Tick-borne Diseases Jason H. Barker, MD Department of Internal Medicine Division of Infectious Diseases April 18, 2017

Educational objectives Recognize the clinical manifestations of the major tick-borne diseases If you do not think of tickborne disease, you will not ask the correct questions and almost certainly fail to treat with an effective regimen Define the vectors and associated epidemiology Now that I have thought of tickborne disease, which ones are most likely in this patient? Understand the approaches to diagnosis and treatment of tick-borne diseases Role of current serology What do I do with this positive Lyme test?

Clinical case History of present illness 31 year old male 3 day history of malaise frontal headache myalgias mild abdominal pain fever to 103 for 24 hr

Clinical case Additional history no significant past history no medications avid hunter and fisherman returned 2 days ago from a hunting trip in Missouri (late June) multiple tick and mosquito exposures

Clinical case Physical exam Temp 39°C; BP 108/60 RR 24 diffuse abdominal pain no rash no neck stiffness

Diseases and Causative Agents Organism(s) Lyme Disease Borrelia burgdorferi Babesiosis Babesia microti Granulocytic Anaplasmosis Anaplasma phagocytophilum Monocytic Ehrlichiosis Ehrlichia chaffeensis Rocky Mountain Spotted Fever Rickettsia rickettsii

Lyme disease - historical Late 1970’s Seasonal arthritis clustered around Lyme, CT Linked to a particular rash finding, erythema chronicum migrans (ECM), and deer tick bites Causative organism is a spirochete, Borrelia burgdorferi Most common tickborne infection in U.S.

Lyme disease - distribution Western blacklegged tick (Ixodes pacificus)   Deer tick (Ixodes scapularis)   

Lyme in Iowa? Yes We have seen cases of Lyme in people who have not recently left Johnson County Practitioners have identified unequivocal erythema migrans rashes in patient who have not traveled out of the area North Dakota now has documented deer ticks, with a small percentage positive for Lyme and/or anaplasmosis

Iowa Tick Epidemiology Source: IA State tick epidemiology

Lyme disease - vectors

Borrelia burgdorferi transmission Ixodes scapularis nymphs responsible for most human cases. Ixodes pacificus is responsible for fewer. Small rodents are the primary reservoir for the spirochete Deer are important for spreading ticks All U.S. strains belong to group 1(B. burgdorferi sensu stricto) In Europe and Asia borreliosis is caused by two species, B. afzelii and B. garinii. All of these strains together can be grouped into B. burgdorferi sensu lato) Duration of tick attachment is critical to transmission (>24 h) The spirochete must upregulate specific virulence genes upon exposure to blood in order to allow transmission from the tick into the source of the blood

Clinical Presentation of Lyme Disease Presentation reflects pathogenesis Three stages: Primary: Systemic symptoms with local evidence of infection at tick bite (rash) Secondary: Manifestations of disease remote from tick bite, > ~ 3-4 weeks Tertiary: Late manifestations, remote from tick bite > ~ 6 months

Three stages of Lyme disease clinical manifestations - 1 Primary stage days to weeks after tick bite Constitutional symptoms ECM lesion 70-80%; typically >5 cm flat red patch May resolve without treatment 50% of patients do not recall a tick bite Erythema Chronicum Migrans

Erythema Chronicum Migrans

Three stages of Lyme disease clinical manifestations - 2 Secondary stage reflects dissemination Few weeks after tick bite Malaise, musculoskeletal symptoms are common Three sites of dissemination: dermatologic: ECM similar to the primary lesion, but at different site than the primary lesion cardiac: A-V conduction abnormalities (usually heart block) neurologic: Bell’s palsy, aseptic meningitis

Three stages of Lyme disease clinical manifestations - 3 Tertiary stage is persistent infection Months after initial infection Systemic febrile symptoms need not be present Two sites primarily: Migratory, recurrent oligoarticular arthritis large joints (knee most commonly) chronic neuroborreliosis (mild confusion, memory difficulties), radiculopathy

Lyme disease Diagnosis - 1 TAKE HOME POINT: Erythema migrans is a clinical diagnosis Therefore, diagnosis of primary and secondary stages is usually clinical and treatment will be initiated based on the history and physical and basic laboratory information

Lyme Disease Diagnosis - 2 Need to do Lyme testing? no yes ELISA negative positive Immunoblot negative Positive (≥ 5 out of 10 bands for IgG, or ≥ 2 out of 3 bands for IgM*) * Within 4 weeks of symptoms only

