Abstract
Objectives:
Treatment of pediatric immune thrombocytopenia (ITP) is guided by the risk of bleeding. Intravenous immunoglobulin (IVIg) is one of the first-line therapy options for new-onset pediatric ITP. However, the exact optimal dose of IVIg has not been determined.
Methods:
This retrospective cohort study included all hospitalized children with newly diagnosed ITP receiving IVIg as first-line therapy during 2010–2020. We compared the safety and efficacy of two common IVIg dose regimens, 1 and 2 g/kg. Outcomes were short and long-term treatment responses and adverse events to the different doses.
Results:
A total of 168 children were included in our cohort. Eighty-two children were treated with 1 g/kg of IVIg and 86 with 2 g/kg. There was no difference in sustained response (platelet count > 20 × 109, > 14 days) between the groups (74.3% vs 76.7%, respectively, p = 0.72) and maximal platelet counts following treatment (p = 0.44). No difference was found regarding the percentage of chronic ITP between the two groups (24.4% in the 1 g/kg group as compared to 17.4% in the 2 g/kg group; p = 0.34). Logistic regression analysis demonstrated there was no effect of the IVIg dose on treatment failure and development of chronic ITP. As anticipated, 47.7% of adverse events were in the 2 g/kg group and 32.9% in the 1 g/kg group, with borderline statistical significance (p = 0.06).
Conclusion:
The initial treatment of newly diagnosed pediatric ITP using a 1 g/kg IVIg regimen may give comparable results to the double dose of 2 g/kg in attaining a prolonged safe hemostatic threshold, without impacting the incidence of chronic disease.
Keywords: ITP, IVIg, new onset, pediatric
Introduction
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by antibody-mediated platelet destruction, leading to an increased risk of bleeding. In children, the presentation is usually acute and often follows a viral illness, with an incidence of 1.9–6.4 per 100,000 children. 1 Pediatric ITP resolves spontaneously in most cases, while 20% will have a chronic course lasting over 1 year.2–8 Although some risk factors have been identified, factors influencing recovery, chronicity, or bleeding complications are yet to be defined.2–6
The treatment of pediatric ITP is guided by the risk of bleeding, usually occurring with severe thrombocytopenia (i.e. platelet count < 20 × 109/L).4,9–13 The aim of therapy is the prevention of intracranial hemorrhage estimated to occur in up to 1% of children with ITP,9,14–16 and other major bleeding manifestations, occurring in 3%–5% of children. 17 Current medical treatment strategies for newly onset pediatric ITP include observation alone, corticosteroids, anti-Rh (D) immune globulin, and intravenous immunoglobulin (IVIg).6,10,11,14–25 Several dosing regimens of IVIg are currently in use for the initial treatment of pediatric ITP. These vary between 0.4, 0.8, and 1 g/kg body weight per day for 1–5 days.6,10,11,14–28 The latest American Society of Hematology (ASH) guidelines recommend a single dose of 0.8–1.0 g/kg per body weight. 18 According to the updated National Health Service (NHS) protocol, a single 1 g/kg IVIg dose regimen is recommended while considering a second dose if there is a suboptimal initial response or ongoing bleeding. 23 Similar recommendations were given by the International Consensus Report. 14 Some published recommendations support the administration of 2 g/kg over 2–5 days,19,20,27 while others leave the decision to the discretion of the treating hematologist. 15 The variation in dosing recommendations highlights the complexity of ITP management; however, data supporting the different recommendations is limited. A randomized controlled trial demonstrated that in pediatric ITP, a single dose of 0.8 g/kg IVIg was sufficient to achieve a platelet count of over 20 × 109/L. 11 Whereas another study, conducted retrospectively on a large cohort of adult ITP patients, supported the use of a single dose of 1 g/kg of IVIg. 28
Higher dosages of IVIg are associated with longer hospitalizations, increased costs, and potentially more side effects (e.g. headache, fatigue, vomiting, aseptic meningitis, and hypotension). 29
In our study, we retrospectively compared the short- and long-term treatment response and adverse events of two commonly used IVIg dosing regimens (1 g/kg × 1 day or 1 g/kg × 2 days), administered to newly onset pediatric ITP.
