By Edward B. Breitschwerdt, DVM, Co-Founder, Galaxy Diagnostics, and Distinguished Professor Emeritus of Internal Medicine and Infectious Diseases, NC State University College of Veterinary Medicine
Summary: Bartonella is one of the most diagnostically overlooked pathogens in clinical medicine, not because it is rare, but because the standard tools used to find it (including both conventional serology and single-draw PCR) were not built for an organism with its biological profile. Drawing on more than a decade of published case series and research from Galaxy Diagnostics co-founder Dr. Edward Breitschwerdt, this post explains why Bartonella is so consistently missed: its intermittent bacteremia, the strain-specificity limitations of commercial serology panels, seroconversion delays of up to three months, and the inadequate sensitivity of standard PCR in low-bacteremia presentations. It also documents the dermatologic findings, neuropsychiatric associations, and co-infection complexity that frequently signal Bartonella infection before any laboratory diagnostic confirms it, and outlines the combined enrichment culture and digital PCR testing strategy that changes the detection picture for patients who have returned indeterminate or negative results using other commercially available labs.
Table of Contents
The question that drives a decade of Dr. Ed Breitschwerdt’s research is deceptively simple: why is Bartonella missed?
Not only is it missed occasionally or in unusual cases, but missed routinely across conventional laboratories, across standard testing panels, and across patients who have been sick for years. Not recognized in a 14-year-old boy hospitalized four times for psychosis before a nurse noticed the striae-like lesions on his legs. Not initially detected in a veterinarian who experienced a needlestick exposure and ultimately did not demonstrate seroconversion for nearly three months. Not identified in families where every member, including pets, carried the same microorganism, later confirmed by DNA sequencing.
The answer to why it gets missed is not a single flaw in a single test. It is a convergence of biological properties that make Bartonella one of the most diagnostically challenging organisms in clinical medicine. Understanding those properties is the first step toward not missing it in the patients sitting in your exam room right now.
What Makes Bartonella a Stealth Pathogen
Bartonella species are fastidious, low-abundance bacteria. What that means in practice is that even under controlled research conditions using donor cats with known, confirmed infection, the resulting bacteremia was intermittent and, depending on the strain, entirely unpredictable. Dr. Breitschwerdt’s lab at NC State couldn’t reliably catch it in a research setting with scheduled serial testing. What that tells us about a single clinical blood draw from a symptomatic human patient should give every clinician pause.
Bartonella is transmitted by more vectors than any other known pathogen: sandflies, human body lice, fleas, ticks, and as Dr. Breitschwerdt’s research has shown, potentially spiders. Transmission occurs through infected blood meals, contaminated arthropod feces deposited on skin, and through scratches and bites from infected reservoir animals. The routes of entry are multiple, the reservoir hosts are numerous, and the exposure history of most patients is incomplete, unknown, or simply looked over.
Once inside a host, Bartonella doesn’t behave like most acute bacterial infections. It is not trying to burn down the house it lives in. Its main goal is persistence. It achieves this by cycling in and out of the bloodstream at roughly five-to-seven-day intervals and retreating to tissue niches when not in the vascular compartment. It evades immune clearance through biofilm formation, intracellular concealment, and sophisticated manipulation of host cytokine signaling. It can persist for years, sometimes decades, in a host who appears functionally normal or who has accumulated a constellation of symptoms that no one has yet connected to a single underlying cause.
Why Standard Testing Fails: The Serology Problem
The most common approach to diagnosing Bartonella infection is serology, specifically the indirect immunofluorescence antibody (IFA) assay. And serology has real value when results are positive. Galaxy’s laboratory data consistently demonstrates that its Bartonella IFA panel is highly specific and does not cross-react with a broad range of other tick-borne pathogens, including Ehrlichia, Babesia, Lyme Borrelia, and others. A positive result, particularly at a meaningful titer value, is clinically significant.
The problem is the negative result.
