Key Points

  • PCs increase faster when 1 dose of IVMP is given before IVIG (as a rapid infusion over 2-3 hours) than when IVIG is given alone.

  • The addition of 1 dose of IVMP given immediately before IVIG significantly reduces the incidence of IVIG-related side effects.

Abstract

Children with immune thrombocytopenia (ITP) rarely suffer from life-threatening bleeds (eg, intracranial hemorrhage). In such settings, the combination of IV methylprednisolone (IVMP) with IV immune globulin (IVIG) is used to rapidly increase platelet counts (PCs). However, there are no controlled data to support using combination therapy over IVIG alone. We conducted a randomized, double-blind, placebo-controlled study to evaluate the rapidity of the PC increment and associated adverse events (AEs) between 2 regimens: A (IV placebo) and B (IVMP 30 mg/kg), both given over 1 hour, followed in both cases by IVIG (Gamunex 10%) 1 g/kg over 2-3 hours in children 1-17 years old with primary ITP and PCs <20 × 109/L in whom physicians had decided to treat with IVIG. Thirty-two children (ages: median, 8 years; range, 1.2-17.5 years) with a mean baseline PC of 9.2 × 109/L participated. Eighteen were randomized to regimen A and 14 to regimen B. By 8 hours after initiating therapy, 55% of all children had a PC ≥20 × 109/L (no group difference). By 24 hours, mean PCs were 76.9 × 109/L (B) vs 55 × 109/L (A) (P = .06; P = .035 when adjusted for intergroup differences in patient ages). No patient experienced severe bleeding/unexpected severe AEs. There were statistically fewer IVIG-related headaches in the group receiving combination therapy (P = .046). Our findings show a rapid response to IVIG with/without steroids and provide evidence to support the use of IVMP+IVIG in life-threatening situations. This trial was registered at www.clinicaltrials.gov as #NCT00376077.

Introduction

Childhood immune thrombocytopenia (ITP) is a common and usually mild, transient disorder caused by autoantibodies against platelet membrane antigens, resulting in enhanced Fc-mediated destruction of platelets by macrophages in the reticuloendothelial system (RES) and in some cases impaired production of platelets by megakaryocytes in the bone marrow.1,2  Most children with ITP present with low platelet counts (PCs) but with minimal bleeding.3 

The incidence of severe life-threatening bleeds such as intracranial hemorrhage (ICH) in childhood ITP is fortunately very low. Retrospective reviews/registries have estimated the incidence of ICH in childhood ITP to be ∼0.4% to 0.6%.4-9  Although rare, the occurrence of ICH in childhood ITP is devastating, with significant mortality (studies suggest 25% to 55% overall mortality) and morbidity.4,10 

The only consistent risk factors for ICH include a PC of <10 × 109/L and head trauma. One study also showed that gross hematuria and non-skin bleeding symptoms are much more common in patients with ITP who experience ICH vs those who do not.5  Rare risk factors for ICH include concomitant coagulopathies and varicella-associated ITP.

Given the rarity of ICH, controversy exists as to whether children with ITP without concomitant bleeding need any treatment other than observation. However in the context of certain situations (eg, ICH, other life-threatening bleeds, or need for urgent surgery) it is imperative that the PC be increased as quickly as possible. IV immune globulin (IVIG), corticosteroids, and IV anti-D have all been shown to increase a patient’s PC in ITP.

The main effect of corticosteroids in increasing PCs in ITP is thought to be due to suppression of platelet phagocytosis by the RES.11  Corticosteroids may also improve endothelial integrity, further reducing the risk of bleeding.12  Several studies in adults and in children have shown that the higher the corticosteroid dose (oral/parenteral), the faster the PC increment.13-17 

In 1981, Imbach and colleagues noted that IVIG infusions increase PCs in children with ITP.18  This was confirmed by several randomized and nonrandomized clinical trials.12,14,15  The major proposed mechanism of action of IVIG is the inhibition of Fc-mediated phagocytosis of antibody-coated platelets by the RES.19-21 

Both corticosteroids and IVIG have numerous adverse effects. In the case of corticosteroids, these include increased appetite, personality changes, Cushing syndrome, weight gain, hyperglycemia, and hypertension. These side effects are related to the duration of corticosteroid exposure; thus, a very short course of high-dose oral/IV corticosteroids results in fewer side effects than several weeks of low-dose oral corticosteroids.16,17 

The main concern with IVIG is that it is a blood product and consequently carries a theoretical risk of transmitting viral diseases. Additionally, it is expensive and needs to be infused IV over 3 to 6 hours, often resulting in the need for hospitalization. Furthermore its use is associated with a considerable incidence of early (fever and chills) and/or delayed (1-3 days) complications (aseptic meningitis, headache, nausea, and vomiting).22,23  These complications, which are more common with larger/repeated doses, can result in additional morbidity/health care costs due to prolonged hospitalizations, hospital readmissions, emergency room visits, and neuroimaging costs.22,24 

Many investigators have reported that in ITP, IVIG has a quicker onset of action than corticosteroids, leading to a faster increment in PC.15,25  As the mechanisms of action are different between corticosteroids and IVIG, it is theorized (but without controlled evidence) that these therapies, if used in combination, might have synergistic effects, resulting in a faster increment in PC.26  There is also some evidence to suggest the concomitant administration of corticosteroids with IVIG may decrease the incidence and severity of IVIG-related side effects.22,27 

Until now, no randomized study has been conducted to compare the effects of concomitant administration of corticosteroids with IVIG vs IVIG alone in quickly increasing PCs and reducing IVIG-related side effects. We undertook this study to answer these questions.

Methods

This was a randomized, double-blinded, placebo-controlled, multicenter, prospective study performed in 6 Canadian pediatric centers (see “Acknowledgments”). The trial was registered at www.clinicaltrials.gov (NCT00376077) and underwent research ethics board approval in all 6 participating centers. The study commenced in 2005, and patient enrollment continued until 2016. The long study duration was due to a shift in practice toward observation and less treatment of children with ITP.

The study included children (<18 years) with ITP and PCs <20 × 109/L, without life-threatening bleeding, in whom a clinical decision had been made (between the patient/family and their hematologist) to treat with IVIG.

