Tick-borne Co-infections:
Presentation, Diagnosis and
Treatment
Amsterdam NL
June 19th 2019
Dr. Richard Horowitz,
Medical Director HVHAC, Hyde Park, N.Y.
Board Certified Internal Medicine
Member, HHS Tick-Borne Disease Working Group &
Co-chair, HHS Other Tick-Borne Diseases and Co-infections 2017-2019
The material contained in this slide presentation
is the property of Dr. Richard I. Horowitz.
Any reproduction or use of this material
requires the author’s permission
Disclaimer: The views expressed in this presentation do not represent the views
of the Tick Borne Disease Working Group, HHS or the United States
© 2019 Richard I. Horowitz M.D
All Rights Reserved
Teaching Objectives
◼ Learn the basic bacterial, parasitic, and viral
infections found in ticks, and their associated
symptoms and health risks
◼ Understand how co-infections evade the immune
system
◼ Review lab testing for co-infections, and how to
establish a differential diagnosis
◼ Create a treatment plan to address multiple
simultaneous co-infections, using both classical and
herbal protocols
© 2019 Richard I. Horowitz, M.D.
Co-Infections & Chronic Disease
◼ Pasteur’s/Koch’s postulates 1800’s: 1 cause for 1
disease: old paradigm
◼ MSIDS model: Takes into account simultaneous
overlapping factors causing the same symptoms
◼ Co-infections such as other bacteria (including
other strains of borrelia), viruses, and parasites are
often responsible for driving chronic
symptomatology. Fungus/mold is also often seen
◼ Treating co-infections often leads to better
outcomes in patients with chronic illness
Nature.com, 2018: 85% Probability
of Co-infections in Lyme disease
Problems with Testing for Co-inf’s
◼ Multiple Borrelia species: Krause PJ, Carroll M, Fedorova N, Brancato J, Dumouchel C,
et al. (2018) Human Borrelia miyamotoi infection in California: Serodiagnosis is complicated by
multiple endemic Borrelia species. PLOS ONE 13(2): e0191725.
◼ Babesia: Akoolo, L., et al. A novel quantitative PCR detects Babesia infection in patients not
identified by currently available non-nucleic acid amplification tests. BMC Microbiology.
201717:16
◼ Bartonella: Edward B. Breitschwerdt , et al. Bartonella Species in Blood of
Immunocompetent Persons with Animal and Arthropod Contact. Emerging Infectious Diseases •
www.cdc.gov/eid • Vol. 13, No. 6, June 2007; Bartonella Henselae: Limitations of Serological
Testing: Evaluation of Elisa and Polymerase Chain Reaction Testing In a Cohort of Lyme Disease
Patients and Implications for Treatment. Horowitz R.I., M.D. et.al. Abstract, 16th International
Scientific Conference on Lyme Disease & Other Tick-Borne Disorders. Hartford, Connecticut, June
2003.
◼ Tularemia: Horowitz RI, Freeman PR (2016) Are Mycobacterium Drugs Effective for
Treatment Resistant Lyme Disease, Tick-Borne Co-Infections, and Autoimmune Disease? JSM
Arthritis 1(2): 1008
◼ Mycoplasma: Eskow E, Adelson ME, Rao RV, Mordechai E. Evidence for disseminated
Mycoplasma fermentans in New Jersey residents with antecedent tick attachment and
subsequent musculoskeletal symptoms. J Clin Rheumatol. 2003; 9: 77-87.
Ixodes Ticks: Co-infections: Beyond LD
↑ South Bay Virus, Phebovirus1, filarial org’s, Mycobacteria
Cross, S. et al. Co-inf Patterns in Individual Ixodes Scapularis Ticks Reveal Associations Between Viral,
Eucaryotic and Bacterial Microorganisms. Viruses 2018, 388;
Co-infections in Ticks Are The Rule
◼ 45% of ticks were co-infected with up to 5 different
pathogens; up to 8 microorganisms identified in the
same tick...7 Lyme spirochetes, 1 relapsing fever
spirochete, 5 Anaplasma, 3 Ehrlichia, 4 spotted
fever rickettsia, Candidatus Neoehrlichia
mikurensis, 1 Bartonella species (henselae), 10 sp of
Babesia and 2 Theileria species
◼ Coxiella burnetii (Q-fever) & Midichloria
mitochondrii (symbiont) = 36 Different Pathogens!
◼ Moutailler S, et al. (2016) Coinfection of Ticks: The Rule Rather Than the Exception. PLoS Negl Trop Dis
10(3): e0004539. doi:10.1371/journal.pntd.0004539
Co-infections Increase Underlying
Symptoms
◼ Babesia makes Lyme patients much sicker:
◼ Krause, P.J. JAMA, June 5, 1996; Vol 275, No. 21 Concurrent LD and Babesiosis, Evidence for increased
Severity and Duration of Illness
◼ Co-infections can increase neurological symptoms:
Bartonella, Mycoplasma, Chlamydia:
◼ Breitschwerdt EB, et al. Bartonella sp. Bacteremia in Patients with Neurological and Neurocognitive
Dysfunction; Journal of Clinical Microbiology. 46(9):2856–2861
◼ Most ticks (worldwide) are now multiply co-
infected:
◼ Aliota MT, et al The prevalence of zoonotic tick-borne pathogens in Ixodes scapularis collected in the
Hudson Valley, New York State. Vector Borne Zoonotic Dis. 2014;14(4):245–50.
