{"product_id":"understanding-spirochete-infection-tests-a-patients-guide-to-lyme-disease-relapsing-fever-and-syphilis-diagnostics","title":"Understanding Spirochete Infection Tests: A Patient's Guide to Lyme Disease, Relapsing Fever, and Syphilis Diagnostics","description":"\u003cp\u003eSpirochete infections—including Lyme disease, relapsing fever, syphilis, and leptospirosis—are notoriously difficult to diagnose because the bacteria that cause them are hard to grow in the laboratory and often escape detection. This comprehensive review, conducted by French researchers and published in 2019, evaluated the performance of all currently available diagnostic tests for these four infections. The authors found that while PCR (a molecular technique that detects bacterial DNA) has become increasingly valuable for direct diagnosis, no single test is perfect, and both false positives and false negatives remain real concerns. Their most important conclusion: doctors must always interpret test results in the context of each patient's symptoms and exposure history, since laboratory tests alone cannot reliably confirm or rule out these infections.\u003c\/p\u003e\n\n\u003ch1\u003eUnderstanding Spirochete Infection Tests: A Patient's Guide to Lyme Disease, Relapsing Fever, and Syphilis Diagnostics\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: What Are Spirochetes and Why Are They Hard to Diagnose?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#quality\"\u003eQuality Standards: How Diagnostic Tests Are Regulated in France and Europe\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#lyme-direct\"\u003eLyme Disease Diagnosis: Direct Detection Methods\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#lyme-serology\"\u003eLyme Disease Diagnosis: Serology (Antibody Testing)\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#lyme-species\"\u003eLyme Disease: Different Species, Different Test Responses\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#lyme-other\"\u003eLyme Disease: Alternative and Unproven Tests\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#relapsing\"\u003eRelapsing Fever Diagnosis\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#syphilis\"\u003eSyphilis Diagnosis\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eKey Limitations of Current Diagnostic Tools\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eWhat This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eNo single diagnostic test for Lyme, relapsing fever, syphilis, or leptospirosis is perfect; false positives and negatives occur.\u003c\/li\u003e\n\u003cli\u003eTwo-tiered Lyme testing (ELISA followed by immunoblot) improves accuracy; single tests can give up to 27% false IgM positives.\u003c\/li\u003e\n\u003cli\u003eLyme serology is often negative in early erythema migrans (\u0026gt;50% in Europe) but very sensitive in late stages (arthritis 95%, acrodermatitis 98%).\u003c\/li\u003e\n\u003cli\u003eUnproven tests like lymphocyte transformation tests and CD57 markers lack validation; use only accredited laboratories for reliable results.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: What Are Spirochetes and Why Are They Hard to Diagnose?\u003c\/h2\u003e\n\n\u003cp\u003eSpirochetes are a unique family of spiral-shaped bacteria that move using internal structures called pseudoflagella, which allow them to swim through thick fluids such as mucus and connective tissue. Several spirochete species cause significant human diseases, and this review focuses on four of them: \u003cstrong\u003eBorrelia burgdorferi sensu lato\u003c\/strong\u003e (the cause of Lyme disease), \u003cstrong\u003erelapsing fever borreliae\u003c\/strong\u003e (transmitted by ticks or lice), \u003cstrong\u003eLeptospira\u003c\/strong\u003e (the cause of leptospirosis, a worldwide animal-borne infection transmitted through contact with rodent urine), and \u003cstrong\u003eTreponema pallidum\u003c\/strong\u003e (the cause of syphilis, a sexually transmitted infection).\u003c\/p\u003e\n\n\u003cp\u003eWhy are these infections so difficult to diagnose? The bacteria share several frustrating characteristics. They do not stain with the standard Gram stain used in most microbiology labs, and they cannot be grown on ordinary culture media. Some species are so fragile or slow-growing that culturing them takes weeks, and a few cannot be cultured at all in the laboratory.\u003c\/p\u003e\n\n\u003cp\u003eThese diagnostic challenges have sparked considerable public debate—particularly from patient advocacy groups and some physicians—who question the reliability of Lyme disease testing. Interestingly, the authors note, there is no comparable debate for the other spirochetal infections. This review was written to assess what the scientific literature actually says about the value of diagnostic tests for all four of these infections.