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Management of childhood idiopathic thrombocytopenic purpura

1999; Wiley; Volume: 105; Issue: 4 Linguagem: Inglês

10.1111/j.1365-2141.1999.01409.x

1365-2141

John Lilleyman,

Renal Diseases and Glomerulopathies

In the 16 years that have elapsed since my previous review on childhood ITP (Lilleyman, 1983) there has been no evident change in the morbidity or mortality of the disorder despite the advent of immunoglobulin and other new therapies. Some things have moved on, however. We are slightly less confused about its natural history. We perhaps have a clearer idea about the risks and outcome of intracranial haemorrhage. Clinical guidelines have appeared (Eden & Lilleyman, 1992; George et al, 1996). An international collaborative group of physicians has been established, and a United Kingdom based patient and parent support group has been set up (details available from the author). But the major debates about diagnosis and management rumble on, fuelled by lack of data from large clinical trials and, unlike other rare childhood disorders, the failure to centralize care of even the most difficult cases. The incidence of (symptomatic) ITP in the U.K. is around 4 per 100 000 children per year, very similar to that of acute leukaemia. Most sufferers will have the acute self-limiting problem typical of childhood, but around 1 in 10 will grumble on for 6 months or more. Of the 6-month offenders, most will eventually remit spontaneously or stabilize with moderate and asymptomatic thrombocytopenia, but there is a small hard core (again perhaps 1 in 10 of these patients) who will remain profoundly thrombocytopenic and haemorrhagic for > 12 months. These rare and difficult-to-treat children with chronic symptomatic ITP (CSITP) are therefore very infrequent with an annual incidence of perhaps 1 per 2 500 000. CSITP is, of course, much commoner in adults and it is worth re-emphasizing that adult ITP overall is a more serious problem with a much higher mortality (George et al, 1996). Paediatricians would not worry about treatment for ITP if they were not transfixed by the fear of death due to intracranial haemorrhage (ICH). It does undoubtedly occur, but very rarely. In the review undertaken by the ITP guideline panel of the American Society of Hematology (ASH), 30 incidents of ICH were cited (George et al, 1996). In another report completed too late to be included in the ASH survey, 13 previously unpublished cases were discovered in a nationwide study from the U.K. (Lilleyman, 1994). The most recent literature review cites another 11 cases (Medeiros & Buchanan, 1996), making 54 in all. This collective experience gives an idea of the frequency, morbidity and mortality of the catastrophe. The figure widely believed to indicate the risk of ICH is around 1% (Blanchette et al, 1994), but this is meaningless unless a denominator is defined. In the 54 cases referred to above, ICH was effectively confined to children with platelet counts < 20 × 109/l. Around half the bleeds occurred over a month from initial presentation, at which stage most children with ITP would no longer have such low platelet counts. 15/54 bleeds occurred > 6 months from diagnosis, by which time only a tiny fraction would still be profoundly thrombocytopenic. The risk, expressed as a proportion of those exposed to it, can thus be seen as one that increases with time as the denominator dwindles. This is what might be expected, but it destroys the widespread belief that ICH is most likely to arise in the first few days following presentation, and weakens the case for aggressive intervention at that stage. The cumulative risk of ICH may eventually rise to 1% of those with < 20 × 109/l platelets after 6–12 months. In the first few days after diagnosis the figure is closer to 0.1–0.2% (Lilleyman, 1994). Apart from problems with denominators, ICH risk has almost certainly been over-estimated in the past because of failure to distinguish between ITP and more serious causes of thrombocytopenia where platelet production or function might be impaired. This is relevant because at the same platelet count the bleeding tendency in ITP is less than in marrow failure syndromes, reflected in a shorter bleeding time and a higher proportion of young (reticulated) platelets. There are two other important points to note about ICH in ITP. First, additional risk factors are often present. Of the 14 events in the U.K. survey, half did not occur spontaneously in uncomplicated ITP. Two (perhaps three) children had cerebral arteriovenous malformations, two had (serious) head injuries, and four had features (associated disease) calling the diagnosis of simple ITP into question (Lilleyman, 1994). Secondly, the incidence of ICH and mortality are not synonymous. Given aggressive management, 50% of the children will survive with minimal sequelae (Medeiros & Buchanan, 1996). So, taking all factors into account, the mortality from spontaneous ICH in simple ITP becomes very low indeed. The diagnosis of ITP is made on the basis of excluding other disorders, as there are no confirmatory laboratory tests. The clinical picture of a well child with bruising/petechiae of sudden or recent onset found to be associated with isolated thrombocytopenia is sufficient for a presumptive diagnosis. The same cannot be said if a low platelet count is discovered incidentally in a child with no abnormal physical signs — such children need closer scrutiny. Note should be