Immune thrombocytopenia (ITP) is one of the most common immune-mediated diseases in children and adults. ITP was previously called idiopathic thrombocytopenic purpura, as platelet destruction is caused by an immune response. ITP is defined as isolated thrombocytopenia without other thrombocytopenia-associated causes [1]. The symptoms of ITP include petechiae, ecchymosis, internal cranial hemorrhage, and hematochezia. In general, ITP is a pathogenesis in which platelets bound to autoantibodies are phagocytosed by macrophages in the spleen. Autoantibodies are then mass-produced by b cells, thereby accelerating platelet destruction [2]. Impairment of regulatory T cells and decreased platelet production due to inhibition of megakaryocyte differentiation and maturation are important causes [3-5].
Treatment may include corticosteroids, intravenous immunoglobulin (IVIG), or anti-Rhesus-D immunoglobulin, either alone or in combination. IVIG is the most common treatment [6]. Most children experience an acute clinical course of the disease. Approximately 70% of cases resolve within 6 months [7]. However, approximately 20% of pediatric patients progress to chronic ITP [1]. There are no sex differences in children with an abrupt onset [8]. ITP is often preceded by an infection in children. By contrast, adults have an insidious onset, and it is twice as common in women as it is in men. Antecedent infections are also common. Approximately 50% of cases progress to chronic disease [9]. This study aimed to identify chronicity predictors of pediatric primary ITP.
This study was approved by the Institutional Review Board (IRB) of Yeungnam University Medical Center (IRB No: YUMC 2022-01-048) on February 4, 2022. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Formal consent was not required for this type of study.
This study was conducted retrospectively with patients diagnosed with between January 1, 2010, and September 30, 2021. The patient population was defined as those aged <18 years, with a platelet count of <20,000/mL at the time of diagnosis, and who were treated with IVIG ±steroids (methylprednisolone, prednisolone, and dexamethasone). The IVIG dose administered was 2 g/kg over 2 days; however, the dose was reduced in some patients who experienced infusion-related adverse reactions, such as fever, headache, and allergic reactions. Patients with insufficient medical records and those diagnosed with hematologic diseases other than ITP were excluded from this study.
As for the policy of ITP treatment in our institution, IVIG was used when there was clinical bleeding with platelets less than 30,000/mL or platelets less than 20,000/mL. Steroid was used according to the decision of the phy-sician.
The phase and response criteria for ITP used in this study were previously defined by an international working group [1]. ITP patients diagnosed within 3 months were defined as in the newly diagnosed (ND) phase. Patients who had been diagnosed for more than 3 months and less than 12 months, and did not reach spontaneous remission or did not maintain a complete response off therapy were defined as in the persistent (P) phase. Patients with ITP lasting >12 months after diagnosis were defined as in the chronic (C) phase.
Treatment response was classified into three categories: complete response (CR), response (R), and no response (NR), considering both platelet counts and bleeding episodes. If the platelet count was >100,000/mL and there were no bleeding episodes, the treatment response was defined as CR. If the platelet count was ≥30,000/mL and bleeding was absent, but the baseline count increased by at least two-fold, the treatment response was defined as R. If the platelet count was less than 30,000/mL or increased by less than twice the baseline count, the treatment response was defined as NR.
Respiratory and gastroenteritis that occurred within 8 weeks of ITP diagnosis was defined as recent infection. Bleeding episodes include any bleeding that appears to be associated with thrombocytopenia, intracranial hemorrhage, epistaxis, melena and petechiae, bruise, and ecchymosis.
IBM SPSS version 25.0 (IBM Corp., Armonk, NY, USA) was used for all data analysis. All values are expressed as means and standard deviation. Patients were divided into three groups according to ITP phase, and the Kruskal-Wallis test was performed to compare continuous variables between the three groups. A linear-by-linear association was used to compare the distribution of proportional data among the three groups. The Mann-Whitney test was used to compare continuous variables between the 3-month and 12-month groups. The chi-square test was used to compare the distribution of proportional data between the two groups. Logistic regression analysis was used to analyze the risk factor for chronic ITP. Statistical significance was set at
A total of 45 patients participated in this study (Table 1). The mean age of the patients was 4.07±3.98 years. Among them, 36 (80%) were under 6 years of age, and 9 (20%) were aged 6 years or older. There were 25 male patients (55.6%) and 20 female patients (44.4%). Eighteen patients (40%) had a history of infection within 8 weeks of ITP diagnosis. The mean dose of prescribed IVIG was 2.00±0.07 g/kg. IVIG was administered at <2 g/kg to 12 patients (26.7%). Fourteen (31.1%) patients were prescribed IVIG alone, and 31 (68.9%) patients received additional steroids.
