criteria for the clinical diagnosis of pneumonia and of severe pneumonia in children presenting to health facilities with fever and cough. Those with pneumonia should be treated with antibiotics, and those with severe pneumonia should be referred to hospital [
      • World Health Organization
      ]. Studies in Asia and Africa have shown that these guidelines are c. 90% sensitive and 70% specific [
      • Lim YW
      • Steinhoff M
      • Girosi F
      • et al.
      Reducing the global burden of acute lower respiratory infections in children: the contribution of new diagnostics.
      ]. In Africa, many children with pneumonia do not have access to a trained health worker, and thus do not receive antibiotics. In Asia and South America, many children receive antibiotics unnecessarily. A simple POC test to identify children who need antibiotic treatment that is at least 95% sensitive and 85% specific, and can be used by a community health worker or pharmacist, could save more than 150 000 lives annually in Africa, and greatly reduce overtreatment in Asia and South America [
      • Lim YW
      • Steinhoff M
      • Girosi F
      • et al.
      Reducing the global burden of acute lower respiratory infections in children: the contribution of new diagnostics.
      ].

       Screening tests for STIs, including human immunodeficiency virus (HIV) infection

      For infectious diseases that cause few or no symptoms but may result in serious sequelae, such as HIV infection and many STIs, diagnostic tests are needed for screening. Early diagnosis and treatment can reduce the risk of development of long-term complications and prevent further transmission, including transmission from mother to child. High-quality POC tests are available for the serological diagnosis of HIV infection and syphilis, but POC tests for other STIs, especially gonorrhoea and chlamydial infection, are urgently needed [
      • Mabey D
      • Peeling RW
      • Ballard R
      • et al.
      Prospective, multi-centre clinic-based evaluation of four rapid diagnostic tests for syphilis.
      ,
      • Aledort JE
      • Ronald A
      • Rafael M
      • et al.
      Reducing the burden of sexually transmitted infections in resource-limited settings: the role of improved diagnostics.
      ].
      POC tests to detect antibodies to HIV-1 and HIV-2 have revolutionized the diagnosis of HIV infection in developing countries, greatly increasing access to screening [
      • Schito ML
      • D’Souza MP
      • Owen SM
      • Busch MP
      Challenges for rapid molecular HIV diagnostics.
      ,
      • Pai NP
      • Tulsky JP
      • Cohan D
      • Colford JM
      • Reingold AL
      Rapid point-of-care HIV testing in pregnant women: a systematic review and meta-analysis.
      ]. A POC test for CD4 count could help clinicians in resource-limited settings to decide when to start antiretroviral treatment, and a POC test for viral load would be of great value in identifying treatment failure and the need for second-line treatment. A POC test that would also detect viral antigen or nucleic acid, and hence identify those with acute infection and a high viral load, could be of great public health value [
      • Stevens WS
      • Scott LE
      • Crowe SM
      Quantifying HIV for monitoring antiretroviral therapy in resource-poor settings.
      ,
      • Pilcher CD
      • Christopoulos KA
      • Golden M
      Public health rationale for rapid nucleic acid or p24 antigen tests for HIV.
      ]. A POC test for early paediatric diagnosis would be useful, as maternal antibodies can be detected in sera of infants for up to 18 months [
      • Aledort JE
      • Ronald A
      • Le Blanq SM
      • et al.
      Reducing the burden of HIV/AIDS in infants: the contribution of improved diagnostics.
      ]. Increased funding in this area has led to the development of several promising POC technologies for measuring CD4 and viral load. Their performance needs to be evaluated before widespread adoption.

       Prenatal care

      POC tests are urgently needed to provide better care for pregnant women, as they have difficulty in walking or travelling long distances to seek antenatal services that can screen them for HIV infection, syphilis, malaria and anaemia. A multiplex POC test that can be used with whole blood from a finger prick would be ideal.

