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Volume 27, Number 10—October 2021
CME ACTIVITY - Dispatch

Recurrence of Human Babesiosis Caused by Reinfection

Jonathan Ho1, Erin Carey, Dennis E. Carey, and Peter J. KrauseComments to Author 
Author affiliations: Yale School of Public Health, New Haven, Connecticut, USA (J. Ho, P.J. Krause); University of Bridgeport, Bridgeport, Connecticut, USA (E. Carey); Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA (D.E. Carey); Yale School of Medicine, New Haven (P.J. Krause)

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Introduction

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Release date: September 17, 2021; Expiration date: September 17, 2022
Learning Objectives

Upon completion of this activity, participants will be able to:

  • Describe clinical findings and course in a previously healthy patient who experienced a second episode of babesiosis 3 years after an initial episode

  • Determine laboratory findings in a previously healthy patient who experienced a second episode of babesiosis 3 years after an initial episode

  • Identify clinical implications of a case of babesiosis in a previously healthy patient who experienced a second episode of babesiosis 3 years after an initial episode

CME Editor

Thomas J. Gryczan, MS, Technical Writer/Editor, Emerging Infectious Diseases. Disclosure: Thomas J. Gryczan, MS, has disclosed no relevant financial relationships.

CME Author

Laurie Barclay, MD, freelance writer and reviewer, Medscape, LLC. Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Authors

Disclosures: Jonathan Ho, MD; Erin E. Carey, MS; and Dennis E. Carey, MD, have disclosed no relevant financial relationships. Peter J. Krause, MD, has disclosed the following relevant financial relationships: received grants for clinical research from Gold Standard Diagnostics.

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Abstract

Babesiosis developed in a 62-year-old immunocompetent physician, who had an uneventful recovery after receiving atovaquone and azithromycin. Three years later, babesiosis developed again, and he was again successfully given treatment. Clinical and laboratory evidence were highly supportive of Babesia reinfection. Healthcare professionals should be aware that reinfection might occur in babesiosis.

Babesia microti, the primary cause of human babesiosis, is an intraerythrocytic protozoan that is transmitted by hard-bodied ticks to mammalian hosts and occasionally to humans (1). White-footed mice are the primary host and once infected may remain so for life. Parasitemia also persists in humans, even after antimicrobial drug therapy (27). Immunocompetent human hosts can experience asymptomatic infection for as long as 1 year after antimicrobial drug therapy, although most patients clear infection within several months. Patients who are immunocompromised generally have a longer duration of infection and may experience relapsing symptoms. These patients might remain parasitemic for as long as 2 years, despite antimicrobial drug therapy (5,7). Most patients recover without long-term complications, although babesiosis can result in fatal illness (1,6).

We report a case of babesiosis in a previously healthy patient who experienced a second episode of babesiosis 3 years after an initial episode. He was given a standard course of antimicrobial drugs for Babesia infection for each episode.

The Study

A 62-year-old physician living in Huntington, Long Island, New York, USA, was in good health until June 9, 2013, when he felt unwell and fever, chills, headache, myalgias, fatigue, sweats, joint pain, poor appetite, and conjunctivitis developed. On the third day of illness, he noted dark urine that lasted for several days. On June 13, he was seen by his family physician, who noted fever but no other abnormality.

A complete blood count (CBC) showed a hemoglobin level of 13.9 g/dL (reference range 13 g/dL‒18 g/dL); a hematocrit of 40.8% (40%‒54%); a leukocyte count of 4,700 cells/μL (4,500 cells/μL‒11,000 cells/μL) with 55% neutrophils (54%‒62%) and 28% lymphocytes (25%‒33%); a platelet count of 68,000 cells/μL (150,000 cells/μL‒400,00 cells/μL); an aspartate aminotransferase level of 65 U/L (1 U/L‒36 U/L); and an alanine aminotransferase level of ALT 70 U/L (1 U/L‒45 U/L). He was told to return for reevaluation if symptoms did not resolve and was seen again on June 16. At that time, he had a fever (temperature 103°F). He was given doxycycline (100 mg orally every 12 h) but did not improve.

Laboratory results on June 16 showed that a B. microti IgM result was strongly positive (IgM titer >1:1,024, IgG titer <1:16), but Anaplasma phagocytophilum antibody was absent (Table). He was then given atovaquone (750 mg, 2×/d for 2 wks) and azithromycin (500 mg, 1×/d for 2 wks). He recovered completely 3 weeks after symptoms began.

Subsequent attempts to perform Babesia whole-genome sequencing on a residual blood sample obtained 3 days after the start of treatment identified B. microti DNA, but it was insufficient to perform full-genomic sequencing. At a follow-up visit to his physician on July 5, a CBC and tests for aspartate and alanine aminotransferase levels showed results within references ranges.