\u003c\/p\u003e\n\n\u003ch2 id=\"quality\"\u003eQuality Standards: How Diagnostic Tests Are Regulated in France and Europe\u003c\/h2\u003e\n\n\u003cp\u003eBefore diving into test performance, the authors emphasize an important fact: laboratories in Europe and France that perform and sell diagnostic tests for humans must follow strict regulatory standards. These include \u003cstrong\u003eCE marking\u003c\/strong\u003e (a certification that a product meets European legal requirements), inspections by the French Agency for the Safety of Health Products (ANSM), and \u003cstrong\u003eCOFRAC accreditation\u003c\/strong\u003e—a national accreditation required for laboratories performing biological tests.\u003c\/p\u003e\n\n\u003cp\u003eFor molecular biology techniques like PCR (polymerase chain reaction, a method that amplifies and detects bacterial DNA), laboratories must have their methods formally validated. This includes additional testing to ensure there is no contamination in the laboratory that could cause false results. The authors stress an important caveat: \u003cstrong\u003ethe quality of tests performed by laboratories that do not meet these standards cannot be guaranteed\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003cp\u003eOne particularly notable regulation: veterinary laboratories have not been allowed to perform human biological tests since May 30, 2013. This matters because some patients, frustrated with conventional testing, have turned to veterinary labs for Lyme testing—a practice that is now illegal in France and whose results are not validated for human diagnosis.\u003c\/p\u003e\n\n\u003ch2 id=\"lyme-direct\"\u003eLyme Disease Diagnosis: Direct Detection Methods\u003c\/h2\u003e\n\n\u003cp\u003eFor most conditions, the most straightforward way to diagnose an infection is to find the bacterium itself. With Lyme disease, this is easier said than done. The bacterium cannot be detected using standard optical microscopy or Gram staining. Specialized techniques like dark-field microscopy or phase-contrast microscopy can theoretically visualize the spiral-shaped bacteria, but in practice, the bacteria rarely appear in blood samples. In Lyme disease—especially in European clinical presentations—bacteremia (bacteria in the bloodstream) is moderate, short-lived, and occurs only at the very beginning of the infection's spread. Testing blood for the bacterium when a patient has no fever is therefore useless. The few reports of \"positive\" microscopy results have actually been shown to be artifacts—not Borrelia bacteria at all. The review authors conclude that microscopy simply does not perform well enough to be a useful diagnostic tool for Lyme disease.\u003c\/p\u003e\n\n\u003ch3\u003eCulture: Slow and Technically Demanding\u003c\/h3\u003e\n\n\u003cp\u003eCulturing Borrelia from tissue samples (such as skin biopsies, synovial membrane, or cerebrospinal fluid) is possible but requires specialized liquid media—BSK-II, MKP, or BSK-H—incubated at 32–34°C (about 90–93°F). Because Borrelia divides very slowly (the mean time to bacterial growth is 7–20 hours), cultures typically take \u003cstrong\u003emore than 15 days\u003c\/strong\u003e to become positive, and sometimes \u003cstrong\u003eup to 8 weeks or longer\u003c\/strong\u003e. Laboratories must check cultures once a week using dark-field microscopy for at least 8 weeks before declaring a negative result. Adding to the difficulty, Borrelia growth does not cloud the culture medium the way many other bacteria do, so special expertise is required to spot it.\u003c\/p\u003e\n\n\u003cp\u003eBorrelia are also extremely fragile bacteria. Specimens must be inoculated directly into culture media at the patient's bedside—they cannot simply be shipped to a lab. Because of these demanding technical requirements, only a few specialized laboratories in Europe perform Borrelia cultures from human specimens. Even then, while cultures perform well with specimens from erythema migrans (the classic \"bull's-eye\" rash), they lack sensitivity when used on other biological specimens such as cerebrospinal fluid, skin biopsies of acrodermatitis chronica atrophicans (a late-stage skin condition caused by Lyme), and synovial fluid (joint fluid), where only a few bacterial isolates are observed. Importantly, \u003cstrong\u003eno strain has ever been isolated from the blood of patients with chronic symptoms appearing years after a tick bite\u003c\/strong\u003e, and blood culture is therefore currently not recommended.\u003c\/p\u003e\n\n\u003ch3\u003ePCR: A Powerful Tool with Limits\u003c\/h3\u003e\n\n\u003cp\u003ePCR testing detects the genetic material (DNA) of the bacterium and avoids many of the constraints of culture. Several PCR techniques are available, and their performance varies in terms of sensitivity, specificity, and the range of bacterial targets they can detect. Several PCR kits are marketed, but their performance is poorly documented. The authors advise that direct detection of Borrelia by PCR should only be performed by official, accredited specialized laboratories.