Acute immune thrombocytopenia following SARS-CoV-2 vaccination in chronic ITP patients and a healthy individual
Введение: Вопрос о дальнейшем совершенствовании базисной терапии иммунной тромбоцитопении (ИТП) по-прежнему широко обсуждается специалистами и является предметом оживленных дискуссий. Цель исследования: оценить эффективность высокогорной климатотерапии при хронической ИТП у детей за 5-летний период наблюдения после ежегодного лечения на высокогорной базе. Материалы и методы: В исследование включено 22 ребенка с хронической ИТП в возрасте от 3 до 14 лет, средний возраст — 6,30 ± 1,02 года, длительность заболевания 2-8 лет. Для лечения детей поднимали на высокогорную базу. Продолжительность лечения в высокогорье составляла 40 дней. Результаты: Из 22 детей, получивших 5 курсов высокогорной климатотерапии, у двоих наблюдали полную ремиссию в виде увеличения тромбоцитов более 100×109/л без кровоточивости. Объективный ответ в виде двукратного увеличения числа тромбоцитов, но менее 100×109/л без кровоточивости установлен у 18 детей, отсутствие эффекта было зарегистрировано у 2 детей. Заключение: Повторные курсы высокогорной климатотерапии способствуют улучшению клинической картины, существенному повышению числа тромбоцитов в периферической крови и достижению ремиссии при ИТП у детей. Background: Further development of basic treatment of immune thrombocytopenia (ITP) is still widely discussed by specialists and is the subject of lively discussions. Objectives: to assess the effi ciency of high-altitude climatotherapy in children with chronic ITP for a 5-year follow-up period after annual treatment at high-altitude base. Patients/Methods: The study included 22 children with chronic ITP from 3 to 14 years, the average age was 6.30 ± 1.02 years, and disease duration was 3-8 years. Children were raised to high-altitude base. Treatment duration was 40 days. Results: 22 children received 5 courses of high-altitude climatotherapy. Complete remission was observed in 2 patients with increasing of platelets more than 100×109/L without bleeding. In 18 children an objective response was found in the form of twofold increasing of platelets number, but less than 100×109/L without bleeding; no effect was recorded in 2 children. Conclusions: Repeated courses of high-altitude climatotherapy improve clinical characteristics, significantly increase the number of platelets in the peripheral blood and contribute to remission in children with ITP.
SummaryApproximately 70% of children have the acute form of immune thrombocytopenia (ITP), which is defined by recovery within six months of presentation with or without treatment. Chronic ITP is to be reserved for patients with platelets < 100 000/μl for more than twelve months and exclusion of other diagnosis like systemic lupus erythematosus or bone marrow failures. In children, the chance of spontaneous recovery is 52% after diagnosis of chronic ITP. The Intercontinental Childhood ITP Study group recommends that children without bleeding may not require therapy regardless of their platelet count. Whereas in patients with bleeding symptoms first line therapy is defined and includes steroids or immunoglobuline, second line therapy in refractory patients with significant hemorrhagic problems is unclear. Guidelines recommend splenectomy, but for more than 50 years patients and physicians look for pharmacological alternatives. It may be that rituximab is a promising option which has been proven to be effective with few adverse effects. Till now the treatment has focused on immunomodulation. Research has now focused on stimulating platelet production. In this review we discuss old and new therapy modalities for children with cITP.