Tick-Borne Co-Infections
◼ Borrelia (multiple species B. sensu lato group) + RF
◼ Bacteria of the genera Neorickettsia, Ehrlichia,
NeoEhrlichia, Anaplasma
◼ Parasites: Babesia: B. microti, B. duncani, B. odocoilei, B.
divergens, B. venatorum, B. major; Theileria, FL1953, filaria
◼ Bartonella & Mycoplasma (multiple species)
◼ Rickettsial inf’s: RMSF, Typhus, Q-fever, New:
Candidatus Rickettsia tarasevichiae (Spotted Fever group),
◼ Tularemia, Brucella, Tick Paralysis
◼ Viruses: Heartland, Bourbon, Powassan, TBEV, SFTS
◼ Nelder M., et al. Human pathogens associated with the blacklegged tick Ixodes scapularis: a systematic
review. Parasites & Vectors (2016) 9:265
MSIDS Map: Diagnostic Testing: Infections
◼ Infections: 4 Types (Bacteria, Parasites, Viruses, Candida/Fungus):
Direct & Indirect Testing
◼ Lyme Elisa, ++C6 Lyme Elisa, IgM & IgG Western Blot
(IgeneX), ? Immunoblot, IFA, Elispot (LTT), PCR, Nanotrap..
◼ Erhlichia/Anaplasma: HME, HGA titers, PCR, CBC, CMP
◼ Babesia IFA (microti, duncani/WA-1), PCR/FISH, CBC, CMP
◼ Bartonella spp. IFA/PCR/FISH (IgeneX), ? Galaxy labs, VEGF
◼ Chlamydia pneumonia IFA, Mycoplasma IFA + PCR (M.
fermentans, M. penetrans), i.e., intracellular infections!
◼ Rickettial Inf’s: RMSF, Q-fever, Typhus, CBC, CMP
◼ ?Brucella IgM/IgG/? Agglutination test, ?Tularemia
◼ Horowitz, R.I. How Can I Get Better? St Martins Press 2017
MSIDS Map: Diagnostic Testing Inf’s
◼ b. Parasites: Babesia IFA (microti, duncani, divergens,
EU-1..), PCR, FISH (RNA), Toxoplasma, ? FL-1953, ? filarial
worms, G.I. parasites (ameba, giardia, round/hookworms)
◼ c. Viruses: IFA’s/PCR’s?: HSV1, HSV 2, EBV, HHV6, CMV,
West Nile, Coxsackie, Encephalitis virus: DTV/ Powassan? ?
EEE
◼ d. Candida/Fungi/Mold: CDSA, Stachybotrys titer, ? Real
Time Labs urine mycotoxin assay, ERMI test (evaluate mold
exposure at home), Nasal Swab (mold, MARCoNS, biofilm),
Histoplasmosis/Coccidiomycosis
◼ Co-Infection of Blacklegged Ticks with Babesia microti and Borrelia burgdorferi Is Higher than Expected
and Acquired from Small Mammal Hosts, Ostfeld, R., et al. June 18, 2014
◼ Lavoisier Akoolo, et al. A novel quantitative PCR detects Babesia infection in patients not identified by
currently available non-nucleic acid amplification tests. BMC Microbiology. 2017:16
Rising Incidence of Tick-Borne Co-
infections in Europe
◼ Rising rates of co-infections: Denmark:
◼ 34% of the samples of ticks were positive for tick-
borne inf’s: 2 types Borrelia, 2 types Babesia,
Borrelia afzelii (39%), Rickettsia spp. (16%, 1° R.
helvetica), Borrelia burgdorferi sensu lato (15%),
Babesia spp. 8%(Babesia microti, 82%; Babesia
venatorum (‘EU1’), 18%), Candidatus Neoehrlichia
mikurensis (1%), and Bartonella spp (0.6%)
◼ Candidatus Neoehrlichia mikurensis: newly
discovered bacteria in ticks and in Europe (Sweden,
Switzerland, Germany, Czech Republic)
◼ Babesia spp. and other pathogens in ticks recovered from domestic dogs in Denmark. Stensvold, C. et al.
Parasites & Vectors (2015) 8:262
Candidatus Neoehrlichia mikurensis
◼ Newly discovered bacteria in ticks and rodents in Europe
(Sweden, Switzerland, Germany, & the Czech Republic),
mimics B cell malignancies!
