1. Epidemiology of Babesiosis, including Transfusion-Associated Infection Barbara L. Herwaldt, MD, MPH Centers for Disease Control and Prevention Parasitic Diseases Branch

2. BabesiosisBasics The views expressed are those of the speaker and do not necessarily represent those of CDC

3. Point … Counterpoint …

4. are intraerythrocytic microbes... are intraerythrocytic microbes  BUT NOTparasites  BUT they are NOT Plasmodium parasites aretickborne in nature... are tickborne in nature  BUT NOT bacteria  BUT they are NOT bacteria are transmissible by transfusion... are transmissible by transfusion  BUTNOT viruses  BUT they are NOT viruses Babesia: Yes... But Babesia: Yes... But...

5. Babesiosis: Don’t assume Don’tmalaria Don’t assume ring forms = malaria  Consider babesiosis Don’ttransmission = tickborne Don’t assume route of transmission = tickborne  Consider blood transfusion, regardless of region or season Don’tB. microti Don’t assume the species = B. microti  Consider other etiologic agents

6. Temporal and spatial dimensions

7. 1979:1 st transfusion case 1979: 1 st described transfusion case (MA; B. microti) 1956:1 st 1956: 1 st documented zoonotic case (Yugoslavia) 1966:1 st 1966: 1 st documented U.S. case (California); species? 1969:1 st 1969: 1 st documented case on Nantucket (B. microti) 1888: 1888: Viktor Babes ― febrile hemoglobinuria in “Rumanian” cattle caused by intraerythrocytic microbe 1893: 1893: Smith & Kilbourne ― Texas cattle fever caused by tickborne parasite (B. bigemina); 1 st 1 st demonstration of an arthropod vector

8. Geographic distribution of reported human cases of babesiosis: USA  the bulk in the USA (several thousand) Europe  some in Europe (several dozen)  a few in various other regions

10. NASA/GSFC/JPL, MISR Team Cape Cod Nantucket

11. Babesia microti

13. NASA/GSFC: J Schmaltz, MODIS Rapid Response Team

14. Tickborne transmission of B. microti is predominantly seasonal and regional, particularly in evolving foci in the Northeast (CT, MA, NJ, NY, and RI) and the upper Midwest (MN and WI) Babesiosis is reportable (under surveillance) in these and multiple other states and will become nationally notifiable in January 2011

15. I. scapularis eg, deer mice (Peromyscus leucopus) Babesia microti Ecologic niche Babesia microti in U.S. foci The risk for zoonotic transmission is dynamic in time & place

16. Don’t expect to “see” TICKS or TETRADS G. Hickling, U of TN

17. “Other” zoonotic Babesia agents Since the 1990s, sporadic U.S. cases caused by other etiologic agents have been described, such as: Since the 1990s, sporadic U.S. cases caused by other etiologic agents have been described, such as:  B. duncani (the WA1-type parasite) and related organisms (CA1-type parasites) in several western states  B. divergens “like” agents (eg, MO1) in various regions Their geographic ranges, tick vectors, and reservoir hosts largely remain unknown Their geographic ranges, tick vectors, and reservoir hosts largely remain unknown Infection with these parasites is not detected by molecular or serologic tests for B. microti Infection with these parasites is not detected by molecular or serologic tests for B. microti

18. Taxonomy 101

19. Babesiosis: Taxonomy Phylum: Apicomplexa Order: Piroplasmidora Family: Babesiidae Genus: Babesia Species:  Reportedly, ~100 Babesia “species” that infect mammals have been described  Traditionally, taxonomy has been based primarily on morphology and host specificity

20. Examples of “novel agents” B. divergens “like” EU1 B. duncani (WA1 type) CA1 type MO1

21. WA1, WA2, WA3 IsolatePatient (year) Index patient (1991) 1 WA1 2 WA2Blood recipient (1994) 3 WA3Blood donor (1994)

22. Asplenic Asplenic (died) Asplenic DNA only DonorTick (presumed)1994Yes WA3 Recipient (elderly patient)Blood (RBCs)1994Yes WA2 Index case-patientTick (presumed)1991Yes WA1 Tick (presumed) Tick (bitten 19d before onset) Tick (presumed) 1994 1993 1992 1991 CA4 CA3 CA2 CA1 Recipient (premature infant)Blood (RBCs)2000Yes CA5 DonorTick (presumed; CA or Oregon)2000Yes CA6 CharacteristicsTransmissionYearIsolated?Name WA’s CA’s The initial WA’s and CA’s

23. Babesia duncani n.sp. Description of Babesia duncani n.sp. differentiation and its differentiation from other piroplasms Conrad, Kjemtrup, Carreno, Thomford, Wainwright, Eberhard, Quick, Telford, Herwaldt 2006 Intern J Parasitol 2006

24. Babesia duncani (WA1 type) (WA1 type)

25. Old name New name WA1 B. duncani B. duncani (syntype isolate) WA2 B. duncani WA3 CA1 CA1-type parasites CA2 CA3 CA4 CA5 CA5 (~ a “WA”!) B. duncani B. duncani (syntype isolate) CA6 CA6 (~ a “WA”!) B. duncani The Christening The Christening

