DISSCUSSION
There is a paucity of references regarding the differences between characteristics of primary and secondary ITP in the pediatric population. This study demonstrates the importance of a correct diagnosis of secondary ITP and highlight different causes of this type of ITP.
Primary immune thrombocytopenic purpura (ITP) remains a diagnosis of exclusion for immune thrombocytopenia. Most cases are considered idiopathic, whereas secondary ITP should be ruled out to predict the outcome and to choose the right treatment [4]. Newly diagnosed ITP is a relatively common disorder of childhood that does not require an exhaustive laboratory workup for diagnosis. 15–20% of cases of ITP in children develop chronic ITP and lead to impaired quality of life, whereas life-threatening bleeding, such as intracranial hemorrhage, is uncommon in these children [7]. In our study, 37% of ITP patients had a chronic ITP and only one presented an intracranial bleeding with good outcome after treatment.
In 75% to 90% of patients, the disease has a transient, self-limiting character. The polymorphisms of FcgR genes may affect disease susceptibility, response to intravenous immunoglobulin treatment, and long-term recovery from childhood ITP [6]. Risk factors associated with an increased risk of developing chronic ITP include older age at diagnosis, less severe thrombocytopenia at initial diagnosis, gradual onset of symptoms, absence of preceding infection or vaccination prior to ITP diagnosis, and absence of mucosal bleeding at presentation [1].
According to previous reports, 80% of ITP are considered idiopathic and 20% are secondary to coexisting conditions [4]. In a recent French population-based study, Moulis and al found that ITP was secondary in only 2.4% of children, in whom primary immune deficiency (PID) and Systemic lupus erythematous (SLE) were the most common cause [3]. In our study we found 86% of primary ITP and 14 % of secondary ITP.
The first important point in our series, is to distinguish the difference between primary and secondary ITP characteristics. We found that the onset of secondary ITP to primary immunodeficiencies (PID) was at a younger age and had more tendency to be insidious, and platelet level was slightly higher than primary ITP. Whereas treatment response was significantly higher in primary ITP and it was worse in PID and SLE patients. Therefore, the presence of these characteristics should alert physicians to recommend periodical studies in order to exclude these disorders.
The second important point of this study is that ITP might also be the first manifestation of an underlying disorder. In our series, 19 patients were diagnosed with an PID, an SLE or HP infection after the initial ITP diagnosis. These patients showed no tendency to remit spontaneously nor under first line treatment. Therefore, the Identification of secondary ITP is important as it predicts outcome. And they should be ruled out periodically as they are usually identified later. Elsewhere, the diagnosis of secondary ITP should be suspected in the presence of medical history of recurrent infections, failure to thrive, eczema and microplatlets and treatment unresponsiveness.
This result is comparable with other reports who find that isolated ITP can be an initial sign of autoimmune disorders in children. Systemic lupus erythematous (SLE), Evans syndrome, autoimmune lymphoproliferative syndrome (ALPS), HIV, viral hepatitis and primary immunodeficiencies may initially present as thrombocytopenia. Further evaluation is warranted in patients who have had recurrent or chronic ITP especially if they have had poor response to IVIG and steroids [2,8,9]. Furthermore, immunoglobulins as a part of a reassessment evaluation should be periodically tested in those children [2].
The risk of developing primary immunodeficiencies (PID) following the onset of ITP has been extensively examined [2]. PID may be present in 2 to 11 percent of ITP patients. PID ITP patients are more likely to fail first line therapy. Therefore treatment- refractoriness may offer some additional guidance regarding which patients require additional screening for PID [4,10,11,12]. In our study, a primary immunodeficiency (such as WISKOTT ALDRICH or ALPS) is found in 4.5% of cases with thrombocytopenic purpura which is equivalent to the finding in the literature.
