tick-borne disease case challenges.ppt - cfavmcfavm.org/notes/dralleman/tick-borne disease case...
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Tick-Borne Disease Case Challenges
The Saga of Leia
8 year old, female, intact German Shepherd dogPresented to the referring veterinarian for an acute onset of lethargy, anorexia and panting
Medical History
Diagnosed bilateral pannus two weeks prior to this presentation
Topical prednisolone acetate 1%, q8hOptimmune ointment (0.2% cyclosporine) q12h
Recent estrus cycle
Physical Exam FindingsRectal Temp. 103.50FMild discomfort in caudal abdomenHR normalCapillary refill time was normalMild petechiation was noted on gumsNo vaginal discharge noted
Work-Up
CBCBiochemical profileAbdominal radiographs
CBCHCT 39.5% (37.0 – 54.0)RBC 5.93 x 106 (5.4 – 7.8)RBC indices WNLPLT 32.0 x 103 (150 – 430)MPV 21.8 fl (8.0 – 16.0)WBC 15.69 x 103 (6.0 – 17.0)Neutrophils 12.54 x 103 (3.9 – 8.0)Band 0.100 x 103 (< 0.3)Lymphs 1.1 x 103 (1.3 – 4.1)Eosin 0.0 x 103
Monos 1.98 x 103 (0.2 – 1.1)
Blood Film Evaluation
Moderate rouleauxNo other erythrocyte abnormalities noted
Most lymphocytes and monocytes reactivePlatelets reduced in number (no clumping)
Some large
Interpretation
Stress leukogramEvidence of nonspecific antigenic stimulationThrombocytopenia
Biochemical Profile
Elevated blood glucose (129 mg/dl; N= 76-119)
Attributed to stress
Hyperglobulinemia (5.3 g/L; N= 2.7 – 4.4)No other significant abnormalities
Abdominal Radiographs
Mild to moderate hepatosplenomegalyGas-filled loops of SI (enteritis?)No radiographic evidence of pyometraLumbar spondylosis
DDx for ThrombocytopeniaBone marrow production
Unlikely, with no other cytopenias(neutropenia or nonregenerative anemia)
Peripheral consumption / utilizationMicrovascular disease (DIC, Vasculitis, thromboembolic disease etc.)Infectious disease (TBD)Immune-mediated / idiopathic (?)
Drugs (topical cyclosporine and prednisolone)
RDVM Plan
Rule out infectious diseasesSNAP 3Dx assay for Lyme, E. canis and HWD were all negativeTiters submitted for RMSF and Babesia spp
Coagulation profilePT, PTT, D-dimers and FDPs all within normal limits
RDVM Dx and Tx
Suspected IMTDog placed on prednisone at 1 mg/lb sidDoxycycline 5 mg/kg sidMonitor for 2 days
Platelet count begin to climb (65,000 cells / l)
Discharge with instructions to continue on oral pred and doxy, ophthalmic treatment for pannus
Return in two weeks
Return Visit to RDVM
Leia doing wellTiters for RMSF and Babesia were negativePlatelet count 212,000 cells / lPrednisone decreased to 0.5 mg/lb sidDoxycycline discontinuedReturn 2 weeks
4 Weeks Later, Leia Returns
Leia is sickLethargic, anorexic, pantingRectal Temp. 1040FCapillary refill time normal
Moderate petechiation present again
Refer to UF VMCStill on ophthalmic medicationsOff of oral prednisone for 2 weeks
Physical Exam Finding
Rectal Temp. 1040FCapillary refill time normal
Moderate petechiation present
Mild generalized lymphadenopathyMinimum Data Base
CBCBiochemical profileUrinalysis
Biochemical Profile
NSF
Urinalysis / Cystocentesis
Light yellowSG 1.018pH 8.0Protein negativeHemoprotein traceSediment
3-5 RBCs / hpf
CBC FindingsHCT 29.0% (37.0 – 54.0)RBC 4.70 x 106 (5.4 – 7.8)MCV 62.5 fl (66 – 75)MCHC 32.0 g/dl (34.0 – 36.0)PLT 28.0 x 103 (150 – 430)MPV 24.5 fl (8.0 – 16.0)WBC 15.80 x 103 (6.0 – 17.0)Neutrophils 11.21 x 103 (3.9 – 8.0)Band 0.63 x 103 (< 0.3)Lymphs 1.2 x 103 (1.3 – 4.1)Monos 3.00 x 103 (0.2 – 1.1)
Reticulocytes (1.3%) 61,000 (>80,000)
Interpretation of Hemogram
Microcytic, hypochromic anemiaPoorly regenerativeChronic blood loss
Fecal exam - Stool dark and tarry (fecal exam for parasites negative)Hemoccult test – positive for blood
Thrombocytopenia with increased MPV More pronounced left shiftLymphopenia and monocytosis
Infectious Cyclic Thrombocytopenia
Anaplasma platys(formerly known asEhrlichia platys)Only intracellular organism known to specifically infect platelets
Infectious Cyclic Thrombocytopenia
Tick vectorSuspected to be Rhipicephalus sanguineus, Brown Dog Tick
Eastern and Southeastern USWestern Indian Reservations (Unpublished data)
Clinical Signs
Mild clinical disease or subclinical infection in most dogs
German Shepherd dogs?Immunosuppressive therapy?