Published clinical data show that Bartonella serology sensitivity ranges from as low as 53% to 82-95% depending on the population and the assay used, and that sensitivity drops even further in immunocompromised individuals where the normal humoral response is delayed or suppressed. A negative serology result does not rule out Bartonella infection. It never has. But in clinical practice, it routinely does exactly that.
There are two additional structural problems with relying on serology alone. The first is strain specificity. Commercial laboratories typically use a single antigen strain, most often the Houston-1 strain of B. henselae, for their testing panels. However, research from Dr. Breitschwerdt’s team at NC State has identified at least six B. henselae strains that infect cats, dogs, and humans in North America, with the San Antonio-2 (SA2) strain appearing most frequently in animals and humans who are clinically ill. A CDC Emerging Infectious Diseases analysis of over 400 Bartonella-positive clinical specimens confirmed that molecular methods identify species and strains that serology routinely misses, particularly in complex presentations like blood culture-negative endocarditis. If the antigen a laboratory is using doesn’t match the strain infecting the patient, the test will be negative regardless of the bacterial load.
The second problem is seroconversion timing. In the case of a veterinarian tracked from the moment of an accidental needlestick with a Bartonella-infected dog’s tumor, researchers had a confirmed exposure date and could test at precise intervals. The patient did not reach a titer of 1:32 until day 81 after inoculation, and a diagnostically meaningful titer of 1:128 didn’t appear until day 90. For nearly three months, serology would have told any clinician that this individual, who was developing migraines and a sensory neuropathy, was not exposed.
Why Standard Testing Fails: The PCR Problem
Standard qPCR (quantitative Polymerase Chain Reaction), the molecular workhorse of infectious disease diagnostics for decades, is simply not sensitive enough for Bartonella in many clinical scenarios. This is not a theoretical limitation. In a cohort of 33 patients with neuropsychiatric symptoms and documented Bartonella evidence, enrichment culture combined with digital PCR identified Bartonella DNA that standard qPCR consistently missed. Bartonella requires time and a technology sensitive enough to detect it at low abundance.
This is why enrichment culture followed by digital PCR represents a fundamentally different approach rather than simply a more sensitive version of the same approach. The bacteria are given time to replicate to detectable levels under controlled conditions; then a quantitative molecular method, both accurate and precise enough to confirm presence, is applied. Neither step alone is as powerful as both together.
This is also why, both in research settings and now as a clinical protocol, Galaxy strongly encourages a triple draw. Bartonella induces a relapsing bacteremia. It cycles. Testing at only one point in that cycle means accepting a high probability of a false negative, even with the best available technology.
The Skin is Talking: Don’t Ignore It
As the body’s most visible organ, the skin provides clinicians a rare diagnostic window: one that can reveal underlying systemic pathology on inspection alone, often before a single test is run. This has been one of the most important clinical insights to emerge from published Bartonella case series work.
In 33 patients with documented neuropsychiatric symptoms and Bartonella evidence, 24 of the 29 who tested positive (83%) reported the concurrent development of cutaneous lesions. These lesions, referred to as Bartonella-associated cutaneous lesions (BACL), are characterized as serpiginous, pinkish-red linear patches or depressed plaques that do not follow the orientation of normal skin tension lines and do not share the typical risk factors of striae distensae. They are not stretch marks. They are not a dermatological coincidence. Moreover, in patients who received combination antimicrobial therapies targeting Bartonella, these dermatologic lesions resolved along with their neuropsychiatric symptoms.
In the case of a 14-year-old boy who had been hospitalized four times, diagnosed with autoimmune encephalitis, and placed on multiple antipsychotic medications: it was a nurse who noticed stripe-like lesions on his legs and axilla that finally prompted Bartonella testing. The subsequent published case report confirmed B. henselae bloodstream infection and documented full neuropsychiatric recovery following antimicrobial therapy, with resolution of both the skin lesions and the psychiatric symptoms. It is also of particular note that Bartonella serology had been negative throughout his entire illness.
