CLINICAL

AND

LABORATORY OBSERVATIONS

A Case of Immune Thrombocytopenic Purpura After Rabies Vaccination Joy M. Fulbright, MD,* Sarah E. Williams, MD, MPH,w and Barbara A. Pahud, MD, MPHz

Summary: We describe a case of immune thrombocytopenic purpura (ITP) occurring 15 days after the first dose of a 4-dose rabies vaccination series. ITP is thought to be an immune-mediated process triggered by an infection or toxin. There is little evidence in the literature beyond case reports of an association of ITP with vaccines other than with the measles, mumps, and rubella vaccine. This is the third reported case of ITP associated with rabies vaccination. Because of the rare occurrence of this adverse event relative to the severity of rabies infection, the benefits of rabies vaccination, when indicated, outweigh the low and possible risk of ITP. Key Words: immune thrombocytopenic purpura, rabies vaccine, vaccines, thrombocytopenia

(J Pediatr Hematol Oncol 2015;37:e427–e428)

I

mmune thrombocytopenic purpura (ITP) is an autoimmune hematological disorder that is characterized by isolated low platelet count. ITP is due to the development of autoantibodies, generally of the IgG subclass, which are directed against the platelet-specific antigens glycoprotein IIB/IIIa and Ib/IX.1 The development of these antibodies is not well understood, but is thought to be due to a trigger such as an infection or toxin.1 The diagnosis of ITP is made clinically based on the typical presentation of the disease and exclusion of other diagnoses (ie, leukemia, hemolytic uremic syndrome). In the pediatric setting, most patients have a benign course, with over two-thirds of the cases resolving in 6 months with or without treatment.1 Because life-threatening hemorrhage occurs in only 0.2% to 0.9% of patients,2 treatment is usually reserved for patients that have bleeding (ie, prolonged epistaxis, blood in stool or urine) or wet purpura to avoid potential complications of treatment.1,3 Vaccines have been proposed as one of the preceding triggers of ITP.4–8 Development of ITP after administration of rabies vaccine has rarely been reported in the literature.9 In this report, we describe a case of ITP after administration of rabies vaccines and a review of the literature of ITP after vaccination.

Received for publication November 14, 2014; accepted June 1, 2015. From the *Division of Hematology/Oncology; zDivision of Infectious Diseases, Children’s Mercy Hospital, Kansas City, MO; and wDivision of General Pediatrics, Vanderbilt University School of Medicine, Nashville, TN. The authors declare no conflict of interest. Reprints: Joy M. Fulbright, MD, Division of Pediatric Hematology/ Oncology, Children’s Mercy Hospital, 2401 Gillham Rd, Kansas City, MO 64108 (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