       Tuberculosis (TB)

      In 2007, an estimated 13.7 million people were living with active TB, 9.3 million developed TB, and 1.8 million died from TB [
      • World Health Organization
      ]. Because it requires treatment with several drugs for a minimum of 6 months, TB cannot be treated presumptively; a definitive diagnosis must be made before treatment initiation. Resistance to first-line treatment is an increasing problem, especially in developing countries [
      • Van Deun A
      • Martin A
      • Palomino JC
      Diagnosis of drug-resistant tuberculosis: reliability and rapidity of detection.
      ]. The mainstay of diagnosis remains sputum microscopy. It is, at best, 70% sensitive, and less so in HIV-positive patients. Moreover, it is laborious and time-consuming, and requires electricity, a functioning microscope, and a well-trained technician. Culture is more sensitive, but takes up to 6 weeks on conventional media. Rapid liquid culture systems can give a result within 10 days, and can also provide data on antimicrobial susceptibility. Nucleic acid amplification methods are now commercially available, but are prohibitively expensive. A simple, affordable POC test for TB that could also identify drug-resistant strains would be of enormous public health benefit [
      • Dorman S
      New diagnostic tests for tuberculosis: bench, bedside and beyond.
      ,
      • Pai M
      • Minion J
      • Sohn H
      • Zwerling A
      • Perkins MD
      Novel and improved technologies for tuberculosis diagnosis: progress and challenges.
      ,
      • Medicins Sans Frontieres
      Defining test specifications for a TB POC test.
      ].

       Neglected tropical diseases

      Human African trypanosomiasis (HAT) and visceral leishmaniasis (VL) are parasitic infections that are almost invariably fatal unless treated. Because they affect mainly poor rural communities, progress in developing new treatments has been slow, and both require courses of parenteral treatment that are potentially toxic. A POC agglutination test for antibody has been developed for HAT, but its performance is suboptimal, and it is only useful for diagnosing the West African form of the disease [
      • Inojosa WO
      • Augusto I
      • Bisoffi Z
      • et al.
      Diagnosing human African trypanosomiasis in Angola using a card agglutination test: observational study of active and passive case finding strategies.
      ]. As treatment of HAT depends on whether or not the central nervous system is involved, it cannot be started until a lumbar puncture has been performed, with a cell count on cerebrospinal fluid. A simple POC test for HAT, which would identify those with central nervous system involvement, would be of great value. A simple lateral-flow POC test, which detects antibody, has been developed for VL. It is highly specific, and has good sensitivity in Asia, but is less sensitive in African populations [
      • Boelaert M
      • El Safi S
      • Hailu A
      • et al.
      Diagnostics tests for kala-Azar: a multi-centre study of the freeze-dried DAT, rK39 strip test, and KA-tex in East Africa and the Indian sub-continent.
      ,
      • Romero HD
      • de Silva LA
      • Silva-Vergara ML
      • et al.
      Comparative study of serologic tests for the diagnosis of asymptomatic visceral leishmaniasis in an endemic area.
      ]. For both VL and HAT, a POC test of cure would also be of great value.

      Challenges in Providing POC Tests in the Developing World

      Lack of access to good-quality diagnostic tests for infectious diseases is a major contributor to the enormous burden of infectious diseases in the developing world. The challenges are gradually being overcome, but progress has been slow.

       Lack of investment in diagnostic research and development and in diagnostic services

      Diagnostics and diagnostics research are often undervalued. The Lewin report on the value of diagnostics noted that although diagnostics comprise <5% of hospital costs and about 1.6% of all USA Medicare costs, their findings influence 60–70% of healthcare decisions [
      • The Lewin Group
      ]. In the developing world, expenditure on diagnostics is often a negligible proportion of healthcare spending. A WHO report showed that only 6% of health expenditure at a district hospital in Malawi is on diagnosis [
      • WHO Task Force on Health Economics
      ].
      The development of a diagnostic test is estimated to take 5–10 years, with an investment ranging from $2 million to $10 million [
      • Kettler H
      • White K
      • Hawkes S
      ]. For products with a viable commercial market, this is driven, funded and managed largely by the private sector, drawing on appropriate expertise as needed. In the developing world, there has been little private sector interest in investing in diagnostic product development, because of a perceived lack of return for investment.