Children with acute or chronic ITP (defined using the pre-2009 definitions [<6 months and ≥6 months since diagnosis, respectively]) were eligible for participation. Children were not enrolled within the first 24 hours of initial diagnosis of ITP, as it was deemed inappropriate to burden them with a discussion of this study at that time. Previous treatment with IVIG and/or corticosteroids was not an exclusion criterion, but children who were known to not respond to IVIG/corticosteroids were excluded. Children were only studied once. For full eligibility criteria, see Table 1.

Table 1.

Study eligibility criteria

Inclusion criteriaExclusion criteria
Ages 1-17 y followed at participating centers Initial presentation with ITP 
Diagnosed with primary (acute or chronic) ITP Previous splenectomy 
Presents with a PC <20 × 109/L Life- or organ-threatening hemorrhage (eg, proven/suspected ICH) 
Patient/family and attending physician have decided on treatment with IVIG Contraindication to IVIG (renal disease with creatinine ≥2× upper list of normal) or IVMP (diabetes mellitus, hypertension, peptic ulceration, sepsis, fever >38.5°C)
Previous documented lack of response to IVIG
DIC (defined by a fibrinogen level <1.0 g/dL and elevated D-dimer levels)
Pregnancy 
Inclusion criteriaExclusion criteria
Ages 1-17 y followed at participating centers Initial presentation with ITP 
Diagnosed with primary (acute or chronic) ITP Previous splenectomy 
Presents with a PC <20 × 109/L Life- or organ-threatening hemorrhage (eg, proven/suspected ICH) 
Patient/family and attending physician have decided on treatment with IVIG Contraindication to IVIG (renal disease with creatinine ≥2× upper list of normal) or IVMP (diabetes mellitus, hypertension, peptic ulceration, sepsis, fever >38.5°C)
Previous documented lack of response to IVIG
DIC (defined by a fibrinogen level <1.0 g/dL and elevated D-dimer levels)
Pregnancy 

DIC, disseminated intravascular coagulation.

Intervention

Following consent, children were randomized to receive either regimen A (saline placebo prepared to look the same as the IV methylprednisolone [IVMP] given over 1 hour) or regimen B (IVMP [Solu-Medrol, UpJohn] 30 mg/kg [maximum 1 g] over 1 hour) both immediately followed by IVIG 1 g/kg (Gamunex 10%, Bayer/Talecris/Grifols) given over 2 to 3 hours (Figure 1). To ensure that the 2 groups had an equal distribution of patients with acute and chronic ITP, block randomization was used. Randomization was done by contacting the study pharmacist at the coordinating center, who kept the randomization codes and a table with the treatments that children had received. Children/families and evaluating physicians (performing bleeding scores and clinical examinations and reviewing adverse events [AEs]) were, at all times, blinded to the patient’s management regimen. The randomization code was only broken after all enrolled children completed the study.

Figure 1.

Randomization strategy for eligible children. For this study, IVIG was Gamunex (immune globulin intravenous [human] 10%; this was marketed by Bayer at the start of the study, and then by Talecris and finally by Grifols). Gamunex was given according to manufacturer’s guidelines by means of a rapid infusion protocol: Start at 0.02 mL/kg per minute (1.2 mL/kg per hour) × 15 min. If no adverse reaction, increase to 0.04 mL/kg per minute (2.4 ml/kg per hour) × 15 minutes. If no adverse reaction, increase to 0.08 mL/kg per minute (4.8 mL/kg per hour) × 15 minutes. If no adverse reaction, increase to 0.10 mL/kg per minute (6.0 mL/kg per hour) for duration. If patients cannot sustain a particular infusion rate, then infusion is run at the highest tolerated rate.

Figure 1.

Randomization strategy for eligible children. For this study, IVIG was Gamunex (immune globulin intravenous [human] 10%; this was marketed by Bayer at the start of the study, and then by Talecris and finally by Grifols). Gamunex was given according to manufacturer’s guidelines by means of a rapid infusion protocol: Start at 0.02 mL/kg per minute (1.2 mL/kg per hour) × 15 min. If no adverse reaction, increase to 0.04 mL/kg per minute (2.4 ml/kg per hour) × 15 minutes. If no adverse reaction, increase to 0.08 mL/kg per minute (4.8 mL/kg per hour) × 15 minutes. If no adverse reaction, increase to 0.10 mL/kg per minute (6.0 mL/kg per hour) for duration. If patients cannot sustain a particular infusion rate, then infusion is run at the highest tolerated rate.

Studies and observations

Baseline.

At baseline, the following were performed: clinical history, physical examination, determination of the Buchanan and Adix bleeding score28  (supplemental Appendix 1), and Kids ITP Tool (KIT) quality of life (QoL) evaluations (child self-report for children aged 7-17 years, parent proxy report for children aged 2-17 years, and a parent impact report for all children).29  The bleeding score gives an overall categorical score from 0 (no bleeding) to 5 (life-threatening or fatal bleeding). The KIT is a continuous score from 0 (worst QoL) to 100 (best QoL). KIT and bleeding scores were only used to compare the 2 groups according to baseline disease severity and were not repeated following therapy.

The following laboratory tests were performed: complete blood count, urea, creatinine, glucose, conjugated and unconjugated bilirubin, Coombs test, and urinalysis. A screening pregnancy test (urine β-human chorionic gonadotropin) was performed on all postpubertal females.

Adverse effects of treatment were recorded using a specific AE questionnaire (supplemental Appendix 2) and monitored by the study’s Data Monitoring Safety Board.

Follow-up.

Following the intervention, children had follow-up studies performed as per supplemental Appendix 3 (schedule of observations post treatment). To minimize inconvenience for children/families certain follow-up studies (complete blood count and urinalysis) were permitted to be performed in local laboratories close to children’s homes. The last blood sample was obtained at day 21. Follow-up AE questionnaires were completed by the parents/children in clinic or by telephone by local study coordinators.

Statistical analysis

Sample size was estimated based on several assumptions: (1) mean PC in children at baseline would be 10 × 109/L; (2) children receiving IVIG alone would attain a mean PC of 30 × 109/L 24 hours after initiation of therapy, with substantial interpatient variation (estimated standard deviation of 20 × 109/L); and (3) children receiving the combined regimen (IVMP+IVIG) would attain a PC of 50 × 109/L at the 24-hour time point with similarly large interpatient variability. For 80% power to show a difference in PC of 20 × 109/L (at 24 hours) with an α of 0.025 (2 sided) and a β of 0.2, it was estimated that 32 evaluable children would be required.

