Marc M. Bransten, MD Independent Researcher — Co-Inventor of CIIT — Collaborator with CNRS and INSERM, France

Chronic Lyme disease (CLD), or Post-Treatment Lyme Disease Syndrome (PTLDS), is a complex, debilitating condition that persists well beyond the resolution of acute Borrelia burgdorferi infection [1]. Despite the use of standard antibiotic regimens, a significant subset of patients experience persistent multisystemic symptoms—neurological, musculoskeletal, cardiovascular, endocrine, and psychiatric—that profoundly impair quality of life [2]. This prolonged disease course implicates mechanisms such as chronic bacterial persistence, immune system dysregulation, autoimmune activation, mitochondrial dysfunction, and systemic inflammation [3].

Conventional serological diagnostics, including ELISA and Western Blot, have demonstrated limited sensitivity and contribute to widespread underdiagnosis and misclassification [4]. This review synthesizes evidence from meta-analyses and longitudinal studies to present a comprehensive immunopathological framework for CLD [5]. Central to this redefinition is the Cold Infection Immune Test (CIIT), a novel immunological assay co-invented by Dr. Marc M. Bransten in collaboration with CNRS and INSERM [6]. CIIT represents a breakthrough in diagnosing active Borrelia infection, including in patients who test negative via standard serological methods [6]. Preliminary validation based on its patented methodology suggests high sensitivity and specificity, but additional multicenter trials are urgently required to confirm its clinical and epidemiological utility as of 02:17 AM CEST on Friday, July 11, 2025 [7].

We critically examine the persistent infection hypothesis, immune exhaustion patterns, neuroinflammation, vascular pathologies, and mitochondrial impairment [8]. Emphasis is placed on integrating advanced diagnostics—such as PET-MRI imaging and CIIT-guided immune profiling—into therapeutic protocols [9]. The article also rebuts the 2006 and 2020 IDSA guidelines, highlighting scientific oversights, exclusion of critical data, and the influence of undisclosed conflicts of interest [10,11]. By consolidating insights from over 125 peer-reviewed studies, this review aims to support a paradigm shift: recognizing CLD as a legitimate chronic infectious and immune-mediated condition that demands robust diagnostics, individualized treatment, and global policy reconsideration [12]. CIIT, in particular, offers a gateway to precision medicine for Lyme disease and deserves immediate attention through formal clinical validation studies [6].

Keywords: Chronic Lyme disease; Borrelia burgdorferi; CIIT; persistent infection; immune dysregulation; autoimmunity; mitochondrial dysfunction; biomarkers; PET-MRI; neuroinflammation; vascular pathology; diagnostic innovation.

Chronic Lyme disease (CLD), or Post-Treatment Lyme Disease Syndrome (PTLDS), remains one of the most misunderstood conditions in modern medicine [13]. Initially defined as a localized zoonotic infection caused by Borrelia burgdorferi, CLD has evolved into a global public health issue with persistent, multisystemic manifestations—neurological, musculoskeletal, cardiovascular, endocrine, and psychiatric—that often extend well beyond the acute infection phase [14]. Despite standard antibiotic treatments, a substantial number of patients experience lingering symptoms.

Alternative transmission mechanisms have gained growing empirical support.

Diagnostics remain a critical bottleneck. The conventional two-tier ELISA/Western Blot approach, endorsed by IDSA, underperforms significantly in chronic stages.

This has prompted development of novel diagnostic strategies. Among them, the Cold Infection Immune Test (CIIT), co-invented in 2019 by Dr. Marc M. Bransten in partnership with CNRS and INSERM, introduces a paradigm shift [6].

Borrelia persistence is no longer a theoretical concern.

The enduring symptoms observed in chronic Lyme disease (CLD) patients—often persisting months or years after initial antibiotic treatment—strongly suggest that Borrelia burgdorferi possesses mechanisms enabling persistent infection and sophisticated immune evasion [32]. These mechanisms undermine the assumption, embedded in many official guidelines, that early antibiotic treatment always leads to bacterial eradication [33]. On the contrary, Borrelia has repeatedly demonstrated an extraordinary capacity for survival within the host, often shielded from both immune clearance and pharmacological targeting [34].

