1. Introduction
Fever, lymphadenopathy, and a history of a cat scratch/bite are the prototypical manifestations of Cat Scratch Disease (CSD), an acute onset illness caused by
Bartonella henselae [
1,
2]. A cutaneous primary inoculation papule is also reported in 60–90% of CSD cases [
3]. Although rare, a spectrum of other dermatological lesions, including maculopapular and urticarial eruptions, granuloma annulare, erythema nodosum, erythema marginatum, thrombocytopenic purpura, leukocytoclastic vasculitis, multiple granulomatous lesions, and erythema annulare, have been reported in CSD patients [
3]. Thus, a spectrum of cutaneous lesions has been historically associated with CSD.
With the advent of increasingly sensitive diagnostic modalities, chronic blood stream infection with
Bartonella spp. has been reported in patients with cardiovascular, neurological, and rheumatological diseases [
1,
2,
4]. If, or to what extent, persistent
Bartonella spp. infection might result in cutaneous manifestations in patients with neuropsychiatric symptoms has not been determined. To our knowledge, linear cutaneous lesions were first clinically associated with
B. henselae infection in 2002 in 10 pediatric patients with a history of abdominal pain, skin rash, mesenteric adenitis, gastritis, and duodenitis following a cat scratch or tick bite [
5]. These cutaneous lesions were described as purpuric, serpiginous, nodular rashes that did not blanche when pressure was applied. Subsequently, cutaneous linear lesions, referred to as “striae”, were described as “prototypical for bartonellosis” in a book published in 2008 [
6]. In 2013, we described
B. henselae infection in a boy whose symptoms included linear cutaneous lesions—at the time, also referred to as “striae”—as well as headaches, memory loss, disorientation, and peripheral neuropathic pain;
B. henselae deoxyribonucleic acid (DNA) was amplified and sequenced from a biopsy of one cutaneous lesion, as well as several blood and serum specimens [
7]. In 2019, we described
B. henselae blood stream infection in another boy diagnosed with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) who had skin lesions described as “Bartonella-associated cutaneous lesions (BACL)”. In this patient, the cutaneous lesions and neuropsychiatric symptoms resolved with antimicrobial therapy [
8]. In 2020, three additional children with neuropsychiatric symptoms and concurrent cutaneous lesions, referred to as “Bartonella tracks”, were described [
9]. Due to variability in the cutaneous lesions in patients with acute-onset CSD and in those with chronic symptoms and blood stream infections, we propose the more inclusive designation encompassing historical terms (striae and tracks) to describe the overall spectrum of lesions as Bartonella-Associated Cutaneous Lesions (BACL).
In retrospect, it is unfortunate that the term “striae” was initially applied to lesions reported in association with clinically suspected or microbiologically confirmed cases of Bartonellosis. In a 2018 retrospective case series of 12 adolescent boys with striae distensae, the authors concluded that horizontal striae distensae of the lower back in adolescent boys is associated with a rapid growth spurt, tall stature, and family (genetic) history of striae distensae [
10]. As only one boy was tested for CSD, the authors stated that the possibility of infection as a trigger for striae distensae could not be excluded based on their study. Although genetics can influence patterns of disease expression in family units, common environmental and vector exposures can also result in familial disease patterns. As summarized in association with a recent familial cluster, familial infection with
Bartonella spp. has been reported in families residing in Australia, Canada, Denmark, the Netherlands, and the United States [
11].
The purpose of this investigation was to describe the largest case series to date involving microbiological testing for Bartonelloses in individuals with self-reported neuropsychiatric symptoms, the majority of whom developed concurrent cutaneous lesions. Dermatologists, neurologists, and psychiatrists should be aware that Bartonella exposure/infection occurs in patients reporting neuropsychiatric symptoms and a spectrum of cutaneous lesions.
3. Discussion
This case series describes 29 people with self-reported neuropsychiatric symptoms and evidence of
Bartonella spp. exposure or infection, the majority of whom (83%) had cutaneous lesions accompanying their illness onset. Combining an enrichment blood culture with ddPCR substantially improved the detection of
Bartonella spp. DNA in this study. Diagnostically, ddPCR is a powerful molecular technique that uses a water–oil emulsion technology driven by microfluidics and surfactant chemistry to massively partition samples into 15,000 to 20,000 1-ηL-sized droplets prior to performing DNA amplification [
12]. DNA targets within the original sample are randomly localized within these droplets—after which, the amplification of DNA within each drop is recorded using fluorescently labeled probe detection. The number and fluorescent output for each droplet is read in a manner similar to flow cytometry, where each individual droplet is then identified as being positive or negative for the template (pathogen gene target) of interest.
The frequency and extent to which
B. henselae or other
Bartonella spp. can induce cutaneous lesions or neuropsychiatric symptoms remains unclear. However, there is increasing case-based data to support an association between
Bartonella spp. and cutaneous lesions, including urticarial papules and plaques along with erythematous, serpiginous patches, and plaques, reported as BACL in this case series. Maculopapular rash [
13,
14], septal panniculitis [
14,
15], and vasculitis [
16,
17] have been reported previously in association with
Bartonella spp. infections and cutaneous lesions.