Table 1 . Characteristics of patients.
Variables | n (%) |
---|---|
No. of patients | 45 (100) |
Age (yr) | 4.07±3.98 |
Age group (yr) | |
<6 | 36 (80.0) |
≥6 | 9 (20.0) |
Sex | |
Male | 25 (55.6) |
Female | 20 (44.4) |
Recent infection history with 8 weeks | |
Yes | 18 (40.0) |
No | 27 (60.0) |
IVIG dose (g/kg) | 2.00±0.07 |
IVIG dose (g/kg) | |
<2 | 12 (26.7) |
≥2 | 33 (73.3) |
Medication | |
IVIG only | 14 (31.3) |
IVIG+steroid | 31 (68.9) |
Laboratory finding | |
WBC (/mL) | 9,350±3,450 |
Neutrophil (%) | 40.3±12.7 |
Lymphocyte (%) | 49.1±12.5 |
Platelet (/mL) | 7,000±5,000 |
ESR (mm/hr) | 10±12 |
CRP (mg/dL) | 1.95±11.41 |
LDH (IU/L) | 593±131 |
IVIG, intravenous immunoglobulin; WBC, white blood cell; ESR, erythrocyte sedimentation rate (normal range: 0-20 mm/hr); CRP, C-reactive protein (normal range: <0.5 mg/dL); LDH, lactate dehydrogenase (normal range: 208-450 IU/L)..
The mean age of the patients seems to be higher in the group with a longer ITP duration; however, the difference was not statistically significant (
Table 2 . Characteristics of patients according to disease phase.
Variables | Newly diagnosed | Persistent | Chronic | |
---|---|---|---|---|
No. of patients | 28 | 6 | 11 | |
Age (yr) | 3.0±2.6 | 4.1±2.1 | 6.9±6.1 | 0.084 |
Age group (yr) | 0.028 | |||
<6 | 25 (89.3) | 5 (83.3) | 6 (54.5) | |
≥6 | 3 (10.7) | 1 (16.7) | 5 (45.5) | |
Sex | 0.864 | |||
Male | 15 (53.6) | 5 (83.3) | 5 (45.5) | |
Female | 13 (46.4) | 1 (16.7) | 6 (54.5) | |
Infection history | 0.293 | |||
Yes | 15 (53.6) | 4 (66.7) | 8 (72.7) | |
No | 13 (46.4) | 2 (33.3) | 3 (27.3) | |
IVIG dose (g/kg) | 2.02±0.06 | 1.99±0.03 | 1.96±0.09 | 0.024 |
IVIG dose (g/kg) | 0.011 | |||
<2 | 4 (14.3) | 2 (33.3) | 6 (54.5) | |
≥2 | 24 (85.7) | 4 (66.7) | 5 (45.5) | |
Medication | >0.999 | |||
IVIG only | 9 (32.1) | 1 (16.7) | 4 (36.4) | |
IVIG+steroid | 19 (67.9) | 5 (83.3) | 7 (63.6) | |
Laboratory finding | ||||
WBC (/mL) | 9,800±3,220 | 7,850±2,930 | 9,010±4,240 | 0.273 |
ALC (/mL) | 5,075±2,243 | 3,795±2,013 | 4,203±2,657 | 0.189 |
Neutrophil (%) | 38.7±11.4 | 40.9±12.6 | 44.4±16.2 | 0.215 |
Lymphocyte (%) | 51.5±11.0 | 46.9±10.1 | 44.3±16.1 | 0.105 |
PLT (/mL) | 7,000±4,000 | 6,000±5,000 | 9,000±6,000 | 0.265 |
ESR (mm/hr) | 9±11 | 5±4 | 14±16 | 0.499 |
CRP (mg/dL) | 0.21±0.31 | 0.31±0.35 | 6.99±22.56 | 0.950 |
AST (IU/L) | 46±37 | 33±6 | 31±10 | 0.301 |
ALT (IU/L) | 33±53 | 15±3 | 16±6 | 0.665 |
LDH (IU/L) | 609±113 | 601±74 | 553±187 | 0.570 |
Bleeding episode | ||||
Epistaxis | 3 (10.7) | 1 (16.7) | 1 (9.1) | >0.999 |
Petechiae, bruise | 22 (78.6) | 6 (100) | 9 (81.8) | 0.829 |
GI bleeding | 4 (14.3) | 0 (0) | 0 (0) | 0.246 |
No bleeding | 5 (17.9) | 0 (0) | 2 (18.2) | >0.999 |
IVIG, intravenous immunoglobulin; WBC, white blood cell; ESR, erythrocyte sedimentation rate (normal range: 0-20 mm/hr); CRP, C-reactive protein (normal range: <0.5 mg/dL); LDH, lactate dehydrogenase (normal range: 208-450 IU/L); ALC, absolute lymphocyte count; AST, aspartate aminotransferase (normal range: 10-35 IU/L); ALT, alanine aminotransferase (normal range: 0-40 IU/L); GI, gastrointestinal; PLT, platelet..