Multiple experimental models and autopsy findings have validated Borrelia’s ability to persist intracellularly.

Beyond intracellular evasion, Borrelia adapts morphologically to survive hostile environments.

Borrelia burgdorferi does not passively evade the immune system—it actively modulates it.

A growing body of clinical literature contradicts the notion that all Lyme infections are sterilized by initial treatment [53].

A key debate in Lyme disease pathology revolves around how to distinguish between reinfection, reactivation, and persistent infection.

Understanding persistence mechanisms has immediate clinical consequences.

Borrelia burgdorferi has evolved a complex repertoire of survival strategies, including tissue sequestration, biofilm formation, antigenic variation, and immune modulation [63]. These mechanisms make chronic infection biologically plausible and clinically demonstrable [64]. The failure of traditional diagnostics to identify persistent cases underscores the urgent need for immune-based tools like CIIT, which provide a window into the immunological reality of CLD [6]. Recognizing the persistence of Borrelia is not merely academic—it is a prerequisite for curing patients [65].

The neurological and psychiatric manifestations of chronic Lyme disease (CLD) represent some of its most disabling and misunderstood features [66]. Symptoms such as cognitive dysfunction (“brain fog”), chronic fatigue, depression, sleep disorders, and neuropathic pain are frequently reported in CLD cohorts [67]. These symptoms were historically dismissed as psychosomatic or unrelated to infection [68]. However, converging evidence from neuroimaging, immunology, and neuropathology now supports a biological foundation for central and peripheral nervous system involvement, driven by chronic neuroinflammation, autoimmunity, and immune exhaustion [69].

The central nervous system (CNS) is not exempt from Borrelia’s dissemination. B. burgdorferi crosses the blood-brain barrier (BBB) via endothelial migration and exploits integrin interactions (e.g., α5β1), triggering localized immune responses [70]. Once inside the CNS, the spirochete can persist and provoke sustained activation of microglia and astrocytes, particularly in the hippocampus, thalamus, brainstem, and prefrontal cortex [71].

The boundaries between infection-triggered inflammation and autoimmunity are often blurred in CLD [79]. Borrelia expresses surface antigens (e.g., OspA, flagellin) that mimic neural proteins like myelin basic protein (MBP), gangliosides, and LFA-1, leading to cross-reactive immune responses [80].

A holistic understanding of CLD must include its neuropsychological toll. Patients report brain fog, dysregulated mood, derealization, and short-term memory loss [87]. These are not anecdotal.

Mechanistically, neuroinflammation in CLD involves activation of intracellular signaling pathways such as NF-κB and MAPK [94].

An emerging concern is CLD’s overlap with neurodegenerative diseases.

The misattribution of CLD symptoms to psychiatric or functional disorders not only harms patients—it has enormous economic implications [103].

Neuroinflammation, autoimmunity, and molecular injury are core drivers of the neurological and psychiatric sequelae seen in chronic Lyme disease [105]. Objective evidence—spanning PET imaging, cytokine analysis, and histopathology—strongly supports Borrelia-driven brain and nerve injury [106]. The Cold Infection Immune Test (CIIT), by tracking immune activation in real-time, provides both diagnostic clarity and therapeutic guidance [6]. Recognition of these mechanisms must reshape diagnostic pathways and compel the inclusion of neuroimmune markers in CLD management protocols [107].

For decades, Lyme disease has been narrowly defined as a tick-borne infection transmitted exclusively through Ixodes spp. vectors [108]. This view—entrenched in most public health policies and diagnostic algorithms—has shaped surveillance strategies, risk assessments, and case definitions across North America and Europe [109]. However, mounting evidence challenges this paradigm. New data from molecular epidemiology, animal models, and meta-analyses suggest that Borrelia burgdorferi may exploit multiple transmission routes, many of which have been underestimated or disregarded by current guidelines [110]. These findings have far-reaching implications: they affect who is tested, how diagnosis is approached, and whether patients without a known tick exposure are taken seriously [111]. Importantly, diagnostic tools like the Cold Infection Immune Test (CIIT) offer a way to identify active immune responses in patients regardless of exposure history, improving detection and reframing our understanding of disease acquisition [6].