Methods
Study design and data collection
The cohort comprised all patients aged 1–18 years with a newly diagnosed ITP treated at Schneider Children’s Medical Center of Israel between January 2010 and December 2020. Inclusion criteria were patients diagnosed with ITP according to international guidelines,2,14,16,17 who were treated with IVIg as the initial line of therapy and had at least 1 year of follow-up at our center. Treatment indications were a platelet concentration of less than 20 × 109/L or moderate-to-severe bleeding tendency, which was defined according to the Updated Bleeding Scale for Pediatric Patients with ITP (Provan et al.). 14 IVIg was indicated when there was no availability to perform a peripheral blood smear prior to treatment initiation (weekends, holidays, etc.). Patients were excluded if they were treated with any other ITP-targeted therapy (e.g. corticosteroids and Anti-D) prior to or in combination with IVIg. Patients with severe bleeding tendencies who were treated with other regimens were also excluded from the study.
Data extracted from medical charts included demographic details (age at presentation, gender), clinical characteristics (fever on admission, recent or concurrent febrile disease, recent vaccination, duration of symptoms, referral cause, relevant comorbidities, physical examination findings), and bleeding tendency according to Provan et al. 14 Laboratory testing before initiation of treatment included complete blood counts, peripheral blood smear, direct antiglobulin test, baseline immunoglobulin level, serum biochemistry values, blood group, Rh type, Epstein-Barr virus, and cytomegalovirus serology, human immunodeficiency virus determined by enzyme-linked immunosorbent assay, and anti-nuclear antibodies titer.
Patients were divided into two groups according to the regimen they received. Group 1 received IVIg at a dose of 1 g/kg. Group 2 received IVIg at a dose of 1 g/kg/day over 2 days for a total of 2 g/kg. Group 2 was further divided into two subgroups, based on the intention to treat; those who were treated with 2 g/kg upfront, regardless of platelet count following the first 1 g/kg, and those who received an initial dose of 1 g/kg IVIg and only received a second dose based on their platelet count response over the following 48 h.
During follow-up, blood samples were taken routinely on days 1, 2, 3, and later according to the patient’s response. All patients were followed for at least 12 months after initial treatment.
Parameters of response were adapted from the recommendations of the International Working Group,2,17 and included: initial response and 1-year status. Parameters investigated in the initial response included a sustained response, defined as platelet count > 20 × 109/L, for 14 days or more, and treatment failure, regarded as platelet count < 20 × 109/L or a response shorter than 14 days. 17 Additional data included time (days) to achieve platelet count over 50 × 109/L, maximal platelet count following treatment, length of response (in those who responded but needed another round of treatment), and the number of patients for whom no repeated treatment was required in the following 3 months. Data regarding status at 1 year from diagnosis included remission (platelet counts higher than 100 × 109/L without ITP therapy at 12 months after diagnosis), chronic ITP (platelet counts less than 100 × 109/L with or without the need for therapy at 12 months after diagnosis), and progression to another disease. In addition, adverse events during initial therapy, including those requiring cession of treatment, were recorded. Adverse events requiring cession of treatment included anaphylaxis, severe headaches, and aseptic meningitis that did not respond to analgesia and hydration. 30
The study was approved by the Rabin Medical Center institutional review board, and a waiver for informed consent was granted.
Statistical analysis
Statistical analysis was performed using IBM SPSS for Windows, version 27 (SPSS Inc., Armonk, NY, USA), and the R statistical software, version 4.1.2, R Core Team 2021. Categorical variables were analyzed using the Chi-square test, and continuous variables were compared by t test, Mann–Whitney, or one-way analysis of variance tests.
A logistic regression model was used to evaluate the association between the IVIg dose and treatment response following 2 weeks of follow-up (i.e. “sustained response”) and at 1 year from diagnosis. To account for baseline differences between the treatment groups, we adjusted the model for the following variables: age, sex, platelet count, fever at admission, preceding viral illness, preceding vaccination, bleeding scale, direct antiglobulin test result, and duration of hemorrhagic symptoms. A p-value of ⩽0.05 was deemed statistically significant.
Results
Patients’ characteristics
Among 446 pediatric patients with a newly diagnosed ITP, 168 (37.7%) received IVIg as their first-line treatment.
Nearly half of the patients diagnosed with ITP and treated with IVIg (82 children, 48.8%) received a single dose of 1 g/kg (Group 1), while the others (86 children, 51.2%) were given a total of 2 g/kg (Group 2). Patients’ characteristics are presented in Table 1.
Table 1.