\u003c\/p\u003e\n\n\u003cp\u003eThe sensitivity of PCR is \u003cstrong\u003emuch higher than culture\u003c\/strong\u003e for the disseminated (spread) skin and joint forms of Lyme disease. However—and this is critical—\u003cstrong\u003ea negative PCR test result cannot rule out Lyme disease\u003c\/strong\u003e. The authors also offer a specific warning: prescribing Borrelia PCR when serology (antibody testing) is negative is not recommended, except for patients with early atypical skin lesions of erythema migrans or very early Lyme neuroborreliosis (neurological Lyme disease).\u003c\/p\u003e\n\n\u003cp\u003eAmong all direct diagnostic techniques, only PCR and culture—despite their limitations—have been validated for detection of Borrelia. Microscopy techniques are too often associated with artifacts and should be avoided.\u003c\/p\u003e\n\n\u003ch2 id=\"lyme-serology\"\u003eLyme Disease Diagnosis: Serology (Antibody Testing)\u003c\/h2\u003e\n\n\u003cp\u003eBecause direct detection is so difficult, the biological diagnosis of Lyme disease today relies mainly on \u003cstrong\u003eserological testing\u003c\/strong\u003e—that is, testing blood for antibodies the immune system produces against the bacterium. In France, as in most European countries and the United States, Lyme disease diagnosis is based on a \u003cstrong\u003etwo-tiered testing strategy\u003c\/strong\u003e. The first test is usually an ELISA (enzyme-linked immunosorbent assay), which is sensitive but not highly specific. If the ELISA is positive or borderline, a second confirmatory test is performed using an immunoblot technique (also called Western blot) to verify the specificity of the anti-Borrelia antibodies. This two-step approach improves the specificity of the final result.\u003c\/p\u003e\n\n\u003ch3\u003eWhat the Research Shows About Test Performance\u003c\/h3\u003e\n\n\u003cp\u003eA recent European meta-analysis (a statistical analysis that combines the results of multiple studies) examined whether immunoblot tests alone performed better than ELISA tests alone for diagnosing Lyme disease in Europe. The findings were striking:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eFor Lyme neuroborreliosis\u003c\/strong\u003e (neurological Lyme disease): ELISA sensitivity was 81% (confidence interval 70–89%), and immunoblot sensitivity was also 81% (confidence interval 57–96%). Specificity was 92% (confidence interval 88–89%) for ELISA and 94% (confidence interval 91–96%) for immunoblot.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eFor Lyme arthritis\u003c\/strong\u003e: ELISA sensitivity was 94% (confidence interval 86–98%) and immunoblot sensitivity was 95% (confidence interval 84–98%). Specificity was 97% (confidence interval 94–98%) for ELISA and 92% (confidence interval 84–96%) for immunoblot.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eIn plain language, this means the two tests perform similarly when used alone—neither is clearly better than the other. The authors also noted a slight—though statistically non-significant—improvement in performance when purified or recombinant antigens (synthetic pieces of bacterial proteins) were used, particularly in patients with Lyme neuroborreliosis.\u003c\/p\u003e\n\n\u003cp\u003eWhy use both tests then? Because the two-tiered process improves the positive predictive value (the chance that a positive result truly means infection) compared with a single test. Using a single ELISA or immunoblot can produce up to \u003cstrong\u003e27% false IgM positive results\u003c\/strong\u003e. IgM antibodies are the first antibodies produced during an infection, and false positives here can lead to unnecessary treatment and anxiety. Since both methods have some degree of specificity, using them in succession increases the reliability of a positive final result.\u003c\/p\u003e\n\n\u003ch3\u003eTest Accuracy Varies by Disease Stage\u003c\/h3\u003e\n\n\u003cp\u003eOne of the most important messages in this review is that serology performance varies dramatically depending on when during the infection the test is performed.\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eErythema migrans (the bull's-eye rash)\u003c\/strong\u003e: No biological test is required for typical cases because the serological test is negative in \u003cstrong\u003emore than 50% of cases in Europe\u003c\/strong\u003e at this stage. Erythema migrans is a localized infection that triggers only a weak immune response. A negative test here should not be used to rule out the diagnosis.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLyme neuroborreliosis (acute phase)\u003c\/strong\u003e: Examination of cerebrospinal fluid (CSF) reveals a lymphocytic cellular reaction (an increase in a type of white blood cell) in \u003cstrong\u003emore than 93% of patients\u003c\/strong\u003e with meningoradiculitis (inflammation of the nerve roots and meninges, a classic neurological manifestation of Lyme). Serum (blood) serology is positive in \u003cstrong\u003e70–89% of cases\u003c\/strong\u003e during the acute phase, and CSF sensitivity is \u003cstrong\u003egreater than 90%\u003c\/strong\u003e.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLate-stage disease\u003c\/strong\u003e: At the stage of Lyme arthritis (joint inflammation), serology sensitivity is \u003cstrong\u003e95%\u003c\/strong\u003e. At the stage of acrodermatitis chronica atrophicans (a late skin manifestation), sensitivity reaches \u003cstrong\u003e98%\u003c\/strong\u003e.