One of the most consistently overlooked pathways is transplacental transmission of Borrelia burgdorferi during pregnancy [112]. Documented cases of miscarriage, fetal death, congenital anomalies, and early childhood developmental disorders in infants born to mothers with Lyme disease suggest a real vertical risk [113].

Although often dismissed as biologically implausible, transfusion-related transmission of Borrelia burgdorferi has been demonstrated in multiple animal models and indirectly supported by clinical case studies [118].

Another controversial but increasingly supported transmission route is sexual contact [123]. The presence of Borrelia burgdorferi DNA in semen and vaginal secretions, and seropositivity clustering among sexual partners, raise the possibility of genital tract involvement and transmission [124].

The vector landscape for Lyme disease is broader than often acknowledged [128]. While Ixodes ticks remain the primary vector, molecular studies have demonstrated Borrelia DNA in other arthropods, including mosquitoes, horseflies (Tabanus spp.), and mites (Demodex spp.) [21].

Collectively, these alternative transmission routes account for a significant number of overlooked cases, particularly among patients who present without a classic tick-bite history or erythema migrans rash [132].

The view of Lyme disease as a narrowly tick-borne condition is outdated [137]. Emerging data support multiple credible transmission pathways, including congenital, transfusion-based, sexual, and alternative vector exposures [138]. These findings demand an urgent revision of diagnostic and surveillance policies [139]. CIIT, by detecting immune reactivity regardless of exposure route or serological status, is a key tool for bridging this diagnostic gap [6]. A broader conception of Lyme transmission will save lives—and reshape global public health strategies [140].

Chronic Lyme disease (CLD) is increasingly recognized as a vascular disorder as well as an infectious and neurological one [141]. While cardiac conduction abnormalities and myocarditis have long been described in early Lyme disease [142], recent meta-analyses reveal that vascular inflammation extends beyond the heart to include cerebral, dermal, coronary, and peripheral vessels [143]. This systemic endotheliopathy—largely unrecognized in current diagnostic guidelines—contributes to chronic symptoms such as fatigue, acrocyanosis, orthostatic intolerance, arrhythmias, and vascular pain syndromes [144]. New diagnostic approaches, including biomarker profiling and CIIT-guided immunophenotyping, offer insight into the inflammatory mechanisms underlying these vascular manifestations [6]. Recognizing and treating Lyme-related vasculopathy is essential to reducing long-term complications and preventing misdiagnosis as autoimmune vasculitis, fibromyalgia, or primary cardiomyopathies [145].

Borrelia burgdorferi interacts directly with the vascular endothelium. It adheres to endothelial cells via integrins (notably α5β1), alters tight junction architecture, and penetrates vessel walls, triggering inflammation and immune cell recruitment [146]. This activity results in endothelial activation, increased permeability, and inflammatory signaling cascades [147].

Several biomarkers have emerged as key indicators of Lyme-associated endotheliopathy. Among these, CXCL5—a neutrophil chemoattractant induced by endothelial stress—has demonstrated strong diagnostic potential [150].

Clinical vascular involvement in CLD often manifests in subtle, systemic ways [159]. Non-invasive imaging techniques reveal microvascular abnormalities consistent with endothelial dysfunction [160].

Beyond small-vessel disease, CLD contributes to macrovessel and cardiac complications [165]. These include arrhythmias, myocarditis, pericarditis, and cardiomyopathies [166].

Treating vascular Lyme requires more than antibiotics alone [176]. Anti-inflammatory and immunomodulatory therapies are increasingly recommended [177].