J Pediatr Hematol Oncol



CASE REPORT A previously healthy 16-year-old male was attacked by several stray dogs (day 0) during a visit to Romania. The patient sustained multiple penetrating lesions to his right lower extremity. The same day, he was taken to the emergency room and received doxycycline and the first dose of rabies vaccine (purified vero cell rabies vaccine, Verorab). While still in Romania, he received dose 2 of the same rabies vaccine on day 3 after the injury. Upon return to the United States, he presented to the emergency room (day 5) and received rabies immunoglobulin near the bite sites intramuscularly. Rabies vaccine doses 3 and 4 (purified chick embryo cell rabies vaccine, RabAvert) were administered in the right arm intramuscularly (days 7 and 14). On day 15, the patient’s mother noted petechiae and development of bruises. He had no epistaxis, hematuria, or blood in his stool. The patient was evaluated in urgent care on day 18 and found to have a platelet count of 5000/mcL. The patient was current with all immunizations per the Advisory Committee on Immunization Practices recommendations except for the second dose of varicella vaccine. Past medical history was negative for any chronic illness or episodes of easy bruising, epistaxis, or petechiae. He reported no prior history of exposure to doxycycline or any rabies vaccine. Family history revealed no history of platelet or bleeding disorders. Review of systems was negative for other concerning symptoms of acute or chronic illness, including headaches or neurological changes. The patient’s parents denied any history of recent symptomatic viral infection. Repeat labs on day 18 demonstrated a white blood cell count of 6870/mcL, hemoglobin of 14.7%, hematocrit of 41.5 gm/dL, platelet count of 2000/mcL, absolute neutrophil count of 3880/mcL with the rest of the differential in the normal range, and normal red blood cell indices. The immature platelet fraction, measured by Sysmex, was 28.1% (normal range, 0% to 7%) resulting in an absolute immature platelet count of 562 peripheral blood smear revealing giant platelets. Epstein-Barr virus and cytomegalovirus titers were consistent with a history of past infection, but no evidence of acute infection. His liver enzymes, electrolytes, and kidney function were within normal limits. Examination was positive for 2 small purpuric lesions on his oral mucosa membranes, multiple petechiae on his chest, back, abdomen, and legs, and a large bruise on his right knee. Lymphadenopathy and hepatosplenomegaly were not noted on examination. He was diagnosed with presumed ITP. No treatment was initiated due to the lack of active bleeding on examination, the patient’s ability to abide by activity restriction, and the known risks of treatment-related side effects. On a repeat complete blood count 1 month later, platelets had increased to 57,000/mcL with a normal immature platelet fraction of 3.7%. Several months later, platelets increased to within the normal range.

DISCUSSION Our patient was diagnosed with presumed ITP due to the classic features of the presentation, the clinical course, and the resolution of thrombocytopenia over time without recurrence. On peripheral smear, platelets were composed of a disproportionately large number of giant, normally granulated platelets (indicating a higher than normally

Volume 37, Number 7, October 2015

www.jpho-online.com |

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

e427

J Pediatr Hematol Oncol

Fulbright et al



Volume 37, Number 7, October 2015

TABLE 1. Reported Cases in Literature of ITP After Rabies Vaccination

References

Interval Between Age 1st Rabies Vaccination (y) and Symptoms of ITP (d)

Type of Rabies Vaccine

Platelet Count at Diagnosis

Sharma et al9

12

8

Purified duck embryo 16,000/mcL

Sharma et al9

53

28

Purified chick embryo 10,000/mcL

This study

16

15

Purified chick embryo 5000/mcL and purified vero cell

Outcome Initially treated with prednisone and then maintained platelets above 50,000/mcL off therapy Initially treated with prednisone and then maintained platelets with dapsone Observation with complete resolution of ITP

ITP indicates immune-mediated thrombocytopenia.

expected population of young platelets). The smear also consisted of normal white and red blood cell lines. Other possible diagnoses such as cytomegalovirus, Epstein-Barr virus, and leukemia were excluded. The patient also received doxycycline before developing symptoms of ITP. Doxycycline has not been reported as a trigger for development of ITP. A database compiling drugs associated with thrombocytopenia can be found online and is updated every 2 years. Doxycycline is currently not included on the list of drugs,10 and has not otherwise been reported as a trigger for development of ITP. There was no evidence of systemic autoimmune disorder as the thrombocytopenia has not returned in over 2.5 years after original diagnosis and the patient remains healthy. Although the occurrence of ITP following measles, mumps, and rubella (MMR) vaccine has been well established,4,6,7,11 there is little evidence of an association of ITP following other vaccines.5 A retrospective cohort study of cases of ITP following routinely recommended childhood vaccines found no increased risk of ITP after administration of any vaccine other than MMR in the youngest age group within 1 to 42 days of immunization.4 On review of the literature, there have been 2 case reports of ITP following rabies vaccine published by Sharma et al.9 One case involved a 12-year-old boy who received 3 intramuscular injections of purified duck embryo vaccine (VaxiRab) on days 0, 3, and 7 following vaccine. On day 8, he developed mild bleeding from his gums and petechiae over his body. The other case involved a 53year-old male who received 5 intramuscular injections (days 0, 3, 7, 14, and 28) of purified chick embryo cell vaccine (Rabipur), and presented with petechial spots over the body after the fifth injection (Table 1). Both patients experienced only partial recovery of platelet counts 8 to 9 months after presentation. The patient reported here received rabies immunoglobulin along with the rabies vaccine. The other 2 previously reported cases did not receive the rabies immunoglobulin or an antibiotic. No reports of rabies immunoglobulin associated with ITP were identified in the review of literature. Despite no prior evidence of doxycycline or rabies immunoglobulin triggering ITP, rabies immunoglobulin and/or doxycycline could not be completely ruled out as the potential trigger, but are unlikely causes. Because of the timing of the development of ITP after the rabies vaccines administration and without other identified causes of thrombocytopenia or a viral prodrome, the most likely trigger for ITP in this case presented is the rabies vaccine. Either the Verorab or the RabAvert could be implicated as the symptoms occurred 14 days from the first dose of Verorab and 7 days after the RabAvert, which is within the biological time

