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

2. 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?

3. 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

4. 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

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

6. 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

7. 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.

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

9. 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

10. Iowa Tick Epidemiology
Source: IA State tick epidemiology

11. Lyme disease - vectors

12. 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

13. 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

14. 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

15. Erythema Chronicum Migrans

16. 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

17. 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

18. 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

19. 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

20. 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:
Early
Late

21. 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

22. 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

23. 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.

24. 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

25. Lyme disease Treatment - 2

26. Lyme disease Treatment - 3

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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 mg IV/PO q 6-8h + quinine 650 mg PO q 6-8h
Consider co-existent Lyme disease or Ehrlichiosis

33. 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

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

35. 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

36. 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%)

37. Ehrlichiosis and Anaplasmosis– treatment
Doxycycline 100 BID
For HME: For three days after resolution of fever
For HGA: 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

38. 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

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

40. 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

41. Rocky Mountain spotted fever

42. 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

43. 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

44. Novel Pathogens
Borrelia miyamotoi

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

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

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

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

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

50. 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:

51. 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.

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

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

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

55. 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)

56. References Lyme disease:
Steere, AC. (2001) N. Engl. J. Med. 345:
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:
Ehrlichiosis:
Bakken JS & Dumler JS. (2000) Clin Infect Dis. 31:
Babesiosis:
Krause et al. (1998) N. Engl. J. Med. 339:
Rocky Mountain Spotted Fever:
Masters et al. (2003) Arch. Intern. Med. 163:

57. 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:
Most recent Lyme guidelines