The Risk of Immune Thrombocytopenic Purpura After Vaccination in Children                                 and Adolescents ...
ARTICLEThe Risk of Immune Thrombocytopenic Purpura AfterVaccination in Children and AdolescentsAUTHORS: Sean T. O’Leary, M...
Immune thrombocytopenic purpura                Colorado, Kaiser Permanente Hawaii,          of resolution, exposure to med...
ARTICLE“Serious adverse events” were defined             administered simultaneously with MMR         laboratory error (n =...
TABLE 1 Characteristics of Medical Record Validated Cases of Immune Thrombocytopenic                                    ch...
ARTICLETABLE 2 The Risk of Idiopathic Thrombocytopenic Purpura in the 1 to 42 Days After Vaccination,                     ...
ITP after MMR because there is a known                 in a large network of managed care                    found no incr...
ARTICLE22. Polat A, Akca H, Dagdeviren E. Severe                    Immunization Monitoring Program. Throm-               ...
APPENDIX 1 International Classification of                 APPENDIX 2 Positive Predictive Value of International Classificat...
The Risk of Immune Thrombocytopenic Purpura After Vaccination in Children                                 and Adolescents ...
Upcoming SlideShare
Loading in …5

Articulos ingles


Published on

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

Articulos ingles

  1. 1. The Risk of Immune Thrombocytopenic Purpura After Vaccination in Children and Adolescents Sean T. OLeary, Jason M. Glanz, David L. McClure, Aysha Akhtar, Matthew F.Daley, Cynthia Nakasato, Roger Baxter, Robert L. Davis, Hector S. Izurieta, Tracy A. Lieu and Robert Ball Pediatrics; originally published online January 9, 2012; DOI: 10.1542/peds.2011-1111 The online version of this article, along with updated information and services, is located on the World Wide Web at: PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from by guest on January 17, 2012
  2. 2. ARTICLEThe Risk of Immune Thrombocytopenic Purpura AfterVaccination in Children and AdolescentsAUTHORS: Sean T. O’Leary, MD, MPH,a,b,c Jason M. Glanz, WHAT’S KNOWN ON THIS SUBJECT: Studies on vaccine safety arePhD,c David L. McClure, PhD,c Aysha Akhtar, MD, MPH,d crucial to the ongoing success of our national immunizationMatthew F. Daley, MD,a,c Cynthia Nakasato, MD,e Roger program. ITP has a known association with MMR in youngBaxter, MD,f Robert L. Davis, MD, MPH,g Hector S. Izurieta, children, occurring in 1 in 40 000 doses. The risk after otherMD, MPH,d Tracy A. Lieu, MD, MPH,h,i and Robert Ball, MD, childhood vaccines is unknown.MPH, ScmdaDepartment of Pediatrics, University of Colorado Anschutz WHAT THIS STUDY ADDS: This study found no increased risk ofMedical Campus, Aurora, Colorado; bChildren’s Outcomes ITP after vaccines other than MMR in young children, confirmedResearch Program, Children’s Hospital Colorado, Aurora,Colorado; cInstitute for Health Research, Kaiser Permanente an association of ITP with MMR, and also found that ITP may occurColorado, Denver, Colorado; dCenter for Biologics Evaluation and after certain other vaccines in older children.Research, Food and Drug Administration, Rockville, Maryland;eCenter for Health Research Hawaii, Kaiser Permanente Hawaii,Honolulu, Hawaii; fKaiser Permanente Vaccine Study Center,Oakland, California; gCenter for Health Research Southeast,Kaiser Permanente of Georgia, Atlanta, Georgia; hCenter for ChildHealth Care Studies, Department of Ambulatory Care andPrevention, Harvard Pilgrim Health Care Institute, Boston, abstractMassachusetts; and iDivision of General Pediatrics, Children’s BACKGROUND: The risk of immune thrombocytopenic purpura (ITP)Hospital Boston, Massachusetts after childhood vaccines other than measles-mumps-rubella vaccineKEY WORDS (MMR) is unknown.immune thrombocytopenia purpura, children, vaccines, adversereactions, thrombocytopenia METHODS: Using data from 5 managed care organizations for 2000 to 2009, we identified a cohort of 1.8 million children ages 6 weeks to 17ABBREVIATIONSCI—confidence interval years. Potential ITP cases were identified by using diagnostic codes andDTaP—diphtheria-tetanus-acellular pertussis vaccine platelet counts. All cases were verified by chart review. Incidence rateHBV—hepatitis B virus vaccine ratios were calculated comparing the risk of ITP in risk (1 to 42 daysHep A—hepatitis A vaccineHib—Haemophilus influenzae type b vaccine after vaccination) and control periods.HPV—human papilloma virus vaccine RESULTS: There were 197 chart-confirmed ITP cases out of 1.8 millionIPV—inactivated poliovirus vaccineIRR—incident rate ratio children in the cohort. There was no elevated risk of ITP after any vaccineITP—immune thrombocytopenic purpura in early childhood other than MMR in the 