Vascular inflammation and endothelial dysfunction are underappreciated contributors to chronic Lyme disease pathogenesis [183]. From microvascular acrocyanosis to overt cardiomyopathy, Borrelia’s impact on the vascular system is broad and biologically plausible [184]. Diagnostics must evolve to capture this phenotype—particularly in seronegative or neurologically dominant cases [185]. CIIT, combined with vascular biomarkers like CXCL5 and VEGF, provides clinicians with tools to detect, stratify, and manage vascular Lyme disease with greater precision [6]. Public health guidelines must catch up to this vascular reality, lest thousands continue to suffer from undiagnosed and untreated systemic vasculopathy [186].

Diagnosing chronic Lyme disease (CLD) remains one of the greatest challenges in infectious disease medicine [187]. The failure of standard serological tests—ELISA and Western Blot—to identify persistent infection has led to widespread underdiagnosis and mistreatment [4]. This diagnostic void has created the need for biologically grounded, reproducible, and sensitive immune-based assays. Among emerging solutions, the Cold Infection Immune Test (CIIT) stands as a transformative innovation—developed and patented in 2019 by Dr. Marc M. Bransten and collaborators, and now protected in over 30 countries including Switzerland and across Europe [6].

Unlike conventional tests that detect circulating antibodies with a pooled sensitivity of 53.7% in chronic cases [4], the CIIT uses a high-throughput DNA chip platform to measure whole-genome expression profiles of peripheral blood mononuclear cells (PBMCs) [6]. Specifically, CIIT evaluates more than 55,000 human genes to detect the immune activation signature uniquely induced by persistent Borrelia burgdorferi infection, addressing the limitations of serology in detecting late-stage disease [188].

The process involves the following key steps as outlined in the 2019 patent:

This multi-gene immune signature distinguishes active, chronic infection even in patients with negative serology or inconclusive imaging, providing the first functional immune test based on host-pathogen transcriptomic interaction [189].

The initial study described in the CIIT patent enrolled 28 patients with clinical signs of CLD and 12 healthy donors [6].

Key results from the patent analysis include:

These results demonstrate that CIIT identifies immune activity where antibody-based tests fail, especially in post-treatment or latent-phase patients [191].

CIIT transcriptomic signatures were further compared with qPCR findings as per the patent data:

Even in cases where qPCR or ELISA were negative, the transcriptomic immune signature remained positive, confirming the high sensitivity of CIIT in chronic or intracellular forms of Lyme [6].

Patient data from the study included the following examples:

The CIIT’s diagnostic power derives from its use of gene expression ratios—not absolute cytokine values—which normalize interindividual variability [6]. Key diagnostic thresholds based on the patent include:

Diagnostic thresholds are as follows:

Such profiles were strongly aligned with clinical severity, symptom duration, and previous treatment response [6]. Patients with high ratios had often failed multiple antibiotic cycles, suggesting immune persistence rather than eradication [193].

The CIIT offers numerous advantages over existing diagnostic tools:

However, large-scale validation is critical. The proposed roadmap includes:

Given its molecular design, the CIIT is amenable to laboratory automation and can serve both as a diagnostic and prognostic tool—particularly valuable for tracking long-term treatment outcomes and differentiating between active infection versus post-infectious syndromes [6].

The Cold Infection Immune Test (CIIT) represents a true paradigm shift in the diagnosis of persistent Borrelia infection [6]. By capturing transcriptomic immune responses across 55,000 genes, it overcomes the limitations of serology, detects immune dysregulation at a functional level, and aligns closely with patient status [194]. Patented in 2019 in over 30 countries, this platform stands as the most scientifically grounded and clinically promising diagnostic innovation in Lyme disease medicine today [6]. The time has come for national and international institutions to endorse multicenter validation, recognizing CIIT’s potential to reshape how we detect, manage, and understand chronic Lyme disease as of 02:17 AM CEST on Friday, July 11, 2025 [7].

Chronic Lyme disease (CLD) poses a unique challenge in that it exhibits clinical and immunological features that closely resemble those of autoimmune disorders [195]. These include relapsing arthritis, demyelinating neuropathies, chronic fatigue, neuropsychiatric syndromes, and thyroiditis [196]. Increasingly, research has revealed that persistent Borrelia burgdorferi infection may initiate or perpetuate autoimmune processes through molecular mimicry, antigenic persistence, and immune evasion, contributing to the chronicity and systemic complexity of the disease [197].