Baseline demographics and clinical characteristics of patients.
| Characteristic | IVIg 1 g/kg, N = 82 | IVIg 2 g/kg, N = 86 | p Value |
|---|---|---|---|
| Age at presentation, mean ± SD, years | 4.95 ± 4.24 | 4.68 ± 4.58 | 0.69 |
| Sex (male), N (%) | 35 (42.6) | 47 (54.6) | 0.12 |
| Preceding viral illness (yes, %) | 56 (68.2) | 52 (60.5) | 0.33 |
| Preceding vaccination (yes, %) | 1 (1.2) | 5 (5.8) | 0.1 |
| Cause of referral, a N (%) | |||
| Skin manifestation (petechial rash, easy bruising) | 60 (73.1) | 80 (93) | 0.0005 |
| Bleeding tendency from other sites of mucosa (oral, nasal, GI, vaginal) | 14 (17) | 38 (44.1) | 0.0001 |
| Thrombocytopenia in blood count | 14 (17) | 4 (4.7) | 0.01 |
| Fever at admission, N (%) | 11 (13.5) | 7 (8.1) | 0.32 |
| Bleeding scale (according to Provan et al. 14 ), N (%) | |||
| Minor to mild | 76 (92.6) | 78 (90.7) | 0.78 |
| Moderate | 3 (3.7) | 5 (5.8) | |
| Severe | 3 (3.7) | 3 (3.5) | |
| Platelet count at presentation (×109/L), mean ± SD | 8.59 ± 7.7 | 5.69 ± 5.22 | <0.005 |
| Positive direct antiglobulin test (%) | 4 (4.8) | 6 (6.9) | 0.56 |
| Duration of hemorrhagic symptoms (days), median [range] | 3 [2–7] | 3 [2–5] | 0.96 |
| Mean platelet volume (fl), mean ± SD | 9.24 ± 1.71 | 9.24 ± 2.43 | 0.99 |
More than one cause may be mentioned.
fl, Femtoliters, GI, gastrointestinal; IVIg, intravenous immunoglobulin; N, number of patients, SD, standard deviation.
Patients in Group 2 had a lower platelet count (mean 5.7 ± 5.2 × 109/L vs 8.6 ± 7.7 × 109/L, respectively, p = 0.005) and a more severe phenotype with more bleeding symptoms such as skin manifestations (petechial rash, easy bruising: 93% vs73.1%, respectively, p = 0.005) and bleeding from other sites (44.1 vs17%, respectively, p = 0.0001) as compared with group 1.
Thrombocytopenia as the reason for referral was more common in Group 1 as compared to Group 2 (17% vs 4.4%, respectively, p = 0.01). There was no significant difference in the duration of hemorrhagic symptoms (median of 3 days in both groups) or in the bleeding scale (minor to mild symptoms in 92.6% of Group 1 patients and 90.7% of Group 2 patients, p = 0.78) (Table 1).
Response to IVIg
The average time to reach a platelet count above 50 × 109/L following treatment was 2.2 ± 1 days in Group 1, as compared to 2.9 ± 1.3 days in Group 2, p = 0.0015 (Table 2). Maximal platelet count was 235.3 ± 169 × 109/L and 214.5 ± 182.3 × 109/L, respectively (p = 0.44). A sustained response was achieved in 74.3% of Group 1 patients and 76.2% of Group 2 (p = 0.72), while 50% of Group 1 patients had a prolonged response (needing no further treatment for at least 3 months) as compared to 60.4% in Group 2 (p = 0.21). The average time for a successive round of treatment, when indicated, was 27.1 ± 6.3 days in Group 1 and 20.3 + 6.6 days in Group 2, p = 0.76 (Table 2).
Table 2.
Response to treatment with IVIg.
