Recently, infections with emerging zoonotic bacteria of the genus Bartonella have been reported in association with a range of central nervous system (CNS) symptoms. Currently, it remains unknown if Bartonella spp. infection is associated with symptoms of schizophrenia/schizoaffective disorder (SCZ/SAD). The objective of this study was to determine if there is an association between Bartonella species infection and SCZ/SAD. A secondary objective was to determine if SCZ/SAD symptoms were more severe among participants with documented Bartonella spp. infection. Using a case–control study design, 17 cases and 13 controls were evaluated with a series of clinical and cognitive assessments. Blood samples were collected and tested for Bartonella spp. infection using serological, microbiological, and molecular techniques. People with SCZ/SAD were more likely than healthy volunteers to have Bartonella spp. DNA in their bloodstream, with 11 of 17 cases (65%) positive by Bartonella spp. droplet digital PCR (ddPCR). In comparison, only one healthy volunteer was Bartonella spp. ddPCR positive (8%, p = 0.0024). Based on serology, Bartonella spp. exposure was common among people with SCZ/SAD (12 of 17) as well as among healthy volunteers (12 of 13), with no significant difference between the groups (p = 0.196). Within the case group of people with SCZ/SAD, there was no significant difference in SCZ/SAD severity scores between people with and without ddPCR evidence of Bartonella spp. infection. This pilot study provides preliminary evidence in support of future investigations that should examine a potential contribution of Bartonella spp. infection to SCZ/SAD.
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References
1.
BreitschwerdtEB, GreenbergR, MaggiRG, MozayeniBR, et al.Bartonella henselae bloodstream infection in a boy with Pediatric Acute-Onset Neuropsychiatric Syndrome. J Cent Nerv Syst Dis, 2019a; 11:1–8.
2.
BreitschwerdtEB, MaggiRG, DuncanAW, NicholsonWL, et al.Bartonella species in blood of immunocompetent persons with animal and arthropod contact. Emerg Infect Dis, 2007; 13:938–941.
3.
BreitschwerdtEB, MaggiRG, FarmerP, MascarelliPE. Molecular evidence of perinatal transmission of Bartonella vinsonii subsp. berkhoffii and Bartonella henselae to a child. J Clin Microbiol, 2010a; 48:2289–2293.
4.
BreitschwerdtEB, MaggiRG, LantosPM, WoodsCW, et al.Bartonella vinsonii subsp. berkhoffii and Bartonella henselae bacteremia in a father and daughter with neurological disease. Parasit Vectors, 2010b; 3:29.
5.
BreitschwerdtEB, MaggiRG, NicholsonWL, CherryNA, et al.Bartonella sp. bacteremia in patients with neurological and neurocognitive dysfunction. J Clin Microbiol, 2008; 46:2856–2861.
6.
BreitschwerdtEB, MaggiRG, QuachC, BradleyJM. Bartonella spp. bloodstream infection in a Canadian family. Vector Borne Zoonotic Dis, 2019b; 19:234–241.
7.
BreitschwerdtEB, MascarelliPE, SchweickertLA, MaggiRG, et al.Hallucinations, sensory neuropathy, and peripheral visual deficits in a young woman infected with Bartonella koehlerae. J Clin Microbiol, 2011; 49:3415.
8.
BreitschwerdtEB, SontakkeS, HopkinsS. Neurological manifestations of bartonellosis in immunocompetent patients: a composite of reports from 2005-2012. J Neuroparasitology, 2012; 3:1–15.
9.
BrouquiP, LascolaB, RouxV, RaoultD. Chronic Bartonella quintana bacteremia in homeless patients. N Engl J Med, 1999; 340:184–189.
10.
ByamW, CarrollJH, ChurchillJH, et al.Trench Fever, a Louse-Borne Disease, 1st edition. Preston: Halewood:ABA:ILAB: Booksellers, 1867.
11.
CannetiB, Cabo-LópezI, Puy-NúñezA, García GarcíaJC, et al.Neurological presentations of Bartonella henselae infection. Neurol Sci, 2019; 40:261–268.
12.
CheslockMA, EmbersME. Human bartonellosis: an underappreciated public health problem?. Trop Med Infect Dis, 2019; 4:69.
13.
DaltonMJ, RobinsonLE, CooperJ, RegneryRL, et al.Use of bartonella antigens for serologic diagnosis of cat-scratch disease at a National Referral Center. Arch Intern Med, 1995; 155:1670–1676.
14.
DingleTC, SedlakRH, CookL, JeromeKR. Tolerance of droplet-digital PCR vs real-time quantitative PCR to inhibitory substances. Clin Chem 2013.
15.
DivyaR, RajajeyakumarM. Can cats cause schizophrenia? An insight into the role of Bartonella henselae in neuropsychiatric disorders. Acta Sci Pharm Sci, 2019; 3:110–110.
16.
DongL, MengY, SuiZ, WangJ, et al.Comparison of four digital PCR platforms for accurate quantification of DNA copy number of a certified plasmid DNA reference material. Sci Rep, 2015; 5:13174.