◼ Symptoms: fever, muscle & jt pain, vascular and
thromboembolic events, including deep vein thrombosis
(DVT), TIA’s, pulmonary embolism (PE), & arterial
aneurysms
◼ Laboratory findings: ↑ C-reactive protein, ↑ WBC count &
neutrophils, & anemia
◼ May be mistaken for recurrence of hematologic (B cell
Lymphomas) or autoimmune diseases and/or unrelated
arteriosclerotic vascular events
◼ Grankvist, A. et al. Oxford University Press March 12, 2014
Wild Birds Are Spreading Infections
◼ Wild birds play key roles in the maintenance & movement
of zoonotic pathogens such as TBEV, Borrelia, Bartonella
and Rickettsia spp
Canada◼ : Scott, J. et al. Infection Prevalence of Borrelia burgdorferi in Ticks Collected from
Songbirds in Far-Western Canada. Open Journal of Animal Sciences, 2015, 5, 232-241
US:◼ Hamer SA, et al., Wild birds and urban ecology of ticks and tick-borne pathogens, Chicago,
Illinois, USA, 2005–2010. Emerg Infect Dis. 2012;18:1589–95.;Bartonella henselae and B. koehlerae
DNA in Birds. Mascarelli PE, et al. EID, Volume 20, Number 3—March 2014;
Europe:◼ Elfving K, et al. Dissemination of spotted fever rickettsia agents in Europe by migrating
birds. PLoS ONE. 2010;5:e8572
◼ Tick species, Distribution map, Europe 2014:
◼ http://www.ecdc.europa.eu/en/healthtopics/vectors/vector-
maps/Pages/VBORNET-maps-tick-species.aspx
The Rising Incidence of Borrelia infections:
>16 New Species (1990-2017)
◼ USA: B. burgdorferi sensu lato, Borrelia sensu stricto (B31)
(297), Borrelia kurtenbachii, B. mayonii, B. californiensis
◼ Europe: Borrelia afzelii (ACA) + Borrelia garinii
(neuroborreliosis) + B. spielmani (early skin disease), + B.
valaisana, B. lusitanea, B. bavariensis
◼ Asia: B. japonica, B. turdi, B. tanukii, B.yangtze
◼ North America: Borrelia andersonii
◼ Southern U.S. : B. americanum, B. carolinensis
◼ Pacific U.S.: B. bissettii & Borrelia lanei were recently
implicated as human pathogens in California
Girard YA, Fedorova N, Lane RS. Genetic diversity of Borrelia burgdorferi and detection of B. bissettii-like
DNA in serum of north-coastal California residents. J Clin Microbiol. 2011;49:945–54. Margos et al.
International Journal of Systematic and Evolutionary Microbiology, 08 Sept 2017
The Rising Incidence of Parasitic
Infections in Ticks: Filariasis
◼ The lone star tick, Amblyomma americanum, was
recently shown to harbor filarial nematodes
◼ Ixodes scapularis ticks collected from Southern
Connecticut were evaluated for filarial nematodes.
Infection rates were 22% (nymphs) & 30% (adults)
◼ ? Microfilarial worms are causing neurological sx?
◼ Discovery of filarial nematode DNA in Amblyomma americanum in Northern Virginia. Tyler C.Henning et
al. Ticks and Tick-borne Diseases. Volume 7, Issue 2, March 2016, Pages 315-318
◼ Filarial Nematode Infection in Ixodes scapularis Ticks Collected from Southern Connecticut. Namrata, P,
Sapi, E. et al. Veterinary Sciences, 2014, 1(1), 5-15
◼ http://www.prnewswire.com/news-releases/lyme-bacteria-hides-inside-parasitic-worms-causing-
chronic-brain-diseases-300270742.html
The Rising Incidence of Tick-Borne Co-
Infections
◼ Deer tick virus (Powassan virus, lineage II): Rates in
Ixodes scapularis ticks in N.Y. increased from 1-2% to 5-6%
over a four year period. NYS: 4 cases, recent deaths
◼ EEE: rates increased to 10% in Ixodes scapularis ticks in
Vermont (while serological evidence of Lyme disease
simultaneously increased from 10% to 16% from in dogs over a three
year period, Vt DOH, 2010 )
◼ Borrelia miyamotoi: ↑ 4% pts in N.E.
◼ Anaplasmosis: rates almost doubled between 2008-2010
(.9% to 1.8%) in Vermont (Vt DOH)
◼ Alan P Dupuis II, et al. Parasites & Vectors 2013, 6:185 doi:10.1186/1756-3305-6-185
◼ https://www.health.ny.gov/press/releases/2017/2017-10-20_powassan_virus_dutchess_county.htm
Ehrlichiosis/Anaplasmosis
◼ The lone star tick, Amblyomma americanum, is the vector
of Ehrlichia chaffeensis (HME) & E. ewingii (HEE), causal
agents of human ehrlichiosis. A. americanum also transmits
other TBD’s: RMSF, tularemia, STARI, & viruses: Bourbon,
Heartland + Alpha Gal HEE/HGA: transfusion risk (mn. TEARS)
◼ Ixodes scapularis ticks transmit human granulocytic
anaplasmosis (HGA), human sennetsu ehrlichiosis (HSE), &
human Wisconsin-Minnesota ehrlichiosis (HWME) (mn.WAS)
◼ False + tests for ehrlichia are possible with: rickettsial inf’s
(RMSF, Q-fever, typhus, Rickettsia amblyommatis), B.
miyamotoi, Brucella, EBV, AI disorders
◼ Relative Risk for Ehrlichiosis and Lyme Disease in an Area Where Vectors for Both Are Sympatric, New
Jersey, USA. Egizi, A., et al. Emerging Infectious Diseases, Vol. 23, No. 6, June 2017.