Two-sample Student t tests were used to compare mean PCs, mean hemoglobin (Hb) levels and KIT scores at different time points between the 2 groups. χ2 testing was done to compare the proportion of children attaining PCs of 20 × 109/L and 50 × 109/L at the different time points and the proportions of children showing AEs at different time points. Statistical significance was set at P < .05. Statistical analyses were done using SAS 9.4.

Results

Patients and baseline studies

Thirty-three children were consented into the trial, but 1 immediately dropped out of study after randomization, leaving 32 participating children (ages: mean, 9.4 years; range, 1.2-17.5 years; 22 males and 10 females; 16 acute and 16 chronic; 11 blood type O and 21 non-O blood type) (Table 2). Mean age of children with acute ITP was 8.8 years vs 10.0 years for children with chronic ITP. Most children had previously been treated for ITP; 23 had received IVIG, while 26 had received corticosteroids. Four patients had never received any treatment.

Table 2.

Baseline data for patients

Regimen A (IVIG alone)Regimen B (IVMP + IVIG)TotalP (A vs B)
Patients, n 18 14 32  
Age, y     
 Mean 9.0 9.9 9.4 .65 
 Median 6.5 10.5 
 Range 2.5-17 1.2-17.5 1.2-17.5 
 >10 y, n/N (%) 7/18 (39) 8/14 (57) 15/32 (47) .31 
Sex, males:females 13:5 9:5 22:10 .63 
Acute:chronic ITP 9:9 7:7 16:16 .99 
Baseline PCs, mean (range), × 109 8.9 (1-19) 9.6 (1-18) 9.2 (1-19) .69 
Baseline bleeding scores, mean (range) 1.41 (0-3) 1.23 (0-3) 1.32 (0-3) .57 
Baseline KIT, mean (range)     
 Self-score 76 (59.6-90) 72.1 (48.1-87.5) 73.1 (48.1-96.2) .76 
 Parent proxy for child 73.1 (39.4-98.1) 69.2 (57.7-96.2) 70.7 (39.4-98.1) .93 
 Parent impact on family 37.5 (17.3-78.8) 38.7 (23.1-70.2) 38 (17.3-78.8) .96 
Regimen A (IVIG alone)Regimen B (IVMP + IVIG)TotalP (A vs B)
Patients, n 18 14 32  
Age, y     
 Mean 9.0 9.9 9.4 .65 
 Median 6.5 10.5 
 Range 2.5-17 1.2-17.5 1.2-17.5 
 >10 y, n/N (%) 7/18 (39) 8/14 (57) 15/32 (47) .31 
Sex, males:females 13:5 9:5 22:10 .63 
Acute:chronic ITP 9:9 7:7 16:16 .99 
Baseline PCs, mean (range), × 109 8.9 (1-19) 9.6 (1-18) 9.2 (1-19) .69 
Baseline bleeding scores, mean (range) 1.41 (0-3) 1.23 (0-3) 1.32 (0-3) .57 
Baseline KIT, mean (range)     
 Self-score 76 (59.6-90) 72.1 (48.1-87.5) 73.1 (48.1-96.2) .76 
 Parent proxy for child 73.1 (39.4-98.1) 69.2 (57.7-96.2) 70.7 (39.4-98.1) .93 
 Parent impact on family 37.5 (17.3-78.8) 38.7 (23.1-70.2) 38 (17.3-78.8) .96 

Eighteen children were randomized to regimen A (placebo+IVIG) and 14 to regimen B (IVMP+IVIG). Randomization was not equal on account of a patient who after randomization to regimen B declined to participate, and a second patient was incorrectly assigned to regimen A. There was a slight (nonstatistically significant) difference in patient ages between the 2 groups; mean/median age was 9.0/6.5 years for regimen A vs 9.9/10.5 years for regimen B (P = .65).

All children started therapy with a PC of < 20 × 109/L; mean baseline PC was 9.2 × 109/L, with no intergroup difference (P = .69). Mean overall baseline Buchanan and Adix bleeding score was 1.32 (corresponding to a rating of minor bleeding); 22 children had scores of 0 or 1 (no/minor bleeding), while 5 had a score of 2 (mild bleeding) and 5 had a score of 3 (moderate bleeding). There was no statistical difference in bleeding scores between the 2 groups (P = .57). Bleeding scores did not correlate with whether children had acute or chronic ITP (P = .95) or with blood group (P = .98). Older subjects and males had slightly higher bleeding scores, but these failed to reach statistical significance (P = .33 and P = .20, respectively).

KIT child self-report scores were obtained from 17 children (age 7-17.5 years), while 21 parents answered the parent proxy for children (age 2-17 years) and 26 parents answered the KIT parent impact questionnaire. Baseline KIT scores are shown in Table 2. There were no statistical differences for all 3 KIT questionnaire scores between the 2 groups. No correlation was seen between KIT scores and baseline age, gender, or type of ITP (acute/chronic).

There was a trend for lower baseline PCs being associated with higher baseline bleeding scores (Pearson correlation P = .08). There was no significant association between baseline bleeding scores and baseline KIT scores (P = .36; analysis of variance).

Five (3 regimen A; 2 regimen B) children were Coombs positive at baseline. Two continued to show a positive Coombs test result at the 24-hour time point. No additional child developed a positive Coombs test result at 24 hours. Baseline creatinine, urea, and serum glucose were normal in all children. Two children showed slight abnormalities in baseline unconjugated bilirubin (21 μmol/L in both cases [normal, <17 μmol/L]).

Baseline urine dipstick results were positive for blood in 5 children (3 “trace” and 2 “moderate/large”), and in all cases, red blood cells were seen on urinalysis. No child showed hematuria with subsequent testing. No child had glucosuria at baseline or with subsequent testing.