12- to 19-month age group. ThereMCV—meningococcal conjugate vaccine was a significantly elevated risk of ITP after hepatitis A vaccine at 7 to 17MMR—measles-mumps-rubella vaccine years of age, and for varicella vaccine and tetanus-diphtheria-acellularMMRV—measles-mumps-rubella-varicella vaccinePCV—pneumococcal conjugate vaccine pertussis vaccine at 11 to 17 years of age. For hepatitis A, varicella,RV—rotavirus vaccine and tetanus-diphtheria-acellular pertussis vaccines, elevated risks wereTdap—tetanus-diphtheria-acellular pertussis vaccine based on one to two vaccine-exposed cases. Most cases were acuteTIV—trivalent influenza vaccineVAR—varicella vaccine and mild with no long-term CONCLUSIONS: ITP is unlikely after early childhood vaccines other thandoi:10.1542/peds.2011-1111 MMR. Because of the small number of exposed cases and potentialAccepted for publication Oct 6, 2011 confounding, the possible association of ITP with hepatitis A, varicella, and tetanus-diphtheria-acellular pertussis vaccines in older children (Continued on last page) requires further investigation. Pediatrics 2012;129:1–8PEDIATRICS Volume 129, Number 2, February 2012 1 Downloaded from by guest on January 17, 2012
  3. 3. Immune thrombocytopenic purpura Colorado, Kaiser Permanente Hawaii, of resolution, exposure to medications,(ITP)was firstdescribedaftera wild-type Kaiser Permanente Georgia, Kaiser Per- sequelae, treatment, medically attendedmeasles virus infection in 1952.1 In 1966, manente Northern California, and Har- illnesswithin6weeksbeforeITPdiagnosis,Oski and Naiman reported thrombocy- vard Vanguard Medical Associates) by and medical setting of the diagnosis.topenia after a live attenuated measles using data from the years 2000 to 2009,vaccine.2 Since then, the association of with Kaiser Permanente Colorado as the Confirmation of ITP Cases Usinglive attenuated measles-mumps-rubella lead site. The study was a retrospective Medical Record Review(MMR) vaccine and ITP has been well es- cohort study, with 1.8 million children For the confirmatory chart review, atablished.3–11 ITP is known to occur after enrolled in the cohort. We included chil- case was defined as a child aged 6many types of infections, including nu- dren in the cohort who had been vacci- weeks to 18 years with a platelet countmerous vaccine-preventable diseases.12–18 nated while actively enrolled in their of ,50 000/mL, with normal red andIn approximately two-thirds of ITP cases, respective health plans. The institu- white blood cell indices, and the pres-there is a history of a preceding in- tional review board of each study site ence of clinical signs and symptomsfectious illness in the days to weeks be- approved the study. of ITP, such as petechiae, significantfore ITP onset.19 A subset of these children bruising, or spontaneous bleeding. Awill have an identifiable virus, such as Ascertainment of Cases of ITP case was excluded if, in the 6 weeksEpstein-Barr virus, varicella zoster virus, before diagnosis, the child was exposedinfluenza virus, or HIV.16 Because vaccines Electronic Identification of Possible to a platelet-depleting medication (suchare designed to induce an immune re- Cases as antiepileptics and sulfonamide anti-sponse that mimics natural infection to Initial identification of possible cases biotics) or infected with wild-type vari-produce immunologic protection, it is was conducted at the lead site by using cella or Epstein-Barr virus. Patients withtheoretically possible that vaccines be- electronic databases, with the analyst no signs or symptoms of ITP, whose lowsides MMR could trigger ITP. In addition, blinded to vaccination status. We re- platelet counts were found incidentallythere have been case reports of ITP after viewed the electronic data to exclude on complete blood count screening, wereother childhood vaccines, including hep- cases of thrombocytopenia from other excluded. Children with probable sepsisatitis B vaccine (HBV), diphtheria-tetanus- known conditions by using the Inter- or meningitis were also excluded. Thepertussis vaccine (DTP), and hepatitis A national Classification of Diseases, Ninth ITP resolution date, determined by med-vaccine (Hep A).20–25 However, the risk Revision (ICD-9) diagnosis codes (such ical chart review, was defined as theof ITP after childhood vaccines other as neonatal thrombocytopenia, aplastic date of the first platelet count of .100than MMR is currently unknown. anemia, disseminated intravascular co- 000/mL with no evidence of a drop inKnown rare severe complications of ITP agulation, acquired hemolytic anemia, platelet count in subsequent months. Ainclude intracranial hemorrhage and se- chronic liver disease, or malignancy). We case with no follow-up platelet countvere bleeding.26–29 Case reports and case