Ehrlichiosis/Anaplasmosis
Symptoms Testing Treatment
Commonly has an -HME & HGA titers -Tetracyclines
acute onset with: (IgM, IgG) & PCRs
-Fever (doxy 100 BID):
-HA (severe) (Cross reactivity possible (RMSF) safe in children <
-Myalgias, Malaise 8 yo & pregnancy
-Occasional diarrhea -CBC: Cytopenias:
-Rarely: toxic shock- ↓ WBC (7-10 days max)
like syndrome (leukopenia) +/-
-Meningitis -Rifampin (#2)
Meningoencephalitis
↓ platelets +/- (150-300 mg BID)
(thrombocytopenia) -treat immediately if
suspecting disease:
- LFT’s (transaminitis) Potentially fatal in
-Morulae in WBC, CSF, very young, old &
immunocompromised
bone aspirate or biopsy
3%
(rare)
Is it Ehrlichia/Anaplasma or a Virus?
Heartland/Bourbon Viruses
◼ The Heartland virus is a phlebovirus (NEJM 2012), &
the Bourbon virus is a thogotovirus (EID, 2014)
◼ Both are transmitted from the lone star tick (AA)
◼ Resembles Ehrlichiosis: causes fatigue, fever, loss of
appetite and non-bloody diarrhea
◼ Laboratory values look like Ehrlichiosis but they are
unresponsive to doxycycline
◼ One of several tick-borne viruses, including TBEV,
deer tick virus (POW), SFTS, CCHF, KFD, Omsk HF..
◼ Kosoy OI, et al. Novel Thogotovirus species associated with febrile illness and death, United States,
2014. Emerg Infect Dis. Volume 21, Number 5—May 2015
Relapsing Fever Borrelia (RF)
◼ There used to be 3 Borrelia species that were known to
cause tick-borne relapsing fever (RF) in the United States:
◼ B. hermsii: soft bodied tick Ornithidoros hermsii
◼ B. turicatae: soft bodied tick Ornithodoros turicata
◼ B. parkeri: soft bodied tick Ornithodoros parkeri
◼ Borrelia miyamotoi: an emerging RF Borrelia (Ixodes ticks)
◼ In adult I. pacificus ticks in the San Francisco Bay area, B.
miyamotoi is as abundant as B. burgdorferi
◼ Salkeld DJ, Cinkovich S, Nieto NC. Tick-borne pathogens in northwestern California, USA [letter]. Emerg
Infect Dis [Internet]. 2014 Mar
◼ Other Borrelia species exist that cause RF worldwide:
◼ Borrelia recurrentis (louse borne RF), Borrelia crocidurae &
Borrelia duttoni (Africa, soft bodied ticks)..In fact, 16 spp!
16 Relapsing fever Borrelia species
Slide provided thanks to J. Shah, IgeneX 2018
Borrelia americana (Rudenko et al. 2010)
Borrelia anserina (Sakharoff 1891) Bergey et al. 1925
Borrelia coriaceae (Johnson et al. 1987)
Borrelia crocidurae (Leger 1917) Davis 1957)
Borrelia duttonii (Novy and Knapp 1906; Bergey et al. 1925)
Borrelia hermsii (Davis 1942; Steinhaus 1946)
Borrelia lonestari (Barbour et al. 1996)
Borrelia miyamotoi (Fukunaga et al. 1995)
Borrelia parkeri (Davis 1942; Steinhaus 1946)
Borrelia persica (Dschunkowsky 1913; Steinhaus 1946)
Borrelia recurrentis (Lebert 1874; Bergey et al. 1925)
Borrelia sinica (Masuzawa et al. 2001) B. miyamotoi sprochetes as viewed with
the use of bright-field microscopy, with
Borrelia theileri (Laveran 1903) Bergey et al. 1925) B. hermsi Giemsa staining and a pH of 7.0. The bar
Borrelia turcica (Güner et al. 2004) indicates 2 μm.- N. Engl. J Med 368;3
Borrelia turicatae (Brumpt 1933: Steinhaus 1946) Emerg Infect Dis. 2003 Sep; 9(9): 1 NEJM.240 org January 17, 2013)
151–1154.
doi: 10.3201/eid0909.030280
Candidatus Borrelia texasensis (Lin et al. 2005)
Rising Incidence Borrelia miyamotoi
Infection in France
◼ Results: 3% of ticks and 5.55% of voles were
infected with B. miyamotoi in France
◼ 12% of B. miyamotoi infected ticks also were co-
infected with B. garinii
◼ No human cases were reported as of this report,
but blood tests for Lyme will not pick up B.
miyamotoi. Would explain “unexplained
syndromes” post tick bite and rising cases CFS…
◼ Cosson et al. Genetic characterization of the human relapsing fever spirochete Borrelia miyamotoi in
vectors and animal reservoirs of Lyme disease spirochetes in France. Parasites & Vectors 2014, 7:233
◼ http://www.parasitesandvectors.com/content/7/1/233
New RF Species Are Emerging:
Consider the IgeneX RF Immunoblot
◼ New RF Immunoblot IgeneX Laboratory: 7 TBRF
species can be detected, IgM and IgG
◼ Borrelia miyamotoi, B. hermsii, B. turcica, B. turicatae, B.
parkerii & B. texasensis, B. coriaceae
◼ US, European and Australian species of TBRF Borrelia are
all represented w/ no cross reactivity to Bb sensu lato spp.