| Characteristic | IVIg 1 g/kg regimen, N = 82 | IVIg 2 g/kg regimen, N = 86 | p Value |
|---|---|---|---|
| Initial response | |||
| Time (days) to reach platelets above 50 × 109/L, mean ± SD | 2.2 ± 1 | 2.9 ± 1.3 | 0.0015 |
| Maximal platelet counts following treatment, mean ± SD (×109/L) | 235.3 ± 169.4 | 214.5 ± 182.31 | 0.44 |
| Sustained response (platelet count > 20 × 109/L, >14 days), N (%) | 61 (74.3) | 66 (76.7) | 0.72 |
| Treatment failure (platelet count < 20 × 109/L or response shorter than 14 days), N (%) | 21 (25.6) | 20 (23.2) | 0.72 |
| No repeated treatment needed in 3 months, N (%) | 41 (50) | 52 (60.4) | 0.21 |
| Length (days) of response, mean ± SD a | 27.1 + 6.3 (range 14–60), 20 patients | 20.3 + 6.6 (range 15–35), 14 patients | 0.76 |
| Status at 1 year from diagnosis, N (%) | |||
| Remission (blood count normal per age) | 60 (73.2) | 69 (80.2) | 0.36 |
| Chronic ITP | 20 (24.4) | 15 (17.4) | 0.34 |
| Progression to other disease | 2 (2.4); SLE, CVID | 2 (2.3); SLE | 0.96 |
| Chronic ITP patients who were treated in the preceding month | 11 (13.4) | 6 (7) | 0.2 |
| Chronic ITP in patients being observed, with no need for therapy | 9 (11) | 9 (10.5) | 1 |
| No treatment needed besides observation (remission or low platelet count without need for therapy) | 69 (84.1) | 78 (90.7) | 0.25 |
| Adverse events, N (%) | |||
| Any | 27 (32.9) | 41 (47.7) | 0.06 |
| Headache alone | 5 (6.1) | 6 (7) | 1 |
| Fever alone | 2 (2.4) | 13 (15.1) | 0.005 |
| Aseptic meningitis (at least two of the following—fever, headache, vomiting, neck stiffness) | 20 (24.4) | 22 (25.6) | 1 |
| Adverse events needing cessation of treatment | 2 (2.4) | 3 (3.5) | 0.68 |
In those who responded but required another round of treatment.
CVID, common variable immunodeficiency; ITP, immune thrombocytopenia; IVIg, intravenous immunoglobulin; N, number of patients; SD, standard deviation; SLE, systemic lupus erythematosus.
Adverse events
Almost 40% of patients receiving IVIg suffered from some side effects. There was a trend toward more side effects in Group 2, as compared with Group 1 (47.7% vs 32.9%, respectively, p = 0.06). Fever was more prevalent in Group 2 when compared to Group 1 (15.1% vs 2.4%, respectively, p = 0.005). Three patients from Group 2 and two in Group 1 suffered from adverse events leading to secession of treatment (p = 0.68) (Table 2).
Status at 1 year from diagnosis
At 1-year following diagnosis, 129 (77.8%) patients were in remission. There was no significant difference between remission rates between the two study groups (73.2% in Group 1 as compared to 80.2% in Group 2). While 20.8% of the study’s cohort were diagnosed with chronic ITP (24.4% in Group 1 and 17.4% in Group 2), only 13.4% of Group 1 and 7% of Group 2 received additional ITP treatment 1 year from diagnosis.
During the study’s 1-year follow-up, four patients, two from each group were diagnosed with secondary ITP (three with systemic lupus erythematosus (SLE), and one with common variable immunodeficiency). All data regarding response to treatment is presented in Table 2.
Subdivision of Group 2
We further divided Group 2 into 2 subgroups; 30 patients who received 2 g/kg upfront (the “2 g/kg upfront” subgroup) and 56 patients who received the additional 1 g/kg due to a lack of “satisfactory” response to the first dose according to the treating physician (the “1 + 1” subgroup). No significant difference was found between the groups in regard to their demographic and clinical background (Table 3). There was a trend toward severe bleeding phenotype in the “2 g/kg upfront” subgroup (16.7% had moderate-to-severe bleeding score according to Provan et al. 14 ). As compared with 5.4% in the “1 + 1” subgroup, p = 0.12), though their initial platelet count was significantly higher (8.8 + 7.1 × 109/L as compared with 4 + 2.7 × 109/L in the “1 + 1” subgroup, p < 0.001). We found no significant differences in their initial response and long-term outcome.
Table 3.