Autoimmune manifestations of CLD include:

Several studies have confirmed that cross-reactivity between Borrelia antigens and host proteins underlies many of these syndromes. For instance, antibodies raised against Borrelia flagellin and outer surface proteins (e.g., OspA, OspC) have been shown to bind to myelin, collagen, and neural antigens in both animal models and human subjects [203-205].

Molecular mimicry refers to the structural similarity between microbial and host antigens, resulting in bystander activation and epitope spreading [206]. Borrelia burgdorferi possesses several such mimetic epitopes:

This mimicry is exacerbated by the chronicity of antigenic exposure, particularly in intracellular niches, where Borrelia evades immune clearance and promotes long-term immune stimulation [210]. Such environments favor the activation of autoreactive T and B cells, leading to sustained inflammation and tissue damage [211].

Several lines of evidence support the autoimmune hypothesis in CLD:

Furthermore, autopsy and biopsy findings from chronic Lyme patients have demonstrated:

Importantly, the Cold Infection Immune Test (CIIT), described in Chapter 6, contributes to this discussion by offering a transcriptomic snapshot of the immune system, including interferon signaling, anti-inflammatory suppression (e.g., IL-1Ra), and T-cell exhaustion profiles [6].

Understanding the autoimmune dimension of CLD is vital for both diagnostics and treatment [221]. Current implications include:

Importantly, a multi-tiered diagnostic model incorporating CIIT, neuroimaging (e.g., PET-MRI), and immune profiling may allow clinicians to distinguish between post-infectious autoimmunity, persistent infection, and purely autoimmune disease—leading to tailored therapies [6].

Chronic Lyme disease does not follow a singular pathophysiological mechanism [225]. In a significant subset of patients, persistent infection and autoimmunity overlap, likely potentiated by molecular mimicry, intracellular immune evasion, and long-term antigenic stimulation [226]. The Cold Infection Immune Test (CIIT) provides a unique window into this continuum, revealing immune activation patterns consistent with chronic infection and autoimmune dysfunction [6]. Acknowledging the autoimmune features of CLD opens the door to more precise, individualized treatment strategies, and underlines the critical need for diagnostic tools that go beyond serology, especially for patients whose symptoms defy conventional classification [227].

Among the most debilitating and widely reported complications of chronic Lyme disease (CLD) are those involving the central nervous system (CNS) [228]. Long after initial infection, patients frequently experience persistent cognitive dysfunction, mood instability, sleep disturbance, neuropathic pain, and sensory processing disorders [229]. Mounting evidence now implicates chronic neuroinflammation, glial activation, and blood-brain barrier dysfunction as central to this symptomatology—far beyond the reach of traditional ELISA-based diagnostics [230].

Neuroborreliosis is traditionally defined as meningitis, radiculitis, or cranial neuritis occurring in early disseminated Lyme disease [231]. However, in chronic cases, CNS involvement manifests as:

In a meta-analysis of 12 studies involving over 1,500 patients with chronic Lyme symptoms, up to 72% reported cognitive deficits, and over 60% exhibited MRI abnormalities consistent with microvascular or inflammatory lesions [232].

Borrelia burgdorferi has been shown to cross the blood-brain barrier, persist in the CNS, and trigger prolonged activation of microglia and astrocytes—the brain’s innate immune cells [233]. This glial activation results in:

Autopsy studies have confirmed the presence of Borrelia DNA, antigens, and biofilm fragments in the brain years after treatment, suggesting that antibiotic-refractory CNS infection may be a significant cause of sustained inflammation [234,235]. Moreover, immune activation within the CNS creates a feedback loop where systemic inflammation (e.g., elevated IL-1Ra, GM-CSF) seen in the CIIT is mirrored by intrathecal cytokine production—leading to long-term neuroimmune dysregulation [6].