◼ Sensitivity 67% in acute, 100% in convalescent
◼ Specificity 96% to 98%: based on CDC samples
◼ Testing: RF antibodies: B. hermsii, B. miyamotoi rGLPQ,
PCR’s (Quest Tick-borne panel has BMD), RF Immunoblot
(IgeneX) is most comprehensive, ? blood smear for TBRF
Testing/Diagnosing Relapsing Fever
◼ DERM: Different types of skin rashes: macular,
diffuse petechiae (?rickettsia), erythema
multiforme (non-specific), EM rashes can be seen
(?B. miyamotoi, Lyme, STARI..)
◼ Testing: Wright-Giemsa stain, w/ paired acute and
convalescent antibody titers (EIA & IFA), Western
immunoblots (IgeneX), PCR’s (& monoclonal
antibodies, rarely culture)
◼ Schwan TG, et al. (July 2009). "Tick-borne relapsing fever and Borrelia hermsii, Los Angeles County,
California, USA". Emerging Infectious Diseases. 15 (7): 1026–1031.
◼ Lee SH, et al. Detection of Borreliae in archived sera from patients with clinically suspect Lyme disease.
Int J Mol Sci (2014) 15: 4284-98;
Relapsing fever: Wright Giemsa Stain
Peripheral blood smear +
Fotso Fotso A(2015). "Laboratory Diagnosis of Tick-Borne African Relapsing Fevers: Latest Developments".
Frontiers in Public Health. 3: 254. doi:10.3389/fpubh.2015.00254
Relapsing Fever Borrelia: Soft Ticks
◼ Incubation period: usually 5-15 days
◼ Acute onset: Non-specific symptoms
◼ Fever – up to 104 (?Babesia, ? Brucella ? Q-fever) w/chills
and sweats (can be drenching)
◼ Headaches (?Lyme, ?Ehrlichia ?Q-fever..)
◼ Myalgias and arthralgias (?Lyme ?Ehrlichia ? RMSF ?Q-
fever..)
◼ Nausea/vomiting (?Lyme, ?rickettsia, ?Ehrlichia ?
Tularemia, typhoidal form), occ conjunctivitis, cough (rare)
◼ Symptoms typically last 2-9 days then recur. Same sx BMD.
◼ https://www.hhs.gov/ash/advisory-committees/tickbornedisease/reports/other-tbds-2018-5-
9/index.html
Co-infections & Gastrointestinal Disorders
◼ Tick-borne co-inf’s can present with varied GI manif’s:
◼ Borrelia hermsii can cause nausea, vomiting, abdominal
pain and hepatitis as well as jaundice and an enlarged
spleen. For these infections, diarrhea occurred in 19% of
the cases (rarely bloody), w vomiting of blood (hematemesis)
◼ Ehrlichiosis/Anaplasmosis: occas. G.I. symptoms of
nausea, vomiting, abdominal pain, and jaundice, (early
stages). Diarrhea occurs in up to 10% of patients
◼ Tick-borne viral inf’s can mimic Ehrlichia/Anaplasma
(Heartland, Bourbon virus) & are unresponsive to tetracyclines
◼ Zaidi SA, et al. Gastrointestinal and hepatic manifestations of tick-borne diseases in the United States.
Clin Infect Dis 34: 1206-1212
Co-infections & Gastrointestinal Disorders
◼ Rickettsial diseases (Rocky Mountain spotted fever and Q-
fever): abdominal pain and tenderness with vomiting, with
or without ↑ LFT’s (Differential: hepatitis, appendicitis,
peritonitis, and cholangitis). Gastrointestinal hemorrhage
has also been reported for RMSF due to inflammation in
the blood vessels.
◼ Tularemia: Typhoidal form. The latter form may cause
nausea, vomiting, abdominal pain and diarrhea, which can
be severe in up to 40% of cases.
◼ Lyme, RF, Babesia: can present with associated ↑ LFT’s
◼ ? Leucopenia, thrombocytopenia, transaminitis (1 or all)
◼ Horowitz, HW, et al. Liver function in early Lyme disease. Hepatology 1996 Jun; Vol 23 (6), pp 1412-7
Relapsing Fever Borrelia: Soft ticks
◼ Atypical Symptoms: “Great Imitator”
◼ GI: : N+, V+, abdominal pain; diarrhea, hepatitis w/ HSM &
jaundice (?rickettsia)
◼ Cardiac: myocarditis, arrhythmias (?Lyme)
◼ Pulmonary: ARDS (?Babesia)
◼ Hematology: Disseminated Intravascular Coagulation
(DIC)
◼ CNS: facial n. palsy, hearing loss, iritis, PNP, psychiatric
symptoms, CVA, meningo-encephalitis (also seen in BMD)
◼ Meningoencephalitis from Borrelia miyamotoi in an Immunocompromised Patient; Joseph L. Gugliotta,
M.D., et al. N Engl J Med 2013; 368:240-245January 17, 2013
Why Do Symptoms Relapse?