Comparison of patients receiving IVIg 2 g/kg regimens, based on intention to treat.
| Characteristic | All patients receiving IVIg 2 g/kg, n = 86 | “1 + 1” g/kg, n = 56 | “2 g/kg upfront,” n = 30 | p Value |
|---|---|---|---|---|
| Demographics | ||||
| Age at presentation, median (range), years | 4.7 (1.2–7.4) | 2.1 (1.1–5.3) | 3.7 (1.5–9) | 0.13 |
| Gender (male), N (%) | 47 (54.6) | 35 (62.5) | 12 (40) | 0.04 |
| Clinical background | ||||
| Preceding viral illness (yes, %) | 52 (60.5) | 35 (62.5) | 17 (56.7) | 0.65 |
| Preceding vaccination (yes, %) | 5 (5.8) | 2 (3.5) | 3 (10) | 0.22 |
| Cause of referral, N (%) a | ||||
| Skin manifestation (petechial rash, easy bruising) | 80 (93) | 54 (96.4) | 26 (86.7) | 0.18 |
| Bleeding tendency from other sites of mucosa (oral, nasal, gastrointestinal, vaginal) | 38 (44.1) | 21(37.5) | 17 (56.7) | 0.08 |
| Thrombocytopenia in blood count | 4 (4.7) | 2 (3.6) | 2 (6.7) | 0.61 |
| Fever at admission, N (%) | 7 (8.1) | 4 (7.14) | 3 (10) | 0.64 |
| Bleeding tendency (according to Provan et al. 14 ), N (%) | ||||
| Minor to mild | 78 (90.7) | 53 (94.6) | 25 (83.3) | 0.12 |
| Moderate | 5 (5.8) | 2 (3.6) | 3 (10) | |
| Severe | 3 (3.5) | 1 (1.8) | 2 (6.7) | |
| Duration of hemorrhagic symptoms (days), median [range] | 3 [2–5] | 3 [2–3.5] | 4.5 [2–10] | 0.12 |
| Platelet count at presentation (×109/L), mean ± SD | 5.7 ± 5.2 | 4 ± 2.7 | 8.8 ± 7.1 | 0.0012 |
| Mean platelet volume (fl) on admission | 9.2 ± 2.4 | 8.9 ± 1.7 | 9.7 ± 3.3 | 0.22 |
| Positive direct antiglobulin test (%) | 6 (7) | 3 (5.4) | 3 (10) | 0.42 |
| Initial response | ||||
| Time (days) to reach platelets above 50,000, mean ± SD | 2.9 ± 1.3 | 3.2 ± 1.3 | 2.3 ± 1.2 | 0.01 |
| Maximal platelet counts following treatment, (×109/L) mean ± SD | 214.5 ± 182.3 | 207 ± 189 | 227 ± 169 | 0.64 |
| Sustained response (platelet count > 20 × 109/L, >14 days), N (%) | 66 (76.7) | 43 (76.7) | 23 (76.6) | 0.99 |
| Treatment failure (platelet count < 20 × 109/L or a response shorter than 14 days), N (%) | 20 (23.2) | 13 (23.3) | 7 (23.3) | 0.99 |
| No repeated treatment needed in 3-month period, N (%) | 52 (60.4) | 36 (64.2) | 16 (53.3) | 0.32 |
| Length of response: N, mean ± SD (range) b | 14, 20.3 + 6.6 (14–35) | 7, 23 + 14.1 (15–35) | 7, 17.58 + 8.1 (14–29) | 0.4 |
| Status at 1 year from diagnosis, N (%) | ||||
| Remission (blood count normal per age) | 69 (80.2) | 49 (87.5) | 20/28 (71.4) | 0.13 |
| Chronic ITP | 15 (17.4) | 7 (12.5) | 8/28 (28.6) | 0.13 |
| Progression to other disease | 2 (2.4); SLE | 0 | 2/30 (6.7) | 0.12 |
| Chronic ITP treated in the preceding month | 6 (7) | 3 (5.4) | 3 (10) | 0.41 |
| Chronic ITP observed, with no need for therapy | 9 (11) | 4 (7.1) | 5 (16.7) | 0.26 |
| No treatment for ITP needed besides observation at 1 year (remission or low platelet count without need of therapy) | 78 (90.7) | 53 (94.6) | 25 (83.3) | 0.12 |
| Adverse events, N (%) | ||||
| Any | 41 (47.7) | 27 (48.2) | 14 (46.7) | 1 |
| Headache alone | 6 (7) | 3 (5.4) | 3 (10) | 0.41 |
| Fever alone | 13 (15.1) | 8 (14.2) | 5 (16.6) | 0.76 |
| Aseptic meningitis (at least two of the following—fever, headache, vomiting, head stiffness) | 22 (25.6) | 11 (28.6) | 3 (10) | 0.36 |
| Adverse events needing secession of treatment | 3 (3.5) | 2 (3.5) | 1 (3.3) | 0.95 |
More than one cause may be mentioned.