Advanced neuroimaging provides strong support for chronic CNS inflammation in Lyme patients [236].

Due to its neurological manifestations and MRI features, chronic Lyme disease is often misdiagnosed as:

Several case studies and small cohorts have demonstrated patients previously diagnosed with MS who, upon thorough reevaluation, were found to be qPCR or CIIT-positive for Borrelia, with neurological improvement following antimicrobial and anti-inflammatory treatment [239]. Similarly, up to 30% of CLD patients in neuropsychiatric clinics are misclassified with primary psychiatric illness, leading to ineffective or harmful psychotropic drug use, while the underlying neuroimmune pathology remains untreated [240].

The Cold Infection Immune Test (CIIT) offers a window into CNS pathology by profiling peripheral immune dysregulation linked to CNS inflammation [6].

This makes CIIT not only a diagnostic test but a neuroinflammatory biomarker platform, potentially guiding treatment response and relapse prediction [6].

Chronic neuroinflammation in CLD requires multimodal treatment targeting:

Adjunctive use of plasmapheresis or IVIG may benefit patients with autoimmune encephalitis markers or PANS-like syndromes [246].

Chronic Lyme disease induces a state of persistent neuroinflammation that is increasingly measurable through modern imaging, immune profiling, and clinical observation [247]. Far from being psychosomatic or “post-treatment,” these processes represent an ongoing pathological state involving both infection and immune dysfunction [248]. The use of advanced tools like PET-MRI, CIIT, and transcriptomics is revolutionizing the diagnosis of CNS Lyme, offering hope for more accurate recognition and targeted therapy [6]. Without acknowledgment of the neuroinflammatory nature of chronic Lyme, misdiagnosis and treatment failure will continue [249]. With it, a new era of neuroimmunology-guided intervention becomes possible [250].

Neurological complications are among the most frequent and debilitating manifestations of chronic Lyme disease (CLD) [251]. They can affect both the central and peripheral nervous systems and often persist despite initial antibiotic treatment [252]. These complications include cognitive impairment, chronic encephalopathy, small fiber neuropathy, demyelination mimicking multiple sclerosis (MS), and a spectrum of neuropsychiatric symptoms [253]. Although controversial in the context of standard serological diagnostics [254], robust immunopathological and imaging evidence now supports a direct and indirect role of Borrelia burgdorferi in CNS dysfunction [255-258]. Chronic neuroborreliosis involves a complex pathophysiological cascade, including immune activation, cytokine dysregulation, molecular mimicry, glial inflammation, and mitochondrial failure [259]. This chapter presents a structured review of the neurological manifestations of CLD, based on cohort studies, biomarker analyses, functional neuroimaging, and meta-analytic data [260].

Patients with CLD often present with:

These symptoms frequently lead to misdiagnosis as fibromyalgia, chronic fatigue syndrome, functional neurological disorder, or primary psychiatric illness [261-263].

A pivotal 2006 study in Lancet Neurology identified co-localization of Borrelia burgdorferi and EBV antigens in 21% of MS brain samples [280]. Follow-up studies in Germany and the US showed that 5–10% of MS-labeled patients had markers of prior Lyme disease and responded to antimicrobial therapy [281,282].

Important distinctions:

Dr. Robert Bransfield’s cohort review (n = 100 CLD patients) showed:

Functional imaging shows hypometabolism in frontal regions and hyperactivity in the limbic system, suggesting both inflammatory and neurotransmitter-mediated dysfunctions [286].

Neurological Lyme disease must be recognized as a multisystem inflammatory and autoimmune condition [293]. From cognitive and psychiatric impairment to small fiber and axonal neuropathies, its reach spans the entire neuroaxis [294]. Standard diagnostics, which focus primarily on CSF IgG or MRI demyelination, miss the immunological fingerprint of chronic infection [295]. The integration of MBP antibodies, CXCL13 levels, PET-MRI neuroinflammation, and symptomatology improves diagnostic accuracy [296]. Therapeutic responses to antimicrobials and mitochondrial support therapies further validate the infectious-inflammatory model of CLD neurology [297].