Sensitivity Insensitive for early or skin-confined disease. Sensitive for later, disseminated disease. WCS, whole cell ELISA (typical) The C6 ELISA is a new ELISA being evaluated Marques, Infect Dis Clin North Am 29:295-307 Early Late

Lyme Disease Diagnosis - 3 When is serology useful? Tertiary cases (i.e. arthritis and meningitis) Some secondary cases (e.g. suspected neurological disease without prior erythema migrans) Atypical presentations PCR can be performed in certain patients to follow therapy of joint disease Note: culture for Lyme disease is not widely available

Pitfalls in Lyme Serology Inappropriate ordering Serology has almost no role in acute EM There is no role for repeating serology after treatment IgM western blots are plagued by frequent false positives >15% (as high as 50%) Meaningless if the ELISA (1st step test) is negative

What do I do with this positive Lyme test? Two questions: Does this patient have an illness consistent with Lyme disease (typically obtained in the context of chronic symptoms) Why was the test obtained? What is meant by “positive?” ELISA? If negative, test is negative despite western blot results Some nonstandard testing obtained by patients. Note the # of bands used to call a positive.

Lyme Disease Treatment - 1 Treatment relieves symptoms, prevents progression to later stage Oral or parenteral therapy? Oral Primary and secondary ECM Bell’s palsy without meningitis Cardiac manifestation in an outpatient First occurrence of late arthritis IV Meningitis Hospitalized cardiac manifestation Option for recurrent arthritis

Lyme disease Treatment - 2

Lyme disease Treatment - 3

Prophylaxis for Tick Bites? Standard guidelines. Appropriate to consider if: Confirmed tick bite with a deer tick in previous 72 hours Attachment >24 hours (or engorgement) Local prevalence of Lyme in deer ticks is ≥ 20% This is the case in WI (very likely in MN, too) No contraindication to doxycycline 200 mg dose x 1 (4 mg/kg for children ≥ 8 yoa) Still watch for 1 month thereafter Evidence for prophylaxis is limited

Chronic Lyme Disease Controversy Some patients have chronic malaise despite adequate antibiotic treatment fatigue, body aches cognitive difficulties U.S. > Europe Optimal treatment of chronic disease remains controversial no efficacy of 90 day antibiotic treatment Unclear whether symptoms reflect: persistent infection continued immune activation by nonviable bacterial remains an unrelated disease

Babesiosis Protozoal parasite of red blood cells Transmission of B. microti mostly by Ixodes scapularis, thus same geographic distribution as Lyme disease. Can be spread by transfusion. 1-4 week incubation period

Babesiosis Most people are asymptomatic, despite weeks of persistent parasitemia (which eventually clears) If symptomatic, fatigue and constitutional symptoms are most common (no rash!) Can persist for months, and even recur (especially in setting of immunosuppression) Worse disease in splenectomized patients Massive hemolysis and organ failure are possible Concurrent infections with Lyme and Babesosis have been reported

Babesiosis – laboratory diagnosis Low hemoglobin and platelets Possible evidence of hemolysis Blood smear shows intraerythrocytic ring forms, resembling malaria parasites Serology-not useful during acute disease PCR

Babesiosis - treatment Most cases resolve without therapy, but recrudescence after splenectomy or immunosuppressive therapy has been observed Atovaquone plus azithromycin, or quinine plus clindamycin for 7-10 days Atovaquone 750 mg po BID + azithromycin 500 mg po x 1 then 250 mg po qD Clindamycin 300-600 mg IV/PO q 6-8h + quinine 650 mg PO q 6-8h Consider co-existent Lyme disease or Ehrlichiosis

Anaplasmosis and Ehrlichiosis Intracellular rickettsia-like organisms infecting WBC Human Granulocytic Anaplasmosis (HGA), caused by Anaplasma phagocytophilum, transmitted by Ixodes ticks disease was formerly known as Human Granulocytic Ehrlichiosis Human Monocytic Ehrlichiosis (HME), caused by Ehrlichia chaffeensis (and Ehrlichia canis), transmitted Amblyomma americanum

Distribution of HGA, HME HME- primarily Lone star tick (Amblyomma americanum)   HGA (hint- same ticks as Lyme)

Ehrlichiosis and Anaplasmosis – clinical manifestations Incubation time 1-3 weeks Same clinical manifestations for HME and HGA Most common are fever, severe headaches, myalgias May have dry cough or scant infiltrates on CXR Exception: rash (variety of types) is present in ~ 30% of cases of HME, while rare in HGA Complications include secondary infections and hemorrhage

