Abstract
Objective
To explore the clinical features and prognostic factors for initial response and long-term prognosis of pediatric immune thrombocytopenia (ITP).
Method
A retrospective cohort study of 910 cases of pediatric patients with ITP was conducted. Demographic data, platelet counts, triggers, bleeding grades, glucocorticoid (GC) tapering time, IVIG status and treatment outcomes were collected. Initial response was defined as a platelet counts ≥ 30 × 109/L and at least doubling baseline at 1 month after first-line therapy. Logistic regression analysis and restricted cubic spline (RCS) analyses were performed to identify the risk factors for initial response and long-term prognosis.
Results
GC tapering time (OR = 0.39, 95% CI:0.16–0.91, p = 0.03) and bleeding grade 5 (OR = 0.26, 95% CI:0.11–0.52, p < 0.001) were significantly associated with initial response. Age ≥ 3 years (OR = 1.83, 95% CI: 1.18–2.84, p = 0.007) was identified as an independent risk factor for long-term prognosis of pediatric ITP. RCS analysis revealed a nonlinear association between age and the progression of persistent and chronic ITP (p = 0.0012), with two inflection points at approximately 3.75 and 8 years. The risk of progression increased rapidly before 3.75 years, stabilized between 3.75 and 8 years, and rose sharply thereafter, indicating that age ≥ 8 years was at particularly high risk. Neither IVIG administration (OR = 0.99, 95% CI: 0.65–1.53, p = 0.98) nor GC tapering time ≥ 7 days (OR = 1.62, 95% CI: 0.76–3.43, p = 0.21) was significantly associated with long-term prognosis.
Conclusion
Age was an independent risk factor for progression to persistent and chronic ITP. Short-course GC regimens could be a rational therapeutic alternative for pediatric ITP patients without severe manifestations or life-threatening bleeding, and age-stratified risk management merits clinical consideration.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s12887-026-07572-1.
Keywords: Pediatric ITP, Initial response, Long-term prognosis, Risk factors
Introduction
Immune thrombocytopenia (ITP) is a common bleeding disorder characterized by platelet (PLT) counts below normal range (< 100 × 109/L) [1]. According to statistics, the incidence in children is approximately 1.9–6.4 per 100,000 person-years [2]. The pathogenesis is closely associated with PLT destruction mediated by autoantibodies against platelets and impaired PLT production by megakaryocytes induced by immune dysregulation [3]. Most children with ITP often have a history of viral infection or vaccination 2 to 4 weeks prior to disease onset [4]. Pediatric ITP typically presents as an acute disorder. The clinical manifestation is mainly dominated by mucocutaneous bleeding, while a small number of severely ITP children present at fatal risk of serious visceral hemorrhage and intracranial hemorrhage [5].
Pediatric ITP is typically a self-limiting disorder. The treatment goal also included prevention if a bleed has occurred in the past at low PLT counts levels [6]. Glucocorticoid (GC) and intravenous immunoglobulin (IVIG) are standard first-line treatments options for patients with ITP [7].Although ITP is often self-limiting, approximately 10%-20% of those present show a poor treatment response and progress to chronic ITP, and a subset of these patients further develop refractory ITP [8].
The chronic and refractory ITP severely affects the quality of life of patients and their caregivers and imposes a substantial economic burden on their families [9]. The side effects of long-term GC therapy across age groups. Infants and young children are prone to develop growth retardation and osteoporosis [10–12], preschool children may develop metabolic disorders (such as obesity and glucose abnormalities) and decreased immunity [13]; and adolescents may experience induced psychotic disorders [14]. Therefore, early identification of risk factors influencing the prognosis of pediatric ITP is important for improving long-term outcomes.
Currently, most clinical studies on pediatric ITP are small sample and single center investigations, lacking large sample studies with systematic and long-term follow-up. Therefore, we enrolled 910 children with ITP and performed more than 1 year follow-up to clarify clinical characteristics and prognostic factors in pediatric ITP patients, with the aim to further optimize treatment regimens, reduce adverse drug reactions, and alleviate the long-term burden on patients and their families.
Methods
Study design and participants
This retrospective cohort study included ITP patients hospitalized (2010–2020) at hematological oncology department in Children’s hospital of Chongqing medical university. Informed consent was obtained from legal guardians of all participants prior to study enrollment. This study was approved by Clinical Ethics Committee of the Children’s hospital of Chongqing Medical University (Approval Number: 2021 Ethical Review (Research) No. 455) and conducted in accordance with the Declaration of Helsinki. This study was registered in the Chinese Clinical Trial Registry with the trial number ChiCTR2200055472 on 10 January 2022.