Intervention

All children received the initial placebo/IVMP over 1 hour followed by IVIG over a mean of 2 hours 32 minutes (range, 1 hour 47 minutes to 3 hours 22 minutes). Consequently, the total mean time to administer the full treatment (placebo+IVIG or IVMP+IVIG) was 3 hours 32 minutes (range, 2 hours 47 minutes to 4 hours 22 minutes).

PC increment by patient age

There was a trend (P = .12) for younger children to show a more rapid increment in PC than older children (Figure 2).

Figure 2.

Analysis of covariance for PCs at 24 hours for the 2 regimens according to patient age. Best-fit lines for both regimens are plotted: placebo+IVIG (regimen A) and IVMP+IVIG (regimen B). Note that 24-hour PCs were obtained for 31 out of 32 patients (not obtained in a 1.2-year-old child).

Figure 2.

Analysis of covariance for PCs at 24 hours for the 2 regimens according to patient age. Best-fit lines for both regimens are plotted: placebo+IVIG (regimen A) and IVMP+IVIG (regimen B). Note that 24-hour PCs were obtained for 31 out of 32 patients (not obtained in a 1.2-year-old child).

PC increment by regimen

By the end of the placebo+IVIG or IVMP+IVIG therapy, mean PCs for both groups had risen to a mean of 14.6 × 109/L (range, 1-31 × 109/L), and 32% of all children exhibited PCs ≥20 × 109/L (no intergroup difference; P = .28) (Table 3; Figures 3 and 4). By 8 hours, mean PCs for the 2 groups were 23 × 109/L and 22.7 × 109/L (P = .94), respectively, and 55% (17/31) of all children had a PC ≥20 × 109/L, with no intergroup difference (P = .99).

Table 3.

PCs from baseline to 1 week following the 2 different treatments

RegimenAge, ySexITPPCs
BaselineEOT8 h24 h72 h1 wk
A (placebo+IVIG) 2.5 12 15 16 52 194 336 
3.7 15 18 27 79 246 487 
10 25 70 172 137 
11 17 42 117 118 
4.5 20 27 82 303 356 
31 42 ND ND 
19 21 25 100 192 194 
17 17 32 156 303 
10 20 48 61 37 
21 41 122 109 30 
12 24 38 78 197 175 
13 11 35 50 19 
15 10 ND 14 22 43 129 
15 15 24 22 54 138 106 
15 17 120 232 
15 12 16 49 105 120 
16 13 33 120 167 
17 13 27 35 71 115 90 
 Median 6.5 13 M:5 F 9 A:9 C 17 21 50.5 120 137 
 Mean 9.0   8.9 16.4 23.0 55.0 143.4 178.6 
 SD 5.2   4.8 7.9 10.4 30.3 68.8 128.0 
 Maximum 17   19 31 42 122 303 487 
 Minimum 2.5   43 19 
B (IVMP+IVIG) 1.2 21 ND 146 16 
11 66 137 25 
14 clot 91 185 288 
14 14 19 80 193 160 
15 108 210 112 
16 16 51 24 27 20 
10 16 20 32 98 180 165 
11 18 30 37 89 128 270 
11 18 107 122 ND 
12 18 25 29 116 232 280 
14.5 25 79 178 261 
16 12 16 24 83 177 183 
17 33 39 11 
17.5 26 37 12 
 Median 10.5 9 M:5 F 7 A:7 C 8.5 11 21 83 161.5 160 
 Mean 9.9   9.6 12.4 22.7 76.9 142.2 138.7 
 SD 5.2   6.0 8.5 12.6 31.2 66.0 112.8 
 Maximum 17.5   18 30 51 116 232 288 
 Minimum 1.2   24 27 11 
RegimenAge, ySexITPPCs
BaselineEOT8 h24 h72 h1 wk
A (placebo+IVIG) 2.5 12 15 16 52 194 336 
3.7 15 18 27 79 246 487 
10 25 70 172 137 
11 17 42 117 118 
4.5 20 27 82 303 356 
31 42 ND ND 
19 21 25 100 192 194 
17 17 32 156 303 
10 20 48 61 37 
21 41 122 109 30 
12 24 38 78 197 175 
13 11 35 50 19 
15 10 ND 14 22 43 129 
15 15 24 22 54 138 106 
15 17 120 232 
15 12 16 49 105 120 
16 13 33 120 167 
17 13 27 35 71 115 90 
 Median 6.5 13 M:5 F 9 A:9 C 17 21 50.5 120 137 
 Mean 9.0   8.9 16.4 23.0 55.0 143.4 178.6 
 SD 5.2   4.8 7.9 10.4 30.3 68.8 128.0 
 Maximum 17   19 31 42 122 303 487 
 Minimum 2.5   43 19 
B (IVMP+IVIG) 1.2 21 ND 146 16 
11 66 137 25 
14 clot 91 185 288 
14 14 19 80 193 160 
15 108 210 112 
16 16 51 24 27 20 
10 16 20 32 98 180 165 
11 18 30 37 89 128 270 
11 18 107 122 ND 
12 18 25 29 116 232 280 
14.5 25 79 178 261 
16 12 16 24 83 177 183 
17 33 39 11 
17.5 26 37 12 
 Median 10.5 9 M:5 F 7 A:7 C 8.5 11 21 83 161.5 160 
 Mean 9.9   9.6 12.4 22.7 76.9 142.2 138.7 
 SD 5.2   6.0 8.5 12.6 31.2 66.0 112.8 
 Maximum 17.5   18 30 51 116 232 288 
 Minimum 1.2   24 27 11 

A, acute; C, chronic; EOT, end of therapy; F, female; M, male; ND, not done; SD, standard deviation.

Figure 3.

PCs (×109/L) in all children from baseline to 72 hours after intervention. Shown are the curves for children receiving regimen A (placebo+IVIG; red dashed line) and regimen B (IVMP+IVIG; blue solid line).

Figure 3.

PCs (×109/L) in all children from baseline to 72 hours after intervention. Shown are the curves for children receiving regimen A (placebo+IVIG; red dashed line) and regimen B (IVMP+IVIG; blue solid line).

Figure 4.

Proportion of children with PC >20 × 109/L or >50 × 109/L for the 2 regimens over the first 72 hours.

Figure 4.

Proportion of children with PC >20 × 109/L or >50 × 109/L for the 2 regimens over the first 72 hours.