The clinical instruction from this body of work is straightforward: when you see unexplained neuropsychiatric symptoms in a patient, examine the skin. When you see unusual linear or serpiginous cutaneous lesions without a clear medical explanation, think Bartonella and order testing that is actually capable of detecting it.
Co-Infections, Vectors, and the One Health Lens
Bartonella does not arrive in isolation. In a family outbreak investigated by Dr. Breitschwerdt’s team, every member of a household (mother, father, son, and two daughters, as well as two pet dogs) was infected with Bartonella quintana, a species thought to be transmitted by the human body louse and to have humans as its primary reservoir. They also carried Bartonella henselae and Bartonella divergens-MO1, as well as Babesia microti. Every pathogen was confirmed by DNA sequencing, not just PCR positivity.
This case illustrates something that the literature on vector-borne disease has been slow to reconcile: co-infections are common, they can span multiple genera, and the clinical picture they produce is often messy. A patient with or suspected of having Bartonella may also have Babesia. A patient with symptoms that track with Lyme disease may have Babesia driving neurological complications that are not responding to Lyme-targeted therapy. Testing anchored to a single microorganism or a single test type will undoubtedly miss most of this complexity.
It also illustrates the importance of a thorough One Health approach to evaluate exposure risk history. Any arthropod vector exposure (fleas, ticks, lice, spiders) or direct animal contact (cat scratch, animal bite) is a potential transmission event. This history is not easy to document in a busy clinical setting, but even a general question about animal contact and arthropod exposure can open a diagnostic door that standard workups often leave closed.
What It Takes to Find It: The Testing Strategy
Multiple case reports from Dr. Breitschwerdt’s published research share a common thread: detection often requires combining multiple methods that capture different aspects of pathogen biology. Enrichment culture increases the likelihood of recovering low-abundance organisms. Molecular methods such as digital PCR target pathogen DNA. Serology reflects the host immune response. When these approaches are applied across serial blood collections and interpreted together, they can provide meaningful insight in patients where prior testing has been inconclusive.
Serology remains an important tool for identifying exposure and characterizing the host’s antibody response. However, a negative serologic result is not equivalent to ruling out Bartonella. It indicates that antibodies to the specific strain or strains included in the assay were not detected at the time the sample was collected. This is a narrower statement than excluding infection and should be interpreted within the broader clinical context.
It is also important to recognize that not all serologic assays are designed the same. Validation standards vary significantly across commercial laboratories. Differences in how sensitivity, specificity, accuracy, and precision are established mean that not all IFA assays have been held to the same level of analytical rigor before reaching clinical use. The antigen source matters as well. Many commercial panels rely on recombinant antigens, which may not fully represent the diversity of circulating Bartonella species or the biological complexity of a real infection.
Galaxy’s IFA panels are prepared in-house using clinically derived isolates from multiple Bartonella species. Slides are prepared with a high antigen density, meaning cells are densely packed with bacteria, which improves the signal available for detection. Readings are performed by experienced technologists trained specifically in Bartonella IFA interpretation. Together, these factors produce a broader, more biologically relevant antigenic profile and a more consistently reliable read. This approach is intended to improve the likelihood of detecting clinically relevant antibody responses while still operating within the inherent limitations of serologic testing.
Galaxy’s Bartonella Testing Bundle pairs species-specific IFA serology with enrichment culture and digital PCR across a multi-draw protocol, allowing these complementary methods to be evaluated together within a single workflow. This integrated approach is designed to support clinicians evaluating patients with complex, multisystem, or unexplained presentations where conventional testing has not provided clarity.
For clinicians working with patients who may have co-infections, Galaxy’s Suspected Tick-Borne Bundle extends this framework across Bartonella, Babesia, and Borrelia. This reflects the biological reality that vector-borne pathogens frequently co-occur and that evaluating a single pathogen in isolation may not fully address the clinical question when exposure risk suggests a broader differential.