Ehrlichiosis and Anaplasmosis– diagnosis Relative leukopenia with increased bands, thrombocytopenia, elevated LFTs Identification of morulae (clusters of organisms) on peripheral smear (only ~10-50% sensitive at best. Smear is particularly low-yield for HME) Serology PCR is available (sensitivity ~ 60-70%)

Ehrlichiosis and Anaplasmosis– treatment Doxycycline 100 BID For HME: For three days after resolution of fever For HGA: 10-14 days in order to treat the patient for uncomplicated primary or secondary Lyme (same distribution as HGA) Possible alternatives may be rifampin- minimal clinical experience with HGA Consider co-infections with Borrelia and babesia

Rocky Mountain Spotted Fever Caused by Rickettsia rickettsii A misnomer: most cases in midwestern and southeastern states Cases have been reported in every state except Maine and Vermont Mortality of untreated disease is 25% Two-thirds of the Rocky Mountain spotted fever cases occur in CHILDREN under the age of 15 > 90% of cases occur from April through September Transmission by Dermacentor variabilis and Dermacentor andersoni

RMSF Distribution Dog tick (Dermacentor variabilis) Wood tick (Dermacentor andersonii)

Rocky Mountain spotted fever Incubation time 5-10 days Early symptoms include: fever, nausea, vomiting, severe headache, muscle pain, lack of appetite  Rash may appear several days later (macular, or more classical petechial). Can include palms, soles, ankle or wrist. Periorbital edema, edema of the dorsa of the hands or feet. Calf tenderness. Later symptoms are: abdominal pain, joint pain, diarrhea Rash is seen infrequently upon initial presentation amd 10-15% of patients may not develop a rash at all

Rocky Mountain spotted fever

RMSF- Treatment Take-home point: Antibiotic treatment should be initiated immediately if Rocky Mountain spotted fever is suspected Treatment: Doxycycline 100 mg Q 12h x 7 days or until afebrile x 3 days Doxycycline is first choice in children as well

Rocky Mountain Spotted Fever- Pitfalls (from Masters et al. 2003) Waiting for the petechial rash (petechiae may appear late) Misdiagnosing gastroenteritis (GI symptoms are common in RMSF) No history of a tick bite (50% do not recall a tick bite) Geographic exclusion (occurrence in most states) Seasonal exclusion (cases occur in any month) Failure to treat early Failure to elicit appropriate history Failure to treat children with doxycyline

Novel Pathogens Borrelia miyamotoi

Novel Pathogens The good news: these infections respond to doxycycline, too

Take home points 1. Most tick-associated infections are treated with:

Take home points 1. Most tick-associated infections are treated with: doxycycline (exception: babesiosis)

Take home points 2.Failure to treat early with doxycycline is associated with a high mortality rate in patients with:

Take home points 2.Failure to treat early with doxycycline is associated with a high mortality rate in patients with: Rocky Mountain spotted fever

Take home points 3.A patient presents after a trip to RI with fever, malaise, and classic ECM. Prior to treating, you should confirm the diagnosis of Lyme disease by:

Take home points 3.A patient presents after a trip to RI with fever, malaise, and classic ECM. Prior to treating, you should confirm the diagnosis of Lyme disease by: Trick question. This patient needs no further testing prior to treatment. The clinical presentation is diagnostic.

Take home points 4. Ixodes scapularis (deer tick) can transmit the following organisms:

Take home points 4. Ixodes scapularis (deer tick) can transmit the following organisms: Borrelia burgdorferi Anaplasma phagocytophilum Babesia microti

Take home points 5. A patient with a recent tick bite develops a febrile illness and Bell’s palsy. You suspect the patients has:

Take home points 5. A patient with a recent tick bite develops a febrile illness and Bell’s palsy. You suspect the patients has : Lyme disease (disseminated, 2nd stage)

References Lyme disease: Steere, AC. (2001) N. Engl. J. Med. 345:115-125. Nadelman, RB. (2001) N. Engl. J. Med. 345:79-84. Klempner, MS. (2001) N. Engl. J. Med. 345:85-92. Lantos, Infect Dis Clin North Am 29:325-340. Ehrlichiosis: Bakken JS & Dumler JS. (2000) Clin Infect Dis. 31:554-60. Babesiosis: Krause et al. (1998) N. Engl. J. Med. 339:160-165 Rocky Mountain Spotted Fever: Masters et al. (2003) Arch. Intern. Med. 163:769-774

References, cont. MMWR report on tickborne rickettsial diseases: Chapman, AS (2006) MMWR. RR-4: 1-27. Excellent, well illustrated review of HGA, HME, RMSF Wormser, GP et al., (2006). The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 43: 1089-1134. Most recent Lyme guidelines