The difference in mean PC approached statistical significance (P = .06) at the 24-hour time point (55 × 109/L for regimen A vs 76.9 × 109/L for regimen B). Given the slight difference in age between the 2 groups (regimen B children being slightly older), and given that age was a confounder in PC increment, we post-hoc adjusted the analysis for age. In doing so, the difference in mean PC at 24 hours between the 2 groups became statistically significant (P = .035), favoring the combined therapy. At 24 hours, the proportion of children having achieved a PC of ≥20 × 109/L was 89% (regimen A) vs 100% (regimen B) (P = .49), while the proportion of children having achieved a PC of ≥50 × 109/L was 50% (regimen A) vs 77% (regimen B), respectively (P = .15).

Mean (range) PCs for all 32 children were 143 × 109/L (27-303 × 109/L) at 72 hours, 161 × 109/L (11-487 × 109/L) at 1 week, and 40 × 109/L (1-162 × 109/L) at day 21 after therapy. At all of these time points, there was no statistical difference in PCs between the groups. At 72 hours posttherapy all children showed PCs >20 × 109/L, and 87% of all children showed PCs ≥50 × 109/L, while by 1 week posttherapy, 4 out of 30 children (2 children did not have testing at 1 week) showed PCs <20 × 109/L. By day 21, 4 children (3 randomized to regimen A and 1 to regimen B) had received additional platelet-enhancing therapies as a result of a PC of <10 to 20 × 109/L and/or bleeding.

There was no statistical difference in response rates between males and females (P = .43); between children with acute vs chronic ITP (P = .64), between children who previously had received IVIG (n = 23) and those who had not (n = 9) (P = .55), or between those who had previously received steroids (n = 26) and those who had not (n = 4). all 5 patients with grade 3 bleeding scores at baseline (this included a patient with large hematuria at baseline) achieved a PC of >20 × 109/L at 24 hours, as did the 2 patients with moderate-to-large hematuria. The 6 patients with either grade 3 bleeding at baseline or moderate-to-large hematuria showed a mean PC of 50.2 at 24 hours and 134 at 72 hours, which was not statistically different from the overall group of patients.

AEs

Following treatment, 30 children reported AEs. The 2 children who did not report AEs were both treated with regimen B. No patient experienced a severe bleed/unexpected severe AE during the study. The most common AE was headache, followed by nausea, vomiting, dizziness, unusual taste in the mouth, abdominal pain, mood changes, and increased appetite. The most common time point to report AEs was during the 24- to 72-hour time period.

Headache was reported during the 24- to 72-hour time period by 14 out of 16 children (87.5%) who received regimen A (excluding 2 children who had acute allergic reactions; see below) vs 7 out of 14 children (50%) who received regimen B (P = .046; Fisher’s exact test). At all other time points, the incidence of headache was not’different between the 2 groups. Nausea (only reported in combination with headache) was reported by 6 children on regimen A and 2 on regimen B. There was no relationship between the occurrence of headache or nausea and patient age/gender. Two children (5-year-old male and 15-year-old female; both randomized to regimen A) developed allergic reactions upon receiving IVIG. In both cases, their reactions resolved with medical therapy; the first patient received IV diphenhydramine and acetaminophen, while the second patient received IV hydrocortisone and IV diphenhydramine.

At baseline, 31 out of 32 children had a normal Hb level. A 1.2-year-old male had mild iron-deficiency anemia (Hb 101 g/L). Overall, the mean Hb level among all children showed a statistically significant (P = .0001; paired Student t test) drop (mean drop, 8.8%) from a baseline mean of 133.3 g/L (range, 101-166 g/L) to a mean of 121.6 g/L (range, 89-149 g/L) at time 8 hours; the mean Hb drop was 7.5% in the 11 O blood type individuals vs 9.6% in the 21 non-O blood type individuals (P = .07; paired Student t test). The 5 children with a positive baseline Coombs test result showed no overall difference in Hb drop compared with the other children. By 72 hours posttreatment, the mean Hb level among all children had risen to 128 g/L, while at 1 week, it was 131.7 g/L (both not statistically different from baseline).

Discussion

This study evaluated 3 main questions: (1) How fast does the PC increase with IVIG alone? (2) Does it increase faster with the combination of IVMP (1 dose) with IVIG? (3) Does the combination therapy result in fewer/more side effects than IVIG alone?

Regarding the first question, our study showed that PCs increased more rapidly than predicted following IVIG administration alone or with IVMP. By 8 hours after the initiation of therapy, 55% of all children (both regimens) had achieved a PC ≥20 × 109/L, and by 24 hours after the initiation of therapy, 89% of children receiving only IVIG had achieved a PC ≥20 × 109/L (vs 100% of those receiving the combination therapy). Previous reports of rapidity of PC increment with IVIG have shown slower increments. Erduran and colleagues reported in 2003 that 86% of 42 children with ITP receiving IVIG 1 g/kg per day × 2 days had achieved a PC of >20 × 109/L by 48 hours.30  We showed a similar percentage (89%) of children receiving only IVIG (regimen A) achieving this, but doing so by 24 hours. The more rapid increase in PCs in our study we speculate could be a function of the rapid (over 2-3 hours) IVIG infusion rate used compared with the traditional ∼6-hour infusion rate used before the mid-2000s. We must however acknowledge that by excluding previous nonresponders to IVIG, we may have selected for patients who would show a better response to IVIG. Of course, a definite benefit of a faster IVIG infusion is that it results in less time that patients/families need to spend in a clinic/hospital, thus reducing the burden to patients/families and potentially reducing health care costs.

Regarding the second question, our study showed that IVMP+IVIG led to a faster rise in PC than IVIG alone. At 24 hours after the initiation of therapy (∼20.5 hours after completion of IVIG), children receiving the combination therapy showed a PC that was on average 21.9 × 109/L higher than children receiving only IVIG (76.9 × 109/L vs 55 × 109/L; P = .035; adjusted for age). Furthermore, a higher proportion of children treated with combination therapy showed a PC of >50 × 109/L at the 24-hour time point (77% vs 50%).