then identified children ,18 years of .100 000/mL was considered acute ifseries have described severe adverse age with either two platelet counts of there was other evidence in the medi-events after MMR-associated ITP.4,7,11,30 ,50 000/mL in a 6-week period or one cal record of ITP resolution. For thisThe risk of severe outcomes of ITP after platelet count of ,50 000/mL and an study, we defined chronic ITP as throm-MMR vaccination is thought to be quite associated ICD-9 code of 287.0 to 287.9, bocytopenia lasting .6 months, consis-low, but few studies have examined se- inclusive, within 6 weeks of the low tent with the definitions used in thevere complications as an outcome.9 platelet count (see Appendix for specific literature at the time.31,32 Since the time ICD-9 codes). this study was designed and conducted,Using a large population from five man- an expert panel has recommended aaged care organizations, we sought to Abstraction of Medical Records definition of chronic ITP as lasting .12ascertain (1) the risk of ITP in children 6 For the remaining possible cases that months33; this definition cannot beweeks to 18 years of age afterall vaccines were not excluded electronically, applied to the current study, becauseroutinely administered during childhood medical records were photocopied, medical record abstraction informationand (2) the risk of serious complications deidentified at participating sites, is not available for .12 months afterof ITP after vaccination in children. and sent to the lead site. Trained medical the onset date. A pediatrician (S.T.O.) abstractors blinded to vaccination status blinded to vaccination status indepen-METHODS used a standardized paper-based instru- dently reviewed all charts to confirmThis investigation was conducted in five ment to collect the following: date of di- the onset date, assign case status, andhealth care systems (Kaiser Permanente agnosis, symptoms, platelet counts, date assign the ITP resolution date.2 O’LEARY et al Downloaded from by guest on January 17, 2012
  4. 4. ARTICLE“Serious adverse events” were defined administered simultaneously with MMR laboratory error (n = 14), ITP as an in-as having any of the following: intracra- or MMRV, because MMR has been highly cidental finding (n = 12), completelynial hemorrhage, bleeding requiring associatedwithITPinpreviousstudies,3–11 missing medical records (n = 10), andhospitalization, bleeding requiring and the measles, mumps, and rubella recurrence of ITP (n = 7).transfusion of packed red blood cells components in MMRV are identical toor platelets, or death. those used in MMR. IRRs were calculated Cases of Immune for each vaccine for the age groups Thrombocytopenic PurpuraAnalytic Methods shown in Table 2. Age groups were se- Table 1 shows the characteristics of all lected based on when the majority ofWe used self-controlled case series chart-confirmed cases of ITP (n = 197). each vaccine was given, with the ex-(SCCS) methods to examine the risk of Cases were spread across all age ception of trivalent influenza vaccineITP after childhood vaccines. The SCCS ranges with similar numbers of cases (TIV), live attenuated influenza vaccinemethod uses exposed and unexposed among boys and girls. Most cases (93%) (LAIV), and Hep A, which are given overperson-time to calculate incident rate received hematology consultation, and a broader age range. For varicella vac-ratios (IRRs) with each case acting as its half the children diagnosed with ITP cine (VAR), 12 to 23 months was chosenown control.34,35 Exposure in this con- had an acute illness in the previous 6 instead of 12 to 19 months to be abletext means exposure to a vaccine in weeks. The majority of cases of ITP in to examine it separately from MMR, be-a prespecified time window preceding younger children were classified as cause most of the doses of VAR in the 12-the onset of ITP. The SCCS method has acute, whereas over one-third in the 11- to 19-month age group had been givenbeen shown to be a valid alternative to 17-year-old age group were chronic. simultaneously with MMR. The riskto traditional cohort and case-control Of 38 total cases exposed to vaccines of ITP attributable to vaccine exposuredesigns.36 in a 1- to 42-day risk window, 31 (81%) was calculated as the difference be-For each child, follow-up time was were acute, 6 (16%) were chronic, and tween the incidence rates of exposedlimited to the 365 days before and after 1 (3%) was unknown. Of 159 unexposed and unexposed children for eachvaccination. We defined the exposed cases, 125 (79%) were acute, 31 (19%) vaccine in the childhood series. Forperiod as 1 to 42 days after vaccination were chronic, and 3 (2%) were un- TIV and LAIV, exposures and casefor all vaccines. The unexposed period known. All cases were included