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe authors highlight that the very high negative predictive value of serology in late-stage disease means doctors should question a Lyme disease diagnosis if serology is negative in a patient with late-stage symptoms. However, they also add a crucial caveat about treatment: after effective treatment, anti-Borrelia antibodies (including IgM) may persist for months or even years after clinical cure. \u003cstrong\u003eSerological testing is therefore not useful for monitoring treated patients\u003c\/strong\u003e, and the presence of IgM antibodies does not indicate an ongoing infection.\u003c\/p\u003e\n\n\u003ch2 id=\"lyme-species\"\u003eLyme Disease: Different Species, Different Test Responses\u003c\/h2\u003e\n\n\u003cp\u003eThe Borrelia burgdorferi sensu lato complex includes several species with different geographic distributions and clinical presentations. The predominant species in Europe are \u003cstrong\u003eBorrelia garinii\u003c\/strong\u003e and \u003cstrong\u003eBorrelia afzelii\u003c\/strong\u003e, while \u003cstrong\u003eBorrelia burgdorferi sensu stricto\u003c\/strong\u003e is most frequently observed in the United States. These differences matter for diagnosis.\u003c\/p\u003e\n\n\u003cp\u003eSerological tests can partially distinguish between these species because of molecular and antigen differences in their surface proteins. In 1994, Wilske and colleagues developed an immunoblot technique using five recombinant antigens that could detect seroreactivity differences between patients infected with B. afzelii, B. garinii, or B. burgdorferi sensu stricto. Two years later, Norman and colleagues developed an immunoblot using several strains of all three species and made an important discovery: \u003cstrong\u003eEuropean patient sera reacted more strongly to B. garinii and B. afzelii strains, while North American patient sera reacted more strongly to B. burgdorferi sensu stricto antigens\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003cp\u003eThe same study found that sera from patients with neurological symptoms reacted more strongly to B. garinii antigens, while sera from patients with dermatological (skin) presentations reacted more strongly to B. afzelii antigens. However, the authors noted that in about \u003cstrong\u003e8% of tested specimens\u003c\/strong\u003e, the Western blot interpretation (positive vs. negative) could vary depending on which strain was used—a troubling level of variability.\u003c\/p\u003e\n\n\u003cp\u003eOther European studies confirmed these patterns: a preferential association of B. garinii with neurological disorders, B. afzelii with late skin manifestations, and a slight predominance of B. burgdorferi sensu stricto in joint manifestations. As early as 1999, researchers suggested standardizing Western blot techniques using B. garinii and B. afzelii strains across Europe, using a panel of patient sera from various European regions provided by the European Union Concerted Action on Lyme Borreliosis (EUCALB).\u003c\/p\u003e\n\n\u003cp\u003eCommercially available tests in European markets vary in composition and performance. Most are prepared with a mixture of recombinant antigens from the three main pathogenic species (B. burgdorferi sensu stricto, B. garinii, and B. afzelii) to improve sensitivity. However, the authors caution that accurate differentiation of Borrelia species can only be achieved through molecular techniques. Reactivity differences observed in serological tests do not always correspond to what culture or PCR reveals, and relying on them may lead to interpretation errors.\u003c\/p\u003e\n\n\u003ch2 id=\"lyme-other\"\u003eLyme Disease: Alternative and Unproven Tests\u003c\/h2\u003e\n\n\u003cp\u003eSeveral alternative tests are sometimes marketed for Lyme disease diagnosis, but the review authors are clear that their scientific validation is lacking.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eLymphocyte transformation tests (LTT)\u003c\/strong\u003e measure how a patient's immune cells respond to Borrelia antigens in the laboratory. The authors report that LTTs currently lack validation, and published studies have substantial methodological biases. In Lyme neuroborreliosis specifically, the diagnostic value is low: only \u003cstrong\u003e36% sensitivity and 82% specificity\u003c\/strong\u003e—meaning the test misses nearly two-thirds of true cases.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eCD57 marker detection\u003c\/strong\u003e (a test that measures a specific type of immune cell) has been promoted by some practitioners. However, little data exists, and the only case-control study performed (the NIH study) reported a \u003cstrong\u003ecomplete lack of specificity\u003c\/strong\u003e for this test.\u003c\/p\u003e\n\n\u003cp\u003eAs for \u003cstrong\u003erapid diagnostic tests for self-testing\u003c\/strong\u003e at home, the authors state that sensitivity and specificity data are currently very limited. They do not recommend these tests.