Abstract Abstract 3693 Introduction: Immune thrombocytopenia (ITP) is a chronic acquired organ-specific autoimmune disorder characterized by the production of antibodies against antigens on the membranes of platelets. Several cytokine studies have shown Th1 polarization in ITP patients. Interleukin-18 (IL-18) plays an important role in Th1 and Th2 immune response. Recent studies showed that single-nucleotide promoter polymorphisms influence the transcriptions of IL-18 mRNA. IL-18 polymorphism has been implicated in autoimmunity, including Crohn's disease, rheumatoid arthritis, and asthma. We examined the single nucleotide polymorphisms (SNPs) in the promoter regions of the IL-18 genes in patients with ITP, and analyzed the relationship between IL-18 SNPs and clinical features. Patients and Methods: One hundred patients (male/female; 22/78, median age; 54.5) diagnosed as chronic ITP and 151 healthy controls were included. Chronic ITP was defined as thrombocytopenia (platelet count < 100×109/L) persisting greater than 12 months, normal or increased marrow megakaryocytes, and no secondary immune or non-immune abnormality that could account for the thrombocytopenic state. ITP with severe thrombocytopenia was defined as thrombocytopenia (platelet count < 10×109/L) at presentation of ITP. The response criteria of the ITP International Working Group was used. A complete response (CR) is defined as any platelet count of at least 100×109/L, and a response (R) was defined as any platelet count between 30 and 100×109/L and at least doubling of the baseline count. Allparticipants gave written informed consent about the study. Genomic DNA was isolated from peripheral blood using the DNA Kit (QIAGEN, Hilden, Germany). An allele-specific polymerase chain reaction was used to analyze polymorphism in IL-18 –607A/C and -137G/C. Genotype and allele frequencies were compared between the study groups using Χ2-test. The characteristics and laboratory features of the ITP patients with each IL-10 promoter polymorphism were compared using X2-tests and student t-tests. Probability values <0.05 were considered statistically significant. Results: The platelet count was at an initial diagnosis ranged from 1×109/L to 98 ×109/L, with a median of platelet count of 15×109/L. Thirty-five patients (35%) had severe thrombocytopenia. Steroid treatment was given to 68 patients (68%), while splenectomy was used in 11 patients (11%).The frequencies of the genotypes were as follows: AA (34%), AC (57%), and CC (9%) for -607; GG (77%), GC (21%), and CC (2%) for -137 loci. The frequencies of each haplotype were as follows: C-G/C-G haplotype (9%), A-G/C-G haplotype (47%), A-C/C-G haplotype (10%), A-G/A-G haplotype (21%), A-G/A-C haplotype (11%) and A-C/A-C haplotype (2%). No significant differences in the genotype or haplotype frequencies demonstrated between chronic ITP patients and control group. However, patients with -137CC genotypes showed severe thrombocytopenia at initial diagnosis compared to those with -137GG/GC genotypes (5×109/L vs. 22×109/L, p=0.002). Furthermore, patients with A-C/A-C haplotype showed severe thrombocytopenic state (5×109/L vs. 22×109/L, p=0.002) compared to those without A-C/A-C haplotype. No significant difference of treatment response was observed according to IL-18 polymorphism. Conclusion: No significant differences in the genotype or haplotype frequencies demonstrated between chronic ITP patients and control. However, -137CC genotypes or AA/CC haplotype was associated with severity of chronic ITP. Our data suggest that the group with low IL-18 inducibility (i.e. -137CC genotype, A-C/A-C haplotype) may have more severe thrombocytopenia. Disclosures: No relevant conflicts of interest to declare.