Persistence through Immune Evasion
◼ B. burgdorferi, through gene recombination, can
modify its surface antigen VlsE, and non-expressed
vls, creating different outer surface antigens,
helping to avoid immune recognition
◼ B. miyamotoi and other relapsing fever spirochetes
have the same pathogenic mechanism, explaining
the relapsing/remitting aspect of the disease
◼ Bb and Bm can also exchange DNA in biofilms
◼ Variable VlsE Is Critical for Host Reinfection by the Lyme Disease Spirochete. Rogovskyy AS, et al. PLoS
ONE 8(4): e61226. http://dx.doi.org/10.1371/journal.pone.0061226
◼ Graves CL, et al. (2013); PLoS Pathog 9(11), e1003766
Treatment for Relapsing Fever
◼ Some patients recover without antibiotics, but:
◼ Relapsing fever can be fatal 2º DIC, hemorrhage,
CVA, ARDS, severe JH, myocarditis w/arrythmias
◼ OB/GYN complications: fetal death, spontaneous
abortion, premature birth w/ perinatal sickness
◼ Treatment: tetracyclines (500 mg QID) x10 days;
◼ CNS: IV Rocephin, ? IV Pen G 3 mil U Q 4
◼ In vitro: susceptible to doxy, zithro, Rocephin, but
Bm is resistant to Amox in vitro..? Need Biofilm agents
◼ Koetsveld, J., et al. In vitro susceptibility of the relapsing fever spirochete Borrelia miyamotoi to
antimicrobial agents. Antimicrob. Agents Chemother. AAC.00535-17; Accepted manuscript posted
online 3 July 2017
RF Borrelia in Biofilms?
Dr Alan McDonald, May 2019: Spiral form B. hermsii spirochetes and a
Biofilm of Hermsii picked up the glpQ Probe
Borrelia Miyamotoi:
An Emerging Borrelia Species in Ixodes ticks
◼ There are over 100 species of Borrelia in the US and over
300 species worldwide. Bb sensu lato: > 18 spp, RF > 16 spp
◼ B. miyamotoi is the first borrelia species to be transmitted
transovarially: up to 84% of larvae from infected female
deer ticks are infected. There is also a transfusion risk
◼ May cause a significant increase in the prevalence of
borreliosis: San Francisco, N.E., Canada, Europe (up to 15%)
◼ Rollend L., et al. Transovarial transmission of Borrelia spirochetes by Ixodes scapularis: A summary of
the literature and recent observations. Ticks and Tick-borne Diseases 4 (2013) 46-51
◼ Wroblewski, D., et al. Detection of Borrelia miyamotoi and other tick-borne pathogens in human clinical
specimens and Ixodes scapularis ticks in New York State, 2012–2015. Ticks-and-tick-borne-diseases. Mar
2017, p 407-411
◼ Thorpe, A., Tonnetti l. Distribution and survival of Borrelia miyamotoi in human blood components.
TRANSFUSION 2016;56;705–711
Transovarial Transmission B. miyamotoi:
Eggs: 90%; Larvae can transmit infection
Rising Incidence Borrelia miyamotoi in
Europe (Germany,Czech Republic)
◼ Ticks were collected from California to New York, in
the United States and from Germany and the Czech
Republic in Europe from 2008 through 2012.
◼ B. miyamotoi infection was in ticks in 16 of the 26
sites surveyed, with infection prevalence as high as
15.4%. These results show a widespread
distribution, indicating an exposure risk to humans
in areas where Ixodes ticks reside
◼ Standard blood tests do not pick up B. miyamotoi
◼ Prevalence of Borrelia miyamotoi in Ixodes Ticks in Europe and the United States. Crowder, C. et al. EID,
Volume 20, Number 10—October 2014; http://wwwnc.cdc.gov/eid/article/20/10/13-1583_article
Testing For B. miyamotoi
◼ Antibody testing for Lyme is not an effective tool for
discovering Bm (no cross reactivity):
◼ Branda JA, Rosenberg, E.S. Borrelia miyamotoi: A lesson in disease discovery. Ann Intern Med (2013)
159: 61-2; Lee SH, Vigliotti JS, Vigliotti VS, Jones W, Shearer DM. Detection of Borreliae in archived sera
from patients with clinically suspect Lyme disease. Int J Mol Sci (2014) 15: 4284-98;
◼ Antibodies to the GlpQ protein can be used in convalescent
illness. Add VMP (variable major protein) to EIA for early dx
◼ https://www.hhs.gov/ash/advisory-committees/tickbornedisease/reports/other-tbds-2018-5-
9/index.html
◼ Consider PCR’s to diagnose BMD w/ IgeneX RF Immunoblot
◼ Hojgaard A, et al: Detection of Borrelia burgdorferi, Anaplasma phagocytophilum and Babesia microti,
with two different multiplex PCR assays; Ticks and Tick-Borne Diseases, online before print, 2014 Jan 18.
pii: S1877-959X(14)00005-3.