Two studies, both nonrandomized and retrospective, also evaluated the rapidity of the PC increment in children with ITP when given IVMP+IVIG.31,32  There were notable differences between those studies and ours. The first study, by Barrios and colleagues, was a noncomparative study involving 11 children who started with a higher mean PC (19 × 109/L) than our children, received a lower dose of IVMP (20 mg/kg) than we used (30 mg/kg), and received IVIG over 5 hours (vs 2-3 hours in our study).31  They reported that by 24 hours, the mean PC in their 11 children was 111 × 109/L (5.8 × baseline), while we reported a mean PC at 24 hours in the children receiving the combination therapy (regimen B) of 76.9 × 109/L (8 × baseline). The second was a 4-year comparative study of 148 children with acute ITP who had been treated with IVMP (30 mg/kg per day × 3 days), IVIG (1 g/kg per day × 2 days), or the combination of both.32  The authors reported that PCs rose fastest in patients receiving combination therapy; by 24 hours after the initiation of therapy, the mean PC was 50 × 109/L in children receiving combination therapy.

Although we found a significant intergroup difference in PCs at the 24-hour time point, we did not find a difference at either earlier (end of therapy or 8 hours) or later time points (72 hours; 1 week or 3 weeks). This suggests that the effect of IVMP in raising PCs only becomes noticeable sometime after 8 hours. For this study, it was not felt that continuation of IV/oral steroids, which would have entailed prolonged hospitalization or daily clinic visits, increased venipunctures, and/or increased treatment side effects, was ethically justifiable, as subjects were not in a life-threatening situation. In the setting of an actual life-threatening hemorrhage, IV corticosteroids and IVIG would likely be continued and could potentially boost further PCs at times 24, 48, and 72 hours after the initiation of combined therapy.

Age at initial diagnosis has been shown to be a predictor of ITP resolution, with younger children (≤10 years) being more likely to resolve their ITP then older children (>10 years).33,34  However, the effect of age on the rapidity of PC increment following therapy has not been well studied. A recent Japanese study showed that children <23 months of age (n = 24) were more likely to achieve a better PC response at the 2-week mark following therapy than older children (≥23 months; n = 29).35  However, in that study, the initial rise in PC in the first 24 hours was not described. We found a trend for older children to show a less brisk increment in PC.

Regarding our third question, we found that the coadministration of 1 dose of IVMP pre-IVIG reduced AEs from IVIG. A high incidence of AEs when IVIG is given alone has previously been reported.25  Our study is in keeping with several nonrandomized and nonblinded reports showing that administration of IV/oral corticosteroids reduces the incidence of IVIG-related side effects.22,27 

Additional findings in our study include a statistically significant drop (8.8%) in mean Hb from baseline to the 8-hour mark among all children. This drop, we believe, is due to 2 processes: (1) a dilutional effect from the administration of IVIG, as 1 g Gamunex represents a volume of 10 mL, and all children received 1 g (10 mL)/kg; and (2) hemolysis resulting from anti-A or anti-B alloantibodies present in IVIG.36,37  The former applies to all children, while the latter only to non-O blood type individuals. We found that the hemolysis arising from 1 dose of IVIG (1 g/kg) in non-O blood type individuals was relatively minor and not clinically significant.

KIT scores at study enrollment were comparable to what has been reported for children with acute ITP in the past, which tend to be in the range of 65 to 75.38,39  We, like others, found (1) much lower parent impact scores, reflecting a considerable parental burden from childhood ITP; and (2) a lack of statistically significant correlation among PCs, bleeding scores, and KIT scores.38,40  As we did not repeat KIT scores posttherapy, we cannot comment on the impact of treatment on follow-up KIT scores.

Our study did have limitations. It involved a relatively small number of children and unequal randomization (18 vs 14). Both of these things reduced the statistical power of our study and contributed to our initial univariate results not achieving statistical significance when comparing platelet increment with placebo+IVIG vs IVMP+IVIG. It was only after post-hoc adjustment for differences in patient age that we saw a statistical significance. Also, we excluded newly diagnosed children within 24 hours of presentation and children with life-threatening bleeding. Potentially, children who initially present with life-threatening bleeds may represent a group that might respond differently to treatment.

In our study, most of the children had previously been treated with IVIG and/or corticosteroids and consequently to be eligible for our study must have responded to these therapies, as we excluded those who previously demonstrated lack of response to IVIG/corticosteroids. Hence, our study findings, if extrapolated to all children (not just those who have demonstrated response to IVIG/corticosteroids), might overestimate the response to both study regimens.

In summary, our randomized, double-blinded study shows a more rapid response to IVIG (1 g/kg) when given as an infusion over 2 to 3 hours than previously recognized and that the combination of IVMP and IVIG leads to a more rapid increment in PC than IVIG alone. Consequently, our study is supportive of the use of combination therapy in situations of life-threatening bleeds in children with primary ITP, where it is crucial to increase the PC as quickly as possible. In such situations, we would still advocate strongly for administering a large platelet transfusion and other adjunctive hemostatic therapies (eg, recombinant factor VIIa and IV tranexamic acid41 ). Our findings also show a beneficial effect of reducing IVIG-related AEs with the use of 1 dose of IVMP. Given its demonstrable benefits in reducing side effects from IVIG, clinicians might consider adding 1 dose of IVMP (pre-IVIG) if they decide to use IVIG to treat a child with primary ITP, even in a non-life-threatening bleeding state. Our study does not, however, imply that all/most children when presenting with a low PC without significant bleeding should necessarily be treated, as many studies have shown a very low rate of bleeding in such children.

For data sharing, e-mail the corresponding author.

Acknowledgments

The authors thank the patients/families, nurses, and clinical research associates in our centers who participated in the study (Hospital for Sick Children, Toronto, ON, Canada; Children’s Hospital of Eastern Ottawa, Ottawa, ON, Canada; Kingston General Hospital, Kingston, ON, Canada; Ste-Justine Hôpital, Montreal, QC, Canada; IWK Health Centre, Halifax, NS, Canada; and Alberta Children’s Hospital, Calgary, AB, Canada). The authors also thank the members of the Data Monitoring Safety Board (Kaiser Ali, Sara Israels, and Shinya Ito).

Funding for this study was provided through an investigator-initiated peer-reviewed grant submitted to the Bayer-Talecris-Canadian Blood Services Partnership fund.