in the dates were limited to the Septemberwas defined as the time before and IRR calculations. There was no seasonal to December influenza vaccinationafter the exposed period within 365 distribution of cases (P = .94).37 season.days of follow-up before or after vac-cination. We compared the incidence of Risk of Immune ThrombocytopenicITP during the 42 days after vaccination RESULTS Purpura After Vaccines(exposed period) with the incidence of A total of 1.8 million children received a The risk of ITP after vaccination byITP during the unexposed period. Day total of 15 million vaccine doses during vaccine and age group is shown in0 (the day of vaccination) was excluded, the study period. Using electronic data- Table 2. None of the routine childhoodbecause any cases occurring at this time bases, among the 1.8 million children vaccines given in the first year of lifewere most likely coincidental. Because who received one or more vaccines, we was significantly associated with an in-a child with ITP cannot become a new identified 696 potential cases of ITP. Of creased risk of ITP. For vaccines rou-case until the current illness resolves, these, we excluded 248 based on the tinely administered at 12 to 19 months ofpatients diagnosed with ITP did not presence of chronic conditions known to age, there was a significant associationcontribute person-time from the date of cause thrombocytopenia, leaving a total of ITP with MMR (IRR, 5.48, 95% confi-ITP onset to the date of resolution. For of 448 possible cases for chart review. dence interval [CI] 1.61, 18.64). For othereach vaccine, person-time was counted Afterchartreview, an additional251were vaccines commonly given in this ageonly during the age when the vaccine is excluded for the following reasons: range (VAR, diphtheria-tetanus-acellularlicensed for use. For example, for MMR, alternative hematologic or oncologic pertussis vaccine [DTaP], pneumococcalperson-time before 12 months of age did diagnoses (n = 94), acute exclusionary conjugate vaccine [PCV], inactivatednot contribute to the calculation. illness such as probable sepsis or poliovirus vaccine [IPV], HaemophilusFor vaccines other than MMR and meningitis (n = 46), ITP in which an influenza type b vaccine [Hib], andmeasles-mumps-rubella-varicella vac- onset date could not be determined HepA), there was no increased risk ofcine (MMRV), IRRs were calculated only from the medical record (n = 40), med- ITP (calculated when not given simul-when the other vaccines were not ications known to cause ITP (n = 28), taneously with MMR or MMRV). TherePEDIATRICS Volume 129, Number 2, February 2012 3 Downloaded from by guest on January 17, 2012
  5. 5. TABLE 1 Characteristics of Medical Record Validated Cases of Immune Thrombocytopenic children having an event that required Purpura (n = 197) transfusion. Age Groups Total The negative findings from this study 6 wk to 11 mo 12–23 mo 24–59 mo 5–10 y 11–17 y are important. In the 12- to 19-monthTotal ITP cases, n 17 30 63 55 32 197 age group (and 12–23 months for Hep AMale, % 77 50 47 44 56 51Platelet count at diagnosis in thousands/mL, 13 9 12 7 10 10 and VAR), age groups when ITP is rel- mean atively common, we found no increasedHematology consultation, % 94 80 91 96 100 93 risk of ITP for VAR, Hep A, DTaP, IPV, Hib,Nonexclusionary acute illnessa within 6 wk 77 60 50 39 44 50 or PCV. The elevated IRR for MMRV before diagnosis, %Nonexclusionary medicationb within 6 wk 29 13 20 20 25 21 in this age group is not surprising, before diagnosis, % because the measles, mumps, and ru-Nonexclusionary acute illnessa at 29 33 17 25 13 22 bella components in MMRV are essen- presentation, %Diagnosis type, % tially identical to MMR. The finding that Acute 94 83 8 80 59 79 the IRR for MMRV does not appear to be Chronic 6 17 16 16 38 19 elevated beyond that of MMR is reas- Unknown 0 0 2 4 3 2For acute cases, mean time to resolution 22 21 45 41 36 36 suring given the recently reported in days twofold increased risk of febrile sei-Serious adverse events, % 0 0 2 5 6 3 zures for MMRV compared with MMRITP, immune thrombocytopenic purpura. and VAR given separately.38 The confir-a Exclusionary acute illnesses included Epstein-Barr virus, varicella, sepsis/possible sepsis, bacteremiab Exclusionary medications included sulfa drugs and antiepileptics such as valproic acid and carbamazepine; nonexclu- matory finding that MMR is associatedsionary medication means that the case was exposed to a medication, but that medication is not known to cause throm- with ITP helps validate the other find-bocytopenia ings of our current study, both positive and negative. While we found several elevated IRRs that approached statis-were 1.9 cases of ITP per 100 000 doses Distribution of Cases tical significance in older