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Home , Lyme disease, Lymphadenopathy, Murine typhus, Rickettsia rickettsii, Spotted fever, Typhus

PRACTICE | CASES CPD

Human granulocytic acquired from a blacklegged in Ontario

Stefan Edginton MD, T. Hugh Guan MD, Gerald Evans MD, Siddhartha Srivastava MD n Cite as: CMAJ 2018 March 26;190:E363-6. doi: 10.1503/cmaj.171243

79-year-old man was admitted to hospital in July after five days of (38°C as measured at home), head- KEY POINTS ache, sensitivity to light, and . Two • granulocytic anaplasmosis should be considered in weeksA earlier, the patient had noticed a tick attached to his skin patients with a history of tick bite who present with fever, after in the forest near his home. Subsequently, a red area , elevated transaminases, and developed around the bite that lasted one day. . The patient had a history of prostate in 2001 that had • Diagnosis involves detecting a fourfold increase in been treated with prostatectomy, postoperative radiation and –specific on immunofluorescence assay. leuprorelin for three years; more recently, he had no medical issues and did not take any regularly. The patient • Prevalence of this is likely to increase as Anaplasma phagocytophilum establishes itself in blacklegged tick lived in southeastern Ontario and had not left the region in the populations in . previous year. • Public health officials could consider making human granulocytic On admission, the patient’s heart rate was 114 beats/min and anaplasmosis a reportable disease to better quantify its regular, with a blood pressure of 125/76 mm/Hg, respiratory rate prevalence and incidence. of 16 breaths/min, oxygen saturation of 97% on room air and a temperature of 36.8°C. He had no stiffness and jolt accen- tuation was negative. Auscultation of the heart and lungs was patient’s platelet count had risen to 93 000 × 106 cells/L. He was normal, and there was no abdominal tenderness or hepato- discharged home to complete a two-week course of . The patient had no , , or palpable with follow-up at an internal medicine clinic. Before follow-up, . the acute-phase serologic testing returned a negative result for Laboratory investigations (Box 1) showed that the patient , and blood smears did not show . How- had thrombocytopenia with leukopenia, lymphopenia, mild ever, IgG antibodies to A. phagocytophilum, murine and R. , mildly elevated total bilirubin and aspartate amino- rickettsii all showed a titer of 1:64. transferase, and elevated lactate dehydrogenase and C-reactive The A. phagocytophilum serologic test involved an indirect protein. Blood cultures showed no growth, and computed tomo- immunofluorescence assay for IgG and was done at the National graphic (CT) imaging of the patient’s head was normal. A rapid Microbiology Laboratory in Winnipeg. Given the clinical and lab- slide test for mononucleosis was negative. Serologic tests for oratory findings, and in consultation with Public Health Ontario, HIV, hepatitis B and hepatitis C virus were nonreactive. A we felt that our patient likely had human granulocytic anaplas- test for Epstein–Barr virus immunoglobulin G (IgG) showed reac- mosis, and the positive tests for and Rocky tivity, but the mononucleosis slide test was negative, suggesting Mountain were false-positives caused by cross- a previous . reactivity between the tests. Alternatively, the patient may have The patient’s presentation was atypical of Lyme disease, but been exposed to these organisms in the past, but was not suggested other tick-borne were possible. Serologic acutely infected. tests for Lyme disease ( burgdorferi), Anaplasma phago- At the follow-up visit, the patient was well; his only symptom cytophilum, Rocky Mountain Spotted Fever ( rickettsii) was minor , which was resolving. His platelet count was and murine typhus were performed, and a peripheral blood film 153 000 × 106 cells/L. Convalescent serologic testing showed no was obtained to test for microti. change in the IgG titres for R. rickettsii and murine typhus. How- Because the patient had been bitten by a tick, he was given ever, the IgG titre for A. phagocytophilum had increased fourfold (100 mg orally, twice daily). Within three days of to 1:256, consistent with a diagnosis of human granulocytic admission, most of the symptoms had resolved, and the anaplasmosis.