Abstract Abstract 2194 Introduction: The severity of immune thrombocytopenia (ITP) depends on the degree of the thrombocytopenia and the extent of bleeding. Some investigators have reported the association between the thrombocytopenia and cytokine dysregulation in ITP. We investigated the association between the severity of thrombocytopenia at diagnosis in ITP patients and several cytokine polymorphisms, including IL-10-1082A/G, -819T/C, -592A/C, IL-17F-7488T/C and IL-18-607A/C, −137G/C. Patients and methods: We examined 102 patients (male/female, 24/78; median age, 42) diagnosed with chronic ITP. The definition, response criteria, including complete response (CR)and response (R), loss of CR,and “corticosteroid-dependence” were assessed according to the criteria of the ITP International Working Group. ITP with severe thrombocytopenia (ST group)was defined as thrombocytopenia (platelet count < 10×109/L) at the initial diagnosis of ITP. Genotyping of IL-10 (rs1800870 − 1082 A/G, rs1800871 − 819 T/C, and rs1800872 − 592 A/C) and IL-17F (rs763780, 7488 T/C) polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the genotyping of the IL-18 polymorphism (rs187238 −137G/C and rs1946518−607 A/C) was determined by the allelic specific polymerase chain reaction technique. To confirm the accuracy of the assay, amplification products of several individuals were sequenced using an ABI Prism Genetic Analyzer. Genotype and allele frequencies were compared between the study groups using χ2-test. The characteristics and laboratory features of ITP patients with each polymorphisms were compared using χ2-tests and student t-tests. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated for each study. All patients were provided written information about the study. This study was approved by the Institutional Research Board of Gunma University Hospital. Results: Clinical features of chronic ITP: The platelet count ranged from 1×109/L to 98×109/L with a mean of platelet count of 32×109/L at the initial diagnosis. Fifty seven patients (49%) had bleeding tendency. Steroid treatment was given to 68 patients (66.7%) and eradication of Helicobacter pylori (H. pylori) was performed in 32 patients (31.4%), while splenectomy was performed in only 11 patients (10.8%). Clinical features of ST group vs. non-ST group in chronic ITP: Of these 102 patients, 17 (16.7%) had severe thrombocytopenia (platelet count < 10×109/L) (ST group). ST group were significantly older (ST group: median 59 years vs. non-ST group: 41 years, p<0.01) and had more severe bleeding tendency (ST group: 100% vs. non-ST group: 54%, p<0.0001). Steroid treatment was frequently given to ST group than to non-ST group (ST group: 100% vs. non-ST group: 59.5%, p<0.001). Though the response to corticosteroids treatment was not significantly different between ST group and non-ST group (CR rate, ST group: 50% vs. non-ST group: 51.0%, p=0.94), corticosteroid-dependent patients in ST group was significantly higher than in non-ST group (76.9% vs. 25.3%, p<0.005). Polymorphism study of ST group vs. non-ST group in chronic ITP: The frequencies of genotypes of cytokines in patients with chronic ITP according to the definition of criteria of ST were as follows: AA (93.3% vs. 97.1%) and AG (6.7% vs. 2.9%, p=0.48) for IL-10–1082; TT (46.7% vs. 33.3%), TC (33.3% vs.55 %) and CC (20% vs. 11.7%) for IL-10–819; AA (46.7% vs. 33.3%), AC (33.3% vs.55 %) and CC (12.2% vs. 11.5%) for IL-10–592; TT (100% vs. 81%) and TC (0% vs. 19%) for IL-17F; GG (82.4% vs. 74.4%), GC (17.6% vs. 23.2%) and CC (0% vs. 2.4%) for IL-18–137; AA (35.3% vs. 34.1%), AC (58.8% vs. 53.7%) and CC (5.9% vs 12.2%) for IL-18–607 loci (ST group vs. non-ST group, respectively). No significant difference was observed between ST group and non-ST group according to IL-10–1082A/G, −819T/C, −592A/C, and IL-18–607A/C, −137G/C polymorphism. However, the numbers of IL-17F 7488TT genotype (higher function type) in ST group were significantly higher than in non-ST group (ST group: 100% vs. non-ST group: 81% p<0.05). Conclusion: These findings suggest that severe thrombocytopenia at diagnosis have an impact of bleeding tendency and corticosteroid-dependency of chronic ITP. Furthermore, IL-17F polymorphism may affect the severity of thrombocytopenia of chronic ITP. Disclosures: No relevant conflicts of interest to declare.