◼ Leucopenia, thrombocytopenia, elevated LFT’s: BMD can
resemble Anaplasmosis
◼ Molloy PJ, Telford SR III, Chowdri HR, et al. Borrelia miyamotoi disease in the northeastern United
States: a case series. Ann Intern Med. 2015;163(2):91-98.
Persistence of Borrelia Miyamotoi
◼ Spirochetemia is being found by PCR in patients
with LD during winter months, after conventional
antibiotic regimens
◼ Findings: The ratio of B. burgdorferi: B. miyamotoi
infections was found to be as high as 3:1
◼ Consider B. miyamotoi/other borrelia in
“unexplained medical conditions”
◼ Non-sp. sx: fever, HA, N+, V+, myalgia, arthralgia..
◼ S. H. Lee, et al. Detection of Borreliae in Archived Sera from Patients with Clinically Suspect Lyme
Disease. Int. J. Mol. Sci. 2014, 15(3), 4284-4298;
◼ http://ajcp.ascpjournals.org/content/133/4/569.long;
◼ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2984391
◼ Krause PJ, Narasimhan S, Wormser GP, Rollend L, Fikrig E, Lepore T, Human Borrelia miyamotoi
infection in the United States. N Engl J Med. 2013;368:291–3.
New Face of Human Lyme Borreliosis:
? Association or Causation…
Diagnosis Location Source
CNS Lymphoma Washington, DC, USA Bahrain et al, 2007
Lupus-like syndrome Munich, Germany Molin et al., 2010
Distal Axonal PNP & France Creange, 2007
Chronic Encephalopathy
Pontine Tumor Germany Latsch et al., 2006
Intracranial Lymphoma Paris, France Louis et al., 2005
Prostate Ca w/paraparesis Netherlands Ruitenberg et al., 2005
MS w/Primary Lymphoma Croatia Batinac et al., 2007
Carditis, Psychiatric Poland Legatowicz-Koprowska et
disorders al., 2008
Hypersomnia Switzerland Dalal et al., 2007
Necrotizing Granulomatous New York, USA Zanchi et al., 2007
Hepatitis
Cerebral Venous Sinus East Germany Adamaszek et al., 2009
Thrombosis
Horner's syndrome USA Morrison et al., 2009
Babesiosis
◼ The genus Babesia comprises > 100 species of tick-
transmitted protozoal pathogens (piroplasms)
◼ US: 1° Babesia microti & B. duncani (WA-1)
◼ Rarely: Babesia MO-1, KO-1, (Babesia odocoilei non-
pathogenic)
◼ Europe: B. divergens, B. venatorum (EU-1), B bovis, B.
microti, B. bigemina, B. major, B. Occultans (7)
◼ Co-infection with Babesia and Lyme is common
◼ Telford,S. et al. Cultivation and Phylogenetic Characterization of a Newly Recognized Human Pathogenic
Protozoan. Journal of Inf Dis. 1994;169:1050-6
◼ Millán, J., et al., Molecular detection of vector-borne pathogens in wild and domestic carnivores and
their ticks at the human–wildlife interface. Ticks Tick-borne Dis. (2015)
◼ Curcio Sabino R., et al. Seroprevalence of Babesia microti in Individuals with Lyme Disease. Vector-
Borne and Zoonotic Diseases. October 2016; Theileria species are also seen:
http://doi.org/10.1371/journal.pntd.0002753
Rising Incidence of Babesia in Belgium
◼ In Europe, most clinical babesiosis cases in humans
have been attributed to Babesia divergens and
Babesia sp. EU1. In a recent study published in
2015, 199 Belgian patients w/ a tick bite &
symptoms were screened for Babesia
◼ 9% + for B. microti, 33.2% + for B. divergens, &
39.7% were + for Babesia sp. EU1:
◼ A retrospective serological survey on human babesiosis in Belgium. Lempereur L. et al. Clin Microbiol
Infect. 2015 Jan;21(1):96.e1-7.
◼ Babesia/Theileria DNA is in 9.94% wildlife in Italy:
◼ Piroplasmosis in wildlife: Babesia and Theileria affecting free-ranging ungulates and carnivores in the
Italian Alps. Stefania, Z. et al. Parasites &Vectors 2014, 7:70;
Babesiosis
◼ Symptoms: ↑ severity of all Lyme symptoms, including
fatigue, joint/muscle pain, headaches, neuropathy,
emotional & cognitive difficulties
◼ Krause, P.J. Concurrent LD and Babesiosis, evidence for increased Severity and Duration of Illness.
JAMA, June 5, 1996; Vol 275, No. 21)
◼ Key: Malaria-like: fevers, chills, flushing, day /& or night
sweats (mild, moderate, severe)
◼ Subclinical presentations common: Hemolytic
anemia, thrombocytopenia & ↑ BUN/Creatinine are rare
(unless immunocompromised, asplenic, B. divergens..)
