Borreliae. Today s topics. Overview of Important Tick-Borne Diseases in California. Surveillance for Lyme and Other Tickborne

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Dwayne Lloyd
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Surveillance for Lyme and Other Tickborne Diseases in California with emphasis on Laboratory role

Surveillance (a brief review) A quick overview of important tick-borne diseases in California

burgdorferi sensu lato Tick-borne relapsing fever group Rickettsiales Rocky Mountain spotted fever

part) Conclusions 2 Notifiable Disease Surveillance: Route of Information for California Reporting

Route of Information for California Reporting hermsii), spotted fever and non-spotted fever group

department (LHD) receives, follows-up, reviews reports LHD submits reports to CDPH LHD submits

1 Surveillance for Lyme and Other Tickborne Diseases in California with emphasis on Laboratory role Anne Kjemtrup, D.V.M., M.P.V.M., Ph.D. Vector-Borne Disease Section California Department of Public Health 1 Today s topics Public Health Surveillance (a brief review) A quick overview of important tick-borne diseases in California Borreliae B. burgdorferi sensu lato Tick-borne relapsing fever group Rickettsiales Rocky Mountain spotted fever (RMSF) Rickettsia philpii (aka 364D Rickettsia) Anaplasma Laboratory considerations (the fussy bug part) Conclusions 2 Notifiable Disease Surveillance: Route of Information for California Reporting mandated by state law (Title 17 CCR) Reportable TBD include: anaplasmosis, babesiosis, Lyme disease, relapsing fever (B. hermsii), spotted fever and non-spotted fever group rickettsia Notifiable Disease Surveillance: Route of Information for California Reporting mandated by state law (Title 17 CCR) Reportable TBD include: anaplasmosis, babesiosis, Lyme disease, relapsing fever (B. hermsii), spotted fever and non-spotted fever group rickettsia Local health department (LHD) receives, follows-up, reviews reports Local health department (LHD) receives, follows-up, reviews reports LHD submits reports to CDPH LHD submits reports to CDPH Reports transmitted to Centers for Disease Control and Prevention (CDC) Reports transmitted to Centers for Disease Control and Prevention (CDC) Overview of Important Tick-Borne Diseases in California Borreliae B. burgdorferi sensu lato Tick-borne relapsing fever group Western black legged tick (Ixodes pacificus ) 1

Lyme disease: Borrelia burgdorferi ss Spirochete Host-associated helical bacteria First identified in 1982 by W.

** Lyme disease is the most common vector-borne disease in the U.S. In California, Ixodes pacificus is the only tick that transmits Lyme disease *** * Burgdorfer et al, 1982.

(41): 239-248 Transmission of Borrelia burgdorferi to Humans in California larva female lays eggs Ixodes pacificus Life cycle adult female Spring and early summer nymph Fall and winter Larvae

Seasonality of Acute Lyme Disease Cases, California Approximate peak adult western blacklegged tick season 2001-2010 The greatest number of acute cases of Lyme disease acquired in California

2 Lyme disease: Borrelia burgdorferi ss Spirochete Host-associated helical bacteria First identified in 1982 by W. Burgdorfer as spirochete * Borrelia burgdorferi is principle etiologic agent of Lyme disease in U.S. ** Lyme disease is the most common vector-borne disease in the U.S. In California, Ixodes pacificus is the only tick that transmits Lyme disease *** * Burgdorfer et al, Science (216): ** Steere, Wien Klin Wochenschr. (118): *** Lane et al J. Med Entomol. (41): Transmission of Borrelia burgdorferi to Humans in California larva female lays eggs Ixodes pacificus Life cycle adult female Spring and early summer nymph Fall and winter Larvae or nymphal ticks acquire the bacteria by feeding on infected mammal hosts People are accidentally infected through the bite of an infected nymph or adult female western blacklegged tick Seasonality of Acute Lyme Disease Cases, California Approximate peak adult western blacklegged tick season The greatest number of acute cases of Lyme disease acquired in California (as evidenced by EM rash) occurs in June, one month after the peak nymphal tick season Approximate peak nymphal western blacklegged tick season Symptoms of Lyme Disease Early Symptoms Non-specific flu-like symptoms Headache Myalgia Fever Malaise Erythema migrans (EM) rash EM Rash Source: Ross Ritter Lyme Borreliosis USA Later symptoms Facial palsy (Bell s palsy) Arthritis in one or more joints Rare cardiac involvement Attached tick and reaction Source: Lake County HD 2

