Vaccination associated thrombocytopenic purpura in children

Vaccine 25 (2007) 1838–1840

Vaccination associated thrombocytopenic purpura in children J. Rajantie a,∗ , B. Zeller b , I. Treutiger c , S. Rosth¨oj d , on behalf of the NOPHO ITP working group and five national study groups a

Helsinki University Central Hospital, Jorvi Hospital, Finland b National Hospital of Norway, Oslo, Norway c Sachs’ Children’s Hospital, Stockholm, Sweden d Aalborg Hospital, Aalborg, Denmark

Received 6 January 2006; received in revised form 1 October 2006; accepted 30 October 2006 Available online 9 November 2006

Abstract Patients who presented with purpura and blood platelets <30 × 109 /l within 1 month after vaccination were collected from a population based material of 506 consecutive pediatric patients with newly diagnosed ITP. Of the 35 such patients, 24 had thrombocytopenia after MMR vaccination giving an estimated ITP risk of approximately 1 in 30,000 MMR inoculations. Symptoms of the 35 patients were nearly always acute. Thrombocytopenia disappeared within a month in 74% of the study patients and lasted longer than 6 months in only 10%. Bleeding episodes were uncommon during the follow-up period. We conclude that the incidence of symptomatic thrombocytopenia after vaccinations is much lower than that after respective natural infections and that the outcome in most cases is excellent. © 2006 Elsevier Ltd. All rights reserved. Keywords: Vaccination; MMR; Thrombocytopenia; ITP; Children

1. Introduction

2. Patients and methods

The majority of cases with idiopathic thrombocytopenic purpura (ITP) in children are noted within a few weeks after viral infections [1]. ITP can occur after natural measles or rubella but is known to follow also immunizations with these viruses, although less frequently [2–4]. Anecdotal reports on thrombocytopenia exist after other virus inoculations as well [5–9]. The clinical picture of post-vaccination ITP is believed to be similar to that of childhood ITP [10]. We prospectively collected population based data on 506 consecutive pediatric patients with ITP [11] and have now focused on vaccination associated cases to shed further light on their clinical presentation and outcome.

A total of 506 children aged 0–14 years were diagnosed to have ITP with platelet count <30 × 109 /l during a 3-year time period in the Nordic countries [11]. The diagnosis was based on findings of purpura and of isolated thrombocytopenia without evidence of associated conditions. The protocol did not specify any recommendations for investigation, transfusion policy or treatment. Practically all pediatric departments in the five Nordic countries participated. All infections and vaccinations before diagnosis were recorded by the local doctors. The type of infection was identified on clinical grounds. The study patients were those whose onset of ITP was associated with a vaccination given within 1 month before diagnosis. The patients were further divided into two groups: (a) patients who did not have any signs of infection within 1 month before diagnosis and (b) patients who also had experienced an acute infection within 1 month before diagnosis. As vaccination against measles, mumps and rubella (MMR) proved to be the most frequent one, we collected two sets

∗

Corresponding author. Tel.: +358 9 8615450; fax: +358 9 8615904. E-mail address: [email protected] (J. Rajantie).

0264-410X/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2006.10.054

J. Rajantie et al. / Vaccine 25 (2007) 1838–1840

of controls to each of the non-infectious patients with MMR inoculation, they were: (a) three next age-matched patients without a preceding vaccination and without any signs of infection and (b) three next age-matched patients who had had an infection within 1 month before diagnosis. Definitions used [1,11]: acute onset, symptoms for less than 2 weeks; insidious onset, symptoms for more than 2 weeks before diagnosis; wet purpura, oozing mucosal bleedings. During the 6 months after diagnosis, all disease-related events were described and dated. The course of the disease was called brief if thrombocytopenia lasted less than 1 month and chronic if still thrombocytopenic at 6 months post-diagnosis. The time from diagnosis to the last platelet count <20 × 109 /l was defined as a risk period. Events during that period were called risk events. Estimation of the risk of ITP after MMR inoculations was based on the following: a total Nordic population of children aged less than 15 years was about 4.6 million. The first dose of MMR is recommended to be given at age of 12–18 months. The vaccination coverage is >95% in all the Nordic countries. Thus, approximately 986,000 children received the first dose of MMR over the study period of 3 years. The study included at least 80% of children with newly diagnosed ITP [1,11]. Differences between groups were analysed by Student’s t-test or χ2 test as appropriate.