\u003c\/p\u003e\n\n\u003ch2 id=\"relapsing\"\u003eRelapsing Fever Diagnosis\u003c\/h2\u003e\n\n\u003cp\u003eRelapsing fever borreliae are mainly found in tropical and subtropical regions, particularly in Africa. The causative species include \u003cstrong\u003eBorrelia duttonii, Borrelia crocidurae, Borrelia recurrentis, Borrelia persica, and Borrelia hispanica\u003c\/strong\u003e. They are transmitted by soft ticks (family Argasidae), and one species—Borrelia recurrentis—is transmitted by body lice. An emerging species, \u003cstrong\u003eBorrelia miyamotoi\u003c\/strong\u003e, is transmitted by hard ticks.\u003c\/p\u003e\n\n\u003cp\u003eRelapsing fever is different from Lyme disease in an important way: these bacteria \u003cstrong\u003edo cause significant bacteremia (bacteria in the bloodstream) during febrile episodes\u003c\/strong\u003e. This makes direct detection much more feasible.\u003c\/p\u003e\n\n\u003ch3\u003eDirect Diagnosis of Relapsing Fever\u003c\/h3\u003e\n\n\u003cp\u003eThe usual diagnostic method is \u003cstrong\u003eoptical microscopy after Giemsa staining\u003c\/strong\u003e of a blood smear or thick blood drop. This technique can detect bacterial concentrations of \u003cstrong\u003e10³ to 10⁵ microorganisms per milliliter\u003c\/strong\u003e of blood. Comparative studies have shown that additional methods can increase the sensitivity of optical microscopy:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eQuantitative buffy coat (QBC)\u003c\/strong\u003e—a technique that concentrates white blood cells and any bacteria in them—is supposed to be \u003cstrong\u003e100 times more sensitive than thick blood drop\u003c\/strong\u003e for diagnosing relapsing fever borreliae. However, it requires specialized laboratory equipment that is often unavailable in the endemic regions where relapsing fever occurs.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eDifferential centrifugation, acridine orange staining, and fluorescence microscopy\u003c\/strong\u003e can also contribute to increased sensitivity.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003ePCR techniques have also been developed and show better sensitivity than microscopy. The review includes specific performance data:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eA multiplex quantitative PCR (qPCR) for B. crocidurae, B. duttonii\/recurrentis, and B. hispanica has a cut-off of \u003cstrong\u003e36 Ct (cycle threshold) = 100 copies of plasmids per 5 µl\u003c\/strong\u003e.\u003c\/li\u003e\n  \u003cli\u003eA B. recurrentis qPCR can detect as few as \u003cstrong\u003e3 copies at cycle 40.94\u003c\/strong\u003e and \u003cstrong\u003e32 copies at cycle 36.92\u003c\/strong\u003e—a remarkably sensitive test.\u003c\/li\u003e\n  \u003cli\u003eThick blood drop detects 10⁴–10⁵ organisms\/mL, while quantitative buffy coat detects down to 10³ organisms\/mL.\u003c\/li\u003e\n  \u003cli\u003eInoculation into mice is another method, detecting live Borrelia that can survive in culture.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eCulture remains possible using the same BSK-H medium used for Lyme Borrelia, but it requires expert skills and is rarely used in routine clinical practice. Notably, \u003cstrong\u003enot all relapsing fever Borrelia species grow on this medium\u003c\/strong\u003e. Antigen detection tests (using specific monoclonal antibodies to detect B. crocidurae and B. hermsii) are being developed but are not yet available in clinical practice. Even an innovative technique called MALDI-TOF has been used experimentally to detect B. crocidurae in Ornithodoros sonrai ticks.\u003c\/p\u003e\n\n\u003ch3\u003eIndirect Diagnosis of Relapsing Fever\u003c\/h3\u003e\n\n\u003cp\u003eSerological tests for relapsing fever use specific antigens called \u003cstrong\u003eGlpQ\u003c\/strong\u003e or \u003cstrong\u003eBipA\u003c\/strong\u003e, which are supposed to be absent from the Lyme disease group of Borrelia. However, several studies have reported \u003cstrong\u003ecross-reactions with Borrelia burgdorferi sensu lato\u003c\/strong\u003e (the Lyme group). For instance, cross-reactions have been observed between B. miyamotoi, B. burgdorferi, and B. hermsii in the United States. Another limitation: serology is often \u003cstrong\u003enegative during the first fever episodes\u003c\/strong\u003e of relapsing fever, meaning it should be used primarily as a retrospective diagnostic tool (to confirm an infection that has already occurred) rather than for early diagnosis.\u003c\/p\u003e\n\n\u003ch2 id=\"syphilis\"\u003eSyphilis Diagnosis\u003c\/h2\u003e\n\n\u003cp\u003eSyphilis, caused by \u003cstrong\u003eTreponema pallidum\u003c\/strong\u003e, is a sexually transmitted infection that has been \u003cstrong\u003eon the rise in France since the year 2000\u003c\/strong\u003e—a significant public health concern. The main obstacle to diagnosis and study of this bacterium is its \u003cstrong\u003einability to be cultured in any artificial laboratory medium\u003c\/strong\u003e. This makes laboratory diagnosis entirely dependent on other methods.