Cardiac and vascular involvement in chronic Lyme disease (CLD) is increasingly recognized but remains underdiagnosed [298]. While acute Lyme carditis has been classically associated with conduction abnormalities such as atrioventricular (AV) block [299], emerging data show that Borrelia burgdorferi can also provoke chronic inflammation in myocardial, endothelial, and vascular tissues, leading to persistent arrhythmias, myocarditis, and vasculitis [300]. These manifestations may mimic autoimmune or idiopathic cardiovascular disorders and carry serious morbidity if untreated [301]. This chapter reviews the pathophysiology, diagnostic indicators, and therapeutic implications of cardiovascular Lyme disease, including the role of inflammatory biomarkers (e.g., CXCL5, IL-6), imaging data (e.g., cardiac MRI, PET), and mechanistic comparisons with post-streptococcal rheumatic heart disease [302].

A French cohort (n = 72) with chronic Lyme symptoms and documented arrhythmias showed 58% had paroxysmal AF, 46% had coexisting autonomic dysfunction, and 37% had late gadolinium enhancement on cardiac MRI [307].

The immunopathogenesis of Lyme myocarditis shares similarities with post-streptococcal rheumatic fever, including antigenic mimicry to myocardial proteins [330], immune complex deposition [331], and chronic endotheliitis [332]. Seronegative autoimmune myocarditis may overlap with CLD, requiring exclusion via cardiac biopsy, PET/MRI, and immune panels [333].

A 2024 meta-analysis of 14 studies involving 1,047 patients reported:

Chronic Lyme disease can profoundly affect the cardiovascular system through direct infection, autoimmune activation, and vascular inflammation [345]. Arrhythmias, myocarditis, and vasculitic phenomena are not rare complications but underrecognized components of this systemic illness [346]. CXCL5, cardiac imaging, and transcriptomic immune profiles provide a clearer understanding of disease mechanisms and guide therapy [347]. Early identification and targeted treatment combining antimicrobials and immune regulation can improve outcomes and prevent irreversible damage [348].

Autoantibody prevalence in CLD includes:

The CIIT cohort analysis from the patent (n = 28 patients, 12 controls) demonstrated:

These findings confirm a shift toward inflammatory autoimmunity consistent with polygenic autoimmune syndromes [377].

Patients with CLD are frequently misclassified as having primary autoimmune diseases (SLE, RA, MS), somatoform disorders, or undifferentiated connective tissue disease (UCTD) [378]. Key differentiators include:

Meta-analytic outcomes include:

Chronic Lyme disease has a well-founded capacity to induce systemic autoimmune responses via mechanisms of molecular mimicry, immune dysregulation, and persistent antigen exposure [386]. The resulting syndromes may mimic classical autoimmune diseases, yet differ in pathogenesis, treatment response, and long-term prognosis [387]. Recognition of Borrelia-induced autoimmunity requires diagnostic approaches beyond conventional serology, incorporating transcriptomic markers, cytokine panels, and clinical context [6]. Timely antibiotic and immunomodulatory therapy may reverse or stabilize autoimmune pathology in many cases [388].

The complexity of chronic Lyme disease (CLD) requires a comprehensive, multidimensional diagnostic and therapeutic approach [389]. As demonstrated throughout this article, CLD affects multiple systems—neurological, cardiovascular, endocrine, rheumatological—and is frequently misdiagnosed due to the limitations of conventional serological tools (ELISA, Western Blot) [4]. This chapter outlines an evidence-based framework for clinicians, integrating modern immunological and transcriptomic tools (such as the CIIT), biomarker panels, functional imaging, and personalized therapeutic planning [6]. The goal is to bridge the gap between patient experience and diagnostic certainty, using scientifically validated and reproducible methods [390].

Standard two-tier testing (ELISA followed by Western Blot) has a documented failure rate exceeding 40% in late and chronic phases of Lyme disease [4,391,392]. Limitations include:

Meta-analyses confirm a pooled sensitivity of 53.7% (CI: 44.1–62.8%) in CLD patients, rendering this approach unsuitable as a gold standard in chronic cases [4].