children,of MMR. Figure 1 shows the distribution of cases such as human papilloma virus vaccineThe risk of ITP after Hep A, VAR, and by week in the risk period after vacci- (HPV), TIV, and meningococcal conju-tetanus-diphtheria-acellular pertussis nation for vaccines for which there gate vaccine (MCV), estimates in oldervaccine (Tdap) was significantly ele- were statistically significantly elevated children are less stable because therevated in three discrete age categories IRRs during the exposed postvaccination are fewer cases of ITP on which toas shown in Table 2. For Hep A and Tdap, period. perform analyses.elevated IRRs were based on two vaccine- The findings related to Hep A, Tdap,exposed cases, whereas, for VAR, there DISCUSSION and VAR should be considered aswas one vaccine-exposed case. In this large multisite study of 1.8 million hypothesis-generating rather than as children, we examined the risk of ITP conclusive evidence that these vaccinesSerious Adverse Events after all childhood vaccines. Our rate are associated with ITP. Our study usedSix of the 197 chart-reviewed cases of ratio estimates were based on medical self-controlled case series analyses, anITP had serious adverse events. All of the chart-confirmed cases of ITP. We did not effective method for studying rare ad-subjects with serious adverse events find an increased risk of ITP for any of verse events after vaccines.34–36 How-developed bleeding requiring hospi- the commonly given childhood vaccines ever, the events in our analysis weretalization and/or transfusion, and none other than MMR in younger children, an very rare, and since we looked at manyhad any known long-term complications. important finding given that the di- possible associations, there is the pos-There were no deaths. Of the 6 cases of agnosis of ITP is most common in the 1- sibility that significant associationsserious adverse events, only one was to 3-year age group. We also present could surface by chance alone. This isa vaccine-exposed case, a 4-year-old important new data showing an asso- particularly true in older children andgirl who developed ITP complicated by ciation of ITP with Hep A, Tdap, and VAR in adolescents. ITP is much more commonhematochezia and hematuria requir- older children. In addition, we provide in the 1- to 3-year age group than ining a packed red blood cell trans- data showing that serious sequelae af- infants ,1 year or in persons .6 yearsfusion 4 weeks after receiving DTaP, ter vaccine-associated ITP are rare, with of age.39 Therefore, in the 1- to 3-yearMMR, and IPV. only one child of 1.8 million vaccinated age groups, there are ample cases4 O’LEARY et al Downloaded from by guest on January 17, 2012
  6. 6. ARTICLETABLE 2 The Risk of Idiopathic Thrombocytopenic Purpura in the 1 to 42 Days After Vaccination, contributing person-time to both the for Vaccines Routinely Administered During Childhood and Adolescencea exposed and unexposed denominators,Vaccine (age group) IRR 95% CI P Exposed Cases, n Unexposed Cases, n creating more stable estimates of risk6 wk to 11 mo2 compared with older children where, Hib 0.53 0.14 1.94 .33 3 10 RV —b — — — 1 0 because of the more pronounced rarity DTaP — — — — 0 7 of ITP, there may be fewer cases con- IPV — — — — 0 7 tributing unexposed person-time. Re- HBV — — — — 0 7 PCV 0.58 0.15 2.18 .42 3 9 garding biologic plausibility, it is also6 to 23 mo unclear why these vaccines would trig- TIV 2.69 0.81 8.88 .11 5 7 ger ITP in older age groups but not in12 to 19 mo MMR 5.48 1.61 18.64 .006 6 5 younger ones. So, although it is impor- MMRV 2.87 0.78 10.56 .11 4 6 tant to consider that the findings DTaP 1 0.21 4.81 .99 2 8 showing an elevated risk of ITP after Hep Hib 0.75 0.16 3.63 .72 2 9 A, VAR, and Tdap in older children may HBV — — — — 0 2 PCV 0.72 0.14 3.97 .70 2 8 be real, these results must be interpreted12 to 23 mo with caution. VAR — — — — 0 8 Hep A 0.22 0.03 1.82 .16 1 11 Reports of ITP in association with vac-2 to 6 y cines other than MMR are uncommon, TIV 1.86 0.41 8.38 .42 3 7 and most previous information on ITP Hep A 1.14 0.34 3.86 .83 4 274 to 6 y after vaccines other than MMR has MMR 3.06 0.42 22.30 .27 2 7 come from vaccine adverse-event sur- MMRV — — — — 0 5 veillance systems. Specifically relating VAR 4.39 0.46 41.65 .20 1 5 DTaP 2.57 0.53 12.37 .24 2 12 to the findings in our present study of an IPV 1.37 0.23 8.32 .73 2 12 increased risk with Hep A, Tdap, and7 to 17 y VAR, there have been three published Hep A 23.14 3.59 149.30 .001 2 3 TIV 5.95 0.54 65.96 .15 2 2 reports of ITP after whole-cell DTP11 to 17 y vaccine20,40 and one after DT vaccine,40 VAR 12.14 1.10 133.96 .04 1 2 but no published case reports of ITP MMR — — — — 0 1 HPV 9.71 0.87 108.92 .07 1 2 after Hep A, VAR, or Tdap. Regarding