26. Examples of “novel agents” B. divergens “like” EU1 B. duncani (WA1 type) CA1 type MO1

27. Babesia divergens “LIKE” (but not “sensu stricto”)

28. MO1 (index case occurred in 1992 in an asplenic patient)

29. Ixodes ricinus “cattle” Babesia divergens Ecologic niche Babesia divergens sensu stricto in European foci

30. Europe: B. divergens vs B. divergens “like” 1956 Yugoslavia 1 st reported human case occurred in 1956 in an asplenic patient in Yugoslavia >30 tickborne cases have been reported: >30 tickborne cases have been reported: B. divergensbut  Most were in asplenic patients and reportedly were caused by B. divergens; but the type and quality of evidence varied 1998 and 2000 “EU1” (European Union 1) Italy and Austria  In 1998 and 2000, the index cases caused by “EU1” (European Union 1) were identified in asplenic patients in Italy and Austria

32. Back to Washington

33. (the case occurred in 2002 in an asplenic patient)

34. Back to the basics

35. Babesiosis: Clinical aspects asymptomatic to severe Regardless of the route of transmission, Babesia infection can range from asymptomatic to severe diagnostic testing is required Regardless of their severity, the manifestations are nonspecific; diagnostic testing is required Symptoms, if any, usually develop within several weeks or months of the exposure  BUTsplenectomy)  BUT they may 1 st appear much later (eg, after splenectomy) severe babesiosis asplenia Risk factors for severe babesiosis include asplenia, advanced age, and various other causes of immune dysfunction  BUT  BUT “immunosuppressed” patients may be afebrile and/or have subacute, remitting-relapsing clinical courses

36. Babesiosis: Clinical aspects Even persons who have asymptomatic infection or whose symptoms resolve may have low-level parasitemia for weeks to months, sometimes for longer than a year People can meet all of the criteria for donating blood despite being infected and infective

37. Persistent parasitemia after acute babesiosis (Krause, et al. N Eng J Med, 1998)

38. Serologic Parasitologic (including molecular) Laboratory evidence of infection

39. Laboratory approaches in different settings

40. Diagnostic testing versus Donor screening

41. What’s the gold standard? gold standard?

42. Cautionary notes no FDA- cleared “test kits” for in vitro diagnostic use (even for B. microti) Although some commercial laboratories offer Babesia serologic and molecular testing, there are no FDA- cleared “test kits” for in vitro diagnostic use (even for B. microti) Testing is done with “reagents” assembled and evaluated by the individual laboratory Inter- and intra-laboratory variability may be noted with respect to the sensitivity, specificity, reliability, and validity of “the assay” (patient data/results)

43. Babesiosis: “Diagnosis” Parasitologic diagnosis (“direct”) Parasitologic diagnosis (“direct”)  Detects parasites (DNA)  BUT not sufficiently sensitive to reliably detect low-level infection Serodiagnosis (“indirect”) Serodiagnosis (“indirect”)  Highly sensitive (an advantage in retrospective transfusion investigations)  BUT may be negative early in infection; does not reliably distinguish active from past infection (an advantage in retrospective transfusion investigations)

44. Babesia: Sensitivity of parasitologic methods ← PCR? Microscopy Animal inoculation Parasites per microliter of blood 10 -5 10 -3 10 -1 10 1 10 3 10 parasites in a unit of blood 100 p’s in unit

45. PCR results are helpful if positive But negative results do not exclude low-level parasitemia (low concentrations of parasites / DNA; small volumes tested vs transfused)

46. Cautionary notes In transfusion investigations, blood donors typically are implicated on the basis of seropositivity (with or without PCR positivity) and epidemiologic plausibility In our experience, segments In our experience, the likelihood of PCR positivity is higher for segments than for follow-up (postdonation) specimens but does not approach 100%

47. Case counts Surveillance(biovigilance)

48. tickborne transfusion-associated How many tickborne and transfusion-associated cases have been “reported” to date?

49. Also... How, where, when, and by whom/what were cases detected, diagnosed,investigated,“reported,” and tallied? Case criteria?

50. Basic tools

51. Case counts: the log scale

52. There’s typically a “story” Even severe cases often are serendipitously detected

54. To date, >100 U.S. transfusion-associated Babesia cases have been “reported”

55. To date... Among “reported” cases...

56. Babesiosis: U.S. transfusion cases Etiologic agents Etiologic agents  MostB. microti  Most cases were caused by B. microti  SeveralB. duncani  Several were caused by B. duncani Blood components Blood components  MostRBCs  Most cases were linked to RBCs  Severalplatelets  Several were linked to platelets Incubation period Incubation period: weeks to many months

57. Multi-donation cluster of cases—Minnesota, 1999-2000 Donor Recipients 7/12/99 RBCs (7/22): PCR+ Platelets (7/16): IFA- 1 9/23/99 RBCs (10/7): PCR+ 2 11/19/99 RBCs (11/29): Index patient Platelets (11/23): IFA-3 1/21/00 Platelets (1/25): IFA+ 4 The donor was still PCR+ in April ‘00, 10 months postexposure (during a camping trip in Minnesota in June ‘99) (Herwaldt, et al. Transfusion, 2002)

58. ─Unrecognized, protracted infection in some donors─ ─Donor travel to & from foci of endemicity─ ─Intraregional distribution & interregional shipment of blood─ Translate into the potential for Transmission by transfusion any time (year-round) any time (year-round) any where ─

59. Transmission in all 4 seasons

60. Babesiosis without borders (but not equal risk)

61. Whither Babesia?

62. Point … Counterpoint …