In the context of chronicity, histopathology confirmed mild, nonspecific lymphoplasmacytic infiltrates in lesional cutaneous biopsies, consistent with a chronic antigenic immune response in two
B. henselae case reports [
7,
8]. As depicted in
Figure 1,
Figure 2,
Figure 3,
Figure 4,
Figure 5,
Figure 6 and
Figure 7, the cutaneous lesions we refer to as linear BACL are often vertical, can be narrow or very wide, and do not occur in areas such as the back, where rapid growth would typically contribute to horizontal striae. No participant with linear BACL in this case series reported an association with conditions with known associations with striae distensae, including pregnancy, rapid growth, weightlifting, Cushing’s syndrome, or Marfans disease. Linear BACL lesions did not develop in a 36-year-old veterinarian infected with
B. henselae, despite treatment for environmental allergies/rash with prednisone for one year prior to study entry. However, in the context of medical complexity, she was examined by 11 medical specialists, including an allergist, dermatologist, and neurologist.
Previously, we proposed that dogs may serve as sentinels for human exposure to
Bartonella spp. [
18,
19]. Additionally, dogs develop similar, if not identical, pathology when persistently infected with a
Bartonella spp. [
20]. In the context of a potential common exposure source, infection with
B. henselae was documented in an elderly man with ulcerated nodular skin lesions and in his dog with histopathologically confirmed panniculitis [
21]. Identical SA2 strain types of
B. henselae DNA were amplified and sequenced from the man’s enrichment blood culture and from the dog’s panniculitis biopsy. Ulcerative skin lesions and
B. henselae infection were also documented by PCR amplification and DNA sequencing in a beagle with vasculitis and superficial erosions of the ear tip [
22]. These and other disease associations shared by dogs and humans suggest that a comparative infectious disease approach might enhance the clinical understanding of these stealth bacteria in a timelier manner [
1,
23].
Based upon questionnaire responses, animal and vector exposures were reported frequently by study participants. The primary mode of
Bartonella spp. transmission is via arthropod vectors, including, but not limited to, fleas, lice, sandflies, and ticks [
1,
2,
4]. Other modes of transmission include animal bites and scratches, blood transfusions, and needle sticks. As further illustrated by this study, veterinary workers and others with frequent exposure to arthropods and animals may be occupationally at risk for acquiring infection and, thus, a sentinel population to enhance disease understanding [
24]. To facilitate the subsequent acquisition by blood-sucking arthropods, vector-borne organisms evolved to avoid immune elimination, to localize in cutaneous tissues, and to downregulate the local inflammatory response, thereby avoiding the induction of obvious skin lesions [
24]. Despite evolutionary adaptations by vectors and vector-borne organisms, skin lesions occur in association with a variety of vector-borne diseases. Three somewhat prototypical examples of acute-onset cutaneous lesions induced by tick-transmitted vector-borne pathogens are: erythema chronicum migrans (ECM) associated with
Borrelia burgdorferi infection [
25], the maculopapular rash with Rocky Mountain spotted fever [
26] caused by
Rickettsia rickettsii and ehrlichiosis [
26] caused by
Ehrlichia chaffeensis and
Ehrlichia ewingii. In contrast, acrodermatitis chronica atrophica (ACA), most commonly caused by
Borrelia afzelii, occurs months to years after infection [
27]. Since
B. henselae and
B. koehlerae are predominantly flea-borne pathogens, flea (and other arthropod) exposures should be a component of each patient’s dermatological and neuropsychiatric histories. In addition, when dermatologists consult with families experiencing flea infestations,
Bartonella spp. testing should be considered if symptoms subsequently develop during the ensuing months or years.
Blood stream infection with
Bartonella spp. has been recently reported in blood donors and other healthy individuals [
28,
29]. Thus, despite PCR documentation of
Bartonella spp. DNA in blood or enrichment blood cultures from the majority (22/29) of the study participants, it is not possible to confirm causation for the neuropsychiatric symptoms or the cutaneous lesions. Controlled treatment trials are likely necessary to determine if or to what extent infections with
Bartonella spp. contribute to the clinical presentations described in this case series. The resolution of skin lesions and neuropsychiatric symptoms with antimicrobial therapy, as described in the boy diagnosed with PANS [
8], provided potential support for causation. Similar to previous studies [
28,
29,
30], a subset (6/29 in this study) of blood stream PCR-positive individuals were not
Bartonella spp. seroreactive. The reason for this discrepancy remains unclear. The detection of antibody reactivity only indicates exposure to one or more
Bartonella spp.; however, seronegative infection is not unusual. Thus, serology, enrichment blood culture, and PCR should be used concurrently prior to and during the treatment of suspected Bartonelloses patients.
The limitations of this study included participant self-selection and self-reporting, as these factors may have positively biased the findings. Participant age, duration and severity of illness, and prior treatment regimens likely influenced the microbiological serology and enrichment blood culture/PCR results. Due to the individual’s concerns over neuropsychiatric symptoms, most participants did not consult a dermatologist; nonprofessional photographs were provided by participants or parents, and skin biopsies were not obtained for histopathology, Bartonella PCR, or immunohistochemical imaging of Bartonella organisms.
Based upon the limited case reports and this case series, it is imperative to design studies that will determine if, or to what extent,
Bartonella spp. might contribute to concurrent cutaneous lesions in patients with neuropsychiatric symptoms. Mechanistically, could long-standing microvascular injury induced by this endotheliotropic bacteria result in chronic vascular inflammation, local mast cell activation, collagen injury, and the development of a spectrum of BACL [
31,
32]? As
Bartonella spp. are predominantly vector-borne pathogens that can localize to the skin, dermatologists should assess vector and animal exposures in patients with unusual or unexplained cutaneous lesions and consider testing patients with BACL and neuropsychiatric symptoms for
Bartonella spp. infection.