Abstract Abstract 3319 Background: An unpredictable subset of patients (∼20–30%) with pediatric immune thrombocytopenia (ITP) progress to chronic ITP; this increases the risk of morbidity and mortality from bleeding, long-term immunomodulation, and/or splenectomy. Furthermore, treatments such as chronic steroid therapy often result in intolerable side effects, raising the need for targeted therapies. We previously tested a novel list of genes that might predict progression to chronic ITP (Zhang et al Blood 2011). Oxidative stress (OS)-related pathways were among those most significantly perturbed in chronic ITP. For further evaluation of the role of OS in ITP, we measured glutathione as a marker of redox capacity and protein carbonyl content as a marker of oxidative cell damage. Methods: Pediatric patients with primary ITP were included, with exclusion of subjects with secondary thrombocytopenia, other autoimmune disorders (ie, lupus), or other chronic illnesses. Healthy pediatric volunteers were recruited as controls. Patients had blood draws within 1 month from ITP diagnosis. Reduced (GSH) to oxidized (GSSG) glutathione ratios were measured from whole blood by tandem mass-spectrometry. Protein carbonyl content (PCC) levels were measured from platelet-rich plasma by enzyme-linked immunosorbent assay (ELISA). Subjects were followed up to 15 months from diagnosis and monitored for disease resolution or progression. Chronic ITP was defined as thrombocytopenia (platelets <100,000/μL) lasting at least 12 months from diagnosis (Rodegheiro et al Blood 2009). Acute ITP was defined as thrombocytopenia resolving within 12 months from diagnosis. Statistical significance was defined as p<0.05. Results: Between July 2009 and December 2011, 67 pediatric patients with ITP were recruited. Thirty-four patients had acute ITP, and 33 patients progressed to chronic ITP. The median age of patients was 7 years (range 18 months – 17 years). Sixty-three percent were female, 37% were male. Twenty-four pediatric controls were also recruited (46% female, 54% male). The median age of controls was 8 years (range 5 years – 17 years). Patients with ITP had significantly lower GSH:GSSG ratios compared to controls, and patients with chronic ITP had lower GSH:GSSG ratios compared to those with acute ITP (Figure 1). Furthermore, patients with ITP had significantly higher PCC levels compared to controls (Figure 2). Conclusions: This data provides further evidence for a role of oxidative stress (OS) in the pathophysiology of ITP. Furthermore, decreased redox capacity, as evidenced by the decreased glutathione ratios, may be associated with progression to chronic ITP. Reactive oxidative species (ROS) may be important in the pathogenesis of autoimmunity in ITP; oxidatively altered cellular by-products induce pathogenic antibodies and become immunogenic. This also raises a potential anti-oxidant mechanism of therapy, which may play a greater role in chronic ITP treatment. Increased understanding of OS in pediatric ITP may reveal markers of disease progression, highlighting those at greatest risk for chronic ITP and creating a role for targeted therapy. Disclosures: No relevant conflicts of interest to declare.
Abstract INTRODUCTION Immune thrombocytopenia (ITP) is a hematological disease characterized by immune-mediated destruction of platelets. Prior to starting therapy for ITP it is critical to determine whether it is idiopathic or related to a secondary underlying condition as this informs treatment. There is significant use of blood products and components in patients with chronic ITP for management of thrombocytopenia and bleeding, including intravenous immune globulin (IVIg). Platelet transfusions are generally reserved for life-threatening bleeding or may be used in the preoperative setting in patients unresponsive to other therapies. The aims of this study are to identify gaps in process of care and to examine the impact of geographical remoteness on health service utilization and outcomes in adults with chronic ITP in Alberta. METHODS Adults who received rituximab, splenectomy, or thrombopoietin receptor agonists (TPO-RA) as second-line therapy for ITP during 2012-2019 in the province of Alberta, Canada were identified via the provincial special drug access database. Diagnostic workup including bone marrow biopsy results, abdominal imaging (ultrasound or CT scan), coagulation parameters, viral serologies for hepatitis, human immunodeficiency virus (HIV), serum protein electrophoresis (SPEP), and quantitative immunoglobulins were recorded and rates of completed tests were calculated. Utilization of IVIg, platelets, and packed red blood cells was assessed. Rates of