In those who responded but needed another round of treatment.
fl, Femtoliters; ITP, immune thrombocytopenia; IVIg, intravenous immunoglobulin; N, number of patients; SD, standard deviation; SLE, systemic lupus erythematosus.
The two subgroups varied in the time to attain an increase in platelets above 50 × 109/L (2.3 + 1.2 days in the “2 g/kg upfront” as compared to 3.2 ± 1.3 days in the “1 + 1” subgroup, p = 0.01). In other parameters comparing the initial response to therapy or side effects, there was no significant difference between the subgroups (Table 3).
After a 1-year follow-up, 71.5% of the “2 g/kg upfront” regimen patients remained in remission as compared with 87.5% of the “1 + 1” subgroup (p = 0.13). Comparing patients only observed (either in remission or with a low platelet count without the need for therapy) found no difference between both subgroups (83.3% in the “2 g/kg upfront” vs 94.6% in the “1 + 1” gr/kg, p = 0.12). Two patients from the “2 g/kg upfront” group were diagnosed with SLE during this time and were not included in the remission/chronic ITP calculations.
Logistic regression analysis
There was no significant difference in the adjusted odds for a 2-week sustained response and treatment response at 1-year follow-up between Group 1 and Group 2 (adjusted odds ratio (aOR), 1.35; 95% confidence interval (CI) 0.62–2.93; p = 0.45 and aOR, 1.37; 95% CI 0.61–3.1; respectively, p = 0.45) (Tables 4 and 5). To note, a positive direct antiglobulin test was associated with a significantly lower risk of a 2 weeks response (aOR 0.09, 95% CI 0.02–0.52, p > 0.01). At a 2 weeks follow-up, there was a 10% decrease in the risk of treatment response for each additional year added to the patient’s age (aOR 0.9, 95% CI 0.82–0.98, p = 0.01). Similar results were found in the 1-year follow-up, where every added year to the patient’s age increased the risk for chronic ITP by 14% (aOR 0.86, 95% CI 0.79–0.94, p < 0.01).
Table 4.
The crude and adjusted OR for the association between IVIg treatment dosage and sustained response to treatment.
| Characteristics | Crude OR | 95% CI | p Value | Adjusted OR | 95% CI | p Value |
|---|---|---|---|---|---|---|
| IVIg dosage (2 g/kg vs 1 g/kg) | 1.01 | 0.52–1.96 | 0.98 | 1.35 | 0.62–2.93 | 0.45 |
| Age (years) | 0.9 | 0.84–0.97 | 0.01 | 0.9 | 0.82–0.98 | 0.01 |
| Sex (females vs males) | 0.63 | 0.32–1.24 | 0.18 | 0.56 | 0.26–1.23 | 0.15 |
| Platelet count | 1.07 | 1–1.15 | 0.06 | 1.11 | 1.03–1.21 | 0.01 |
| Fever on admission | 3.65 | 0.81–16.52 | 0.09 | 3.07 | 0.6–15.59 | 0.18 |
| Preceding viral illness | 1.21 | 0.62–2.36 | 0.59 | 0.78 | 0.35–1.76 | 0.55 |
| Preceding vaccination | 0.47 | 0.05–4.17 | 0.50 | 0.57 | 0.05–6.83 | 0.66 |
| Bleeding scale (according to Provan et al. 14 ), respectively to mild | ||||||
| Moderate | 0.51 | 0.16–1.63 | 0.26 | 0.3 | 0.08–1.1 | 0.07 |
| Severe | 0.97 | 0.25–3.73 | 0.96 | 2.12 | 0.41–10.98 | 0.37 |
| Positive direct antiglobulin test | 0.16 | 0.04–0.63 | 0.01 | 0.09 | 0.02–0.52 | >0.01 |
| Duration of hemorrhagic symptoms | 1 | 0.96–1.04 | 0.93 | 1.04 | 0.98–1.1 | 0.21 |
CI, confidence interval; IVIg, intravenous immunoglobulin; OR, odds ratio.
Table 5.