Lyme Borreliosis California Reported confirmed cases per 100,000 person-years, 2005-2014* Trinity 4.5 Humboldt 3.9 > 3.0 Mendocino 3.9 Sierra 3.2 1.5 2.9 Nevada 2.7 Santa Cruz 1.6 Sonoma 1.5 Mono 1.

9 No cases reported *Though Lyme disease cases have been reported in nearly every county, cases are reported based on the county of residence, not necessarily the county of infection.

3 Lyme Borreliosis California Reported confirmed cases per 100,000 person-years, * Trinity 4.5 Humboldt 3.9 > 3.0 Mendocino 3.9 Sierra Nevada 2.7 Santa Cruz 1.6 Sonoma 1.5 Mono Amador 1.4 Mariposa 1.1 Marin 1.1 Others No cases reported *Though Lyme disease cases have been reported in nearly every county, cases are reported based on the county of residence, not necessarily the county of infection. Lizards and Lyme disease in California Key Points about the Epidemiology of Lyme Disease in California Western fence lizard Alligator lizard Nymphal ticks feed on lizards Borreliacidal protein in lizard blood kills Lyme disease spirochetes- zooprophylaxis Where examined, proportion of infected adult ticks in California lower than NE USA (average 1-2%, range=0-10%) while nymphal I. pacificus infection prevalence greater (up to 10-30%) 15 Exposure to ticks more likely in recreational rather than peridomestic setting. Travel exposure common Ixodes pacificus tick vector of Lyme disease in California Nymphal ticks important because of high infection prevalence and small size Active in the spring Adult ticks most active in the fall Western Fence lizard clears infection in an infected tick that feeds on it Dusky-footed woodrat, tree squirrels important reservoirs 16 Treatment Early disease oral doxycycline Oral amoxicillin for children and pregnant women Late and/or neurologic disease intravenous ceftrioxone Slow recovery (i.e. weeks to months) can occur 17 Lyme Disease Diagnosis- General Approach Exposure potential (history of tick-bite or being in tick-infested area) Symptoms E.M. rash (no serologic test needed) Other symptoms (e.g. facial palsy, arthritis, etc ) Requires serologic confirmation Serologic tests 2-test approach Sensitive ELISA or IFA If positive, followed by Western Blot 18 3

Borrelia bissettii Found in ticks and rodents in California Closely related species found in humans in Slovenia and Czech Republic (arthritis-type presentation) Indirect evidence of human infection

May be included as Lyme disease Few infections documented also co-infected with B. burgdorferi B.

with B. burgdorferi on whole-cell antigen tests (But reacts very specifically with GlpQ- B. miyamotoi antigen Human infections with Borrelia miyamotoi 46 cases described in Russia (Platonov et al.

burgdorferi Fever EM Fatigue Arthralgia Headache Neck Stiffness Symptoms: Similar to Lyme borreliosis, but high fever, fatigue and headache more common in B. miyamotoi infections.