In the ND group (n=28), the mean age was 3.0±2.6 years, while in the P+C group (n=17), the mean age was 5.9±5.2 (
As shown in Table 3, we analyzed the prognosis according to platelet response on specific days after IVIG infusion.
Table 3 . Prognosis according to treatment response by period.
Time | Response | Newly diagnosed (n=28) | Persistent+chronic (n=17) | OR | 95% confidence interval | |
---|---|---|---|---|---|---|
D+3 | CR vs. non-CR | |||||
CR | 15 (53.6) | 7 (41.2) | 0.542 | 1.648 | 0.487-5.574 | |
Non-CR | 13 (46.4) | 10 (58.8) | ||||
R vs. NR | ||||||
R | 23 (82.1) | 16 (94.1) | 0.385 | 0.288 | 0.031-0.700 | |
NR | 5 (17.9) | 1 (5.9) | ||||
D+14 | CR vs. non-CR | |||||
CR | 25 (89.3) | 4 (23.5) | <0.001 | 27.083 | 5.253-139.636 | |
Non-CR | 3 (10.7) | 13 (76.5) | ||||
R vs. NR | ||||||
R | 27 (96.4) | 11 (64.7) | 0.008 | 14.727 | 1.583-136.971 | |
NR | 1 (3.6) | 6 (35.6) | ||||
D+30 | CR vs. non-CR | |||||
CR | 26 (92.9) | 6 (35.3) | <0.001 | 23.833 | 4.147-136.973 | |
Non-CR | 2 (7.1) | 11 (64.7) | ||||
R vs. NR | ||||||
R | 27 (96.4) | 14 (82.4) | 0.144 | 5.786 | 0.550-60.875 | |
NR | 1 (3.6) | 3 (17.6) |
Time indicates the number of days after IVIG infusion (D)..
CR, complete response; R, response; NR, no response; OR, odds ratio..
Three days after IVIG, 15 (53.6%) patients in the ND group and seven (41.2%) patients in the P+C groups showed CR (
Fourteen days after IVIG, 25 (89.3%) patients in the ND group and 4 (23.5%) patients in the P+C group showed CR (
At 30 days after IVIG, 26 (92.9%) patients in the ND group and four (35.3%) patients in the P+C group showed CR (
In univariate analysis of risk factor for chronic ITP, age 6 years or older and IVIG dose <2 g/kg were found to be risk factors for chronic ITP, and these two factors were also confirmed as significant risk factors in multivariate analysis (Table 4, 5).
Table 4 . Univariate analysis of risk factor for chronic ITP.
Variables | Odds | 95% confidence interval | |
---|---|---|---|
Age ≥6 yr | 0.023 | 6.250 | 1.287-30.349 |
Female | 0.44 | 1.714 | 0.4366-6.742 |
Infection history within 8 weeks | 0.327 | 2.105 | 0.475-9.338 |
IVIG dose <2 g/kg | 0.022 | 0.179 | 0.041-0.783 |
IVIG only | 0.666 | 0.729 | 0.174-3.056 |
Table 5 . Multivariate analysis of risk factor for chronic ITP.