◼ Atypical Symptoms: Unexplained cough, air hunger,
rarely ARDS (avoid steroids), ? Warm AI hemolytic anemia
◼ Wooley, A. et al. Post-Babesiosis Warm Autoimmune Hemolytic Anemia. N Engl J Med 2017; 376:939-
946. March 9, 2017
Atypical Presentations of Babesiosis
◼ Atypical cough +/- SOB without malarial signs or
symptoms in a chronic Lyme patient
◼ ARDS has been described in patients with malaria,
& can rarely be seen in patients with babesiosis (+RF)
◼ Gordon et al. ARDS in babesiosis. Chest 1984 Oct;86(4):633-4)
◼ Severe hemolytic anemia as a presenting complaint
in immunocompetent patients with intact spleens
◼ Iacopino, et al. Life threatening babesiosis in a woman from Wisconsin; Arch Intern Med 1990
Jul;150(7):1527-8)
◼ Death due to reactivation of latent babesia
infections w/ high-dose corticosteroid therapy
◼ Herwaldt BL, et al. Am J Trop Med Hyg 1995 Aug;53(2):146-51)
Babesiosis: Testing & Prevalence
◼ Testing: Giemsa smear, IFA (test for B. microti, WA-
1/duncani, ? B. divergens), FISH (18s), PCR
◼ Smears are negative unless parasitemia is > 5 %.
◼ FISH testing (Fluorescent In Situ Hybridization) may
find active Babesia, despite a neg PCR, IFA
◼ Seroprevalence of different Babesia species such as
Babesia microti and Babesia WA-1/duncani are
rising in the US, with ↑ # of species in Europe
◼ Shah, J., Horowitz, R., Human Babesiosis and Ehrlichiosis-Current Status. Eur Infect Dis, Vol 6, Issue 1,
Spring 2012
◼ Hamera S., et al. Increased diversity of zoonotic pathogens and Borrelia burgdorferi strains in
established versus incipient Ixodes scapularis populations across the Midwestern United States. Infect
Genet Evol. 2014 Oct;27:531-42
Babesia Testing: Antibody, PCR,
Giemsa Stain, FISH
Horowitz, R., Freeman P. International Journal of General Medicine 2019:12 101–119
Babesiosis in Pregnancy
◼ Mothers w/ prepartum Lyme + subclinical Babesia can
transmit the infection. Fetuses may require a transfusion
◼ Saetre, K. et al. Congenital Babesiosis After Maternal Infection With Borrelia burgdorferi and Babesia
microti. Journal of the Pediatric Infectious Diseases Society, 16 Sept 2017
◼ Treatment: Clindamycin (oral) 600mg TID + Quinine 650
mg TID X 7 days: effective/safe in 3rd trimester (high dose
quinine can cause abortion in the 1st trimester)
◼ Krause, et al. Babesiosis in Pregnancy. NEJM 2003; 349: 195-196. July 10, 2003;
◼ We have used Clindamycin + Mepron & Zithromax safely in
the 3rd trimester→ healthy babies (Horowitz, R. unpublished study)
◼ Must differentiate HELLP Syndrome from Babesiosis
◼ Gulersen, M., et al. Acute Babesiosis in Pregnancy: A Novel Imitator of Hemolysis, Elevated Liver
Enzymes, and Low Platelet Count Syndrome. Obstetrics & Gynecology, 2016 Jul;128(1):197-200.
Multiple Babesia Species Are in the Blood
Supply: Transfusion/Transplantation Risk
◼ 115,000 blood donations from the Midwest & New
England: 4/1,000 + for Babesia. Also now + South
◼ The 1st transfusion-transmitted case/5th case of B.
divergens–like/MO-1 infection occurred in 2017
◼ Transplantation Risk is also possible
◼ Moritz, D. et al. Screening for Babesia microti in the U.S. Blood Supply. N Engl J Med 2016; 375:2236-
2245December 8, 2016.
◼ Cases of transfusion-transmitted babesiosis occurring in nonendemic areas: a diagnostic dilemma.
Transfusion Volume 57, Issue 10, 7 AUG 2017
◼ Burgess M., et al. Possible Transfusion-Transmitted Babesia divergens–like/MO-1 Infection in an
Arkansas Patient. Clin Infect Dis, Volume 64, Issue 11, 1 June 2017, Pages 1622–1625.
◼ Brennan, M. et al. Transmission of Babesia microti Parasites by Solid Organ Transplantation. Emerging
Infectious Diseases • Vol. 22, No.11, November 2016
Chronic Persistent Babesiosis
◼ A longitudinal study of Babesia microti infection in
seropositive blood donors was performed
◼ 21% had evidence of persistent parasitemia:
Specimens tested + by PCR (25 specimens/16 persons),
hamster inoculation (13 specimens/8 persons), & blood
smear)
◼ Conclusion: Seropositive blood donors can have
protracted low-level parasitemia that is variably
and intermittently detected by parasitologic and
molecular methods. Use a panel approach to test!
◼ Leiby, D. A., et al (2014), A longitudinal study of Babesia microti infection in seropositive blood donors.
Transfusion, 54: 2217–2225.