4 Borrelia bissettii Found in ticks and rodents in California Closely related species found in humans in Slovenia and Czech Republic (arthritis-type presentation) Indirect evidence of human infection in CA (actual infectiousness/disease-causing potential unknown) Impact on disease incidence unknown Extent of cross-reactivity with B. burgdorferi tests unknown. May be included as Lyme disease Few infections documented also co-infected with B. burgdorferi B. miyamotoi characteristics Only relapsing-fever spirochete in the Ixodes ricinus species complex Like other relapsing fever group spirochetes, culture is not good method of detection May cross-react with B. burgdorferi on whole-cell antigen tests (But reacts very specifically with GlpQ- B. miyamotoi antigen Human infections with Borrelia miyamotoi 46 cases described in Russia (Platonov et al., EID, 2011) 18 probable cases, eastern US (Krause et al., 2013) 1 case (meningoencephalitis), New Jersey (Gugliotta et al., 2013) Borrelia burgdorferi & B. miyamotoi in CA I.pacificus B. miyamotoi B. burgdorferi Fever EM Fatigue Arthralgia Headache Neck Stiffness Symptoms: Similar to Lyme borreliosis, but high fever, fatigue and headache more common in B. miyamotoi infections. Lyme disease surveillance impact: Will likely not impact LD case numbers but LD surveillance system may facilitate identification of such cases Tick-Borne Relapsing Fever Tick-borne Relapsing Fever (TBRF) Agent Borrelia hermsii, B. parkerii, B. turicatae Visible on stained red blood smear Ornithodoros hermsi Vector Soft (Argasid) ticks, Ornithodoros spp. Source: Gary Green, M.D., Sonoma Co. In U.S., O. hermsi, O. parkeri, O. turicata Transmitted from infected female tick to her progeny (transovarial transmission) and from one life stage to next (transtadial transmission) Reservoir Peridomestic rodents Chipmunks, squirrels, rats, mice Infected animals carry the organism in their blood A soft tick acquires infection when they take a blood meal from an infected animal 4

Tick-borne Relapsing Fever TBRF is a serious disease However, if treated the case

of fetal loss (up to 50%) Symptoms Incubation period: 1 to 14 days Fever, headache,

5 (up to 20) days Up to 10 relapses Reported Cases of Tick-borne Relapsing United

pdf Tick-borne relapsing fever in California, 1997 2014* The majority of TBRF cases

Exposure High risk sites: Rodent-infested cabins 3000-9000 feet elevation

when rodents vacate nest Humans vulnerable when sleeping on floor or in beds in

Rickettsiales Rocky Mountain spotted fever (Rickettesia rickettsii) 364D

rickettsii and Rickettsia 364D Genus Rickettsia is in bacterial tribe Rickettsieae,

All intracellular pathogens Called spotted fever group due to the rashes typically

5 Tick-borne Relapsing Fever TBRF is a serious disease However, if treated the case fatality rate is less than 5% If acquired during pregnancy, TBRF poses a high risk of fetal loss (up to 50%) Symptoms Incubation period: 1 to 14 days Fever, headache, chills, myalgia Febrile episodes 1 to 7 days separated by afebrile periods of 1 to 5 (up to 20) days Up to 10 relapses Reported Cases of Tick-borne Relapsing United States Tick-borne relapsing fever in California, * The majority of TBRF cases in California are acquired in mountainous regions Tick-borne Relapsing Fever Exposure High risk sites: Rodent-infested cabins feet elevation coniferous forest Soft ticks live in rodent nests in building Seek out blood meal when rodents vacate nest Humans vulnerable when sleeping on floor or in beds in contact with walls Rodent nest in crawl space * CDPH surveillance data Rickettsiales Rocky Mountain spotted fever (Rickettesia rickettsii) 364D (Rickettsia philpii ) Anaplasma 29 Spotted Fever Group Rickettsia: Rickettsia rickettsii and Rickettsia 364D Genus Rickettsia is in bacterial tribe Rickettsieae, family Rickettsiaceae, and order Rickettsiales Related to Ehrlichia and Anaplasma All intracellular pathogens Called spotted fever group due to the rashes typically seen with these infections Source: CDC Dumler and Walker, 2001; Lancet Infectious Diseases; April