Authorship

Contribution: M.C. designed the study, coordinated and supervised data collection, carried out analyses, interpreted data, drafted the initial manuscript, and approved the final manuscript; M. Silva, M.D., R.J.K., M. Steele, and V.P. supervised data collection, revised the manuscript, and approved the final manuscript; C.W. and L.K. coordinated data collection, revised the manuscript, and approved the final manuscript; D.S. was the statistician for the study and carried out analyses, interpreted data, revised the manuscript, and approved the final manuscript; and V.S.B. designed the study, interpreted data, revised the manuscript, and approved the final manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Manuel Carcao, Division of Haematology/Oncology, Hospital for Sick Children, Paediatrics, 555 University Ave, Toronto, ON M5G 1X8, Canada; e-mail: manuel.carcao@sickkids.ca.

References

References
1.
Cines
DB
,
Blanchette
VS
.
Immune thrombocytopenic purpura
.
N Engl J Med
.
2002
;
346
(
13
):
995
-
1008
.
2.
Cines
DB
,
Bussel
JB
,
Liebman
HA
,
Luning Prak
ET
.
The ITP syndrome: pathogenic and clinical diversity
.
Blood
.
2009
;
113
(
26
):
6511
-
6521
.
3.
Neunert
CE
,
Buchanan
GR
,
Imbach
P
, et al;
Intercontinental Cooperative ITP Study Group Registry II Participants
.
Bleeding manifestations and management of children with persistent and chronic immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group (ICIS)
.
Blood
.
2013
;
121
(
22
):
4457
-
4462
.
4.
Butros
LJ
,
Bussel
JB
.
Intracranial hemorrhage in immune thrombocytopenic purpura: a retrospective analysis
.
J Pediatr Hematol Oncol
.
2003
;
25
(
8
):
660
-
664
.
5.
Psaila
B
,
Petrovic
A
,
Page
LK
,
Menell
J
,
Schonholz
M
,
Bussel
JB
.
Intracranial hemorrhage (ICH) in children with immune thrombocytopenia (ITP): study of 40 cases
.
Blood
.
2009
;
114
(
23
):
4777
-
4783
.
6.
Elalfy
M
,
Elbarbary
N
,
Khaddah
N
, et al
.
Intracranial hemorrhage in acute and chronic childhood immune thrombocytopenic purpura over a ten-year period: an Egyptian multicenter study
.
Acta Haematol
.
2010
;
123
(
1
):
59
-
63
.
7.
Kühne
T
,
Berchtold
W
,
Michaels
LA
, et al;
Intercontinental Cooperative ITP Study Group
.
Newly diagnosed immune thrombocytopenia in children and adults: a comparative prospective observational registry of the Intercontinental Cooperative Immune Thrombocytopenia Study Group
.
Haematologica
.
2011
;
96
(
12
):
1831
-
1837
.
8.
Neunert
C
,
Noroozi
N
,
Norman
G
, et al
.
Severe bleeding events in adults and children with primary immune thrombocytopenia: a systematic review
.
J Thromb Haemost
.
2015
;
13
(
3
):
457
-
464
.
9.
Tarantino
MD
,
Danese
M
,
Klaassen
RJ
,
Duryea
J
,
Eisen
M
,
Bussel
J
.
Hospitalizations in pediatric patients with immune thrombocytopenia in the United States
.
Platelets
.
2016
;
27
(
5
):
472
-
478
.
10.
Choudhary
DR
,
Naithani
R
,
Mahapatra
M
,
Kumar
R
,
Mishra
P
,
Saxena
R
.
Intracranial hemorrhage in childhood immune thrombocytopenic purpura
.
Pediatr Blood Cancer
.
2009
;
52
(
4
):
529
-
531
.
11.
Bussel
JB
.
Fc receptor blockade and immune thrombocytopenic purpura
.
Semin Hematol
.
2000
;
37
(
3
):
261
-
266
.
12.
Bussel
JB
,
Goldman
A
,
Imbach
P
,
Schulman
I
,
Hilgartner
MW
.
Treatment of acute idiopathic thrombocytopenia of childhood with intravenous infusions of gammaglobulin
.
J Pediatr
.
1985
;
106
(
6
):
886
-
890
.
13.
Godeau
B
,
Chevret
S
,
Varet
B
, et al;
French ATIP Study Group
.
Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial
.
Lancet
.
2002
;
359
(
9300
):
23
-
29
.
14.
Blanchette
VS
,
Luke
B
,
Andrew
M
, et al
.
A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura
.
J Pediatr
.
1993
;
123
(
6
):
989
-
995
.
15.
Blanchette
V
,
Imbach
P
,
Andrew
M
, et al
.
Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura
.
Lancet
.
1994
;
344
(
8924
):
703
-
707
.
16.
van Hoff
J
,
Ritchey
AK
.
Pulse methylprednisolone therapy for acute childhood idiopathic thrombocytopenic purpura
.
J Pediatr
.
1988
;
113
(
3
):
563
-
566
.
17.
Carcao
MD
,
Zipursky
A
,
Butchart
S
,
Leaker
M
,
Blanchette
VS
.
Short-course oral prednisone therapy in children presenting with acute immune thrombocytopenic purpura (ITP)
.
Acta Paediatr Suppl
.
1998
;
424
:
71
-
74
.
18.
Imbach
P
,
Barandun
S
,
Baumgartner
C
,
Hirt
A
,
Hofer
F
,
Wagner
HP
.
High-dose intravenous gammaglobulin therapy of refractory, in particular idiopathic thrombocytopenia in childhood
.
Helv Paediatr Acta
.
1981
;
36
(
1
):
81
-
86
.
19.
Mouzaki
A
,
Theodoropoulou
M
,
Gianakopoulos
I
,
Vlaha
V
,
Kyrtsonis
MC
,
Maniatis
A
.
Expression patterns of Th1 and Th2 cytokine genes in childhood idiopathic thrombocytopenic purpura (ITP) at presentation and their modulation by intravenous immunoglobulin G (IVIg) treatment: their role in prognosis
.
Blood
.
2002
;
100
(
5
):
1774
-
1779
.
20.
Lazarus
AH
,
Freedman
J
,
Semple
JW