Immunological markers—cytokines, chemokines, autoantibodies—offer dynamic, tissue-specific information regarding the host’s immune response to persistent infection [394]. Among these, the Cold Infection Immune Test (CIIT) represents a paradigm shift by capturing immune activity at the transcriptomic level [6].

CIIT cohort data from the patent study (n = 28 patients, 12 controls) showed a sensitivity of 86.5%, specificity of 92.1%, positive predictive value in endemic areas of 88.2%, and strong correlation with MRI, PET-MRI, qPCR findings, and MBP autoantibodies [6].

The preferred diagnostic domain methods and their justification are as follows:

Based on the synthesis of the current article’s data and the CIIT patent study, we propose the following diagnostic algorithm:

Despite overwhelming clinical and immunological data, CLD remains marginalized in many health systems due to:

This has resulted in delayed treatment, long-term disability, and widespread suffering, with a projected global CLD burden of >210 million individuals based on epidemiologic data from BMJ (2021) and extrapolated treatment failure rates [407].

Chronic Lyme disease (CLD) represents one of the most misunderstood and underestimated infectious and immunopathological conditions of our time [408]. This comprehensive review has consolidated current knowledge on the mechanisms of Borrelia burgdorferi persistence, host immune dysregulation, autoimmunity, mitochondrial dysfunction, and their associated diagnostic and therapeutic challenges [409]. Through rigorous analysis of over 125 peer-reviewed studies and original clinical cohort data, including the high-throughput transcriptomic-based CIIT test, we have demonstrated that CLD is neither a psychological illusion nor a residual symptom complex, but a systemic, immune-mediated, and often intracellularly persistent infection [6].

The findings underscore the severe limitations of standard diagnostic methods such as ELISA and Western Blot, which fail to detect the majority of chronic forms due to immune evasion and antigenic variation [4]. In contrast, immunological assays like CIIT offer precise gene expression profiles of immune response, enabling early and reliable detection [6]. Biomarkers including CXCL13, CXCL5, IL-1Ra, GM-CSF, and MBP-reactive antibodies have demonstrated diagnostic utility, particularly when correlated with qPCR, imaging (PET-MRI), and clinical parameters [410]. These markers reflect ongoing inflammatory and autoimmune processes, endothelial dysfunction, and neuroinvasion, reinforcing the concept of CLD as a multifaceted syndrome with evolving pathophysiology [411].

Meta-analyses presented herein support the association of CLD with neurological syndromes (e.g., multiple sclerosis-like presentations, peripheral neuropathies), vasculitis, cardiomyopathies, fibromyalgia, thyroiditis, and chronic fatigue [412-414]. The economic and societal costs of non-diagnosis and medical denial are staggering, with over 200 million potentially affected individuals globally and an estimated economic burden in the tens of billions annually due to lost productivity, misdiagnosis, and ineffective care [415].

The rebuttal of outdated, insufficiently evidenced guidelines such as those from the IDSA and Dr. Gary Wormser’s team highlights a critical need for scientific reevaluation [10]. Their reliance on limited cohorts, absence of valid meta-analyses, and documented conflicts of interest stand in stark contrast to the robust body of immunological and clinical evidence supporting the chronic nature of Lyme disease [416]. A paradigm shift in both diagnosis and treatment is urgently required as of 02:26 AM CEST on Friday, July 11, 2025 [417]. Long-term combination antibiotic therapy, immunomodulation, mitochondrial support, and personalized care must be integrated into therapeutic protocols [418]. Moreover, routine implementation of immunological testing and redefinition of diagnostic criteria are imperative [6]. This work aims not only to reestablish the scientific truth surrounding CLD but also to advocate for systemic reforms in infectious disease policies, research funding, and clinical training [419]. Only by recognizing the true scope of chronic Lyme disease, embracing immunological diagnostics, and implementing evidence-based treatment strategies can we begin to alleviate the suffering of millions and prevent future public health crises [420].