6 Rocky Mountain Spotted Fever (RMSF) Most severe tick-borne illness in the United States 3-5% case fatality if treated 20% case fatality if untreated * Recent studies suggest case fatality has decreased to as low as 0.5% Higher risk of fatality in children 5-9 years ** Most cases occur during summer months Primary California tick vectors American dog tick (Dermacentor variabilis) wood tick (Dermacentor andersoni) Family Rickettsiaceae Rickettsia rickettsii Small, intracellular bacteria Rickettsia rickettsii in endothelial cells of a blood vessel from a patient with fatal RMSF Source: CDC * Chapman et al., MMWR Recomm Rep 55: 1 27 ** Openshaw et al., Am. J. Trop. Med. Hyg., 83(1), 2010, pp Clinical Features of RMSF Sudden fever, myalgia, nausea, headache 2 to 14 days after tick bite Rash (81%-91% of patients * ) Usually 3 to 5 days after tick bite Starts as blanching macular rash Eventually become papular ** Often on palms and soles (36-82% cases) * Often spreads to entire body The later the rash appears, the higher the mortality* Thrombocytopenia Leads to severe complications Acute respiratory distress syndrome (ARDS), abdominal pain, neurologic or bleeding disorders, loss of circulation (gangrene) Source: CDC * Mandell et al, Principals and Practices of Infectious Diseases, 2005 pp **CDC Rocky Mountain Spotted Fever: a 2012 a County of residence of confirmed RMSF human cases Rocky Mountain Spotted Fever in California a, b Since 2002 there have been 13 confirmed cases of RMSF reported in California a Travel history out of county b Fatality 2002, 2014 a,b 2014 a 2014 b Diagnosis and Treatment Diagnosis Serology Rising antibody titers (four-fold change in acute and convalescent samples) IFA or ELISA tests PCR, immunohistochemical staining of tissue (difficult to obtain), culture Treatment Doxycycline Adults and children (not pregnant women) * Source: Centers for Disease Control and Prevention Do not wait for diagnosis must treat on suspicion! * Mandell et al, Principals and Practices of Infectious Diseases, 2005 pp Other Spotted Fever Rickettsiae Tick-Borne Spotted Fever Rickettsiae in the United States May cause similar signs and symptoms to those observed for RMSF Pathogens in the U.S. include several species of Rickettsia Rickettsia parkeri Transmitted by Amblyomma maculatum (Gulf Coast tick) Eastern and southern U.S., particularly along the coast Rickettsia species 364D (Rickettsia philipii) Transmitted by Dermacentor occidentalis (Pacific Coast tick) 6

364D: Rickettsia philipii First detected in ticks in 1966 in California Pacific Coast ticks (Dermacentor occidentalis) tick vector First human case from Lake County, California July 2008 Common sign

Parapox virus Source: CDC.gov Source: http:// www.textbookofbacteriology.net /Anthraxlesion.

Positive ticks (adult Pacific Coast ticks: 2.6% N. California; 6% S.

(VRDL; add details/contact) at time of identification and convalescent sample 3-4 weeks later Collect two samples from wound under eschar with dry cotton swabs, store in vials, send to VRDL for PCR

7 364D: Rickettsia philipii First detected in ticks in 1966 in California Pacific Coast ticks (Dermacentor occidentalis) tick vector First human case from Lake County, California July 2008 Common sign includes a local cutaneous eschar (dark crusted ulcer) Treated with doxycline Challenges for Diagnosing Many look-alikes Tick-bite reaction Cutaneous anthrax Source: Mariposa Environmental Health Parapox virus Source: CDC.gov Source: /Anthraxlesion.gif Eschar on forearm Eschar on arm Source: Colorado State University Extension Distribution of Rickettsia philipii Cases and Infected Ticks in California Human case Human case and positive ticks Positive ticks (adult Pacific Coast ticks: 2.6% N. California; 6% S. California) If You Identify A Suspect Dermacentor Tick-Bite Associated Eschar: Submit whole blood sample for Spotted Fever Group Rickettsia testing to CDPH, Viral and Rickettsial Disease Laboratory (VRDL; add details/contact) at time of identification and convalescent sample 3-4 weeks later Collect two samples from wound under eschar with dry cotton swabs, store in vials, send to VRDL for PCR Reported Human Cases in California 2014: 1 case 2013: 3 cases 2012: 4 cases 2011: 5 cases 2008: 1 case Anaplasmosis Anaplasmosis Western blacklegged tick (Ixodes pacificus ) Source: CDC Clinical Fever, headache, malaise, myalgia common Respiratory and/or GI symptoms (cough/dyspnea, nausea, diarrhea, vomiting) in some Leukopenia and thrombocytopenia common Rash rarely observed with anaplasmosis Incubation period typically 1 week Fatal outcomes rare, often associated with immune-compromised conditions Treatment: Doxycyline Weil et al. Mayo Clin Proc 2012: 87 (3):