MCV 6.02 0.64 56.18 .12 1 4 cases of ITP reported from surveillance Tdap 20.29 3.12 131.83 .002 2 3 systems, as opposed to published casea For vaccines other than MMR and MMRV, relative risks are shown only for vaccines when not given in conjunction with MMR reports, a study from Canada based onor MMRV; LAIV is not shown, because there are no vaccine-exposed cases in any age category.b Vaccines for which there are either no exposed or unexposed cases will have no IRR or CI reported. an active surveillance system for vac- cine adverse events reported 28 cases of ITP after DTP or DTaP vaccine com- pared with 77 reported after MMR, with only 10 reports after VAR (and no reports after Hep A, because children do not routinely receive Hep A in Can- ada).41 In a recently published report from the US Vaccine Adverse Events Reporting System (VAERS), although there were 478 reports of ITP after MMR alone or in combination with other vaccines, there were 47 cases reported after VAR, 32 after Hep A, and only 8 after Tdap.42 It is important to recognize that reports from surveil-FIGURE 1Distribution of cases of immune thrombocytopenic purpura, date of onset in relation to timing of receipt lance systems are subject to reportingof vaccine (week 0), for vaccines with statistically significantly elevated incident rate ratios. bias, and so providers may overreportPEDIATRICS Volume 129, Number 2, February 2012 5 Downloaded from by guest on January 17, 2012
  7. 7. ITP after MMR because there is a known in a large network of managed care found no increased risk for most of theassociation. organizations with a large sample size vaccines in the childhood series, an un-The characteristics of our vaccine- and all cases were confirmed by med- surprising finding of an increased risk ofassociated ITP cases are important to ical record review. However, although ITP after MMR, and, less expected, we alsoconsider. The vast majority of our cases the sample size was large, ITP is a rare found possible increased risk of ITP forwere acute and mild. In addition, we had disease; therefore, the number of con- Hep A, VAR, and Tdap in older vaccine-exposed cases that went on firmed ITP cases was relatively low. In Additional studies are needed to betterto develop serious permanent compli- addition, it is difficult to examine the explore these possible associations.cations. Our findings are consistent with risk of ITP after vaccines routinely givenprevious studies of vaccine-associated with MMR, a vaccine known to be as- ACKNOWLEDGMENTSITP in this regard. ITP after vaccination sociated with ITP. As discussed, the This publication was supported bymay have a similar clinical course as study was also limited by the method- a subcontract from Kaiser PermanenteITP from other causes. Studies on the ologies currently available for examining with funds provided by the Food andgenetics of ITP are ongoing, but it is rare adverse events. Drug Administration. Its contents arethought that there is likely a genetic Vaccine safety is a priority of national solely the responsibility of the authorspredisposition asin other immune-related immunizationpolicy,andstudiesdesigned and do not necessarily represent the of-diseases, such as insulin-dependent to investigate vaccine adverse events are ficial views of Kaiser Permanente or thediabetes mellitus.43 crucial to the ongoing success of our Food and Drug Administration.There are several strengths and limi- national immunization program. In our The authors thank Jo Ann Shoup at thetations in this study. It is the first study to present study, we have used the best Institute for Health Research at Kaiserexamine in a systematic way the risk of available science to help define the risk of Permanente Colorado and Melisa Rett,ITP after vaccines other than MMR. In a rare and usually benign vaccine adverse MPH, at the Harvard Pilgrim Health Careaddition, the study was performed event, ITP, after all childhood vaccines. We Institute for project management.REFERENCES 1. Fisher OD, Kraszewski TM. Thrombocyto- pharmacovigilance centres and Pasteur- 14. Ozsoylu S, Kanra G, Savas G. Thrombocyto- penic purpura following measles. Arch Dis Mérieux Sérums et Vaccins. Pediatr Infect penic purpura related to rubella infection. Child. 1952;27(132):144–146 Dis J. 1996;15(1):44–48 Pediatrics. 1978;62(4):567–569 2. Oski FA, Naiman JL. Effect of live measles 8. Kiefaber RW. Thrombocytopenic purpura 15. Polat A, Inan M, Cakaloz I, Karakus YT. A vaccine on the platelet count. N Engl J Med. after measles vaccination. N Engl J Med. case of symptomatic idiopathic thrombo- 1966;275(7):352–356 1981;305(4):225 cytopenic purpura during mumps. Pediatr 3. Autret E, Jonville-Béra AP, Galy-Eyraud C, 9. Mantadakis E, Farmaki E, Buchanan GR. Hematol Oncol. 