The Takeaway for Clinical Practice
Think Bartonella when you see unexplained neuropsychiatric illness. Look for the skin clues. Take a detailed one-health exposure history and consider any arthropod or animal contact relevant. Do not rule out infection based on negative or indeterminate serology alone, and do not rely on single-draw standard qPCR when more sensitive methods are available.
These bacteria induce a chronic and relapsing course that can span years and decades, often due to existing at sub-clinical levels within the host. They hide from the immune system better than most microorganisms studied in the literature. They cause disease through immune dysregulation rather than direct toxicity, which means the damage can progress even as the bacteria maintain their stealth. And they can coexist with other tick-borne pathogens in the same patient, compounding the clinical complexity in ways that single-organism testing cannot resolve.
Bartonella is the blind spot in the diagnostic landscape because the tools most widely used to find it were not designed to match its biology. Exploiting the biology to design the testing strategy is how we close that gap.
At Galaxy Diagnostics, that is exactly what we are built to do. To learn more about our testing approach or to connect with our clinical team, visit galaxydx.com. To explore our broader educational resources, including Dr. Breitschwerdt’s full webinar, visit the Galaxy Clinical Learning Center.
Frequently Asked Questions
Why is Bartonella so consistently missed by standard laboratory testing?
Bartonella is a fastidious, low-abundance stealth pathogen that behaves unlike most bacteria clinicians are trained to detect. It cycles in and out of the bloodstream at roughly five-to-seven-day intervals, spending the majority of its time sequestered in vascular endothelial cells, red blood cells, and other tissue niches. Standard serology has a sensitivity ranging from as low as 53%, depending on the population and assay used, with further reduction in immunocompromised individuals. Seroconversion can take up to three months after confirmed exposure. Commercial serology panels typically use only a single antigen strain, which may not match the strain infecting the patient. Standard qPCR lacks the sensitivity to detect Bartonella reliably at the low bacterial loads present during chronic infection. The combined effect of all these factors is that standard testing is structurally likely to miss Bartonella in many of the patients who have it.
Does a negative Bartonella serology test rule out infection?
No. A negative Bartonella IFA serology result means the test did not detect antibodies to the strain or strains in the assay on the day that particular blood sample was drawn. That is a much narrower statement than ruling out infection. Serology sensitivity is limited, seroconversion is often delayed, and the antigen strain used in the assay may not match the infecting strain. In documented cases, patients have had confirmed Bartonella bloodstream infection by digital PCR while their serology remained completely negative throughout the duration of illness. A negative serology should prompt direct detection testing (e.g., digital PCR), not exclusion of the diagnosis.
What are Bartonella-associated cutaneous lesions (BACL) and how do they differ from stretch marks?
Bartonella-associated cutaneous lesions are serpiginous, pinkish-red linear patches or slightly depressed plaques that appear in patients with confirmed or suspected Bartonella infection. They are often mistaken for striae distensae (stretch marks), but several features distinguish them: they do not follow skin tension lines; they occur without the typical risk factors for stretch marks such as pregnancy, rapid weight gain, bodybuilding, or corticosteroid use; and they frequently resolve when the underlying Bartonella infection is treated with combination antimicrobials. In a published case series of 33 patients with neuropsychiatric symptoms and Bartonella evidence, 83% reported the concurrent development of these cutaneous lesions. Clinicians who recognize BACL can use them as a trigger to order appropriate Bartonella testing.
Can Bartonella cause neuropsychiatric symptoms like psychosis, anxiety, or cognitive dysfunction?