\u003c\/p\u003e\n\n\u003ch3\u003eDirect Diagnosis of Syphilis\u003c\/h3\u003e\n\n\u003cp\u003e\u003cstrong\u003eDark-field microscopy\u003c\/strong\u003e of chancre (the primary ulcer) or skin lesion samples is highly contributory and gives immediate results. However, performance varies by laboratory and staff expertise, and specialized equipment and qualified personnel are required. Both false positives (caused by commensal spirochetes, especially in the mouth or anus) and false negatives (a negative examination should not rule out syphilis) can occur. Sensitivity is higher during the primary and secondary phases and in early congenital syphilis (when chancres, condyloma latum, mucous patches, and adenopathy are present).\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDirect immunofluorescence\u003c\/strong\u003e (a technique that uses fluorescently labeled antibodies to detect the bacterium) has shown satisfactory results on mucous, skin, or tissue samples, with sensitivity close to \u003cstrong\u003e80%\u003c\/strong\u003e. However, these techniques have become obsolete since PCR tests were commercialized.\u003c\/p\u003e\n\n\u003cp\u003eVarious PCR methods—standard PCR, nested PCR, RT-PCR, and quantitative PCR—have been developed, targeting several genes including bmp, tpp47, tmpA (genes encoding surface lipoproteins), and polA (a gene involved in genome replication). Recent studies found \u003cstrong\u003eno performance differences\u003c\/strong\u003e between PCR tests targeting the 47 Kd membrane protein gene and those targeting the polA polymerase gene. Overall, PCR sensitivity is approximately \u003cstrong\u003e80%\u003c\/strong\u003e, with \u003cstrong\u003e95% specificity\u003c\/strong\u003e. The negative predictive value is \u003cstrong\u003e95%\u003c\/strong\u003e and positive predictive value is \u003cstrong\u003e89%\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003cp\u003eAs with other spirochetes, PCR performance depends on the biological sample tested and the infection stage. Patients with secondary syphilis or HIV co-infection with low CD4 lymphocyte counts have \u003cstrong\u003ehigher rates of spirochetemia\u003c\/strong\u003e (bacteria in the blood) than patients with primary syphilis or early latent syphilis. Blood PCR therefore has better sensitivity in these patients. PCR has been evaluated on swabs of chancres, cutaneous biopsies of secondary syphilis, bone samples, and biological fluids such as serum and cerebrospinal fluid.\u003c\/p\u003e\n\n\u003ch3\u003eNon-Treponemal Tests (NTT)\u003c\/h3\u003e\n\n\u003cp\u003eNon-treponemal tests detect antibodies against \u003cstrong\u003elipids (fats)\u003c\/strong\u003e released when tissues are damaged by the infection, rather than antibodies against the bacterium itself. They use a complex antigen made of cardiolipin, lecithin, and cholesterol. The two most commonly used are the \u003cstrong\u003eVDRL (Venereal Disease Research Laboratory)\u003c\/strong\u003e test and the \u003cstrong\u003eRPR (rapid plasma reagin)\u003c\/strong\u003e test, which uses charcoal particles coated with a mixture of lipid antigens.\u003c\/p\u003e\n\n\u003cp\u003eBecause these tests detect anti-lipid antibodies, they are not specific to Treponema infection—any disease causing tissue damage can produce positive results. This means:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eFalse positives can occur\u003c\/strong\u003e in acute conditions such as hepatitis, infectious mononucleosis, pneumonia, chickenpox, measles, pregnancy, and malaria.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eChronic conditions\u003c\/strong\u003e such as autoimmune diseases (mainly lupus), cancers, leprosy, and intravenous drug use may also cause positive results.\u003c\/li\u003e\n  \u003cli\u003eTherefore, NTTs alone \u003cstrong\u003ecannot confirm a syphilis diagnosis\u003c\/strong\u003e.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eIn terms of timing, NTTs become positive \u003cstrong\u003e10 to 15 days after the primary chancre appears\u003c\/strong\u003e, which is about \u003cstrong\u003e6 weeks after the infectious contact\u003c\/strong\u003e. Without treatment, antibody levels reach their highest point between one and two years after infection, then remain positive at lower levels during the late phases. Complete seronegativity (antibodies disappearing) during tertiary syphilis is extremely rare.