Inclusion and exclusion criteria
The inclusion criteria were: (1) Primary ITP patients diagnosed from 2010 to 2020; (2) those aged < 18 years; (3) those with a follow-up duration of more than 1 year after diagnosis who were hospitalized at our center. A total of 1258 patients were screened, and 910 were finally included after excluding: (1) those with receiving GC therapy at other hospital (n = 131); (2) those with concurrent comorbidities (n = 105): leukaemia and other oncological diseases, history of bone marrow transplantation or immunosuppressive therapy, aplastic anaemia, myelodysplastic syndromes (3) those with missing data on treatment response (n = 112). A patient selection flow chart was shown in Fig. 1. Baseline information and treatment effectiveness were collected, including age, gender, initial PLT counts, IVIG status (only GC or IVIG + GC), GC tapering time, bleeding grades, triggering factors, initial response status, and diagnosis type [11].
Fig. 1.
Study flowchart of participant recruitment
Definition and outcomes
Initial response: PLT counts ≥ 30 × 109/L and at least doubling baseline at 1 month [15]. No response: PLT counts < 30 × 109/L post-treatment or increase < twice the baseline or presence of bleeding [16]. ITP types were classified by illness duration from diagnosis: newly diagnosed ITP (< 3 months), persistent ITP (3–12 months) and chronic ITP (> 12 months) [16]. Long-term prognosis is classified into three categories based on the duration of low PLT counts: newly diagnosed ITP, persistent ITP and chronic ITP. Initial PLT counts were defined as the PLT counts measured prior to first-line therapy administration. Bleeding symptoms of pediatric ITP at the initial diagnosis were classified into six grades (0 to 5), corresponding to no bleeding, minor bleeding, mild bleeding, moderate bleeding, severe and life-threatening or fatal bleeding respectively [17].
The first-line treatment in the early stage referred to the therapeutic drugs used from the first administration of GC or IVIG until achieving early initial response. GC included methylprednisolone and prednisone. Treatment regimens for pediatric ITP were stratified based on bleeding severity and PLT counts. For children with PLT counts < 10 × 109/L or presenting with severe active bleeding, high dose intravenous methylprednisolone (10 mg/kg/day) was administered for three consecutive days, followed by a transition to oral prednisone (2 mg/kg/day) according to clinical response, with gradual tapering and discontinuation once PLT counts stabilized. For patients not meeting these above high-risk criteria, a low- dose intravenous methylprednisolone regimen (4 mg/kg/day) was given for three days, subsequently followed by oral prednisone (2 mg/kg/day) as maintenance therapy, which was progressively tapered and withdrawn after PLT counts recovery. IVIG was administered at 1.0 g/kg once daily for 1 to 2 days; a second infusion was administered when severe bleeding persisted or PLT counts failed to increase sufficiently after the first dose.The response duration was calculated starting from the first day of initiating first-line medication.
Study design
The primary outcome concentrated on analysis factors influencing initial response and long-term prognosis. Pediatric ITP patients were stratified according to clinical characteristics, such as gender, age, PLT counts, the presence of triggers and choice of the first-line therapy (IVIG status: only GC or IVIG + GC), GC tapering time and bleeding grade to evaluate the impact of these variables.
Statistical analysis
SPSS 29.0 and R.4.41 were used for statistical analysis. For descriptive statistics, categorical data were presented as frequencies and percentages (%). For regression analyses, ordinal logistic, and binary logistic regression models were performed to assess factors influencing initial response and long-term prognosis. The proportional odds assumption for the ordinal logistic regression model was tested using the Brant test, and no violation was detected (p > 0.05). To adjust for potential confounding factors, demographic characteristics including gender and age, together with variables with p < 0.1 in univariate analysis, were entered into the multivariate logistic regression model using the enter method to identify independent prognostic factors. Restricted cubic spline (RCS) was performed to explore the nonlinear relationship. Spearman correlation analysis was performed to explore the relationship between bleeding grade and initial PLT counts. A two-tailed p < 0.05 was considered statistically significant.