2005;22(3):215–218 Hessel L. Thrombocytopenic purpura after Thrombocytopenic purpura after measles- 16. Rand M. Virus associated idiopathic throm- isolated or combined vaccination against mumps-rubella vaccination: a systematic bocytopenic purpura. Transfus Sci. 1998;19 measles, mumps and rubella [in French]. review of the literature and guidance for (3):253–259 Therapie. 1996;51(6):677–680 management. J Pediatr. 2010;156(4):623– 17. Yeager A. Varicella associated thrombocy- 4. Beeler J, Varricchio F, Wise R. Thrombocy- 628 topenia: clues to the etiology of childhood topenia after immunization with measles 10. Miller E, Waight P, Farrington CP, Andrews idiopathic thrombocytopenic purpura. Johns vaccines: review of the vaccine adverse N, Stowe J, Taylor B. Idiopathic thrombo- Hopkins Med J. 1980;146:270–274 events reporting system (1990 to 1994). cytopenic purpura and MMR vaccine. Arch 18. Yenicesu I, Yetgin S, Ozyürek E, Aslan D. Pediatr Infect Dis J. 1996;15(1):88–90 Dis Child. 2001;84(3):227–229 Virus-associated immune thrombocytope- 5. Black C, Kaye JA, Jick H. MMR vaccine and 11. Nieminen U, Peltola H, Syrjälä MT, Mäkipernaa nic purpura in childhood. Pediatr Hematol idiopathic thrombocytopaenic purpura. Br A, Kekomäki R. Acute thrombocytope- Oncol. 2002;19(6):433–437 J Clin Pharmacol. 2003;55(1):107–111 nic purpura following measles, mumps 19. Blanchette V, Bolton-Maggs P. Childhood im- 6. France EK, Glanz J, Xu S, et al; Vaccine and rubella vaccination. A report on 23 mune thrombocytopenic purpura: diagnosis Safety Datalink Team. Risk of immune patients. Acta Paediatr. 1993;82(3):267– and management. Hematol Oncol Clin North thrombocytopenic purpura after measles- 270 Am. 2010;24(1):249–273 mumps-rubella immunization in children. 12. Hudson JB, Weinstein L, Chang TW. Throm- 20. Arya LS, Ghai OP, Saraya AK. Thrombocyto- Pediatrics. 2008;121(3). Available at: www. bocytopenic purpura in measles. J Pediatr. penic purpura following DPT vaccination. 1956;48(1):48–56 Pediatr Hematol Oncol. 1993;10(4):381–383 7. Jonville-Béra AP, Autret E, Galy-Eyraud C, 13. Morse EE, Zinkham WH, Jackson DP. Throm- 21. Neau D, Bonnet F, Michaud M, et al. Immune Hessel L. Thrombocytopenic purpura after bocytopenic purpura following rubella in- thrombocytopenic purpura after recombinant measles, mumps and rubella vaccination: fection in children and adults. Arch Intern hepatitis B vaccine: retrospective study of sev- a retrospective survey by the French regional Med. 1966;117(4):573–579 en cases. Scand J Infect Dis. 1998;30(2):115–1186 O’LEARY et al Downloaded from by guest on January 17, 2012
  8. 8. ARTICLE22. Polat A, Akca H, Dagdeviren E. Severe Immunization Monitoring Program. Throm- contrasting limitations. J Clin Epidemiol. thrombocytopenia after hepatitis B vaccine bocytopenia after immunization of Cana- 2006;59(8):808–818 in an infant from Turkey. Vaccine. 2008;26 dian children, 1992 to 2001. Pediatr Infect 37. Naus J, Wallenstein S. Temporal surveil- (51):6495–6496 Dis J. 2003;22(2):119–122 lance using scan statistics. Stat Med. 2006;23. Poullin P, Gabriel B. Thrombocytopenic pur- 31. Blanchette V, Bolton-Maggs P. Childhood 25(2):311–324 pura after recombinant hepatitis B vaccine. immune thrombocytopenic purpura: di- 38. Klein NP, Fireman B, Yih WK, et al; Vaccine Lancet. 1994;344(8932):1293 agnosis and management. Pediatr Clin North Safety Datalink. Measles-mumps-rubella-24. Ronchi F, Cecchi P, Falcioni F, et al. Throm- Am. 2008;55(2):393–420, ix varicella combination vaccine and the risk bocytopenic purpura as adverse reaction 32. Glanz J, France E, Xu S, Hayes T, Hambidge of febrile seizures. Pediatrics. 2010;126(1). to recombinant hepatitis B vaccine. Arch S. A population-based, multisite cohort Available at: Dis Child. 1998;78(3):273–274 study of the predictors of chronic idiopathic full/126/1/e125. Sakha K, Malekian A, Aslandabadi S. Hepatitis thrombocytopenic purpura in children. 39. Yong M, Schoonen WM, Li L, et al. Epidemiol- B vaccination and infantile idiopathic throm- Pediatrics. 2008;121(3). Available at: www. ogy of paediatric immune thrombocytopenia bocytopenic purpura. Med J Islam World in the General Practice Research Database. Br Acad Sci. 2005;15(4):149–151 33. Rodeghiero F, Stasi R, Gernsheimer T, et al. J Haematol. 2010;149(6):855–86426. Bolton-Maggs P. Severe bleeding in idiopathic Standardization of terminology, definitions 40. Bernheim M, Mouriquand C, Germain D, Gilly thrombocytopenic purpura. J Pediatr Hematol and outcome criteria in immune thrombo- Oncol. 2003;25(suppl 1):S47–S51 R, Nicolas A. 2 cases of prolonged throm- cytopenic purpura of adults and children: report from an international working group. bopenic purpura following an antidiphtheria-27. Butros L. M.D., Bussel, J., M.D. Intracranial Blood. 