hospitalization, mortality, and ITP-related deaths were calculated and compared according to geographic region. RESULTS Of the 204 patients identified for analysis 106 were female (52%). Most patients (123; 60%) lived within a major centre, whereas 21 (10%) lived over 250 km from a major centre. Review of diagnostic laboratory parameters revealed incomplete coagulation parameters in 117 patients (58%), and no coagulation parameters checked in 16%. Eighty-nine patients (44%) did not have quantitative immunoglobulins tested, and 57 (28%) did not have an SPEP performed. Fifty-three (26%) did not have any abdominal imaging performed to assess for splenomegaly or liver disease. Thirty-five (17%) did not have any viral serologies for hepatitis B, C, or HIV completed. Bone marrow aspirate and biopsy was performed in 110 patients (54%). Eighty-six (77%) of these biopsies yielded a normal result. Eight biopsies (7%) displayed a lymphoproliferative disorder or plasma cell disorder which was suspected or known prior to completing the test. There was significant geographic discrepancy in utilization of blood products and hospitalizations. During 527 patient years of follow up, 83 patients received a total of 343 doses of platelets. Eleven patients (13%) received platelet transfusions for inappropriate indications, and eight (9%) for unclear indications. One hundred twenty-seven patients received IVIg (mean 1290 g) with comparable usage across geographic regions. Compared to patients within 250 km from a major centre, those with geographic remoteness (>250 km from a major centre) utilized more platelets (mean 5.2 vs 1.2 doses; Figure 1) and packed red blood cells (mean 4.3 vs 1.2 units; Figure 2). Those with geographic remoteness also experienced a higher rate of ITP-related hospitalizations (mean 1.5 vs 1.1) and deaths (24% versus 9%). At a median follow-up of 3.42 years from ITP diagnosis, 27 patients (13%) were deceased. Fourteen of these deaths were ITP-related due to bleeding or infection (52%). There appears to be a gradient of rates of both all-cause and ITP-related deaths by distance from a major centre (Figures 3 and 4). DISCUSSION This study highlights gaps in quality of care in patients with chronic ITP in Alberta, Canada. A significant number of patients have an incomplete workup for ITP at the time of diagnosis with the most forgotten tests being coagulation studies, SPEP, quantitative immunoglobulins, viral serologies, and abdominal imaging. Additionally, we identified an unexpectedly high rate of bone marrow biopsies performed in our population. Most of these bone marrow examinations did not result in any change in management. Finally, this study identified that geographic remoteness is associated with increased health services utilization and ITP-related deaths. These data can be used to inform further quality improvement initiatives in chronic ITP and help address geographic inequities in healthcare outcomes. Figure 1 Figure 1. Disclosures Sun: Bayer: Consultancy; Novo Nordisk: Consultancy; Pfizer: Consultancy; Shire: Consultancy; Octapharma: Consultancy, Research Funding.
Abstract Introduction. Children diagnosed with Immune thrombocytopenia (ITP) will develop a chronic disease (plt < 100 x 109/L lasting >12 months since the onset) in 20-30% of cases. The transition from ITP started in childhood to adulthood has been scarcely studied and no specific studies have been published Aims.To present the results of a single center retrospective survey on ITP pts diagnosed in childhood who were sent in an adult setting to continue the management Methods. Charts of ITP pts diagnosed in childhood (1-17 yrs) in our Pediatric Dept who developed a chronic disease, need at least one line of therapy and were sent to our adult ITP office from Jan 2013 to Feb 2018, were retrospectively reviewed. Demographic and clinical data were collected and outcome was assessed based on established guidelines Results. Our Pediatric Dept accounts for a mean of 37 newly ITP diagnosis/year in children aged 1-17 yrs, with 32.8% of pts developing a chronic disease. During the selected observation time, 60 pts was expected to become > 18 yrs old with a chronic ITP. Overall 28 pts (14 female) pts were sent to our Adult ITP office at pediatrician's discretion (46.6% of expected). Table 1 summarizes demographic and clinical characteristics of pts. Median age at ITP diagnosis was 9.5 yrs (12 moths to 17 yrs). Median age of pts coming to the adult ITP office was 21 yrs (18 to 37 yrs) and the reason they were sent for was the need to continue a pharmacological treatment in 8 cases (eltrombopag-Elt-), bleeding in 3 cases, pregnancy in 4 cases, plt count < 50 x 109/L in 13 cases. The median n of lines of treatment already received in childhood was 1 (1 to 4). 