Three years later, on June 19, 2016, the patient had a fever (temperature 100°F), chills, sweats, headache, myalgias, anorexia, and difficulty concentrating develop. He also noted dark urine for several days. On June 22, he was seen by his physician, who obtained a CBC, which showed a hemoglobin level of 12.6 g/dL and hematocrit of 38.3%; a leukocyte count of 4,700 cells/μL with 55% neutrophils and 30% lymphocytes; and a platelet count of 41,000 cells/μL. A blood smear showed a Babesia parasitemia level of 1%. We amplified B. microti DNA by using PCR. Results for B. microti antibody were positive (IgM titer 1:256, IgG titer >1;1,024) (Table). He was then given atovaquone (750 mg every 12 h) and azithromycin (500 mg on day 1 and then 250 mg 1×/d) for 10 days, at which time symptoms had resolved. A repeat blood smear did not show any parasites. The patient has subsequently been in good health.

Conclusions

This patient had 2 separate episodes of B. microti babesiosis 3 years apart. He lived in an area where B. microti was hyperendemic and showed typical symptoms of Babesia infection during each episode, including dark urine that is indicative of hemoglobinuria (8). In the first episode, he did not have a blood smear or PCR performed, but a high B. microti IgM response was suggestive of B. microti infection (1,9). B. microti infection was subsequently confirmed by identification of B. microti DNA. In the second episode, B. microti infection was confirmed by blood smear and PCR.

Both clinical and laboratory evidence support reinfection rather than relapse of infection for this patient. He was repeatedly exposed to ticks in an area where babesiosis is commonly reported (1). He was in good general health without evidence of immunosuppression, whereas all cases of relapsing babesiosis have been reported in immunocompromised persons. After the first episode of babesiosis, he had complete clinical recovery 2 weeks after the onset of infection and did not experience the second episode until 3 years later. In contrast, those persons who have had relapsed B. microti infection have all been immunocompromised, experienced relapses of infection 2 weeks to 3 months after the previous episode, and usually lack full clinical recovery between relapses (37). Finally, our patient had a robust B. microti IgM response 2 weeks after the onset of his first infection and an anamnestic antibody response with a high IgG titer on day 4 of the second infection, which is characteristic of reinfection rather than relapse. Patients who have experienced relapse have conditions that impair antibody response (e.g., B cell lymphoma, rituximab therapy, HIV/AIDS). A minimal or absent B. microti antibody response has been demonstrated in patients who have had relapsing babesiosis and have been tested for B. microti antibody (5,7).

Previous studies describe the persistence of human B. microti infection and clinical immunity. In a prospective study of babesiosis patients who were tested for B. microti DNA by PCR every 3 months after acute illness until infection cleared, parasitemia persisted up to 13 months in 22 antimicrobial drug‒treated patients and up to 27 months in 23 untreated patients (2). In another study, a patient was reported as having relapsing infection that persisted for 27 months (5). The immediate host response to B. microti infection is provided by innate immune elements that include the spleen, macrophages, and neutrophils. In contrast, long-term clearance of B. microti parasites depends in large part on antibody (27). Studies of the duration of B. microti antibody have demonstrated persistence for as little as 6 months and as long as 6 years (2,6,1011).

Although there is strong evidence that our patient experienced reinfection, we do not have absolute confirmation, and it is possible that he could have had persistent B. microti infection that relapsed after 3 years. No B. microti PCR (or blood smear) was obtained after the initial infection. We attempted to further distinguish between relapse and reinfection by genetic sequencing of B. microti DNA from blood samples obtained from both episodes of infection. Unfortunately, we were unable to obtain sufficient DNA from the first episode for sequencing because a blood sample was only available 3 days after antimicrobial drug therapy was initiated, leaving few viable parasites.

In summary, our study shows evidence of reinfection after successful treatment of a B. microti infection. Although the evidence is highly supportive, it is not definitive. Whether our patient experienced reinfection or relapse 3 years after the initial infection, investigation of similar patients could provide useful information about the immune response to B. microti infection. Patients who have experienced babesiosis, and their healthcare professionals, need to be aware that babesiosis reinfection might occur, as for Lyme disease (12,13). Tickborne disease preventive measures should be maintained for patients with or without a history of babesiosis (14).

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Acknowledgment

This study was supported in part by the Gordon and Llura Gund Foundation.