Results
Clinical characteristics of ITP patients
A total of 910 patients with ITP were enrolled, comprising 535 males (58.8%) and 375 females (41.2%). The age distribution was as follows: age < 3 years (520, 57.1%) and age ≥ 3 years (390, 42.9%). 604 (66.4%) cases had a PLT counts < 10 × 10⁹/L at diagnosis. 603 (66.3%) cases received only GC and 307 (33.7%) cases received IVIG + GC. 104 (11.4%) cases had GC tapered within 7 days. Regarding trigger factors, 658 cases (72.3%) had no obvious triggering factors, and 130 (14.3%) cases had a history of vaccination, and 111 (12.2%) cases had a history of viral infection, and 11 (1.2%) cases had a history of vaccination combined with viral infection. Bleeding score distribution: grade 1 (358, 39.3%), 2 (442, 48.6%), 3(39, 4.3%), 4 (37, 4.1%) and 5 (34, 3.7%); no response: grade 1 (42, 11.7%), grade 2 (49, 11.1%), grade 3 (4, 10.3%), grade 4 (9, 24.3%) and grade 5(13, 38.2%). ITP type distribution was as follows: newly diagnosed ITP (806, 88.6%), persistent ITP (67, 7.4%) and chronic ITP (37,4.1%). Regarding treatment response: 793 (87.1%) cases achieved initial response, while 117 (12.9%) cases presented no response. The age-stratified distribution of initial response at point time of 1 months after first-line therapy and ITP disease course subtypes were shown in Figure S1 and S2. Baseline clinical characteristics of the retrospective cohort were summarized in Table 1.
Table 1.
Demographics and clinical characteristics of patients with ITP
| Category | Total | No response | Initial response | |
|---|---|---|---|---|
| 910 | 117 (12.9%) | 793 (87.1%) | ||
| Sex | male | 535 (58.8%) | 68 (12.7%) | 467 (87.2%) |
| female | 375 (41.2%) | 49 (13.1%) | 326 (86.9%) | |
| Age group | < 3 years | 520 (57.1%) | 59 (11.3%) | 461 (88.7%) |
| ≥ 3 years | 390 (42.9%) | 58 (14.9%) | 332 (85.1%) | |
| Initial platelet count | PLT counts < 10 × 10⁹/L | 604 (66.4%) | 77 (12.7%) | 527 (87.3%) |
| PLT counts ≥ 10 × 10⁹/L | 306 (33.6%) | 40 (13.1%) | 266 (86.9%) | |
| IVIG status | Only GC | 603 (66.3%) | 68 (11.3%) | 535 (88.7%) |
| IVIG + GC | 307 (33.7%) | 49 (16.0%) | 258 (84.0%) | |
| GC tapering time | ≤ 7 days | 104 (11.4%) | 6(6.0%) | 98 (94.0%) |
| > 7days | 806(88.6%) | 111(13.8%) | 695(86.2%) | |
| Trigger factors | no obvious factor | 658 (72.3%) | 93 (14.1%) | 565 (85.9%) |
| vaccination | 130 (14.3%) | 10 (7.6%) | 120 (92.3%) | |
| viral infection | 111 (12.2%) | 13 (11.7%) | 98(88.2%) | |
| vaccination+viral infection | 11 (1.2%) | 1 (10.0%) | 10 (90.0%) | |
| Bleeding score | 1 | 358(39.3%) | 42 (11.7%) | 316 (88.3%) |
| 2 | 442 (48.6%) | 49 (11.1%) | 393 (88.9%) | |
| 3 | 39 (4.3%) | 4 (10.3%) | 35 (89.7%) | |
| 4 | 37 (4.1%) | 9 (24.3%) | 28 (75.7%) | |
| 5 | 34 (3.7%) | 13 (38.2%) | 21 (61.7%) | |
| Diagnostic type | newly diagnosed ITP | 806 (88.6%) | 73 (9.1%) | 733 (90.9%) |
| persistent ITP | 67 (7.4%) | 32 (47.8%) | 35 (52.2%) | |
| chronic ITP | 37 (4.1%) | 12 (32.4%) | 25 (67.6%) | |
Logistic regression analysis of initial response
Binary logistic regression analysis was performed to identify potential risk factors influencing the early initial response at the time point of 1 month after first-line treatment. Univariate analysis results revealed that gender, initial PLT counts and age showed no significant association with the initial response. GC tapering time and bleeding grade 5 were significantly associated with the initial response, as shown in Fig. 2. Subsequently, multivariate logistic regression analysis further showed that children with GC tapering time > 7 days (OR = 0.39, 95% CI:0.16–0.91, p = 0.03) and bleeding grade 5 (OR = 0.26, 95% CI:0.11–0.52, p < 0.001) were significantly with poor initial response. Notably, In univariate analysis, children receiving IVIG combined with GC were less likely to achieve an initial response compared with those receiving GC alone (OR = 0.67, 95% CI: 0.45–0.99, p = 0.05). However, this association was not significant after adjustment for potential confounders in multivariate analysis (OR = 0.76, 95% CI: 0.50–1.16, p = 0.20). These results indicated that adding IVIG to GC as first-line therapy does not independently affect the initial response in children with ITP. The detailed results were summarized in Fig. 3.