The crude and adjusted OR for the association between IVIg treatment dosage and treatment response at 1-year follow-up.
| Characteristics | Crude OR | 95% CI | p-Value | Adjusted OR | 95% CI | p-Value |
|---|---|---|---|---|---|---|
| IVIg dosage (2 g/kg vs 1 g/kg) | 1.55 | 0.77–3.09 | 0.21 | 1.37 | 0.61–3.1 | 0.45 |
| Age (years) | 0.84 | 0.78–0.91 | <0.01 | 0.86 | 0.79–0.94 | <0.01 |
| Sex (females vs males) | 0.57 | 0.28–1.15 | 0.12 | 0.85 | 0.38–1.9 | 0.69 |
| Platelet count | 0.94 | 0.9–0.99 | 0.02 | 0.96 | 0.9–1.01 | 0.12 |
| Fever on admission | 1.27 | 0.4–4.1 | 0.69 | 1.05 | 0.26–4.19 | 0.94 |
| Preceding viral illness | 1.09 | 0.54–2.18 | 0.81 | 1.07 | 0.46–2.45 | 0.88 |
| Preceding vaccination | 0 | 0.99 | 0 | 0.99 | ||
| Bleeding scale (according to Provan et al. 14 ), respectively to mild | ||||||
| Moderate | 1.49 | 0.32–6.94 | 0.61 | 1.27 | 0.22–7.35 | 0.79 |
| Severe | 1.95 | 0.45–8.46 | 0.37 | 0.9 | 0.14–5.71 | 0.91 |
| Positive direct antiglobulin test | 0.51 | 0.14–1.89 | 0.31 | 1.19 | 0.23–6.23 | 0.84 |
| Duration of hemorrhagic symptoms | 0.95 | 0.91–0.99 | 0.02 | 0.97 | 0.92–1.02 | 0.21 |
CI, confidence interval; IVIg, intravenous immunoglobulin; OR, odds ratio.
Discussion
In children requiring treatment for new-onset ITP, data regarding therapeutic protocols for children with ITP is scarce. IVIg is an accepted proven, safe, and effective first-line therapy for newly onset pediatric ITP14,16,17 and is generally well tolerated with transient and mostly mild adverse events.6,31 Several IVIg dosing regimens are used in treating ITP, varying between 0.8 and 2 g/kg. However, there have been no head-to-head comparisons of these different dosing regimens, specifically within the pediatric population suffering from primary ITP.14–16,19,20,23,27 Therefore, the optimal dose for pediatric ITP has not been determined.
In this study, we demonstrated that doubling the dose of IVIg did not result in a significant difference in the sustained therapeutic response rate after 2 weeks of follow-up and after 1 year.
The HaemSTAR Collaborators study showed similar results in a 961 cohort of adult patients with ITP, with no difference between a 1 g/kg infusion of IVIg and two consecutive 1 g/kg doses in any of the parameters tested (speed of response, duration of response, and side-effect risk). 28 A recent meta-analysis by Ren et al. yielded results consistent with our findings regarding the effectiveness and safety of the 1 g/kg IVIg regimen in comparison to the 2 g/kg regimen in the treatment of children with newly diagnosed ITP. 32
Our study’s initial response rate is slightly lower than other studies reporting an 80% early response rate to IVIg treatment.6,14,33 This may be explained by the different definitions of the response to treatment. In our study, the response to treatment was defined as the maintenance of platelet counts above 20 × 109/L for at least 14 days. This definition is slightly different from the ASH definition, which considers a platelet count above 30 × 109/L and doubling the nadir count at 1 week as an early response. 16
After 1 year of follow-up, approximately 80% of patients in the study’s cohort remained in remission,16,18 while 21% were diagnosed with chronic ITP. This is in accordance with data published in other studies that reported chronic ITP in 11%–28% of the pediatric population.3,4,6,25
In our cohort, patients’ age had a significant influence on treatment response. This observation is in accordance with previous studies describing the nondependent association between age and chronic ITP, regardless of which treatment they received.3,6,20,34
Almost 40% of the study cohort receiving IVIg suffered from side effects. Adverse reactions to IVIg in children, according to previous studies, are mostly mild (e.g. nausea, vomiting, and fever), and their prevalence varies from 5% to 75%,6,10,11 with higher rates in increased doses of 2 g/kg. 10 While there was no significant difference in our study between the two dose groups in overall side-effect rates and need for withdrawal of treatment, fever was significantly more common in the 2 g/kg regimen. A possible explanation for the similarity between the groups is the routine use of maximal preventive measures in our institution (pretreatment with paracetamol and diphenhydramine). One may also assume that some patients were not treated with a subsequent IVIg dose due to poor tolerance to the first dose.