Variables | Odds | 95% confidence interval | |
---|---|---|---|
Age >6 yr | 0.026 | 0.156 | 0.030-0.803 |
IVIG dose ≥2 g/kg | 0.027 | 7.235 | 1.252-41.821 |
This study investigated predictors of chronic ITP by performing a retrospective study of patients from a single institution.
Regarding the association between the prognosis and age of chronic ITP, Higashide et al. reported that age ≥23 months and platelet count <9,000/mL were poor prognostic factors for short-term response [10]. Ahmed et al. found that age >8.5 years, WBC count <6,250/mL, and absolute lymphocyte count (ALC) <3,050/mL were associated with a significant risk of developing persistent ITP beyond 6 months [11] . Glanz et al. reported that children whose illness was diagnosed at ≥10 years of age and who had a platelet count ≥20,000/mL had an approximately five-fold risk of progressing to chronic disease compared with children who were under 2 years of age at diagnosis with a platelet count <20,000/mL [12]. A recent meta-analysis conducted by Heitink-Pollé et al. revealed that older age at presentation is one of the strongest risk factors for chronic ITP [13].
In our study, there were 6.25 times more patients with chronic ITP aged over 6 years than those aged under 6 years (
Several studies have proposed that acute ITP is more closely related to a history of recent infection than chronic ITP. The association between recent infection history and acute ITP has been controversial [14-16]. However, Choi et al. reported that a recent history of infection was not statistically related to the disease phase [15]. In our study, the proportion of patients with a history of infection within the last 8 weeks was higher in the chronic group than in the ND group. However, this difference was not statistically significant (72.7% vs. 53.6%,
In several ITP studies, IVIG was used as a protocol with a 1 g/kg/day infusion for 1-2 days [17]. The recent American Society of Hematology guidelines recommend a single dose of 0.8 g/kg [7].
Morimoto et al. and Higashide et al. conducted studies in which the IVIG treatment doses were 2 g/kg and 1.4 g/kg, respectively, and found no difference in IVIG response between the two studies [10,18]. Choi et al. compared IVIG doses of 1 g/kg/day and 2 g/kg/day, and reported that the treatment effect was similar even at a low dose with fewer side effects [19].
In a study by Kim et al., there was no significant difference in the dose of IVIG treatment for patients with ITP in the recovery of platelet counts [20]. Parodi et al. reported that IVIG had no effect on the natural outcome of the disease [21]. In a previous study conducted by Benesch et al. on patients with acute child ITP, the group administered with IVIG 2 g/kg had a higher platelet level on the third day than the group administered 0.6 g/kg [22].
In our study, the therapeutic dose of IVIG was set on the basis of a dose of 2 g/kg, where the IVIG dose was gradually decreased in patients with ND, persistent, and chronic diseases (
In a study of prognostic factors for pediatric ITP conducted by Jung et al., among ITP patients who received IVIG for treatment, the proportion of patients with platelet counts exceeding 45,000/mL after 1 month of treatment was significantly higher in the acute ITP group [14]. Moreover, in a study conducted by Choi et al., patients with ITP who received IVIG had a significantly lower probability of progressing to chronic disease when their platelet count was restored to 100,000/mL within 3 months, than those who did not restore their platelet count [15]. Kim et al. reported that the diagnosis of chronic ITP was high in the group with a slow response to IVIG treatment; therefore, it could be used as an early predictor of chronic ITP [20]. In a study by Elalfy et al., the response to platelet treatment was prolonged in patients with chronic ITP compared to that in patients with acute ITP [23].
In our study, the proportion of patients with CR on days 14 and 30 after IVIG infusion in the ND group was higher than those in the persistent and chronic groups.
A limitation of our study is that it was a retrospective study conducted with a small number of patients at a single center.
In conclusion, in our study, patients over 6 years of age, and those who received IVIG doses less than 2 g/kg were more likely to progress to chronic ITP.
This work was supported by a 2021 Yeungnam University research grant.
Supplementary materials can be found via https://doi.org/10.15264/cpho.2022.29.2.44.
cpho-29-2-44-supple.pdfThe authors have no conflict of interest to declare.