\u003c\/p\u003e\n\n\u003cp\u003eNTT titers (concentration levels) correlate with infection activity, which makes them useful for \u003cstrong\u003emonitoring treatment effectiveness\u003c\/strong\u003e. Sensitivity varies by disease stage:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePrimary phase\u003c\/strong\u003e (chancre stage): RPR sensitivity is \u003cstrong\u003e86%\u003c\/strong\u003e, VDRL sensitivity is \u003cstrong\u003e78%\u003c\/strong\u003e\n\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eSecondary phase\u003c\/strong\u003e: Both tests are \u003cstrong\u003e100% sensitive\u003c\/strong\u003e\n\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLate phase\u003c\/strong\u003e: Both VDRL and RPR drop to \u003cstrong\u003e71% sensitivity\u003c\/strong\u003e\n\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eSpecificity is 98%\u003c\/strong\u003e at all infection stages\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eA particularly tricky problem with NTTs is the \u003cstrong\u003eprozone reaction\u003c\/strong\u003e—a phenomenon observed in up to \u003cstrong\u003e2% of patients with secondary syphilis\u003c\/strong\u003e. In serum specimens with an extremely high number of antibodies, the normal antigen-antibody reaction is inhibited, leading to weakly positive, doubtful, or even negative results. The authors explain the solution: samples should be diluted so that titers first increase, then progressively decrease—a classic pattern that alerts the laboratory to the prozone effect.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eKey Limitations of Current Diagnostic Tools\u003c\/h2\u003e\n\n\u003cp\u003eAcross all four infections, the authors identify recurring limitations:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eDirect detection methods lack sensitivity.\u003c\/strong\u003e Whether microscopy, culture, or PCR, all direct methods can miss infections, especially when bacterial loads are low or transient.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eSerological tests have variable sensitivity depending on disease stage.\u003c\/strong\u003e Testing too early (as with erythema migrans in Lyme, or primary syphilis) may produce false negatives because antibodies haven't developed yet.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eCross-reactions between species occur.\u003c\/strong\u003e Antibodies against one spirochete can react with antigens from another, leading to false positives.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAntibodies persist after cure.\u003c\/strong\u003e For Lyme disease and other infections, antibodies can remain detectable for months or years after successful treatment, meaning a positive test doesn't necessarily mean active infection.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eSome widely promoted tests lack scientific validation.\u003c\/strong\u003e Tests like lymphocyte transformation tests and CD57 markers for Lyme disease have poor or unproven performance in peer-reviewed studies.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLaboratory quality varies.\u003c\/strong\u003e Tests performed outside accredited laboratories—including veterinary labs—may not meet quality standards, and their results cannot be trusted.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe authors also note that the medical literature includes claims about microscopy-based detection of Lyme disease that have been shown to be \u003cstrong\u003eartifacts, not real bacteria\u003c\/strong\u003e—a cautionary tale about the importance of properly validated testing.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eWhat This Means for Patients\u003c\/h2\u003e\n\n\u003cp\u003eBased on this comprehensive review, patients and healthcare providers should keep several key principles in mind:\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eClinical context is king.\u003c\/strong\u003e Test results must always be interpreted alongside symptoms, physical examination findings, tick exposure history, and geographic risk. A positive test in someone with no compatible symptoms—or a negative test in someone with classic symptoms—should prompt discussion, not blind acceptance.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eTwo-tiered testing matters.\u003c\/strong\u003e For Lyme disease, the standard two-step approach (ELISA followed by immunoblot for confirmation) significantly improves accuracy compared with a single test. Up to 27% of single-test IgM results can be false positives.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eNegative tests don't always rule out infection.\u003c\/strong\u003e In early Lyme disease (erythema migrans), more than 50% of serology tests are negative in Europe. In such cases, the characteristic rash itself is sufficient for diagnosis—no test is needed.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePositive tests don't always mean active infection.\u003c\/strong\u003e Antibodies can persist for years after successful treatment. Serology is not useful for monitoring treatment success or determining whether a patient is \"cured.\"\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eUse accredited laboratories.\u003c\/strong\u003e Only use laboratories that meet regulatory standards (CE marking, ANSM inspection, COFRAC accreditation). Since 2013, veterinary laboratories in France are not permitted to perform human tests.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eBe wary of unproven tests.\u003c\/strong\u003e Lymphocyte transformation tests, CD57 markers, and home self-testing kits for Lyme disease lack proper scientific validation. Money spent on these tests might be better directed toward evaluation by a knowledgeable physician.