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.