2009;113(11):2386–2393 antitetanus vaccination. Splenectomy. Cure Hemorrhage in Immune Thrombocytopenic Purpura: A Retrospective Analysis. J Pediatr [in French]. Pediatrie. 1960;15:433–438 34. Farrington P, Pugh S, Colville A, et al. A new Hematol Oncol. 2003;25(8):661–664 method for active surveillance of adverse 41. Sauvé LJ, Scheifele D. Do childhood vac-28. Krivit W, Tate D, White JG, Robison LL. Idio- events from diphtheria/tetanus/pertussis cines cause thrombocytopenia? Paediatr pathic thrombocytopenic purpura and in- and measles/mumps/rubella vaccines. Lancet. Child Health (Oxford). 2009;14(1):31–32 tracranial hemorrhage. Pediatrics. 1981;67 1995;345(8949):567–569 42. Woo EJ, Wise RP, Menschik D, et al. Throm- (4):570–571 35. Whitaker HJ, Farrington CP, Spiessens B, bocytopenia after vaccination: case reports to29. Woerner S, Abildgaard C, French BN. In- Musonda P. Tutorial in biostatistics: the the US Vaccine Adverse Event Reporting Sys- tracranial hemorrhage in children with self-controlled case series method. Stat tem, 1990-2008. Vaccine. 2011;29(6):1319–1323 idiopathic thrombocytopenic purpura. Pe- Med. 2006;25(10):1768–1797 43. Bergmann AK, Grace RF, Neufeld EJ. Genetic diatrics. 1981;67(4):453–460 36. Glanz JM, McClure DL, Xu S, et al. Four studies in pediatric ITP: outlook, feasibility,30. Jadavji T, Scheifele D, Halperin S; Canadian different study designs to evaluate vac- and requirements. Ann Hematol. 2010;89 Paediatric Society/Health Cananda cine safety were equally validated with (suppl 1):S95–S103(Continued from first page)Address correspondence to Sean O’Leary, MD, MPH, Sections of Pediatric Infectious Diseases and General Academic Pediatrics, Children’s Outcomes Research,Children’s Hospital Colorado, Mail Stop F443, 13199 E. Montview Blvd, Suite 300, Aurora, CO 80045. E-mail: sean.o’leary@childrenscolorado.orgPortions of this work were presented at the National Immunization Conference, Washington, DC, March 28 to 31, 2011, and the Pediatric Academic Societies’ AnnualMeeting, Denver, Colorado, April 30 to May 3, 2011.PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).Copyright © 2012 by the American Academy of PediatricsFINANCIAL DISCLOSURE: Dr Baxter receives research support from Sanofi Pasteur, GlaxoSmithKline, Novartis, Merck, and Pfizer. None of the other authors haveany relevant disclosures.PEDIATRICS Volume 129, Number 2, February 2012 7 Downloaded from by guest on January 17, 2012
  9. 9. APPENDIX 1 International Classification of APPENDIX 2 Positive Predictive Value of International Classification of Diseases, Ninth Revision Diseases, Ninth Revision (ICD- (ICD-9) Diagnosis Codes and Platelets Counts in Predicting a Confirmed Cases of 9) Diagnosis Codes Used in Immune Thrombocytopenic Purpura upon Chart Review Electronic Database Search Platelet Counts Diagnosis Code Group ITP Case PPV, %ICD-9 Code Category Yes No287.0 Allergic purpura287.1 Qualitative platelet defects Years 2000–2004a287.2 Other nonthrombocytopenic purpura 1 count ,50K and 287.31 ITP 0 0 —287.3 Primary thrombocytopeniaa 1 count ,50K and Other TP codeb 50 70 41.7287.4 Secondary thrombocytopeniab 2 counts ,50K and No code 2 15 11.8287.5 Thrombocytopenia, unspecified Total 52 85 38.0287.8 Other specified hemorrhagic conditions Years 2005–2008287.9 Unspecified hemorrhagic conditions 1 count ,50K and 287.31 ITP 90 24 78.9a 1 count ,50K and Other TP codeb 63 113 35.8 Includes primary thrombocytopenia, unspecified 2 counts ,50K and No code 1 20 4.8(287.30), immune (idiopathic) thrombocytopenic purpura(ITP) (287.31), other primary thrombocytopenia (287.39) Total 154 157 49.5and congenital and hereditary thrombocytopenias. PPV, positive predictive value; TP, thrombocytopenic purpura; ITP, immune thrombocytopenic purpura.b Includes thrombocytopenia caused by dilution, drugs, a Immune thrombocytopenic purpura (287.31) was not routinely used until 2005.extracorporeal circulation of the blood, and platelet b 287, 287.0, 287.1, 287.2, 287.3 287.30, 287.39, 287.4, 287.5, 287.8, 287.9.alloimmunization.8 O’LEARY et al Downloaded from by guest on January 17, 2012
  10. 10. The Risk of Immune Thrombocytopenic Purpura After Vaccination in Children and Adolescents Sean T. OLeary, Jason M. Glanz, David L. McClure, Aysha Akhtar, Matthew F.Daley, Cynthia Nakasato, Roger Baxter, Robert L. Davis, Hector S. Izurieta, Tracy A. Lieu and Robert Ball Pediatrics; originally published online January 9, 2012; DOI: 10.1542/peds.2011-1111 Updated Information & including high resolution figures, can be found at: Services /peds.2011-1111 Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: tml Reprints Information about ordering reprints can be found online: PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from by guest on January 17, 2012