17.
DrancourtM, CartaA, RaoultD, MainardiJL, et al.Bartonella (Rochalimaea) quintana endocarditis in three homeless men. N Engl J Med, 1995; 332:419–423.
18.
EndresD, LeypoldtF, BechterK, HasanA, et al.Autoimmune encephalitis as a differential diagnosis of schizophreniform psychosis: clinical symptomatology, pathophysiology, diagnostic approach, and therapeutic considerations. Eur Arch Psychiatry Clin Neurosci, 2020a; 270:803–818.
19.
EndresD, MaierV, LeypoldtF, WandingerK-P, et al.Autoantibody-associated psychiatric syndromes: a systematic literature review resulting in 145 cases. Psychol Med, 2020b; 7:1–12.
FondG, MacgregorA, TamouzaR, HamdaniN, et al.Comparative analysis of anti-toxoplasmic activity of antipsychotic drugs and valproate. Eur Arch Psychiatry Clin Neurosci, 2014; 264:179–183.
22.
FuglewiczAJ, PiotrowskiP, StodolakA. Relationship between toxoplasmosis and schizophrenia: a review. Adv Clin Exp Med, 2017; 26:1031–1036.
23.
Fuller TorreyE, SimmonsW, YolkenRH. Is childhood cat ownership a risk factor for schizophrenia later in life?. Schizophr Res, 2015; 165:1–2.
24.
GoodrichI, McKeeC, KosoyM. Longitudinal study of bacterial infectious agents in a community of small mammals in New Mexico. Vector Borne Zoonotic Dis, 2020; 20:496–508.
Gutiérrez-AguirreI, RačkiN, DreoT, RavnikarM. Droplet digital PCR for absolute quantification of pathogens. Methods Mol Biol, 2015; 1302:331–347.
27.
KaySR, OplerLA, LindenmayerJP. Reliability and validity of the positive and negative syndrome scale for schizophrenics. Psychiatry Res, 1998; 23:99–110.
28.
KeefeRSE, GoldbergTE, HarveyPD, GoldJM, et al.The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res, 2004; 68:283–297.
29.
KoeslingJ, AebischerT, FalchC, SchüleinR, et al.Cutting edge: antibody-mediated cessation of hemotropic infection by the intraerythrocytic mouse pathogen Bartonella grahamii. J Immunol, 2001; 167:11–14.
30.
Köhler-ForsbergO, PetersenL, GasseC, MortensenPB, et al.A nationwide study in Denmark of the association between treated infections and the subsequent risk of treated mental disorders in children and adolescents. JAMA Psychiatry, 2019; 76:271–279.
31.
KolpakovaJ, BedwellJS. Childhood cat bites and disorganized symptoms of schizotypy in adulthood. Schizophr Res, 2013; 146:370–371.
32.
KordickDL, BreitschwerdtEB. Relapsing bacteremia after blood transmission of Bartonella henselae to cats. Am J Vet Res, 1997; 58:492–497.
33.
KordickDL, BreitschwerdtEB. Persistent infection of pets within a household with three Bartonella species. Emerg Infect Dis, 1998; 4:325–328.
34.
La ScolaB, RaoultD. Serological cross-reactions between Bartonella quintana, Bartonella henselae, and Coxiella burnetii. J Clin Microbiol, 1996; 34:2270–2274.
35.
LantosPM, MaggiRG, FergusonB, VarkeyJ, et al.Detection of Bartonella species in the blood of veterinarians and veterinary technicians: a newly recognized occupational hazard?. Vector Borne Zoonotic Dis, 2014; 14:563–570.
36.
MaggiRG, MascarelliPE, PultorakEL, HegartyBC, et al.Bartonella spp. bacteremia in high-risk immunocompetent patients. Diagn Microbiol Infect Dis, 2011; 71:430–437.
37.
MaggiRG, MozayeniBR, PultorakEL, HegartyBC, et al.Bartonella spp. bacteremia and rheumatic symptoms in patients from Lyme disease–endemic region. Emerg Infect Dis, 2012; 18:783–791.
38.
MaggiRG, RichardsonT, BreitschwerdtEB, MillerJC. Development and validation of a droplet digital PCR assay for the detection and quantification of Bartonella species within human clinical samples. J Microbiol Methods, 2020; 176:106022.
39.
MascarelliPE, MaggiRG, HopkinsS, MozayeniBR, et al.Bartonella henselae infection in a family experiencing neurological and neurocognitive abnormalities after woodlouse hunter spider bites. Parasit Vectors, 2013; 6:98.
40.
MaurinM, EbF, EtienneJ, RaoultD. Serological cross-reactions between Bartonella and Chlamydia species: implications for diagnosis. J Clin Microbiol, 1997; 35:2283–2287.
41.
MorickD, KrasnovBR, KhokhlovaIS, GottliebY, et al.Transmission dynamics of Bartonella sp. strain OE 1-1 in Sundevall's jirds (Meriones crassus). Appl Environ Microbiol, 2013; 79:1258–1264.
42.