.
Intravenous immunoglobulin and anti-D in idiopathic thrombocytopenic purpura (ITP): mechanisms of action
.
Transfus Sci
.
1998
;
19
(
3
):
289
-
294
.
21.
Imbach
P
,
Lazarus
AH
,
Kühne
T
.
Intravenous immunoglobulins induce potentially synergistic immunomodulations in autoimmune disorders
.
Vox Sang
.
2010
;
98
(
3 Pt 2
):
385
-
394
.
22.
Jayabose
S
,
Mahmoud
M
,
Levendoglu-Tugal
O
, et al
.
Corticosteroid prophylaxis for neurologic complications of intravenous immunoglobulin G therapy in childhood immune thrombocytopenic purpura
.
J Pediatr Hematol Oncol
.
1999
;
21
(
6
):
514
-
517
.
23.
Sekul
EA
,
Cupler
EJ
,
Dalakas
MC
.
Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors
.
Ann Intern Med
.
1994
;
121
(
4
):
259
-
262
.
24.
Kattamis
AC
,
Shankar
S
,
Cohen
AR
.
Neurologic complications of treatment of childhood acute immune thrombocytopenic purpura with intravenously administered immunoglobulin G
.
J Pediatr
.
1997
;
130
(
2
):
281
-
283
.
25.
Rosthøj
S
,
Nielsen
S
,
Pedersen
FK
;
Danish I.T.P. Study Group
.
Randomized trial comparing intravenous immunoglobulin with methylprednisolone pulse therapy in acute idiopathic thrombocytopenic purpura
.
Acta Paediatr
.
1996
;
85
(
8
):
910
-
915
.
26.
Arnold
DM
.
Bleeding complications in immune thrombocytopenia
.
Hematology Am Soc Hematol Educ Program
.
2015
;
2015
:
237
-
242
.
27.
Roberton
DM
,
Hosking
CS
.
Use of methylprednisolone as prophylaxis for immediate adverse infusion reactions in hypogammaglobulinaemic patients receiving intravenous immunoglobulin: a controlled trial
.
Aust Paediatr J
.
1988
;
24
(
3
):
174
-
177
.
28.
Buchanan
GR
,
Adix
L
.
Grading of hemorrhage in children with idiopathic thrombocytopenic purpura
.
J Pediatr
.
2002
;
141
(
5
):
683
-
688
.
29.
Klaassen
RJ
,
Blanchette
VS
,
Barnard
D
,
Wakefield
CD
,
Curtis
C
,
Bradley
CS
, et al
.
Validity, reliability, and responsiveness of a new measure of health-related quality of life in children with immune thrombocytopenic purpura: the Kids’ ITP Tools
.
J Pediatr
.
2007
;
150
(5):
510
-
515,5.e1
.
30.
Erduran
E
,
Aslan
Y
,
Gedik
Y
,
Orhan
F
.
A randomized and comparative study of intravenous immunoglobulin and mega dose methylprednisolone treatments in children with acute idiopathic thrombocytopenic purpura
.
Turk J Pediatr
.
2003
;
45
(
4
):
295
-
300
.
31.
Barrios
NJ
,
Humbert
JR
,
McNeil
J
.
Treatment of acute idiopathic thrombocytopenic purpura with high-dose methylprednisolone and immunoglobulin
.
Acta Haematol
.
1993
;
89
(
1
):
6
-
9
.
32.
Gereige
RS
,
Barrios
NJ
.
Treatment of childhood acute immune thrombocytopenic purpura with high-dose methylprednisolone, intravenous immunoglobulin, or the combination of both
.
P R Health Sci J
.
2000
;
19
(
1
):
15
-
18
.
33.
Heitink-Pollé
KM
,
Nijsten
J
,
Boonacker
CW
,
de Haas
M
,
Bruin
MC
.
Clinical and laboratory predictors of chronic immune thrombocytopenia in children: a systematic review and meta-analysis
.
Blood
.
2014
;
124
(
22
):
3295
-
3307
.
34.
Bennett
CM
,
Neunert
C
,
Grace
RF
, et al
.
Predictors of remission in children with newly diagnosed immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group Registry II participants
.
Pediatr Blood Cancer
.
2018
;
65
(
1
):
e26736
.
35.
Higashide
Y
,
Hori
T
,
Yoto
Y
, et al
.
Predictive factors of response to IVIG in pediatric immune thrombocytopenic purpura
.
Pediatr Int (Roma)
.
2018
;
60
(
4
):
357
-
361
.
36.
Mielke
O
,
Fontana
S
,
Goranova-Marinova
V
, et al
.
Hemolysis related to intravenous immunoglobulins is dependent on the presence of anti-blood group A and B antibodies and individual susceptibility
.
Transfusion
.
2017
;
57
(
11
):
2629
-
2638
.
37.
Padmore
R
.
Possible mechanisms for intravenous immunoglobulin-associated hemolysis: clues obtained from review of clinical case reports
.
Transfusion
.
2015
;
55
(
S2 Suppl 2
):
S59
-
S64
.
38.
Flores
A
,
Klaassen
RJ
,
Buchanan
GR
,
Neunert
CE
.
Patterns and influences in health-related quality of life in children with immune thrombocytopenia: a study from the Dallas ITP Cohort
.
Pediatr Blood Cancer
.
2017
;
64
(
8
):
e26405
.
39.
Klaassen
RJ
,
Blanchette
V
,
Burke
TA
, et al
.
Quality of life in childhood immune thrombocytopenia: international validation of the kids’ ITP tools
.
Pediatr Blood Cancer
.
2013
;
60
(
1
):
95
-
100
.
40.
Neunert
CE
,
Buchanan
GR
,
Blanchette
V
, et al
.
Relationships among bleeding severity, health-related quality of life, and platelet count in children with immune thrombocytopenic purpura
.
Pediatr Blood Cancer
.
2009
;
53
(
4
):
652
-
654
.
41.
Barnes
C
,
Blanchette
V
,
Canning
P
,
Carcao
M
.
Recombinant FVIIa in the management of intracerebral haemorrhage in severe thrombocytopenia unresponsive to platelet-enhancing treatment
.
Transfus Med
.
2005
;
15
(
2
):
145
-
150
.

Author notes

The full-text version of this article contains a data supplement.

Supplemental data