© 2018 Joule Inc. or its licensors CMAJ | MARCH 26, 2018 | VOLUME 190 | ISSUE 12 E363 PRACTICE E364 tion of caused by locytic anaplasmosisinOntario.Thisdiseaseisatick-borneinfec- Here, wedocumentacaseofdomesticallyacquiredhumangranu- Discussion *Treatment ofdisseminated Lyme involves parenteral therapy. Variable babesiosis Box 2:Clinical presentation, testing andtreatment for humangranulocytic anaplasmosis, Lyme disease and treatment, d Duration of Treatment* Laboratory presentation Clinical Alkaline phosphatase, U/L Alanine aminotransferase, mg/L Erythrocyte sedimentationErythrocyte rate, mm/hr Aspart aminotransferase,Aspart U/L C-reactive protein, mg/L Lactate dehydrogenase, U/L Total bilirubin,μmol/L Estimated glomerularfiltration rate, mL/min Creatinine, μmol/L Carbon dioxide, mmol/L Chloride, mmol/L Potassium, mmol/L Sodium, mmol/L White bloodcells, ×10 Neutrophils, ×10 , ×10 Hemoglobin, g/L Variable reference, from a79-year-old manwithhumangranulocytic anaplasmosis Box 1:Results of laboratory investigations onpresentation andat follow-up, withnormalranges for the Kingston General Hospital for adults. *Reference values are affected by many variables, including patient population andthelaboratory methods used.The ranges provided here are thoseused at Platelets, ×10 6 6 cells/L 6 cells/L 6 cells/L transaminitis mild anemia,moderate Thrombocytopenia, leukopenia, Uncommon gastrointestinal symptoms Flu-like symptoms, headache, . The bacterium is A. phagocytophilum. The bacterium is 6 cells/L Human granulocytic anaplasmosis 10–14 CMAJ Doxycycline, 100mgorally, twice perday | MARCH 26,2018 mild transaminitis Normal hematologic panel, migrans atErythema site oftickbite cardiac, neurologic complications Disseminated: rheumatologic, lymphadenopathy Localized: flu-like symptoms, Reference range 150 000–400 000 4000–10 500 2000–7500 1300–4000 | 120–315 133–145 138–170 VOLUME 190 60 -150 64–133 3.7–5.3 97–110 adult* 10–46 0–110 19–27 8–45 0–17 6.3 casespermillion. 2012, themeanreportedannualincidenceinUnitedStateswas sis werereportedinMinnesotaandWisconsin1994.From2008to ­ scapularis.Thefirstcasesofhumangranulocyticanaplasmo- most commonlytransmittedbybitesfromtheblackleggedtick, < 20 0–1 Lyme disease 14–21 | ISSUE 12 presentation 1 Thefirstcaseofhumangranulocyticanaplas- 32 000 2400 1830 21.5 368 138 101 124 260 On 4.3 48 32 47 20 77 83 30 7 1000 mgorally, daily per day, orazithromycin, 250– Atovaquone, 750mg orally, twice mild transaminitis anemia, acute injury, kidney Thrombocytopenia, hemolytic Uncommon psychiatric symptoms nausea, hepatosplenomegaly, Flu-like symptoms, anorexia, Babesiosis At follow-up visit 7–10 153 000 4800 3130 1280 138 PRACTICE E365 This This 9 10 8 No clinical trials have been done to guide trials have been done No clinical 3 Lyme disease is typically treated for 14–21 days. is typically treated Lyme disease 6 ISSUE 12 ISSUE | beyond its previously described range described range A. phagocytophilum beyond its previously . B. burgdorferi Werden L, Lindsay LR, Barker IK, et al. Prevalence of Anaplasma phagocytophi- scapularis from a newly established lyme dis- microti in Ixodes lum and Babesia ease area, the Thousand Islands Region of Ontario, Canada. Borne Zoonotic Dis 2015;15:627-9. Shadick N, Maher N, Hoak D. Tickborne disease of the : a reference manual for healthcare providers. 4th ed. Atlanta: Centers for Disease Control and Prevention; 2017. Dahlgren FS, Heitman KN, Drexler NA, et al. Human granulocytic anaplasmosis in the United States from 2008 to 2012: a summary of national surveillance data. Am J Trop Med Hyg 2015;93:66-72. Parkins MD, Church DL, Xiu YJ, et al. Human granulocytic anaplasmosis: first reported case in Canada. Can J Infect Dis Med Microbiol 2009;20:e100-2. Bakken JS, Krueth J, Asanovich K, et al. Clinical and laboratory characteristics of human granulocytic . JAMA 1996;275:199-205. Ogden N, Koffi J, Pelcat Y. et al. Environmental risk from Lyme disease in cen- tral and eastern Canada: a summary of recent surveillance information. [Inter- net]. Can Commun Dis Rep 2014:40-5. Enhanced surveillance of emerging in previously in previously Enhanced surveillance of emerging pathogens –infected blacklegged in Canada and the ticks in Canada and the B. burgdorferi–infected blacklegged