Fig. 2.
Univariate analysis of factors associated with initial response in ITP patients
Fig. 3.
Multivariate analysis of factors associated with initial response in patients with ITP
Logistic regression analysis of long-term prognosis
Subsequently, ordinal logistic regression analysis was performed to identify the potential factors influencing long-term prognosis of pediatric ITP. Univariate analysis results showed that gender, initial PLT counts, IVIG status and GC tapering time showed no significant association with the long-term prognosis. While age, trigger factors and bleeding grade were significantly associated with ITP progression, as shown in Fig. 4. Multivariate logistic regression analysis further showed that patients with age ≥ 3 years (OR = 1.83, 95% CI: 1.18–2.84, p = 0.007) had 1.83 times the risk of progression to persistent or chronic ITP compared with those with age < 3 year, as shown in Fig. 5. RCS analysis was conducted to explore the non-linear relationship between age and long-term prognosis. The RCS curve revealed a nonlinear association between age and the probability of progression to persistent and chronic ITP. The probability of progression increased rapidly from 0 to approximately 45 months (3.75 years), followed by a period of relative stability between 45 and 96 months (8 years), after which it increased sharply again. This pattern suggested that older age (≥ 8 years ) confers a particularly elevated risk of persistent and chronic ITP, as shown in Fig. 6. Bleeding grade 4 (OR = 3.38, 95% CI: 1.55–7.38, p = 0.002) and 5 (OR = 3.59, 95% CI: 1.57–8.23, p = 0.003) remained independently associated with ITP progression, whereas grade 2 and 3 continued to show no significant association. Additionally, we found the bleeding grade is not significantly negatively associated with the initial PLT counts by spearman correlation analysis (r=-0.05, p = 0.16), as shown in Figure S3.
Fig. 4.
Univariate analysis of factors associated with long-term prognosis in ITP patients
Fig. 5.
Multivariate analysis of factors associated with long-term prognosis in ITP patients
Fig. 6.
A nonlinear association between age and the probability of progression to persistent and chronic ITP
Discussion
In this study, we found that pediatric ITP has a higher prevalence in age < 3 years, with male predominance. age ≥ 3 years was identified as an independent risk factor for long-term prognosis. Particularly, age ≥ 8 years conferred a high risk of progression to persistent or chronic ITP. The development of pediatric immune system is age-dependent, with distinct maturational stages from infancy through adolescence [18]. The immune system is immature in those < 3 years, and immune tolerance possesses strong plasticity [19–22]. Consequently, it is plausible that children < 3 years with ITP are more likely to achieve favorable outcomes and a lower risk progression to persistent and chronic ITP due to greater immune plasticity, although the underlying mechanisms warrant further investigation.
In this study, GC tapering time > 7 days was significantly associated with poor initial response at the 1-month time point after first-line therapy, but did not affect progression to persistent and chronic ITP, indicating that short-duration high pulse GC strategy may be a reasonable approach in eligible patients, as prolonged tapering does not confer additional long-term benefit. In early-stage pediatric ITP, platelet dynamics are primarily governed by the non-specific immunosuppressive and anti-inflammatory effects of GC [23, 24]. In contrast, progression to chronic ITP reflects failure to re-establish self-immune tolerance, characterized by T cell-mediated dysregulation, persistent anti-platelet antibodies, and ongoing splenic or hepatic macrophage clearance [25–27]. The observed association between GC tapering time > 7 days and poor initial response may be explained by several factors: first, patients with prolonged tapering may exhibit greater GC dependence, delayed responsiveness, or more severe disease. Second, our retrospective cohort study has an inherent limitation: although patients with definite secondary and hereditary ITP were excluded at enrollment, genetic and secondary etiology screening was not conducted for all hospitalized patients. Therefore, occult hereditary or secondary factors may exist in some participants with GC tapering time > 7 days, which may partially account for their poor initial response. Importantly, this factor was not associated with progression to chronic ITP, consistent with the distinct immunological mechanisms underlying early response versus long-term outcomes. Given this association, clinicians should consider early evaluation and timely transition to second-line therapies in patients with GC tapering time > 7 days to avoid prolonged ineffective GC exposure and related adverse effects, though the effectiveness of this strategy requires prospective validation. Notably, IVIG use showed no significant impact on either initial response or long-term prognosis.
