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Laboratory Diagnostic Testing for Borrelia Burgdorferi Infection1 4 Laboratory Diagnostic Testing for 1 Borrelia burgdorferi Infection Barbara J.B. Johnson 4.1 Introduction tests include culture of Borrelia from skin or blood and occasionally cerebrospinal fluid Serology is the only standardized type of (CSF), and detection of genetic material by laboratory testing available to support the PCR in skin, blood, synovial fl uid and CSF. clinical diagnosis of Lyme borreliosis (Lyme These tests have specialized roles in research disease) in the USA. It is also the only type of and in academic and reference laboratories diagnostic testing approved by the US Food but are not available for routine use. Culture and Drug Administration (FDA). Of the 77 and PCR each have distinct limitations that devices cleared by the FDA for in vitro will be noted in this chapter. diagnostic use for Lyme disease, all are Diagnostic tests are of clinical value designed to detect immune responses to only if they are used appropriately. This has antigens of Borrelia burgdorferi sensu stricto, become particularly important in the fi eld of particularly IgM and IgG (FDA, 2010). diagnostic testing for Lyme disease, as both Serological tests do not become positive until patients and doctors hear conflicting an infected individual has had time to information about the risk of Lyme disease develop antibodies. In Lyme disease, this in various environments. Furthermore, means that early acute disease characterized patients are sometimes given laboratory by an expanding rash (erythema migrans or diagnostic tests when they lack objective EM) at the site of a tick bite cannot be reliably signs of Lyme disease and a history of diagnosed by serology. Aft er a few weeks potential exposure to infected vector ticks. A of infection, however, immunocompetent healthcare provider must estimate the pre- people will have made enough antibodies test likelihood that a patient has Lyme that serology is useful for confirming disease in order to under stand the positive exposure to B. burgdorferi in all subsequent and negative predictive values of tests for stages of Lyme disease. Antibody levels Lyme disease. Fortunately, there are remain elevated for months to years aft er the resources available to assist providers in in fection is cured. making this judgement. A variety of direct tests for the agent of It is important to know that laboratories Lyme borreliosis have been developed. Direct may off er ‘in-house’ testing for Lyme disease 1 The fi ndings and conclusions in this article are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention. © CAB International 2011. Lyme Disease: An Evidence-based Approach (ed. J.J. Halperin) 73 74 B.J.B. Johnson that does not require review and approval by 4.2 Two-tiered Serology: the Current the FDA. Because some in-house tests have Standard for Serodiagnosis in North not been rigorously developed and validated, America the Centers for Disease Control and Prevention (CDC) and FDA recommend that The public health agencies of the USA and these tests only be used when their accuracy Canada advocate a two-step process for and clinical usefulness have been documented measuring antibodies in blood when Lyme in peer-reviewed scientifi c literature (CDC, disease is suspected. The CDC recommends 2005). Unvalidated tests as of 2010 include two-tiered testing both for the evaluation of capture assays for antigens in urine, individual patients (CDC, 1995) and for immunofl uorescence staining or cell sorting epidemiological surveillance for Lyme of cell wall-defi cient or cystic forms of B. disease (CDC, 1997). This recommendation burgdorferi, lymphocyte transformation tests, was developed with the participation of the quantitative CD57 lymphocyte assays, relevant major agencies of the USA, including ‘reverse Western blots’ (Feder et al., 2007), the FDA, the National Institutes of Health, in-house criteria for interpretation of im- the Council of State and Territorial muno blots and measurements of anti bodies Epidemiologists, the Association of Public in synovial fl uid. Health Laboratories and the Clinical This chapter considers the diagnostic Laboratory Standards Institute2 (ASTPHLD testing for B. burgdorferi sensu stricto and CDC, 1995). The Canadian Public Health infection, the only organism established to Laboratory Network (2007) guidelines also cause Lyme disease in North America. Lyme recommend two-tiered testing. The Infectious disease also results from infection by Borrelia Diseases Society of America (IDSA) has garinii or Borrelia afzelii in Europe and Asia, as endorsed two-tiered serology to support the well as by the recently described Borrelia diagnosis of Lyme disease in patients who spielmanii in Europe (Wang et al., 1999; Richter have manifestations other than acute EM et al., 2006; Fingerle et al., 2008). Borrelia (Wormser et al., 2006). valaisiana and Borrelia lusitaniae have been A schematic summarizing the features of associated anecdotally with Lyme disease in two-tiered serology is shown in Fig. 4.1. The some parts of Europe (Crowder et al., 