In common variable immunodeficiency, ITP occurred in 7.6% of the patients and it should be suspected in patients with recurrent ITP, Elsewhere ALPS can be found in 1% of IPT. [10,13]. Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disease (PID) characterized by thrombocytopenia, eczema, recurrent infections, and an increased incidence of autoimmunity and malignancies [15]. Its incidence is estimated to 1 to 10 per million children in the United States and Europe [16]. WAS in children are often first diagnosed with ITP, potentially leading to both inappropriate treatment and a delay in definitive life-saving therapy. WAS is detected in 7% of ITP patients [15,16,17]. It has traditionally been distinguished from ITP by the small size of the PLTs seen in WAS patients. As a result, the WAS gene diagnosis should be considered in all males with ITP-like symptoms, particularly those with a very early onset age, decreased MPV (6.5 fl), higher EOS counts, and elevated IgE level, increased NK cell number and diminished CD8+T lymphocyte count [15,16]. In our study we found 5 cases of WAS (3.7%) revealed by ITP of which 3 are confirmed genetically. All of these patients were males with the clinical triad: thrombocytopenic purpura, eczema and recurrent infections.
The systemic lupus erythematosus (SLE) is a connective tissue disorder with variable presentations in children. The usual presentation includes arthritis, malar rash, nephritis, hemolytic anemia, and fever. Isolated hematological manifestation of SLE in children is a rare entity, and it occurs in the form of hemolytic anemia, thrombocytopenia, and persistent leukopenia [18]. In general, it’s a female child with isolated bleeding and low platelet count. When platelet count didn’t go up despite appropriate treatment in lines of ITP, further investigations are done to make diagnosis of SLE [18]. Positive ANA are reported in 10% of ITP patients and 4% of them developed criteria consistent with SLE [2]. In our study, 4 patients (2.9%) with ITP presented positive AAN and were transferred to the rheumatological unit to further assessment and specific treatment.
Other causes of secondary ITP can be seen such as infections like HIV, hepatitis c, and HP infection. Approximately two-thirds of children with ITP have a history of an infection during the prior month. Viruses commonly identified as triggers include cytomegalovirus, hepatitis C, herpes, varicella zoster, Epstein-Barr, influenza, and HIV [19]. Among HIV positive patients, thrombocytopenia is a common feature. Various studies indicated that about 5% to 10% of HIV infected patients develop thrombocytopenia during the course of the disease, and ITP may be the sole clinical manifestation of HIV infection. Steroids, IVIGs, and antiretroviral therapy have all been tried with fall in platelet count on withdrawal of therapy [5]. Hepatitis C virus has been reported to be associated with the occurrence of autoimmune disorders, including ITP. A study with 150 subjects reported that the prevalence of severe thrombocytopenia was significantly higher in ITP patients compared with that in chronic HCV patients [5]. During the SARS-CoV-2 pandemic, it is important to remember the association between isolated thrombocytopenia and COVID-19 and to include the PCR for SARS-CoV-2 in the laboratorial investigation and follow-up, as ITP can develop [20].
Immune thrombocytopenia has been shown to be linked to H. pyloriinfection. The prevalence of H. pylori infection is 70% in Japanese ITP patients, 22% in North American chronic ITP patients, 29% in patients with ITP of white French origin [5]. In our study we found this HP infection in 6.6% of ITP patients. The pathogenic link between H. pylori infection and PIT might be the molecular mimicry between platelet surface glycoproteins and amino acid sequences of H. pylori [21]. Based on recent systematic reviews, more than half of patients have successfully recovered platelet counts following H. pylori eradication treatment [22,23]. However, response rates vary widely across geographic regions, with highest response rates reported in Japan and Italy [5,24]. Therefore, they suggest that the group of ITP patients from highly endemic regions should be considered for H. pylori detection testing and therapy [5].
The ITP patients are usually treated with steroids or immunoglobulin as a first line treatment. For chronic ITP the traditional therapies is rituximab and splenectomy. Thrombopoietin receptor agonists are newer agents for the treatment of chronic ITP and hold promise, however, their cost currently precludes use in most of the patients in low-middle-income countries [7]. Mortality from ITP in children is rare and mainly due to complications from catastrophic bleeding, specifically intracranial hemorrhage. The majority of mortality and morbidity in pediatric chronic ITP comes from complications of long-term immunosuppressive treatment, mainly infections [1,7].
CONCLUSION
The IPT can reveal an underlaying disease or condition such as a primary immunodeficiencies, a systemic lupus or un HP infection. The diagnosis of secondary ITP should be suspected in the presence of medical history of recurrent infections, failure to thrive, eczema and microplatlets and treatment unresponsiveness.