       Lack of regulatory standards for the approval of diagnostics

      National and international regulatory processes for drugs provide safeguards for their safety and efficacy. Most countries have a process for reviewing research evidence from drug trials to determine whether a new drug should be introduced and how it should be used. Unfortunately, apart from tests used for blood banking, regulatory standards are often lacking for diagnostic tests, especially tests for diseases that are uncommon in industrialized countries [
      • World Health Organization
      Regulation of in vitro diagnostics: a global Perspective.
      ,
      • Peeling RW
      • Smith PG
      • Bossuyt PM
      A guide for diagnostic evaluations.
      ]. As a result, diagnostic tests are often sold and used in the developing world without any evidence of effectiveness.

       Variable quality of laboratory services

      Laboratory diagnosis improves patient care most efficiently within well-managed healthcare systems. This requires the following: technical competence, access to good-quality reagents, and an understanding of quality control; healthcare providers who value and are able to interpret laboratory results to guide clinical management; and a system for timely communication between the laboratory and the healthcare provider. Even when laboratory services are available, there are often problems with the quality of the services, owing to lack of resources, supplies, and trained personnel [
      • Petti CA
      • Polage CR
      • Quinn TC
      • Ronald AR
      • Sande MA
      Laboratory medicine in Africa: a barrier to effective health care.
      ]. These problems lead to physicians not trusting laboratory results, which in turn leads to further neglect of laboratory services.

      The Way Forward

      The year 2008 marked the 30th anniversary of the declaration of Alma-Ata at the International Conference of Primary Health Care, at which United Nations member states committed to strengthen primary healthcare for the attainment of health to permit people to lead socially and economically productive lives [
      • Haines A
      • Horton R
      • Bhutta Z
      Primary health care comes of age. Looking forward to the 30th anniversary of Alma-Ata.
      ]. The use of appropriate technology that is affordable, relevant to the needs of the population and scientifically sound was emphasized. In terms of diagnostics, what are technologies that can be used in primary-healthcare settings to improve global health?

       The ideal POC test

      The acronym ASSURED was coined at a 2003 WHO Special Programme for Research and Training in Tropical Diseases (WHO/TDR), for the ideal characteristics of a test that can be used at all levels of the healthcare system [
      • Kettler H
      • White K
      • Hawkes S
      ] (Table 2).
      TABLE 2The ideal rapid test: ASSURED criteria
      A = Affordable
      S = Sensitive
      S = Specific
      U = User‐friendly (simple to perform in a few steps with minimal training)
      R = Robust and rapid (can be stored at room temperature and results available in <30 min)
      E = Equipment‐free or minimal equipment that can be solar‐powered
      D = Deliverable to those who need them
      Few existing tests fulfil all of these criteria. In 2004, the Bill & Melinda Gates Foundation convened a Global Health Diagnostics Forum to determine the attributable benefits of improved diagnostics for global health [
      • Hay Burgess DC
      • Wasserman J
      • Dahl CA
      Global health diagnostics.
      ]. The conclusion was that investment in increasing access to diagnostics will have a greater impact than improvements in test performance.

       Advocacy for appropriate diagnostics

      Major efforts are needed to draw attention to the importance of improved diagnostics for global health. Advocacy should be aimed at donors, at policy-makers in developing countries, and at the private sector, including both the diagnostics and the pharmaceutical industries, as better diagnostics can decrease the cost of clinical trials and facilitate evidence-based use of drugs in the developing world.
      In the last decade, donors and funders, notably the Bill & Melinda Gates Foundation, the US National Institutes of Health, the Wellcome Trust, the UK Department of International Development, and the European Commission, have increasingly invested in the development of improved diagnostics for the developing world. It is hoped that this increase in funding will result in a robust pipeline of candidates and products along the diagnostic developmental pathway. But advocacy for diagnostic leadership in developing countries to create or strengthen the health infrastructure for better utilization of existing and improved diagnostics is still needed.