Our study has some limitations. First, while 2 g/kg appeared to have similar outcomes to the 1 g/kg, these results should be interpreted with caution due to a possible selection bias of the groups. Although the groups appeared to have similar bleeding tendencies according to their bleeding scale proportions, the decision for a dose reduction may have followed the patient’s less severe manifestation in the 1 g/kg group (group 1). The choice of the treatment regimen was dependent on various uncontrolled factors, including physician preference, financial considerations, and patient’s tolerance. Second, the retrospective nature and the small sample size of our study limit our study’s generalization potential. Additionally, the data collected is subject to reporting bias. The almost identical sample size and similar demographic and clinical characteristics of the study groups and the unity of the treatment approach and protocols may minimize this effect.
Conclusion
Our findings suggest that the initial treatment of newly diagnosed pediatric ITP using a 1 g/kg IVIg regimen may give comparable outcomes to the higher 2 g/kg dose in attaining a prolonged safe hemostatic threshold, without increasing the risk for a chronic disease course. Future prospective studies are warranted to confirm these conclusions.
Acknowledgments
None.
Appendix
Abbreviations
aOR adjusted odds ratio
CVID common variable immunodeficiency
ICH intracranial hemorrhage
ITP immune thrombocytopenia
IVIg intravenous immune globulin
NHS National Health Service
SLE systemic lupus erythematosus
Footnotes
ORCID iD: Eyal Elron 
https://orcid.org/0000-0002-5144-4993
Contributor Information
Eyal Elron, Department of Neonatology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel; School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Joanne Yacobovich, School of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Hematology-Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel.
Orly Efros, School of Medicine, Tel Aviv University, Tel Aviv, Israel; Thrombosis & Hemostasis Unit, Sheba Medical Center, Tel Hashomer, Israel; Clalit Health Services, Israel, Tel Aviv, Israel; National Hemophilia and Thrombosis Center, Sheba Medical Center, Tel Hashomer, Israel.
Osama Tanous, Clalit Health Services, Israel, Tel Aviv, Israel.
Sarina Levy-Mendelovich, National Hemophilia and Thrombosis Center, Sheba Medical Center, Tel Hashomer, Israel; Amalia Biron Research Institute of Thrombosis and Hemostasis, School of Medicine, Tel Aviv University, Tel Aviv, Israel; The Sheba Talpiot Medical Leadership Program, Tel Hashomer, Israel; School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Esti Shamba, Department of Hematology-Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel.
Orna Steinberg-Shemer, School of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Hematology-Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel.
Tracie Goldberg, Department of Hematology-Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel.
Shai Izraeli, School of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Hematology-Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel.
Oded Gilad, Department of Hematology-Oncology, Schneider Children’s Medical Center of Israel, 14 Kaplan street, Petah Tikva 4920235, Israel; School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Declarations
Ethics approval and consent to participate: The study received approval from the Ethics Committee at Rabin Medical Center, under study number 0636-20. Notably, no participant consent was required for this study.
Consent for publication: Not applicable.
Author contributions: Eyal Elron: Data curation; Formal analysis; Investigation; Methodology; Project administration; Visualization; Writing – original draft; Writing – review & editing.
Joanne Yacobovich: Investigation; Supervision; Writing – review & editing.
Orly Efros: Formal analysis; Writing – review & editing.
Osama Tanous: Data curation; Formal analysis; Writing – review & editing.
Sarina Levy-Mendelovich: Data curation; Formal analysis; Writing – review & editing.
Esti Shamba: Investigation; Writing – review & editing.
Orna Steinberg-Shemer: Investigation; Writing – review & editing.
Tracie Goldberg: Formal analysis; Writing – review & editing.
Shai Izraeli: Investigation; Methodology; Supervision; Writing – review & editing.
Oded Gilad: Conceptualization; Formal analysis; Investigation; Methodology; Supervision; Validation; Visualization; Writing – original draft; Writing – review & editing.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
Sarina Levy-Mendelovich is a recipient of research grants from Novo Nordisk and Pfizer and has an Honorium from Roche and Pfizer. The other authors have no conflicts of interest relevant to this article to disclose.
Availability of data and materials: Not applicable.
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