Incidence by Age Group for Anaplasmosis in the United States 2000-2010 The frequency of reported cases of anaplasmosis is highest among males and

tick habitats may be at increased risk for infection California Human Cases of Anaplasmosis 1994-2012* HGA (16 cases) Case associated with travel

gov/anaplasmosis/stats/ * CDPH surveillance data, county of residence Reported Anaplasmosis cases, California, 2004-2013 Laboratory Considerations

EIA/IFA) followed by IgM western blot for early (< 1 month) or IgG western blot for later disease Many commercial labs now reflex test in event

8 Incidence by Age Group for Anaplasmosis in the United States The frequency of reported cases of anaplasmosis is highest among males and people over 50 years of age A compromised immune system may increase the risk of severe outcome Individuals who reside near or spend time in known tick habitats may be at increased risk for infection California Human Cases of Anaplasmosis * HGA (16 cases) Case associated with travel through endemic area * CDPH surveillance data, county of residence Reported Anaplasmosis cases, California, Laboratory Considerations (The fussy bug part) N=16 Mean age= 50 years 9 (56%) male 46 Borreliae For non-em cases Lyme disease requires two step procedure (sensitive EIA/IFA) followed by IgM western blot for early (< 1 month) or IgG western blot for later disease Many commercial labs now reflex test in event only one test (EIA/IFA or western blot) ordered: if positive western blot, run EIA/IFA and vice versa Borreliae Many commercial non-fda tests available that do not fit surveillance criteria Culture + PCR system from PA lab Lyme Urine antigen Many, many other

9 Lyme Disease Diagnosis- A few notes on the western blot IgM : two of three specific bands: 24 kda (OspC), 39 kda (BmpA), 41 kda (Fla) Outer surface protein C (OspC) early immunogenic antigen. Different strains elicit slightly different immunoglobulins to this same antigen. Depending on the spirochete strain, that same antibody to OspC can range from 21 kda to 25kDa. 49 Diagnosis- A few notes on the western blot IgM appears 2-4 weeks after EM and peaks at 6-8 weeks. IgM can persist after treatment and thus Lyme IgM serologic results should be considered informative only during acute phase of disease. For surveillance purposes, IgM results are considered uninformative for specimens collected more than 30 days after onset 50 Diagnosis- A few notes on the western blot IgG: five of 10 bands: 18 kda, 21 kda (OspC), 28 kda, 30 kda, 39 kda (BmpA), 41 kda (Fla), 45 kda, 58 kda (not GroEL), 66 kda, Other diagnostic tests C 6 ELISA test A recombinant antigen based on a conserved region of the VlsE gene, the immunodominant variable surface antigen of B. burgdorferi Equivalent specificity to two tiered testing and more sensitive in both acute (erythema migrans) and later disease stages* 1-2 kits have been approved by FDA as stand-alone tests Useful for diagnosing B. burgdorferi sensu lato (e.g. European strains) *Bacon et al. Serodiagnosis of LD by Kinetic ELISA using Recombinant VlsE1 or 93 kda 51 Peptide Antigens of B. burgdorferi Compared with 2-Tiered Testing Using Whole-Cell Lysates. Journal of Infectious Diseases 2003; 187: Patient Recommendations: I ve been bitten by a tick What do I do now? Promptly remove tick Cleanse the area with soap and water If you develop any compatible symptoms 1-30 days after bite, consult your physician Let your physician know that you were bitten by a tick 53 Should an attached tick be tested for Borrelia? Tick testing can provide an opportunity for patientphysician communication Helpful to know if it is a tick Not for clinical management Results may take a while If a tick tests positive, the patient may not necessarily get Lyme disease If a tick tests negative, this does not necessarily mean that the patient will not become ill False negative Could have been bitten by another infected tick, not detected 54 9

Relapsing Fever spirochetes B. hermsii & B.

) Serologically, may cross-react with B. burgdorferi on whole-cell antigen tests But reacts very specifically with GlpQ protein- species specific for B. hermsii or B. miyamotoi Extent of B.