In this study, we found that no significant correlation was observed between bleeding grade and initial PLT counts, consistent with previous study [28], suggesting that PLT counts alone is not the sole determinant of bleeding severity in pediatric ITP. Bleeding grade 5 was significantly associated with no response at the 1-month time point after first-line therapy. Bleeding grade 4 and 5 were significantly associated with progression to chronic ITP. However, one previous study has reported no significant association between bleeding score and disease course of pediatric ITP [28], one adult prospective study found no significant correlation between baseline bleeding symptoms and chronic ITP [29]. In the pediatric population, Schmidt et al. included mucosal bleeding in a predictive model for persistent ITP, but concluded that it had a negligible impact on the outcome [8]. Thus, there remains some controversy regarding the relationship between bleeding grades and the prognosis of pediatric ITP. These discrepancies may stem from varied study populations, bleeding grade systems, ethnic differences and follow-up duration. Notably, despite our study revealing a significant association between bleeding grades and the progression to persistent and chronic ITP, the limited number of cases in the bleeding grade 4 and 5 subgroups resulted in relatively wide 95% CIs for OR in the multivariate analysis. Therefore, future research should conduct larger and multi-center studies to further validate whether bleeding grades serve as independent predictors of pediatric chronic ITP.
Limitation
This retrospective single-center study has several limitations. First, the design carries inherent selection and referral biases. We excluded 131 transferred patients who received treatment at external hospitals, whose detailed records were unavailable; these may represent more severe refractory cases, potentially biasing initial response. Second, 112 patients were excluded due to missing treatment response data, potentially causing missing data bias, as randomness could not be confirmed. Therefore, multi-center prospective trials with complete standardized data collection are needed to validate our findings in the future.
Conclusions
Age was significantly associated with long-term prognosis in pediatric ITP, exhibiting a nonlinear relationship with progression to persistent and chronic ITP. Progression risk increased rapidly before 3.75 years, stabilized between 3.75 and 8 years, and rose sharply thereafter, with age ≥ 8 years conferring the highest risk. Short-course GC regimens could be a rational therapeutic alternative for pediatric ITP patients without severe manifestations or life-threatening bleeding, as prolonged GC tapering did not confer long-term prognostic benefit, and age-stratified risk management merits clinical consideration.
Supplementary Information
Supplementary Material 1: Figure S1. Age of ITP patients with different treatment response at point time of 1 month after first-line therapy.
Supplementary Material 2: Figure S2. Age of ITP patients with different course.
Supplementary Material 3: Figure S3. The association between bleeding grade and PLT counts.
Supplementary Material 4: Graphical abstract.
Acknowledgements
The authors sincerely thank the patients, their guardians and all investigators involved in this study. Additionally, the authors sincerely thank the Qiankun Yang’s guidance for this design and writing of manuscript.
Clinical trial number
ChiCTR2200055472.
Authors' contributions
Jie Yu and Li Xiao supervised the entire research process, from formulating the research design to performing data analysis and guiding the writing of the article. Li Zhang undertook the statistical analysis, interpretation of results, and wrote the initial manuscript, and completion of the revised manuscript. Jiebin Qin, Lan Huang, Xianhao Wen, Haiyan Liu, Yuxia Guo, Xingtian Xuan and Chunmei Xu assisted in collecting data extraction, cleaning and analysis.
Funding
No funding supported this study.
Data availability
Data and materials are available on a reasonable request from the corresponding authors.
Declarations
Ethics approval and consent to participate
This study was approved by clinical Ethics Committee of the Children Affiliated hospital of Chongqing Medical University (Approval Number: 2021 Ethical Review (Research) No. 455)) and conducted in accordance with the Declaration of Helsinki.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Li Zhang and Jiebin Qin contributed equally to this work.
Contributor Information
Li Xiao, Email: feeceebee@hospital.cqmu.edu.cn.
Jie Yu, Email: yujie@hospital.cqmu.edu.cn.
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Supplementary Materials
Supplementary Material 1: Figure S1. Age of ITP patients with different treatment response at point time of 1 month after first-line therapy.
Supplementary Material 2: Figure S2. Age of ITP patients with different course.
Supplementary Material 3: Figure S3. The association between bleeding grade and PLT counts.
Supplementary Material 4: Graphical abstract.
Data Availability Statement
Data and materials are available on a reasonable request from the corresponding authors.