1. 2. 3. 4. 5. need for enhanced surveillance is highlighted in a Canadian a Canadian in highlighted is surveillance enhanced for need review on emerging vector-borne . unknown areas is needed. Through better surveillance, the surveillance, the unknown areas is needed. Through better preventive measures evolving infection can be characterized and a reportable disease, developed. In the US, anaplasmosis is of its epidemiology, as which contributes to the understanding areas unexpected in emergence its of detection the to as well risks. health human associated of identification the and 6. Conclusion ticks as prevalent more becoming are infections Tick-borne as A. phagocytophi- capable of carrying human pathogens such tick-borne illnesses lum migrate further north. Consideration of encountering patients other than Lyme disease is needed when for Testing areas. tick-endemic in findings clinical atypical with should be infections such as human granulocytic anaplasmosis of a tick bite present considered when patients with a history counts, and elevated with fever, low white blood cell and platelet health agencies could hepatic transaminases. Provincial public a reportable consider making human granulocytic anaplasmosis disease, which would enhance surveillance and subsequent knowledge of this emerging infectious . References Public health implications the establishment of Anaplasma Our patient’s case confirms andblacklegged ticks resident among infection phagocytophilum in Ontario. Discovery of human illnessresident populations from the risk of emerging vector-borne diseasesprovides evidence of Lyme on research from Evidence environment. changing the in the expanding range and establishment disease has catalogued of change. contributory role of climate the duration of treatment, but a current guideline suggests suggests a current guideline of treatment, but the duration 10–14 days therapy for possible to provide appropriate with in older adults or immunocompromised patients can lead to to lead can patients immunocompromised or adults older in who did not 1 in 7 patients In one study, adverse outcomes. died. receive antibiotics VOLUME 190 VOLUME |

6 5 6 Since then, Since 2 DNA by poly- Many areas of 4 in recent years, in recent years, MARCH 26, 2018 | In addition, a mild-to- 7 CMAJ scapularis . 3 When patients present with nonspe- When patients present 5 = 867). Cross-reactivity between Anaplasma and Rickett- 6 Patients with Lyme disease generally have normal white bloodPatients with Lyme disease generally have A recent Canadian report postulated that the risk of tick-borneA recent Canadian report Laboratory testing can help distinguish these infections. PatientsLaboratory testing can help distinguish these = 465) and 3.2% (n n including southeastern Ontario and the Thousand Islands region. including southeastern cell and platelet counts, and may have a mild increase in hepaticcell and platelet counts, and may have a mild thrombocytopenia and,transaminases. Babesiosis presents with on a peripheral blood in most cases, the presence of parasites formations. cross” “Maltese with often film, to increased creati- Hemolytic anemia may be present in addition transaminases. nine and urea, and mildly elevated hepatic infections will continue to rise as populations of I. scapularis spreadinfections will continue rate of 33–55 km per year. north at an estimated moderate increase in hepatic transaminases is common. moderate increase in hepatic transaminases cific symptoms in tick-endemic areas, serologic testing for Lymecific symptoms in tick-endemic is) is often done. However,I. scapularis disease (B. burgdorferi including A. phagocyto- known to be a carrier of other pathogens, philum and (which causes babesiosis). merase chain reaction. This method is most sensitive within the antibi- after decreases typically sensitivity and illness, of week first otics have been started. The second method is to show a fourfold antibodyimmunofluorescence by antibody IgG–specific in increase assay in serial samples. The first sample is typically sent within the first week of symptom onset, and the second should be sent two to four weeks later. Human granulocytic anaplasmosis can be diagnosed by two meth- phagocytophilum of A. detection ods. The first is Diagnosis