Study 1 (Hinkley et al, CID, 2014) LD testing from Commercial laboratories in endemic states reviewed Seven participating laboratories performed ~3.4 million LD tests on ~2.

10% to 18.5%. Applied to the total numbers of specimens, this yielded an estimated 240,000 to 444,000 infected source patients in 2008.

10 Relapsing Fever spirochetes B. hermsii & B. miyamotoi Like other relapsing fever group spirochetes, culture is not good method of detection Stained blood smear often shows spirochetes in febrile period (confirmed!) Serologically, may cross-react with B. burgdorferi on whole-cell antigen tests But reacts very specifically with GlpQ protein- species specific for B. hermsii or B. miyamotoi Extent of B. hermsii and B. miyamotoi GlpQ crossreactivity unknown. Where Did Those Numbers Come From? Study 1 (Hinkley et al, CID, 2014) LD testing from Commercial laboratories in endemic states reviewed Seven participating laboratories performed ~3.4 million LD tests on ~2.4 million specimens nationwide Two-tiered testing accounted for at least 62% of assays performed; The estimated frequency of infection among patients from whom specimens were submitted ranged from 10% to 18.5%. Applied to the total numbers of specimens, this yielded an estimated 240,000 to 444,000 infected source patients in (A lot of inappropriate costly testing) Where Did Those Numbers Come From? Study 2 (Nelson et. al; EID, Sept 2015) Physician diagnostic codes (ICD-9) reviewed from endemic states Rash treated with appropriate antibiotics but not reported as LD + Laboratory tests result in patient treatment but not coded as Lyme disease as final diagnosis Supports notion of under-reporting Has Something Changed? CDC has long maintained that Lyme disease is likely 10X under-reported Not a biological phenomenon Methodological issue principally related to underreporting What role could medical claims data play in surveillance? Does not change epidemiological model (the who, what, where, when ) Like West Nile virus where we know (and accept) that all cases are not reported It does better define burden of disease which may impact: Resource allocation Research priorities Rickettsiae Diagnosis Serology Rising antibody titers (four-fold change in acute and convalescent samples) Often only one sample taken: (probable if positive) Sometimes sample taken post acute and second sample will not show more increase. (still probable if both positive at same dilution) IFA or ELISA tests PCR, immunohistochemical staining of tissue (difficult to obtain), culture Source: Centers for Disease Control and Prevention 10

Crossreactivity between and among Rickettsia species and other bacteria common 61 Only way to confirm 364D R.

Experimental diagnostic technique at this time Serology (acute and convalescent using R.

Diagnostics If You Identify A Suspect Dermacentor Tick-Bite Associated Eschar: Submit whole blood sample for

details/contact) at time of identification and convalescent sample 3-4 weeks later Collect two samples from

gov http://www.cdph.ca.gov/programs/vrdl/pages/whatsnew.

11 Crossreactivity between and among Rickettsia species and other bacteria common 61 Only way to confirm 364D R. philipii is to test a dry swab sample of tissue under eschar (scab) or piece of scab by PCR (OmpA gene) Experimental diagnostic technique at this time Serology (acute and convalescent using R. rickettsii antigen required for confirmation. Diagnostics If You Identify A Suspect Dermacentor Tick-Bite Associated Eschar: Submit whole blood sample for Spotted Fever Group Rickettsia testing to CDPH, Viral and Rickettsial Disease Laboratory (VRDL; add details/contact) at time of identification and convalescent sample 3-4 weeks later Collect two samples from wound under eschar with dry cotton swabs, store in vials, send to VRDL for PCR CDPH Resources Tick Identification Core Education Program The Vector-Borne Disease Section regularly identifies ticks submitted by public and health care providers. Information Broad Distribution Presentations to medical/local agencies 65 Public Outreach School-age programs Twice a year LDAC meetings 66 11

12 Questions? 69 12

Lyme Disease (Borrelia burgdorferi)

Lyme Disease (Borrelia burgdorferi) Rancho Murieta Association Board Meeting August 19, 2014 Kent Fowler, D.V.M. Chief, Animal Health Branch California Department of Food and Agriculture Panel Members