Fever, anorexia, sometimes petechiation or epistaxis1 to 2 weeks post-infection
Laboratory Findings
Cyclic thrombocytopenia occurring at 1 to 2 week intervals
Platelets below 20,000 cells / l initially, but rapidly increaseMild thrombocytopenia coinciding with parasitemic episodes
DiagnosisVisualization of organisms in peripheral bloodConfirmation
PCR analysisIFA test (L.S.U.)
Cross reactivity Anaplasma phagocytophilumon SNAP 4Dx assayCross-reactivity with Ehrlichia spp. (E. canis) minimal if any
Not an EhrlichiaLeia was SNAP 3Dx negative
Treatment and PrognosisTreatment same as other Ehrlichias and Anaplasmas (doxycycline)Prognosis excellent
Leia’s Serology
SNAP 3DxLyme, HWD and E. canis
all negative
IFA for A. platys1:160
Treatment Plan for Leia
Doxycycline 5 mg/ kg BID for 30 daysFerrous sulfate (10 mg/kg po bid with meal)
continued until PCV and red cell indices return to normal.
Continue on ophthalmic therapy for pannus
Ocular lesions resolving
Follow-upPlatelet count 2 days later
91,000 cells / l
Discharged to RDVM to recheck in two weeksMaintain on Doxycycline therapy for entire 30 days
The Saga Continues
7 weeks after discharge from UF VMCReturns to referring DVM
Panting, anorexic, rectal temp 1040FBilateral epistaxisMild peripheral lymphadenopathy
Refer to UF VMC for re-evaluation
Return to UF VMC
Physical Exam FindingsPanting, anorexic, rectal temp 103.50FBilateral epistaxisPeripheral lymphadenopathy, most prominent in submandibular nodesNo obvious petechiation
CBC FindingsHCT 34.0% (37.0 – 54.0)RBC 5.10 x 106 (5.4 – 7.8)MCV 67.5 fl (66 – 75)MCHC 34.0 g/dl (34.0 – 36.0)PLT 105.0 x 103 (150 – 430)MPV 18.0 fl (8.0 – 16.0)WBC 17.50 x 103 (6.0 – 17.0)Neutrophils 14.18 x 103 (3.9 – 8.0)Band 0.87 x 103 (< 0.3)Lymphs 1.05 x 103 (1.3 – 4.1)Monos 1.4 x 103 (0.2 – 1.1)
Reticulocytes (1.7%) 86,700 (>80,000)
Blood Film Evaluation
Moderate anisocytosis and polychromasia
Occasional NRBC
Most lymphocytes and monocytes reactivePlatelets mildly reduced in number (no parasites seen)
Problem List
FeverMild thrombocytopenia
Bilateral epistaxis, more in left nostril??
Generalized lymphadenopathy (mild) Very prominent submandibular lymph nodes especially on left side
Plan?
PlanAspirate left submandibular LN
PlanAspirate left submandibular LN
New Plan
Remember what you learned from E.B.B.Sick dog with a history of TBD (A. platys) that responded to doxy only to relapse when discontinuedEpistaxis without significant thrombocytopeniaGranulomatous/pyogranulomatous lymphadenitis
New PlanSend serum to NCSU Vector Borne Disease Diagnostic LaboratoryBartonella vinsonii subsp. berkhoffii and Bartonella henselaeAzithromycin
5-10mg/kg PO Q24 for 5 to 7 daysSame dose every other day for 5 more weeks
Follow-up
72 hours laterTemperature normalEpistaxis resolvedPlatelet count normal
SerologyPositive for B. henselae (1:256)
Leia had uneventful recovery
Co-InfectionsAP and Lyme
Same vector and co-infections common in upper Midwest and Northeastern USCo-infected animals more likely to have severe diseaseTreatment same
AP and Bartonella spp. ( Diroff et al. JVIM 2006, 20:762)
Dogs in Northeastern US that were Bartonella positive on serology
25% also AP positive; no significant association with LymeBartonella but not AP associated with peripheral lymphadenopathyDoxy ineffective in treatment of Bartonellosis
Co-InfectionsLiterature full of data regarding co-infections with tick-transmitted organismsE. canis and epistaxis
Epistaxis has not been reported in experimental E. canis infectionsEpistaxis associated with Bartonella infection
Thrombocytopenia or not (endothelial cell invasion)Vasculitis, vascular weakness
Warrants testing for co-infection
Non-responders or relapses after appropriate therapy
L.S.U. Butterfly
Dog Case - Coco6 year oldfemale spayedmixed breedVomited 2 days agoPresented to rDVM
CBC marked lymphocytosisSuspected lymphoid leukemia
Referred to UFVMC
Dog Case - CBC PCV % 33 L (37.0-54.0) RBC Indicies WNLP.P. g/dL >14 H(6.0-7.8)Fibrinogen mg/dL N/A (100-400)WBC/µL 13,400 (6.0-17.0103)Segs/µL 3,200 LN (3.0-11.5103)Bands/µL 130 (0.0-0.3103)Lymphs/µL 9,700 H (1.0-4.8103)Monos/µL 400 (0.2-1.4103)Platelets/µL 106,000 L (160-430103)