16 pts have received only steroid since diagnosis (on demand treatment for bleedings), 8 pts were treated with thrombopoietin receptor agonists (TPO-RA) and 1 also with rituximab. One patient, 8 yrs old, was splenectomized because of grade 3 multiple bleedings, with complete response (CR). He was sent to adult ITP office at 37 yrs when ITP relapsed, with grade 3 bleeding. Overall the median follow up from diagnosis, after the transition to adult ITP office is 18 yrs (4-39 yrs), the median n of lines at data cut-off was 2.5 (1-5) and the overall outcome is summarized in Fig 1. 11 patients were treated with TPO-RA (8 pts received Elt since childhood, 2 pts started Elt and 1 Rom in adulthood), ORR was 81.8% (CR=7). Since the transition 4 patients switched the TPO-RA because response to the first TPO-RA was suboptimal or minor side effect (headache) was reported or limited compliance was suspected. Splenectomy was offered to all patients treated with TPO-RA to avoid chronic pharmacological treatment, and to other selected patients with a low plt count and a history of bleeding. 8/11 patients accepted splenectomy. Median time since diagnosis to splenectomy was 8 yrs (1 to 18 yrs) and in all pts a stable CR (plt > 100 x 109/L) was achieved, with a median follow up after surgery of 36.5 months (10-48 months). Surgery was performed also in the previous splenectomized pt (29 yrs later) because an accessory spleen was detected, and a CR was achieved (follow up 40 months). 2 patients stopped TPO-RA on a personal decision, refused splenectomy or other treatments: their plt count is < 30 x 109/L without bleeding. 15 pts were on active follow up without therapy (median plt count 58 x 109/L) and without any bleeding. One patient is waiting for splenectomy, taking prednison. The 4 pregnant patients were treated with steroids and IVIG, had natural labour without adverse events and their babies had a normal plt count. After pregnancy one pt was treated with Elt for 1 year, then she refused treatment and splenectomy. All 4 women returned to a number of plts similar to pre-gestational count. In 1 pt a MYH9 related-disorder was confirm at 21 yrs. Overall a CR was achieved during TPO-RA treatment in 9/11 pts and 9/28 (32%) achieved a stable CR after splenectomy Conclusions. The transition from childhood to adulthood in chronic ITP pts leads clinicians to challenges related to growing age, especially in female pts approaching the fertility and pregnancy specific needs. However only a minority of children with ITP developed a chronic disease which required a prolonged treatment. TPO-RA seems to be effective and well tolerated but chronic administration has limited compliance. Splenectomy, even if performed in adulthood after many yrs since diagnosis, allows to achieve a stable CR sparing young adults from chronic pharmacological treatment. Disclosures Gambacorti-Passerini: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy.
Abstract Introduction Growing evidence has implicated gut microbiota in the pathogenesis of immune thrombocytopenia (ITP). In a previous research study, we found dysbiosis in the phylogenetic composition and function of gut microbiome in ITP and that corticosteroid treatment may have a strong effect on gut microbiota [Sci China Life Sci, 2020]. Corticosteroids have been widely used in the initial treatment of newly diagnosed ITP patients, but most adult patients relapse upon cessation of steroid treatment. Patients on agents in subsequent therapy may improve at any time, but which patients improve and when is unpredictable. The gut microbiome has been increasingly used in the assessment and prediction of immunomodulatory therapy in autoimmune diseases and cellular immunotherapy in cancers. Here, we provide evidence that gut microbiota and function signatures can be used to predict immune thrombocytopenia patients at high risk of relapse/resistance after corticosteroid treatment and to identify patients that are more likely to benefit from TPO-RAs in subsequent therapy. Methods Seventy-five fecal samples from 60 patients with newly diagnosed ITP (60 specimens before corticosteroid therapy and 15 specimens after corticosteroid therapy) and 41 samples from persistent/chronic ITP before and after treatment with TPO-RAs, including eltrombopag and avatrombopag were collected for deep shotgun metagenomic sequencing. To identify the microbial biomarkers related to relapse/resistance after corticosteroid treatment, we constructed a random forest classifier using machine learning to determine the risk of relapse/resistance of a training cohort of 30 patients from baseline samples and validated the