MüllerN, SchwarzMJ. Immune system and schizophrenia. Curr Immunol Rev, 2010; 6:213–220.
43.
MuñanaKR, VitekSM, HegartyBC, KordickDL, et al.Infection of fetal feline brain cells in culture with Bartonella henselae. Infect Immun, 2001; 69:564–569.
44.
NodenBH, TshavukaFI, van der ColfBE, ChipareI, et al.Exposure and risk factors to Coxiella burnetii, spotted fever group and typhus group rickettsiae, and Bartonella henselae among volunteer blood donors in Namibia. PLoS One, 2014; 9:e108674.
45.
NevilleAJ, ZachSJ, WangX, LarsonJJ, JudgeAK, DavisLA, et al.Clinically available medicines demonstrating anti-toxoplasma activity. Antimicrobial Agents and Chemotherapy. 2015; 59:7161–7169.
46.
OteoJA, MaggiR, PortilloA, BradleyJ, et al.Prevalence of Bartonella spp. by culture, PCR and serology, in veterinary personnel from Spain. Parasit Vectors, 2017; 10:553.
47.
PitassiLHU, de Paiva DinizPPV, ScorpioDG, DrummondMR, et al.Bartonella. spp. bacteremia in blood donors from Campinas, Brazil. PLoS Negl Trop Dis 2015; 9: e000, 3467.
48.
PonsMJ, GomesC, AguilarR, BarriosD, et al.Immunosuppressive and angiogenic cytokine profile associated with Bartonella bacilliformis infection in post-outbreak and endemic areas of Carrion's disease in Peru. PLoS Negl Trop Dis, 2017; 11:e0005684.
49.
PortilloA, MaggiR, OteoJA, BradleyJ, et al.Bartonella spp. prevalence (serology, culture, and PCR) in sanitary workers in La Rioja Spain. Pathogens, 2020; 9:189.
50.
PultorakEL, MaggiRG, MascarelliPE, BreitschwerdtEB. Serial testing from a 3-day collection period by use of the Bartonella Alphaproteobacteria growth medium platform may enhance the sensitivity of Bartonella species detection in bacteremic human patients. J Clin Microbiol, 2013; 51:1673–1677.
51.
R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria; 2019.
52.
RegneryRL, OlsonJG, PerkinsBA, BibbW. Serological response to “Rochalimaea henselae” antigen in suspected cat-scratch disease. Lancet, 1992; 339:1443–1445.
53.
RelmanDA, LoutitJS, SchmidtTM, FalkowS, et al.The agent of bacillary angiomatosis. N Engl J Med, 1990; 323:1573–1580.
54.
RitsnerM, KursR, GibelA, RatnerY, et al.Validity of an abbreviated Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-18) for schizophrenia, schizoaffective, and mood disorder patients. Qual Life Res, 2005; 14:1693–1703.
55.
Rodriguez-BarradasMC, BandresJC, HamillRJ, TrialJ, et al.In vitro evaluation of the role of humoral immunity against Bartonella henselae. Infect Immun, 1995; 63:2367–2370.
56.
ScheideggerF, QuebatteM, MistlC, DehioC. The Bartonella henselae VirB/Bep system interferes with vascular endothelial growth factor (VEGF) signalling in human vascular endothelial cells. Cell Microbiol, 2011; 13:419–431.
57.
SteinA, RaoultD. Return of trench fever. Lancet, 1995; 345:P450–P451.
58.
SutterlandAL, FondG, KuinA, KoeterMWJ, et al.Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systematic review and meta-analysis. Acta Psychiatr Scand, 2015; 132:161–179.
59.
TorreyEF, YolkenRH. Schizophrenia as a pseudogenetic disease: a call for more gene-environmental studies. Psychiatry Res, 2019; 278:146–150.
60.
TsukamotoK, ShinzawaN, KawaiA, SuzukiM, et al.The Bartonella autotransporter BafA activates the host VEGF pathway to drive angiogenesis. Nat Commun, 2020; 11:3571.
61.
VandenbrouckeJP, Von ElmE, AltmanDG, GøtzschePC, et al.Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. PLoS Med, 2007; 4:1628–1654.
62.
VermeulenMJ, VerbakelH, NotermansDW, ReimerinkJHJ, et al.Evaluation of sensitivity, specificity and cross-reactivity in Bartonella henselae serology. J Med Microbiol, 2010; 59:743–745.
63.
YanagiharaM, TsuneokaH, TanimotoA, OtsuyamaKI, et al.Bartonella henselae DNA in seronegative patients with cat-scratch disease. Emerg Infect Dis, 2018; 24:924–925.
64.
YolkenRH, BachmannS, RouslanovaI, LillehojE, et al.Antibodies to Toxoplasma gondii in individuals with first-episode schizophrenia. Clin Infect Dis, 2001; 32:842–844.
65.
ZangwillKM, HamiltonDH, PerkinsBA, RegneryRL, et al.Cat scratch disease in Connecticut—epidemiology, risk factors, and evaluation of a new diagnostic test. N Engl J Med, 1993; 329:8–13.
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