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References

  1. Vannier  E, Krause  PJ. Human babesiosis. N Engl J Med. 2012;366:2397407. DOIPubMedGoogle Scholar
  2. Krause  PJ, Spielman  A, Telford  SR III, Sikand  VK, McKay  K, Christianson  D, et al. Persistent parasitemia after acute babesiosis. N Engl J Med. 1998;339:1605. DOIPubMedGoogle Scholar
  3. Lemieux  JE, Tran  AD, Freimark  L, Schaffner  SF, Goethert  H, Andersen  KG, et al. A global map of genetic diversity in Babesia microti reveals strong population structure and identifies variants associated with clinical relapse. Nat Microbiol. 2016;1:16079. DOIPubMedGoogle Scholar
  4. Simon  MS, Westblade  LF, Dziedziech  A, Visone  JE, Furman  RR, Jenkins  SG, et al. Clinical and molecular evidence of atovaquone and azithromycin resistance in relapsed Babesia microti infection associated with rituximab and chronic lymphocytic leukemia. Clin Infect Dis. 2017;65:12225. DOIPubMedGoogle Scholar
  5. Raffalli  J, Wormser  GP. Persistence of babesiosis for >2 years in a patient on rituximab for rheumatoid arthritis. Diagn Microbiol Infect Dis. 2016;85:2312. DOIPubMedGoogle Scholar
  6. Bloch  EM, Kumar  S, Krause  PJ. Persistence of Babesia microti infection in humans. Pathogens. 2019;8:102. DOIPubMedGoogle Scholar
  7. Krause  PJ, Gewurz  BE, Hill  D, Marty  FM, Vannier  E, Foppa  IM, et al. Persistent and relapsing babesiosis in immunocompromised patients. Clin Infect Dis. 2008;46:3706. DOIPubMedGoogle Scholar
  8. Hunfeld  KP, Hildebrandt  A, Gray  JS. Babesiosis: recent insights into an ancient disease. Int J Parasitol. 2008;38:121937. DOIPubMedGoogle Scholar
  9. Krause  PJ, Ryan  R, Telford  S III, Persing  D, Spielman  A. Efficacy of immunoglobulin M serodiagnostic test for rapid diagnosis of acute babesiosis. J Clin Microbiol. 1996;34:20146. DOIPubMedGoogle Scholar
  10. Ruebush  TK II, Chisholm  ES, Sulzer  AJ, Healy  GR. Development and persistence of antibody in persons infected with Babesia microti. Am J Trop Med Hyg. 1981;30:2912. DOIPubMedGoogle Scholar
  11. Moritz  ED, Winton  CS, Tonnetti  L, Townsend  RL, Berardi  VP, Hewins  ME, et al. Screening for Babesia microti in the U.S. blood supply. N Engl J Med. 2016;375:223645. DOIPubMedGoogle Scholar
  12. Nadelman  RB, Hanincová  K, Mukherjee  P, Liveris  D, Nowakowski  J, McKenna  D, et al. Differentiation of reinfection from relapse in recurrent Lyme disease. N Engl J Med. 2012;367:188390. DOIPubMedGoogle Scholar
  13. Krause  PJ, Foley  DT, Burke  GS, Christianson  D, Closter  L, Spielman  A; Tick-Borne Disease Study Group. Reinfection and relapse in early Lyme disease. Am J Trop Med Hyg. 2006;75:10904. DOIPubMedGoogle Scholar
  14. Piesman  J, Beard  CB. Prevention of tick-borne diseases. J Environ Health. 2012;74:302.PubMedGoogle Scholar

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Table

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Article Title: 
Recurrence of Human Babesiosis Caused by Reinfection
CME Questions
  • Your patient is a previously healthy 64-year-old man diagnosed with babesiosis. According to the case report by Ho and colleagues, which of the following statements about clinical findings and course in a 62-year-old male physician with apparent babesiosis reinfection is correct?

    • The patient was immunocompromised because of rheumatoid arthritis and its treatment

    • Symptoms were fever, chills, and cough productive of purulent sputum

    • Examination findings included fever, joint swelling, and erythema around a tick bite

    • Treatment with a standard course of anti-Babesia antibiotics (atovaquone and azithromycin) for each episode led to complete recovery in each

  • According to the case report by Ho and colleagues, which of the following statements about laboratory findings in a patient with apparent babesiosis reinfection is correct?

    • Hemogram showed strikingly low white blood cell (WBC) and normal platelet count

    • Liver function tests were normal

    • In the first episode, Babesia microti immunoglobulin (Ig) M antibody was strongly positive (IgM ≥ 1:1024, IgG < 1:16), and Anaplasma phagocytophilum antibody was absent

    • Full genomic sequencing was performed in the first episode

  • According to the case report by Ho and colleagues, which of the following statements about clinical implications of a patient with apparent babesiosis reinfection is correct?

    • Healthcare providers should be aware that babesiosis reinfection may occur and that tick-borne disease prevention is needed in patients with or without a history of babesiosis

    • Clinical and laboratory evidence in this patient support relapse of infection rather than reinfection

    • Anamnestic antibody response with high titer IgG antibody early in the course of the second episode suggests relapse

    • The evidence proves that this patient was reinfected with B. microti

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Cite This Article

DOI: 10.3201/eid2710.211240

Original Publication Date: September 17, 2021

1Current affiliation: Brown University, Providence, Rhode Island, USA.

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Table of Contents – Volume 27, Number 10—October 2021

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Peter J. Krause, Yale University, 60 College St, New Haven, CT 06510; USA

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Page created: July 11, 2021
Page updated: September 17, 2021
Page reviewed: September 17, 2021
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
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