       Technological advances

      The human genome and genomes of major infectious disease pathogens have been sequenced, making it possible to identify novel microbial diagnostic targets and biomarkers as ‘signatures’ of infection. Rapid progress in microbial genetics and proteomics, together with breakthroughs with innovative technologies, are currently creating opportunities for the field to move rapidly forwards if funding is made available. New technologies have the potential to improve specimen processing, to enrich diagnostic targets, and to amplify signals for rapid detection [
      • Mabey D
      • Peeling RW
      • Ustianowski A
      • Perkins M
      Diagnostics for the developing world.
      ,
      • Yager P
      • Domingo GJ
      • Gerdes J
      Point of care diagnostics for global health.
      ].
      Promising technologies that are being marketed or in the late stages of development include the following: the use of magnetic beads to concentrate nucleic acid or antigens in clinical samples without the need for centrifugation [
      • Nargessi D
      • Ou C-Y
      MegaZorb: a simple tool for rapid isolation of viral nucleic acids.
      ]; a variety of isothermal nucleic acid amplification techniques, which can provide the sensitivity of current nucleic acid amplification techniques without the need for thermal cycling—some of these, such as recombinase polymerase amplification technology, can provide a result in 15 min with the use of a battery-powered instrument [
      • Piepenburg O
      • Williams CH
      • Stemple DL
      • Armes NA
      DNA detection using recombination proteins.
      ]; nanobiosensors, which can detect low levels of microbes in a biological sample in seconds [
      • Zelada-Guillen GA
      • Riu J
      • Duzgen A
      • Rius FX
      Immediate detection of living bacteria at ultralow concentrations using a carbon nanotube based potentiometric aptasensor.
      ]; hand-held microfluidic devices, which are gradually being commercialized for multiplex detection of infectious diseases [
      • Rodriguez WR
      • Christodoulides N
      • Floriano PN
      • et al.
      A microchip CD4 counting method for HIV monitoring in resource-poor settings.
      ,
      • Sia SK
      • Linder V
      • Parviz BA
      • Siegel A
      • Whitesides GM
      An integrated approach to a portable and low cost immunoassay for resource-poor settings.
      ,
      • Sorger PK
      Microfluidics closes in on point of care assays.
      ]; and cost-efficient and robust optical instrumentation for reading fluorescent signals, which are being developed to further increase the sensitivity of POC tests [
      • Obeid PJ
      • Christopoulis TK
      Continuous flow DNA and RNA amplification chip combined with laser-induced fluorescence detection.
      ].
      Enormous investments have been made by governments in the development of rapid detection technologies for agents of bioterrorism. The convergence of these detection technologies with those for diagnostic target concentration and amplification has led to the development of promising POC tests on integrated platforms that will require little user input other than loading the specimen. The result will be displayed in hand-held devices or, if necessary, built-in communications modules will allow data transmission for surveillance purposes.

       Product development partnerships

      In recent years, partnerships such as the Foundation for Innovative New Diagnostics, the Program for Appropriate Technology in Health, the Infectious Diseases Research Institute and the US National Institutes of Health consortia for Point of Care Diagnostics have been working with diagnostic companies to develop POC tests for TB, malaria, STIs, and neglected tropical diseases. These partnerships create opportunities for researchers in both the public and private sectors with disease expertise and knowledge of diagnostic targets to work with those in science and engineering. Test development grants should include funding for scientists to spend time in developing country settings where the test would be deployed before the target product profile can be finalized and the development plan made [
      • Urdea M
      • Penny LA
      • Olmsted SS
      • et al.
      Requirements for high impact diagnostics in the developing world. Nature supplement: determining the global health impact of improved diagnostic technologies for the developing world.
      ]. Recently, the Canadian government announced a 5-year programme, Grand Challenges Canada, whose first call is for proposals for POC test development.