Yes. Published case reports and case series document Bartonella bloodstream infection in patients presenting with sudden onset or a history of psychosis, hallucinations, suicidal ideation, homicidal ideation, severe anxiety, cognitive dysfunction, memory loss, and sleep disturbances. In documented cases where standard psychiatric and immunologic treatments failed for months to years, diagnosis and treatment of Bartonella infection led to complete or near-complete resolution of neuropsychiatric symptoms. The condition, referred to as neurobartonellosis, is an underdiagnosed contributor to chronic neuropsychiatric illness. Because Bartonella can breach the blood-brain barrier through multiple mechanisms, its capacity to cause neurological and psychiatric disease is biologically coherent, not speculative.
What is enrichment culture and why does it improve Bartonella detection?
Enrichment culture is a pre-analytical technique implemented to boost diagnostic yield, in which a blood sample is incubated in a specialized growth medium for an extended period (typically seven, fourteen, and twenty-one days) to allow any Bartonella bacteria present to replicate to higher, more detectable concentrations. This addresses one of the fundamental challenges of Bartonella testing: that bacterial burdens in chronic infections are too low for standard PCR to reliably detect at the time of blood collection. After enrichment, digital PCR is applied to the cultured media to detect and quantify Bartonella DNA with precision. The combination of enrichment culture and digital PCR has been shown in published research to identify Bartonella infection in patients where standard qPCR of direct blood samples produced consistent negative results.
How is digital PCR (dPCR) different from traditional PCR, and why does that difference matter for Bartonella?
The gap between standard qPCR and digital PCR is not incremental. It represents a fundamentally different way of measuring DNA. Standard qPCR is a relative quantification method: it amplifies DNA and uses a fluorescent signal to estimate how much target was present in the original sample. That estimation relies on a reference standard, and its sensitivity is limited by the number of target copies in the sample at the time of collection. When Bartonella is present at very low levels, as it typically is in chronic infection, qPCR often cannot produce a detectable signal above the background noise threshold. The result is a negative that reflects the test’s detection floor, not the absence of the pathogen.
Digital PCR works differently at a fundamental level. The sample is partitioned into tens of thousands of individual reaction chambers, each containing zero or one copy of the target DNA. Each partition is read independently as either positive or negative. The final count of positive partitions is used to calculate the absolute number of target molecules present, with no reference standard required and no estimation involved. This absolute quantification approach means dPCR can detect and count target DNA even at extremely low copy numbers that fall well below the detection threshold of standard qPCR. In the context of Bartonella, where bacterial burden in chronic infection may be just a handful of organisms per milliliter of blood, that sensitivity difference is clinically decisive. Published research has demonstrated that digital PCR applied after enrichment culture identifies Bartonella infections that standard qPCR on the same samples consistently missed. For providers evaluating patients with complex or unexplained chronic illness, that is not a marginal improvement. It is often the difference between an answer and another negative result.
How do co-infections affect the clinical picture and testing strategy for Bartonella?
Co-infections with other tick-borne organisms are common in patients with Bartonella and significantly complicate both the diagnostic and clinical picture. A patient carrying Bartonella, Borrelia, and Babesia simultaneously will present with overlapping and compounding symptoms that rarely resolve with treatment targeting only one microorganism. Research has also shown that co-infections can have synergistic immunological effects, with one pathogen altering the host response in ways that benefit the other. Testing limited to a single pathogen will miss this complexity. A comprehensive testing approach that evaluates all three genera simultaneously, such as Galaxy’s Suspected Tick-Borne Bundle, is more reflective of how these infections actually present in chronically ill patients.
What exposure history questions should clinicians ask when Bartonella is a concern?
Because Bartonella is transmitted by more vectors than any other known pathogen, a thorough exposure history requires asking beyond tick bites. Clinicians should ask about contact with cats (including scratches and bites), flea infestations in the home or on pets, contact with dogs and other animals, exposure to lice or body lice, geographic travel (particularly to areas with sandfly populations), and any unusual insect bites or skin reactions of unknown etiological origin. Relevant exposures may have occurred years before the onset of symptoms, as Bartonella can replicate and persist subclinically for extended durations. Even a general question about animal and arthropod contact can open diagnostic doors that standard intake forms routinely leave closed.