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case of thrombocytopenia in older children after a subsequent MMR doses was reported. Thirteen of the 24 patients had also experienced an acute infection. The number of “pure” MMR patients was 11. Thus, approximately 1:30,000 children having been immunized with MMR vaccine with or without infection developed platelet count <30 × 109 /l within 1 month after the first dose of vaccine. None of the patients had had episodes of thrombocytopenia previously. The rest of the group of post-vaccination ITP consisted of five children who had received DTP (diphtheria, tetanus and pertussis) +/− polio and two children immunized against hepatitis A or B. In four cases, the type of vaccination was not specified but was not MMR. The vaccinated patients were usually in their second year of life at the time of diagnosis of ITP and had a slight male predominance. Their thrombocytopenia usually presented with acute symptoms. No cases of insidious onset was seen in the MMR group. The initial platelet count of the MMR patients was 5–12 (mean 10) ×109 /l being similar to that in the other patient groups. All patients presented with purpura. The “pure” MMR patients had the highest percentage of wet purpura and the lowest percentage of diagnosis during the winter months between December 1 and March 31. 3.2. Management The vaccinated patients had a bone marrow examination and received red blood cell and/or platelet transfusions and medical treatments as often as the reference patients (Table 1).

3. Results 3.1. Presentation

3.3. Outcome A total of 305 of the 506 patients (60%) had a preceding infection and/or vaccination. Thirty-five patients (7%) had been vaccinated within 1 month before diagnosis. Twentyfour patients had had a first dose of MMR (Table 1). No

Follow-up data were available for most children in all groups (Table 1). The thrombocytopenia usually subsided quickly. The highest percentage of remission within 1 month

Table 1 Clinical characteristics, management and outcome in children with post-vaccinal ITP compared with age-matched reference patients MMR without infection (n = 11)

MMR with infection (n = 13)

Other vaccines (n = 11)

References without infection (n = 33)

References with infection (n = 33)

Presentation Mean age at diagnosis (months) Boy:girl (ratio) Insidious (%) Mean platelet count (×109 /l) Wet purpura (%) Onset in winter months (%)

16 1.8 0 8 55 27

14 0.9 0 11 54 39

18 0.8 18 11 18 45

14 1.4 21 10 36 36

14 2.3 12 11 39 58

Management Bone marrow (%) Transfusion (%) IVIG (%) Corticosteroids (%)

36 18 64 18

23 8 46 0

73 0 55 0

45 15 67 21

27 0 58 12

Follow-up (n) Brief course <1 months (%) Chronic course >6 months (%) Risk duration (mean days)a Risk events (mean number)

10 90 0 14 0.10

11 73 9 8 0.0

10 60 20 44 0.90

29 67 31 54 0.69

30 63 13 34 0.30

a

P < 0.05 between the groups of the vaccinated and the reference patients.

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J. Rajantie et al. / Vaccine 25 (2007) 1838–1840

post-diagnosis was seen in the “pure” MMR group of patients, of whom none developed chronic disease. The risk period with blood platelets <20 × 109 /l was significantly shortest in the MMR patients who also had fewer risk events than others. None of the other observed differences reached statistical significance.

4. Discussion Natural infections are sometimes followed by acute thrombocytopenia. Its incidence after rubella has been estimated to be 1:3000 and after measles even higher [10,12]. Our data show that clinically significant thrombocytopenia can appear also after vaccinations but significantly more rarely than after natural infections. Thus our data confirms the findings of other studies that have reported frequencies of post-MMR vaccinal ITP to be 1:22,300–1:33,800 [3,10,13,14]. Thus, immunization with MMR seems to reduce the risk of subsequent thrombocytopenia to less than 10% of that after natural infections. Studies reporting a link between MMR vaccination and ITP have been criticized because concomitant viral infections have not usually been excluded [14,15] and therefore a causal relationship has remained unproven except in a study of Miller et al. [3] who by using immunization/hospital record linkage seemed to be able to confirm such association. We grouped our patients according to a history of recent infection and may have been able to define a group of “pure” postvaccinal patients. ITP in this group was shown to be typically acute, with profound thrombocytopenia and frequent oozing mucosal bleedings requiring medical treatments equally frequent as in other ITP patient groups. However, this postvaccinal ITP seemed to have an unusually benign course; remission was achieved within a few weeks, and chronic disease was exceptional. These results are in accordance with findings reported elsewhere [3,10,13]. Two mechanisms of post-vaccinal thrombocytopenia have been proposed. Findings of Nieminen et al. suggested an autoimmune response [10] while Oski and Naiman have noted a decrease in the number of marrow megakaryocytes [16]. All aspirates obtained in our patients showed normal or increased megakaryocytes in the bone marrow (performed in 43% of the patients, data not shown). It has been suggested that patients with a history of ITP must be checked for thrombocytopenia after vaccination [17,18]. In our material, no patient were reported to have had a recurrent thrombocytopenia following a MMR booster, nor after other repeated immunizations. This suggests that checking the platelet count after immunizations in patients with a history of ITP may not be necessary. We conclude that there exists an association at least in time between vaccination, notably MMR, and ITP as shown previously [3]. However, the risk is much smaller than after natural infections with these viruses. Although the thrombocytopenia is initially profound with frequent mucosal bleeding the

subsequent course is benign and short lasting. The benefits of vaccination programs greatly exceed the significance of this possible side-effect.

Acknowledgements We thank all the members of the national study groups who entered patients into the study and carefully reported the necessary data.

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