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eFor syphilis, combination testing is essential.\u003c\/strong\u003e Non-treponemal tests (VDRL\/RPR) must be combined with specific treponemal tests (like PCR or immunofluorescence) to confirm diagnosis. NTTs alone are vulnerable to false positives from many common conditions.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is the most reliable way to test for Lyme disease?\u003c\/h3\u003e\n\u003cp\u003eThere is no single perfect test. Doctors in Europe and the US usually use a two-tiered strategy: first an ELISA, and if that is positive or borderline, a second confirmatory immunoblot. This two-step approach significantly improves accuracy because a single test can produce up to 27% false IgM positive results.\u003c\/p\u003e\n\u003ch3\u003eCan a negative Lyme disease test completely rule out the infection?\u003c\/h3\u003e\n\u003cp\u003eNo. A negative test cannot reliably rule out Lyme disease, especially early on. In Europe, more than 50% of serology tests are negative when a patient has erythema migrans, the classic bull's-eye rash. In that situation, the rash itself is enough to diagnose, and no test is needed.\u003c\/p\u003e\n\u003ch3\u003eAre home self-testing kits for Lyme disease reliable?\u003c\/h3\u003e\n\u003cp\u003eThe review authors state that data on sensitivity and specificity for rapid diagnostic tests for self-testing at home are very limited. They do not recommend these tests. For accurate results, it is better to use a laboratory that meets regulatory standards, such as CE marking and COFRAC accreditation.\u003c\/p\u003e\n\u003ch3\u003eWhat is the prozone reaction in syphilis testing?\u003c\/h3\u003e\n\u003cp\u003eThe prozone reaction is a problem with non-treponemal tests like VDRL or RPR. In up to 2% of patients with secondary syphilis, extremely high antibody levels inhibit the antigen-antibody reaction, causing weakly positive, doubtful, or even negative results. Diluting the sample reveals the true titer.\u003c\/p\u003e\n\u003ch3\u003eHow is relapsing fever diagnosed?\u003c\/h3\u003e\n\u003cp\u003eRelapsing fever bacteria do appear in the blood during fever episodes. The usual method is microscopy of a Giemsa-stained blood smear or thick drop. PCR is also available and shows better sensitivity than microscopy. Serology is often negative during early episodes, so it is mainly a retrospective tool.\u003c\/p\u003e\n\u003ch3\u003eIs it legal or safe to use a veterinary laboratory for human Lyme testing?\u003c\/h3\u003e\n\u003cp\u003eSince May 30, 2013, veterinary laboratories in France are not allowed to perform human biological tests. Results from such laboratories are not validated for human diagnosis, and the quality of tests performed outside accredited facilities cannot be guaranteed. Patients should only use accredited human diagnostic laboratories.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal Article Title:\u003c\/strong\u003e Médecine et maladies infectieuses 49 (2019) 102–111\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e \u003ca href=\"https:\/\/doi.org\/10.1016\/j.medmal.2019.01.009\" target=\"_blank\" rel=\"noopener\"\u003e10.1016\/j.medmal.2019.01.009\u003c\/a\u003e\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Carole Eldin, Benoit Jaulhac, Oleg Mediannikov, Jean-Pierre Arzouni, Didier Raoult\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eJournal:\u003c\/strong\u003e Médecine et maladies infectieuses, Volume 49, 2019, pages 102–111\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication Details:\u003c\/strong\u003e Received October 26, 2018; Accepted January 21, 2019; Available online February 11, 2019. DOI: 10.1016\/j.medmal.2019.01.009\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAffiliations:\u003c\/strong\u003e The authors are affiliated with IRD, AP–HM, VITROME, IHU-Méditerranée Infection, Aix-Marseille Université (Marseille, France); the National Reference Center for Borrelia, Strasbourg University Hospitals (Strasbourg, France); and the Plateforme de sérologie bactérienne, IHU-Méditerranée Infection.\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research originally published in a scientific journal. While every effort has been made to accurately represent the findings, this article is intended for educational purposes and does not constitute medical advice. Patients with concerns about Lyme disease, relapsing fever, syphilis, or leptospirosis should consult a qualified healthcare professional.\u003c\/em\u003e\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eNote: The original article also covered leptospirosis, which was mentioned in its abstract and introduction. The section on leptospirosis diagnostics was not included in the source text provided for this translation.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47439664382108,"sku":null,"price":0.0,"currency_code":"EUR","in_stock":true}],"url":"https:\/\/diagnosticdetectives.cn\/products\/understanding-spirochete-infection-tests-a-patients-guide-to-lyme-disease-relapsing-fever-and-syphilis-diagnostics","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}