frame one would expect ITP to develop after vaccination.7 Because the causal relationship cannot be proven, it is important that future patients who develop thrombocytopenia after rabies vaccination are investigated for other important causes of thrombocytopenia and that future cases are reported to VAERS (Vaccine Adverse Event Reporting System-this is a postmarketing safety program sponsored by the CDC and FDA). Even if we could be certain that ITP was due to rabies vaccination, the occurrence of ITP is likely rare as few cases have been reported. If and when rabies vaccination is indicated, the benefits of vaccinating to prevent rabies, an almost universally fatal disease of the nervous system, outweigh the risk of developing ITP, a condition that is generally benign and frequently resolves without treatment.

REFERENCES 1. Blanchette V, Bolton-Maggs P. Childhood immune thrombocytopenic purpura: diagnosis and management. Pediatr Clin North Am. 2008;55:393–420. 2. Nugent DJ. Immune thrombocytopenic purpura of childhood. Am Soc Hematol. 2006;97–103. 3. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood. 1996;88:3–40. 4. O’Leary ST, Glanz JM, McClure DL, et al. The risk of immune thrombocytopenic purpura after vaccination in children and adolescents. Pediatrics. 2012;129:248–255. 5. Grimaldi-Bensouda L, Michel M, Aubrun E, et al. A casecontrol study to assess the risk of immune thrombocytopenia associated with vaccines. Blood. 2012;120:4938–4944. 6. Sauve LJ, Bettinger J, Scheifele D, et al. Postvaccination thrombocytopenia in Canada. Pediatr Infect Dis J. 2010;29: 559–561. 7. Rajantie J, Zeller B, Treutiger I, et al. Vaccination associated thrombocytopenic purpura in children. Vaccine. 2007;25: 1838–1840. 8. Chang SK, Farrell DL, Dougan K, et al. Acute idiopathic thrombocytopenic purpura following combined vaccination against measles, mumps, and rubella. J Am Board Fam Pract. 1996;9:53–55. 9. Sharma SK, Seth T, Agrawal N, et al. Immune thrombocytopenic purpura following anti-rabies vaccines. Platelets. 2012;23:317–318. 10. George JN. Database for drug-induced thrombocytopenia from group patient reports: an update. 2014. Available at: http://www.ouhsc.edu/platelets/internetpostingsingleframes2014. htm. Accessed March 11, 2015. 11. Black C, Kaye JA, Jick H. MMR vaccine and idiopathic thrombocytopaenic purpura. Br J Clin Pharmacol. 2003;55: 107–111.

e428 | www.jpho-online.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

A Case of Immune Thrombocytopenic Purpura After Rabies Vaccination.

We describe a case of immune thrombocytopenic purpura (ITP) occurring 15 days after the first dose of a 4-dose rabies vaccination series. ITP is thoug...
96KB Sizes 1 Downloads 13 Views