       Drive for innovation in the developing world

      The product pipeline of diagnostics for infectious diseases of public health importance in the developing world is weak, as large diagnostics companies have shown little interest, and companies in the developing world generally do not have sufficient research funding or expertise. The WHO/TDR has recently initiated an African Network for Drugs and Diagnostics Innovation, aimed at promoting and building research and development capacity for target discovery and product development [
      • Mboya-Okeyo T
      • Ridley RG
      • Nwaka S
      The African network for drugs and diagnostics innovation.
      ]. This initiative is supported by the WHO/TDR, the African Development Bank, the European Union, pharmaceutical companies, and governments in the region.
      Discovery research and innovation in public health have often been hampered by issues with intellectual property. The Inter-governmental Working Group on Innovation, Intellectual Property and Public Health, convened by the WHO, has developed a Global Strategy and Plan of Action to lower the barriers for innovation in public health by exploring different options for dealing with intellectual property and patent fees.

       Development of harmonized regulatory standards

      The lack of regulatory standards in developing countries has resulted in POC tests of low quality being sold and used in many developing countries [
      • World Health Organization
      Regulation of in vitro diagnostics: a global Perspective.
      ]. Companies with high-quality tests cannot compete in markets flooded with cheap, low-quality tests. There is an urgent need for countries to adopt quality standards in the approval of diagnostic tests. As most companies do not have funds to conduct trials in every country, securing agreements among countries to reduce regulatory bureaucracy by adopting harmonized regulatory standards with an international or regional platform would reduce the cost for companies seeking to register their products in multiple countries. Those savings can be passed onto the customers, while ensuring purchasing options and competition to maximize the choice of proven diagnostic technologies.
      Although there are diagnostic manufacturers’ associations in Europe, the USA, Japan, China, and India, the establishment of an international federation of diagnostic manufacturers’ associations would give the diagnostics industry a single voice and an enhanced ability to negotiate with governments and international agencies. Like the International Federation of Pharmaceutical Manufacturers’ Association, this federation should set quality standards and develop a Code of Conduct for its members, so that the industry has credibility. Like the pharmaceutical industry, this federation would need to work with governments to deal with counterfeit products entering the health system. Creative solutions are also needed to regulate Internet services that promote and sell unproven diagnostic tests.

       Bridging the gap between research and policy

      Even when diagnostic products are available, many governments do not have clearly defined processes to select tests and develop policy and guidelines for their appropriate use. The criteria for selection and procurement should be based on test performance, reproducibility, heat stability, cost, the indications for use, and the settings in which the tests will be used. However, the evaluation of test performance and other operational characteristics often suffers from a lack of rigour, such as insufficient sample size or inappropriate study population. To address the lack of quality standards in diagnostics evaluations, the WHO/TDR has assembled a Diagnostics Evaluation Expert Panel to provide advice on the design and conduct of diagnostic evaluations. In collaboration with the Nature Publishing Group, supplements (http://www.who.int/tdr) on Evaluating Diagnostics have been published for malaria, STIs, and VL.