Human granulocytic anaplasmosis and Lyme disease are both both are disease Lyme and anaplasmosis granulocytic Human effectively treated with doxycycline (100 mg orally, twice per day). Most patients given doxycycline for human granulocytic anaplas- mosis will show rapid recovery and cure, but a delayed diagnosis Treatment Clinical presentation granulocytic anaplas- The initial clinical presentations of human nonspecific (Box 2). mosis, Lyme and babesiosis are often mosis that originated in Canada was reported in 2009. reported in was in Canada that originated mosis Canada have become endemic for I Canada have become Human granulocytic anaplasmosis typically presents one to two Human granulocytic anaplasmosis typically , , severe weeks after exposure, with fever, chills, Rash is uncommon, headache and gastrointestinal symptoms. whereas it is often reported in Lyme disease. have thrombocyto- with human granulocytic anaplasmosis typically penia, and about half will have leukopenia. in ticks is increasing; in 2009 and in ticks is increasing; Prevalence of A. phagocytophilum - Islands region collected by drag sam 2010, ticks in the Thousand of infection with A. phagocytophilum of 3%pling had a prevalence ( further cases have been documented in Manitoba, the only prov- in Manitoba, the have been documented further cases began to be disease. Since cases it is a reportable ince for which which were in been reported, 17 of 2015, 21 have tracked in January anaplas- of human granulocytic case series of 42 cases 2016. A US a mortality of 4.9%. mosis found sia is rare; we were unable to find previous reports in the literature. PRACTICE E366 10. 7. 9. 8.

Health (Guan); Division of Infectious Diseases, Health (Guan);DivisionofInfectiousDiseases, Frontenac, andLennox&AddingtonPublic Medicine (Guan),Queen’sUniversity;Kingston, Medicine Residency, Department of Family Srivastava); PublicHealthandPreventive Medicine, DepartmentofMedicine(Edginton, Affiliations: DivisionofGeneralInternal The authorshaveobtainedpatientconsent. This articlehasbeenpeerreviewed. Competing interests:Nonedeclared. 2015;4:e33. notic diseasesofpublichealthimportanceinCanada.EmergMicrobesInfect Kulkarni MA,Berrang-FordL,BuckPA,etal.Majoremergingvector-bornezoo- Am JTropMedHyg2011;85:124-31. chaffeensis andAnaplasmaphagocytophilumintheUnitedStates,2000-2007. Dahlgren FS,MandelEJ,KrebsJW,etal.IncreasingincidenceofEhrlichia ada. CMAJ2009;180:1221-4. Ogden NH, Lindsay L, Morshed M, et al. The emergence of Lyme disease in Can- Infect Dis2001;32:862-70. tologic counts during the active phase of human granulocytic ehrlichiosis. Bakken JS,Aguero-rosenfeldME,TildenRL,etal.Serialmeasurementsofhema- CMAJ ease expertise and reviewed and revised the ease expertiseandreviewedrevisedthe Gerald Evansprovidedclinicalinfectiousdis- epidemiology andpublichealthimplications. initial manuscript. T. Hugh Guan described the erature, describedthecaseanddrafted manuscript. StefanEdgintonreviewedthelit- substantially totheconceptanddesignof Contributors: Alloftheauthorscontributed (Edginton, Evans,Srivastava),Kingston,Ont. University; KingstonHealthSciencesCenter Department ofMedicine(Evans),Queen’s | MARCH 26,2018 Clin Clin

| VOLUME 190 sity. Seeinformationforauthorsatwww.cmaj.ca. aged. Consentfrompatientsforpublicationoftheirstoryisaneces- tial diagnosis,clinicalfeaturesordiagnosticapproach)areencour- (1000 wordsmaximum).Visualelements(e.g.,tablesofthedifferen- maximum), andadiscussionoftheunderlyingconditionfollows mon problems.Articlesstartwithacasepresentation(500words tant rareconditions,andimportantunusualpresentationsofcom- tical lessons.Preferenceisgiventocommonpresentationsofimpor- The section Cases presents brief case reports that convey clear, prac- | ISSUE 12 [email protected] Correspondence to:SiddharthaSrivastava, expertise. ratories forprovidingclinicalmicrobiology Samir Patel from Public Health Ontario Labo- Acknowledgements: The authors thank Dr. and agreedtoactasguarantorsofthework. final approvaloftheversiontobepublished intellectual content.Alloftheauthorsgave and revisedthe manuscript for important manuscript. SiddharthaSrivastavareviewed