classifier for 30 patients. Patients with persistent/chronic ITP were divided into responders and nonresponders according to their response to TPO-RA treatment in subsequent therapy. After identifying the microbial species and functional biomarkers related to the response to TPO-RA therapy, a random forest classifier was constructed using a training set of 20 patients and validated using a validation set of 21 patients. Results We used a metagenomic sequencing technique to investigate the differences among gut microbiota associated with relapse within 3 months of corticosteroid treatment. We observed that the diversity and composition of the microbial community in ITP patients after corticosteroid therapy (Post-C) changed significantly from the baseline (Pre-C), whereas the gut microbiota of the remission group was similar to that of the HC group, which implies that a shift in the gut microbiome could represent a return to homeostasis. To identify the microbial biomarkers related to early relapse after corticosteroid treatment, the Pre-C samples were divided into a remission group and a resistant/relapse group according to the response to corticosteroid therapy within 3 months. Nine significant associations with the microbial species and function were identified between the remission and resistant/relapse groups. A risk index built from this panel of microbes and functional pathways was used to differentiate remission from resistant/relapsed patients based on the baseline characteristics. The receiver operating characteristic (ROC) curve demonstrated that the risk index was a strong predictor of treatment response, with an area under the curve (AUC) of 0.87. Furthermore, to predict the response to TPO-RAs in subsequent therapy, the baseline gut microbiomes of responders and nonresponders before TPO-RA treatment were compared. Patients who responded to treatment exhibited an increase in Ruminococcaceae, Clostridiaceae and Bacteroides compared to nonresponders, with elevated abundance of the phosphotransferase system, tyrosine metabolism and secondary bile acid biosynthesis pathways according to KEGG analysis. Our prediction model based on the gut microbiome for TPO-RA response was robust across the cohorts and showed 89.5% and 79.2% prediction accuracy for persistent/chronic ITP patients in the training and validation sets, respectively. Conclusions The gut microbiome and function signatures based on machine learning analysis are novel potential biomarkers for predicting resistance/relapse after corticosteroid treatment and response to TPO-RAs, which may have important manifestations in the clinical. Disclosures No relevant conflicts of interest to declare.
Abstract Background: Immune thrombocytopenia (ITP) usually is a mild and self-limited disease; however, 25-30% of children develop chronic ITP. Nordic score is a validated clinical prediction tool, yet its use in children is limited and evidence for other prognostic factors is unclear. Purpose: To evaluate clinical outcomes among pediatric ITP patients, and examine their relationship to patient characteristics, including Nordic score. We hypothesized that Nordic score and patient characteristics will be predictive of ITP resolution or development of chronic ITP. Methods: We conducted a retrospective chart review of all children diagnosed with ITP at our institution between May 2008 to May 2019. Data extraction included patients' age, sex, presenting signs and symptoms, laboratory values, treatment decisions, and clinical outcomes. Nordic score calculated with 6 clinical features from diagnosis: abrupt onset <14 days, age < 10 years, preceding infection <1 month, platelet count < 5x10 9/L, wet purpura, and male sex. High scores (10-14) predict a brief disease course (<3 months), whereas low scores (0-4) predict a more prolonged course. Primary outcomes included complete response (CR) (platelets 100 x10 9/L on 2 occasions >7 days apart), recurrence (platelets < 100 after achieving CR), development of chronic ITP, and resolution (long term normal platelet count). Secondary outcomes included early response (platelets 30 x10 9/L in <1 week), time to CR, duration of CR (months between CR and recurrence), and time to resolution. Data presented as odds ratio (OR) with 95% confidence intervals. OR for Nordic score presented per 5-unit increase correlating with Nordic score categories (low 0-4, moderate 5-9, high 10-14). Results: A total of 308 patients were included (median age 5 years, IQR 2.0-10.8; 54.5% male) (Table 1). About 56% presented with platelets < 10 x10 9/L and 42% had bleeding at diagnosis (bleeding score 3 or higher), only 3% were severe. Median Nordic score was 10 (IQR 6-11). Overall, 64% of