Global Infectious Disease Surveillance and Detection Assessing the Challenges–Finding Solutions: Workshop Summary (2007) / Chapter Skim
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3 Detection and Diagnostics
3 Detection and Diagnostics
Pages 158-212
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that while emerging diseases and bioterrorism threaten public health, infectious diseases such as tuberculosis and malaria have long imposed a severe burden on the developing world. In their contribution to this chapter, Perkins and Peter Small of the Gates Foundation discuss the need for rapid, accurate, inexpensive, robust diagnostics in developing countries -- a need that could be met by recent advances in genomics, proteomics, and materials science if there was a profitable market.
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Rapid diagnostic tools are also improving infectious disease surveillance in animals. Workshop presenter Alex Ardans, who directs the California Animal Health and Food Safety Laboratory System, described the development of polymerase chain reaction-based (PCR-based)
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Small, M.D. Bill and Melinda Gates Foundation Timely and accurate diagnosis is critical to the global efforts to prevent and treat infectious diseases. And yet, those on the front lines of this battle struggle to make do with inadequate and antiquated testing technology.
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We contend that innovative mechanisms are needed to produce, develop and deploy new and better diagnostic tools for infectious diseases in developing countries. Global Public Health Goals at Risk Acknowledging the impact of the global tuberculosis epidemic in the early 1990s, the World Health Assembly of the World Health Organization (WHO; Geneva)
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Massive investment in biodefense has generated a range of diagnostic technologies intended for front-line use. The growing diagnostics industry can develop new diagnostic tests at a fraction of the cost and time needed to bring drugs and vaccines to licensure.
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tuberculosis using phage-based or molecular methods allow tuberculosis detection and screening for rifampin resistance within 48 hours (Albert et al., 2002; Johansen et al., 2003)
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FIGURE 3-1 Product development path for microbial diagnostics. 3-1 Broadside
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Army Medical Research Institute of Infectious Diseases Rapid disease diagnostics ("serving to identify a particular disease or pathogen") for many infectious agents are not as well developed as other laboratory technologies.
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Ultimately, future rapid diagnostics will shift the window to a point soon after exposure, giving the clinician the greatest opportunity to intervene in the disease process. Orthogonal diagnostic testing is the key to improving the reliability of rapid diagnostic technologies.
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. The Department of Defense has an acquisition program to acquire quality diagnostic products that satisfy the needs of commanders with missions to support the warfighter.
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The acquisition process for developing and fielding a rapid infectious disease diagnostic assays system is designed around an evolutionary strategy. By leveraging commercial technologies that currently exist in the commercial market, and furthering development on those platforms, the final field-deployable system will be quicker and cheaper than trying to obtain the final product up front.
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Immunodiagnostics is the standard against which many agent detection, identification, and diagnostic technologies are compared. Antibody-based assays continue to serve as preliminary and confirmatory diagnostic formats for many infectious and noninfectious diseases.
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The strengths of TRF are its increased sensitivity and the potential for multiplexing. TRF uses the differential fluorescence life span of lanthanide chelate labels compared to background fluorescence.
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The advantage of multiplex assays is that multiple results are available from one sample without individual testing. Up to 100 different biomolecules (proteins, peptides, or nucleic acids)
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However, companies that may have the capability to manufacture these diagnostic tests, and to gain FDA approval for them, typically are not interested in doing so for tests to diagnose tropical
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. diseases or biological threat agents because the commercial demand is low.
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Many characteristics of those future systems are discussed above, but one that is showing some promise is DNA microarrays. Microarrays or DNA chips are one of the latest methods for rapid infectious disease diagnostics.
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. The future for rapid infectious disease diagnostics is the lab-on-a-chip approach, where all sample processing, assay technologies, detection, and reporting are fully integrated into one unit.
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Immunodiagnostics Automated sample processing BW Module Anthrax positive Nucleic acid detection Disposable cassette 3-6A B A Analyte Analyte - Micro Micro C Crude Operator Sample C Specific specific Controller controller Detection Sample sample Interface interface Preprocess preprocess Detection Binding binding D Power Power Microfluidic backbone Subsystem subsystem FIGURE 3-6 Comprehensive integrated diagnostic system. Integrated systems that employ more than one technology along with the sample handling component are being investigated for the next-generation diagnostic systems.
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EMERGING TOOLS FOR MICROBIAL DIAGNOSIS, SURVEILLANCE, AND DISCOVERY W Ian Lipkin, M.D.6 Columbia University Thomas Briese, Ph.D.6 Columbia University Introduction Here we describe methods and perspectives for pathogen surveillance and discovery, and discuss challenges associated with proving causality.
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However, implication of viruses in chronic diseases may be confounded because persistence requires restricted gene expression, classical hallmarks of infection are absent, and/or mechanisms of pathogenesis are indirect or subtle. In the final analysis, investigators are occasionally left with what amounts to an assessment of strength of epidemiological association based on the presence of the agent, its footprints (nucleic acid, and preferably, an immune response)
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Host responses to infection may contribute to pathogenesis. Acute infection with influenza virus or severe acute respiratory syndrome (SARS)
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Over the past decade, the application of molecular pathogen discovery methods resulted in identification of novel agents associated with both acute and chronic diseases, including Borna disease virus, hepatitis C virus, Sin Nombre virus, HHV-6, HHV-8, Bartonella henselae, Tropheryma whippelii, West Nile virus, and SARS coronavirus (Challoner et al., 1995; Chang et al., 1994; Choo et al., 1989; Lipkin et al., 1990; Nichol et al., 1993; Relman et al., 1990, 1992; VandeWoude et al., 1990)
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, employs short, degenerate primer sets designed to hybridize to viral genes that represent larger taxonomic categories than can be resolved in cPCR. Although this modification allowed us to identify West Nile virus as the causative agent of the 1999 New York City encephalitis outbreak (Briese et al., 1999)
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To address the need for highly multiplexed assays, we created MassTag PCR, a platform wherein digital mass tags rather than fluorescent dyes serve as reporters (Figure 3-8)
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Detection and pathogen identification B A Abundance 3. Elution into 96 well loading plate for mass spectrometer analysis Mass Size FIGURE 3-8 Schematic representation of MassTag PCR procedure.