       Capacity building for uptake and delivery of POC tests

      Technological advancement is only one side of the coin [
      • Pang T
      • Peeling RW
      Diagnostic tests for infectious diseases in the developing world: two sides of the coin.
      ]. Even when a test with acceptable performance is available, there are considerable challenges and difficulties in introducing new tests in developing countries. Test introduction and sustainable adoption depend on a robust healthcare system and many other factors, including supply chain management, to avoid frequent stockouts of diagnostics and/or drugs.
      Screening of pregnant women for syphilis is recommended policy in most countries, yet it is estimated that 500 000 babies die each year of congenital syphilis in sub-Saharan Africa, because of lack of access to antenatal screening [
      • Schmid G
      Economic and programmatic aspects of congenital syphilis prevention.
      ]. Although several rapid syphilis tests have been found to have acceptable performance characteristics and to be cost-effective, and a rapid chlamydial test has been shown to lead to more cases being treated than PCR, few countries have taken advantage of these new tools [
      • Mabey D
      • Peeling RW
      • Ballard R
      • et al.
      Prospective, multi-centre clinic-based evaluation of four rapid diagnostic tests for syphilis.
      ,
      • Gift TL
      • Pate MS
      • Hook EW
      • Kassler WJ
      The rapid test paradox: when fewer cases detected led to more cases treated.
      ,
      • Peeling RW
      • Mabey D
      • Holmes KK
      Diagnostics for sexually transmitted infections: the way forward.
      ,
      • Senior K
      The complex art of making diagnostics simple.
      ]. The Bill & Melinda Gates Foundation is funding a multi-country project on the feasibility and cost-effectiveness of using rapid syphilis tests for screening prenatal women and high-risk populations. It is hoped that these implementation projects will identify barriers, build capacity for stock management and procurement, and encourage the uptake of POC tests.
      Global health initiatives, such as the Global Fund for AIDS, TB, and malaria, the President's Emergency Program for AIDS Relief, and the President's Malaria Initiative, in addition to funding improved care and treatment, have made significant progress in terms of improving the capacity of developing countries to offer healthcare, including quality diagnostic services. Other non-governmental organizations and universities have also increased their efforts at building capacity for diagnostic testing and quality management of laboratories [
      • Plate DK on behalf of the Rapid HIV Test Evaluation Working Group
      Evaluation and implementation of rapid HIV tests: the experience in 11 African countries.
      ,
      • Martin R
      • Hearn TL
      • Ridderhof JC
      • Demby A
      Implementation of a quality systems approach for laboratory practice in resource-constrained countries.
      ,
      • Bates I
      • Maitland K
      Are laboratory services coming of age in sub-Saharan Africa?.
      ].

       Quality assurance

      Quality assurance is often considered to be a luxury in developing countries and, perhaps as a result of this, many doctors have little confidence in the results of diagnostic tests. Once POC tests have been introduced, it will be important to make proficiency panels widely available to ensure that they are correctly used [
      • Senior K
      The complex art of making diagnostics simple.
      ,
      • Plate DK on behalf of the Rapid HIV Test Evaluation Working Group
      Evaluation and implementation of rapid HIV tests: the experience in 11 African countries.
      ].

       Educating healthcare providers

      Health providers need to be educated on how to use and interpret POC tests correctly. This should be included in medical and nursing school curricula, and continuing medical education should be provided to doctors, with updates on diagnostics, similar to those for drugs provided by the pharmaceutical industry.

      Conclusion

      Many high-quality diagnostic tests for infectious diseases are commercially available, but they are neither accessible nor affordable to most patients in the developing world, where laboratory services are often limited to major urban centres. By increasing access to appropriate diagnosis and treatment, POC tests for infectious diseases could save many lives in developing countries. Reliable and affordable POC tests are available for HIV infection, malaria, syphilis, and some neglected tropical diseases, and it is likely that POC tests for other diseases will become available in the near future. POC tests can be used to improve global health, but only if they are rigorously evaluated, correctly used, and effectively regulated.

      Transparency Declaration

      Prof. Peeling has received grants for diagnostics research from the Bill and Melinda Gates Foundation. Prof. Mabey has received grants for diagnostics research from the Wellcome Trust and from the International Trachoma Initiative, which is funded by Pfizer Inc. Neither author has a commerical relationship with the diagnostics industry, and neither has any conflict of interest related to the submitted manuscript.

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