patients were treated upfront, majority (98%) receiving intravenous immunoglobulin (IVIG). Treatment at diagnosis was more likely for patients with platelets < 10 x10 9/L (OR 21, 10.4-42.5), bleeding score 3 or higher (OR 2.0, 1-4), and higher Nordic score (OR 6.2, 5.6-6.9) (Table 2). Treatment was predictive only of early response in multivariate analysis, not of CR, recurrence, development of chronic ITP, or disease resolution. Additionally, treatment at diagnosis was not associated with reduction in ITP-related complications, such as major bleeding episodes, need for platelet or red cell transfusions, or iron deficiency anemia. Overall rate of CR was 90% over a median of 1 month (IQR 0.3-4 months), while 13% had recurrence after median 19 months (IQR 8.3-26.0 months) and 32% developed chronic ITP. Overall, 80% of all study patients had resolution of ITP after median 1 month (IQR 0.3-5), with 86% achieving this before 12 months. About 36% of patients with chronic ITP had disease resolution over median 25 months (IQR 16.3-46.5 months). Univariate analysis showed significant variation across subgroups for age, viral symptoms, abrupt onset, Nordic score, hospital admission at diagnosis, platelet count, and treatment. Using multivariate regression analysis adjusted for the above variables, Nordic score was the only independent predictor of all primary outcomes. Higher Nordic score group had increased likelihood of CR (OR 6.2, 5.6-6.8) and disease resolution (OR 6.8, 5.1-8.9). Lower Nordic score group was associated with increased likelihood of recurrence (OR 6.5, 5.3-6.9) and development of chronic ITP (OR 8.6, 6.5-11.4). Additionally, higher Nordic score group was associated with increased time to recurrence and duration of response, decreased time to CR and resolution. Conclusions: In our cohort, low platelet count and bleeding symptoms were drivers of upfront treatment in pediatric ITP. Treatment initiation, associated with Nordic score, was predictive of faster increase in platelet count; however, it had no impact on overall disease trajectory or likelihood of complications. Our analysis demonstrate that Nordic score is an independent predictor of CR, resolution, recurrence, and development chronic ITP. Nordic score is a useful, simple prognostic tool that has the potential to help predict clinical course of pediatric ITP and identifying patients who may benefit from closer monitoring. Figure 1 Figure 1. Disclosures Badawy: Bluebird Bio Inc: Consultancy; Sanofi Genzyme: Consultancy; Vertex Pharmaceuticals Inc: Consultancy.
Immune thrombocytopenia (ITP) is the most common cause of thrombocytopenia in children. This retrospective study was designed to analyze presenting features of ITP cases in Benha, evaluate outcomes in children and determine prognostic factors. This research was accepted by Research Ethics Committee (REC) of Faculty of Medicine, Benha University (chairman: Prof. Nermeen Adly Mahmoud). Ethics comittee refrence number MS 40-3/2019. Records of 308 children with ITP in Benha University Hospitals and Benha Children Hospital haematology clinics between May 2014 and January 2021 were retrospectively analyzed. Socio-demographic, clinical, and laboratory data of the studied children such as age, gender, the type of residence, the date of diagnosis, complaints at presentation, preceding vaccination or infection, the type of bleeding, initial platelet count, LDH (lactate dehydrogenase) level, initial treatment, and outcomes were recorded. A total of 308 children diagnosed with ITP were included, clinical courses were determined as newly diagnosed and chronic in 71.4% and 28.6%, respectively. The median age of patients at diagnosis was 5 ± 3.4 years. The male/female ratio was 1.14. The median age at diagnosis was significantly higher in chronic ITP patients (p < 0.001); patients ≥ 10 years were more likely to develop chronic ITP than younger ones (p = 0.029). Regarding residency, seasonality, type of bleeding and history of preceding infection or vaccination, the difference was not statistically significant. Initial platelet counts > 20 × 109 were significantly more prevalent in chronic ITP (p < 0.001). LDH level at presentation was significantly higher in chronic cases (p = 0.046). Initial lines of treatment were the following: steroids, IVIG, and IVIG with steroids (in 88%, 5.2%, and 2.9% of the cases, respectively). A total of 3.9% of the children did not receive any treatment. There was no significant difference in the outcomes between the initial lines of treatment (p = 0.105). In our study, age > 10 years, female gender, higher platelet count and high LDH level at presentation were found to increase the probability of chronic ITP.