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Establishment of the Greene Microbial Database A critical early step in the development of the MassTag PCR and microarray tools was the establishment of a viral sequence database. This effort was facilitated in 2002 by the move of the ICTVdB (International Committee on Taxonomy of Viruses Database)
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GreeneChips DNA microarrays have potential to provide a platform for highly multiplexed differential diagnosis of infectious diseases. The number of potential features far exceeds that with any other known technology.
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Together with Agilent Technologies, we created a DNA array platform suited to analysis of clinical materials without amplification in culture. Investigation by MassTag PCR and viral DNA 3-9 microarray of blood collected during the 2005 Angola Marburg virus outbreak from an individual who died of hemorrhagic fever failed to yield a pathogen; however, implementation of a panmicrobial DNA array, GreeneChipPm, implicated Plasmodium falciparum infection (Palacios et al., 2007)
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representing a microbe in samples from affected subjects is a primary objective in pathogen discovery. Nonetheless, evidence of infection is bolstered by coterminous evidence of gene expression consistent with an activated host immune response.
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To assess sensitivity, viral RNA extracted from infected cell supernatants (adeno-, West Nile, St. Louis encephalitis, respiratory syncytial, entero-, SARS corona-, and influenza viruses)
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Vignettes in Pathogen Discovery Borna Disease Virus and Neuropsychiatric Disease In 1985, Rott and Koprowski reported that serum from patients with bipolar disorder reacted with cells infected with Borna disease virus (BDV) , an unclassified infectious agent named after a town in Saxony (eastern Germany)
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West Nile Virus Encephalitis In late August 1999, health officials reported an outbreak of encephalitis accompanied by profound weakness in Queens, New York. There was neither an apparent increase in the frequency of encephalitis in New York, nor an automatic reporting event that resulted in detection of the outbreak.
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. Although 70 percent of emerging infectious diseases are zoonoses and the coincidence between the human and nonhuman outbreaks was striking, McNamara was unable to persuade her colleagues in human infectious disease surveillance to review materials.
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. This outbreak illustrates the power of molecular methods for addressing the challenges of emerging infectious diseases.
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It is conceivable that biomarkers will be found that are specific for classes of infectious agents and/or provide insights that can guide clinical management. In chronic diseases the most substantive advances are likely to come not from technical improvements, but from investments in prospective serial sample collections and an appreciation that many diseases reflect intersections of genes and environment in a temporal context.
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The current health-care system is economically unsustainable. One solution to this crisis is to convert standard health practice from one that treats symptoms to one that detects disease very early -- even presymptomatically.
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DETECTION AND DIAGNOSTICS FIGURE 3-10 The Bio-Maginot Line. SOURCE: Johnston (2006)
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Valley of the Decision Risk shadow of driven ∆ death Antibiotic resistance Natural pathogens 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 Time Recombinant DNA shuffling Reverse viral genetics DNA Bio revolution Genome RNA i sequencing Chemical gene synthesis FIGURE 3-11 Changing spectrum of biothreat risk. SOURCE: Johnston (2006)
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of host–pathogen interactions and the human immune response to infection. As stated above new technologies are being developed at a rapid pace.
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GLOBAL INFECTIOUS DISEASE SURVEILLANCE AND DETECTION Sequence Knowledge of all of host, bugs, microbes and disease New mechanisms technologies HTP Anything screening you want FIGURE 3-13 The combination of rapid knowledge and technological growth will create the potential to make new pathogens. SOURCE: Johnston (2006)
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The premise for this concept is presented in Figure 3-15. All of the factors that determine a person's health status could be monitored in near-real time by Genes Environment Serum/cell components Age Sex State of health FIGURE 3-15 Biosignature pattern recognition in human diseases.
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A DocInBox diagnostic device relevant to biodefense would have to be capable of detecting the early events of infection against the background of all other causes of change in health status. This type of biosignature diagnosis has two distinctive features.
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If the goal is presymptomatic diagnosis obviously well people need to be monitored. Particularly for infectious disease, it follows that the diagnostic devices should be in the homes or places of work.
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from a model of cowpox infection in mice that the infected mice can be distinguished from mock-infected mice three hours after infection, also by microarray analysis of blood cells. Clearly, more definitive studies of the limitations of presymptomatic diagnosis are needed.
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It will require either reducing care or revolutionizing medicine. If we opt for the latter, the key aspect will be converting medicine to a focus on presymptomatic diagnosis.
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0 $4T 2016 Total U.S. health-care expenditures ($)
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Total U.S. health-care expenditure Gross Domestic Product 18% FIGURE 3-21 In 2005, 18 percent of GDP was spent on health care.
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0 GLOBAL INFECTIOUS DISEASE SURVEILLANCE AND DETECTION Total U.S. energy spending Total U.S.
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2000. The West Nile Virus outbreak of 1999 in New York: The Flushing Hospital experience.
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1994. RNA splicing contributes to the generation of mature mRNAs of Borna disease virus, a non-segmented negative strand RNA virus.
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Nucleic Acids Research 22(25)
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1999. Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States.
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1994. RNA splicing in Borna disease virus, a nonsegmented, negative-strand RNA virus.
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. Rapid infectious disease diagnostic assays.
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