ChemistryTotal protein g/dL 13.8 H (5.6-7.4)
Albumin g/dL 1.4 L (2.8-3.8)
Globulins g/dL 12.4 H (2.3-4.2)
A:G 0.1 L (.7-1.4)
ALT 326 H (10 – 109)
AST 275 H (13 – 15)
Total Bil. 0.2 (0.1 – 0.3)
Calcium 8.1 L (8.7-11.5)
Rest WNL
CBC
Lymphocytosis
Bicytopenia (anemia, thrombocytopenia)with low normal neutrophils
Hyperproteinemia
Serum chemistry
Hyperproteinemia due to hyperglobulinemiaHypoalbuminemiaElevated ALT and ASTNormal total bilirubin
Problem List
Reasons for Additional Tests
Serum protein electrophoresisHyperproteinemia due to hyperglobulinemia
Liver aspirate / bile acidsBone marrow aspirate
Monomorphic lymphoidpopulation Bicytopenia w/ low normal neutrophils
AnemiaThrombocytopenia
Dog Case - SPE
Normal Dog This Dog
α γβ
albumin
albumin
α β
γ
Dog Case - SPE
Normal Dog This Dog
α γβ
albumin
albumin
α β
γ
Monoclonal gammopathy !!!with a polyclonal base
Serum protein electrophoresisMonoclonal gammopathy
Bone marrow aspirateLymphoplasmacytic infiltrate
Lymphocytes: 56% (<1%)Plasma cells: 8% (< 2%)Adequate megakaryocytes
Bile acids –normal pre and post
Ionized calciumNot performed
Additional TestsSerum protein electrophoresis
Monoclonal gammopathy
Bone marrow aspirateLymphoplasmacytic infiltrate
Lymphocytes: 56% (<10%)Plasma cells: 8% (< 2%)Adequate megakaryocytes
Is it a tumor?Is it infection?Immune-mediated disease?
Additional Tests
Serum protein electrophoresisMonoclonal gammopathy
Bone marrow aspirateLymphoplasmacytic infiltrate
Lymphocytes: 56% (<10%)Plasma cells: 8% (< 2%)
Tick-borne disease titerSNAP 3Dx positive
Additional Tests
Serum protein electrophoresisMonoclonal gammopathy
Bone marrow aspirateLymphoplasmacytic infiltrate
Lymphocytes: 56% (<10%)Plasma cells: 8% (< 2%)
Tick-borne disease titerSNAP 3Dx positiveEhrlichia canis positive IFA tier (1:10,240)
Additional Tests Outcome
Treatment with Doxycycline10 mg/kg BID for 30 days
Dog recovered uneventfullyStill positive??
Lost to follow-up
Canine Monocytic Ehrlichioses
Intracellular agents that reside in the monocytes and lymphocytes of infected hostsCan cause clonal proliferation of lymphocytsesMost often E. canis and E. chaffeensis (HME)Diagnosis problematic due to scarcity of circulating organisms
Monocytic Ehrlichiosis vs. Multiple Myeloma
EhrlichiaPlasmacytosishyperglobulinemiaMonoclonal GammopathySerology positive
Multiple MyelomaPlasmacytosishyperglobulinemiaMonoclonal GammopathyHypercalcemia, lytic bone lesions, Bence-Jones proteins
Acute phase
1 - 3 weeks after infectionClinical signs mild and nonspecific (fever, lethargy, weight loss, anorexia)Thrombocytopenia +/- anemia, leukopeniaTiters may be negative
Subclinical PhaseFew if any clinical signsThrombocytopenia (usually mild)Hyperglobulinemia with positive titerMay last months to years?
Chronic PhaseReappearance of clinical disease
breed, stress, concurrent disease
Mild to severeage, breed, strain of organism
Weakness, anorexia, weight loss, fever, pallorLymphadenopathy, hepatomegaly, splenomegaly, nephropathies, retinal lesions, edema, nonseptic polyarthritis, CNS disease, and mortality
DiagnosisPresumptive diagnosis based on clinical and routine laboratory findings
+/- history of tick exposureConfirmed with serology or PCR analysisPCR used to speciate infectious agents
Not as sensitive as serology
PCR
False negative, particularly in chronically infected dogs
Must do PCR analysis on splenic aspirates or bone marrow aspirates to evaluate therapy
Snap3Dx (IDEXX Laboratories Inc.)Uses P30 and P30-1 antigens of E. canisHigh specificity (100%), but low sensitivity (79.2%)(Bélanger et al., J. Clin Microbiol, 2001
High positive and negative predictive values in low prevalence populationsCannot differentiate between E. canis and E. chaffeensis infections
Treatment and PrognosisDoxycycline (5 mg/kg PO bid for 21 -30 days) or tetracycline (20 mg/kg PO tid)Eliminates clinical signs (titers may persist)Prognosis excellent in acute cases and mild chronic casesPrognosis guarded in dogs with severe pancytopenia or aplastic bone marrow