2010), fi rst tier consists of a sensitive initial particularly B. lusitaniae in Portugal (Collares- serological test or tests that detect class- Pereira et al., 2004). Borrelia bisett ii has been specifi c antibodies (IgM and IgG, either cultured from a few patients in Europe (Strle together or separately). First-tier tests are et al., 1997), but has not been shown to cause enzyme immunoassays (EIAs) such as human disease in North America. Diagnostic ELISAs or, rarely today, indirect im- tests for B. burgdorferi sensu stricto will not munofl uorescence assays (IFAs) as they necessarily perform well for infections by require a skilled microscopist and cannot be other genospecies of Lyme disease bacteria, scored objectively. If the result of fi rst-tier although some do (e.g. assays based on the testing is negative, the serum is reported to be C6 peptide of the variable surface antigen negative for antibodies to B. burgdorferi and is (VlsE) or the whole VlsE protein). Guidelines not tested further. If the result is positive or for laboratory diagnosis of European Lyme indeterminate (a value that is sometimes borreliosis are available online in English called ‘equivocal’ or ‘borderline’), a second (Health Protection Agency of the UK, 2010; step should be performed. The indeterminate German Society for Hygiene and Micro- category is the range of test values that biology, 2000). overlaps between Lyme disease patients and 2 The latter two were known at the time as the Association of State and Territorial Public Health Laboratory Directors (ASTPHLD) and the National Committee for Clinical Laboratory Standards (NCCLS), respectively. Laboratory Diagnostic Testing for Borrelia burgdorferi Infection 75 controls and is specifi c to each test. Further (ASTPHLD and CDC, 1995; CDC, 1995). information is needed from a second test in Immunoblots and the recommended criteria order to call the specimen positive or for scoring them are shown in Fig. 4.2. These negative. scoring criteria have been validated for The second tier consists of standardized antibodies to B. burgdorferi sensu stricto, the immunoblott ing, either by using Western agent of Lyme disease in North America, but blots or blots striped with diagnostically not for immune responses to other geno- important purifi ed antigens. When an IgG species of Borrelia. immunoblot is scored as positive (Dressler et Two-tiered serology is considered al., 1993; CDC, 1995), two-tiered testing is positive only if the EIA (or IFA) and the reported as positive. When an IgM immunoblot are both positive. Skipping immunoblot is scored as positive (Engstrom either step increases the frequency of false- et al., 1995; CDC, 1995), Lyme disease serology positive results (see below). is reported as positive with the caveat that First-tier tests commonly use whole-cell this fi nding is clinically relevant only in early antigens of B. burgdorferi grown in vitro. The disease, that is, in the fi rst month of illness immunodominant antigen VlsE also has been Two-tiered serology (immunoblotting conditionally supplements EIAs) Tier 1: IgG or IgM EIAs (combined or separate) Positive or indeterminate Negative Reported as negative; two-tiered protocol complete Tier 2: IgG and/or IgM immunoblots (separate) Either blot positive Negative IgG-positive reported as positive Reported as negative IgM-positive reported as positive BUT clinically relevant only in early disease of less than 1 month duration Fig. 4.1. Two-tiered serology for Lyme disease. 76 B.J.B. Johnson test in 2001 (Liang et al., 1999; FDA, 2010). A diagnostic assay containing entire VlsE molecules expressed as recombinant proteins from both B. burgdorferi and B. garinii (Diasorin) became available as a fi rst-tier test in 2007 (Ledue et al., 2008; FDA, 2010). C6- and VlsE-based assays have the additional feature of detecting antibodies to Eurasian genospecies of Borrelia (i.e. B. garinii and B. azfelii) as well as B. burgdorferi sensu stricto. An extensive peer-reviewed scientifi c literature supports the rationale for and performance of two-tiered serological testing. This algorithm has been validated in both retrospective and prospective studies. The specifi city of two-tiered testing is high – 99% or greater in diagnostic reference centres. The sensitivity is also high aft er the acute phase of EM. Patients with Lyme arthritis or late neuroborreliosis are nearly always sero- positive (97–100%). The rate of seropositivity is lower in patients with acute-phase early neurological disease (80–100%, depending on the population studied). This stage of Lyme disease in particular is the subject of research to improve the sensitivity of serodiagnosis Fig. 4.2. Examples of conventional IgM (left panel) (Dressler et al., 1993; Engstrom et al., 1995; and IgG (right panel) immunoblots. Bands that are Johnson et al., 1996; Bacon et al., 2003; recommended for scoring are labelled. Two Peltomaa et al., 2004; Aguero-Rosenfeld et al., additional bands in the IgG blot are also labelled 2005; Steere et al., 2008; Branda et al., 2010; (OspA and OspB at 31 and 34 kDa, respectively; see text).
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