taken of any recent vaccinations but a history of antecedent infection is useful only if specific (such as varicella). Upper respiratory infections in young children are too frequent to be of any importance. Conditions that are occasionally confused with ITP in children include congenital thrombocytopenias, evolving marrow failure syndromes such as Fanconi anaemia or acquired aplastic anaemia, or marrow failure caused by leukaemia. Also, immune thrombocytopenias that are part of more complex diseases should not be considered as ITP. These include congenital and acquired immune deficiency syndromes (including HIV infection and Hodgkin's disease), Evans syndrome (relapsing immune thrombocytopenia and haemolytic anaemia), and systemic lupus erythematosus. Such disorders present different management problems beyond the scope of this article. How vigorously a differential diagnosis should be pursued at the time of presentation depends on the clinical picture and the plan of management. There is continuing debate whether bone marrow cytology is necessary at the outset to exclude leukaemia, particularly if steroid therapy is planned. The consensus has swung against this, provided the history and clinical picture is entirely typical of acute onset ITP and the peripheral blood is entirely normal apart from profound and isolated thrombocytopenia. It must be admitted, however, that the mistake of missing a diagnosis of leukaemia (or other disorder) is occasionally made (Bolton-Maggs & Moon, 1997) and the threshold for marrow examination should be low if there is the slightest clinical doubt. In any event, there is agreement that if thrombocytopenia persists or recurs after therapy (or a period of observation) then marrow examination is appropriate and necessary (George et al, 1996). Platelet serology is generally unhelpful, but estimating the proportion of reticulated platelets may be useful in distinguishing between short platelet survival and production failure as the basis for a low count (Saxon et al, 1998). Existing guidelines (Eden & Lilleyman, 1992; George et al, 1996) are based more on opinion than evidence, and are not adhered to (Bolton-Maggs & Moon, 1997). Many arguments remain about how to manage newly diagnosed children — should they be treated at all, and if so with what and on what criteria? The medical literature is rather disappointing. In the last 20 years only 13 relatively small randomized trials of therapy in untreated acute childhood ITP have been reported. The largest had 160 patients; six had fewer than 50. 11 are detailed in the ASH guideline review (George et al, 1996); two are more recent (Rosthoj et al, 1996; Warrier et al, 1997). All trials used the speed of rise in platelet count as a surrogate clinical outcome. They (mostly) attempted to compare varying analogues and schedules of corticosteroids with (in the case of four trials) no therapy or (in the case of six trials) with polyvalent intravenous immunoglobulin (IVIg) at varying doses. One simply compared different doses of IVIg. One of the best designed, a multi-centre Canadian study, included intravenous anti-D in a four-way randomization between two schedules of IVIg and oral prednisone (Blanchette et al, 1994). In all trials there was a consistent trend to support the conclusion that the average time for the platelet count to rise is shortest using IVIg or high-dose steroids, next shortest using conventional dose steroids (or anti-D) and slowest on no treatment. Lower doses of IVIg (one dose of 0.8 g/kg or two at 250 mg/kg) are apparently enough for a prompt response in most children. The median time taken to reach a platelet count > 20 × 109/l in the 30 untreated patients from the two trials where this was assessable was from 3 to 5 d, whereas for treated patients the corresponding figure was 1–3 d (Buchanan & Holtkamp, 1984; Blanchette et al, 1993). There is little doubt that this difference is statistically significant, but a more important question, so far unanswered, is whether it is clinically important. The Canadian group argued that any means of increasing the platelet count as rapidly as possible will reduce the risk of ICH — a risk they consider in newly diagnosed patients to be 1% (an overestimate, see above). On this basis they conclude that IVIg at 'low' dose (a single infusion of 0.8 g/kg) is the initial treatment of choice for all children with ITP and platelet counts of < 20 × 109/l (Blanchette et al, 1994). That recommendation was conditionally supported by the ASH panel in their 1996 guideline where they recommend IVIg (1 g/kg) in children with platelets < 20 × 109/l, but who also have purpura or more important haemorrhagic signs (George et al, 1996). For children with no such signs they give no clear recommendation. The Canadian group was challenged, however, for regarding a relatively small difference in time to platelet recovery as clinically important. An independent calculation from their published trial data suggested that even with the (overestimated) risk of ICH of 1%, 555 children with ITP would have to be treated with IVIg to prevent one ICH, an event that might have a favourable outcome anyway (Vermeulen, 1994). This goes to the nub of the debate about treatment for newly diagnosed ITP. Is the advantage gained by therapy big enough to justify the risks and side-effects? IVIg has all the hazards and distress of i.v. infusions and hospitalization, frequently causes fever, flushing and headache, occasionally causes aseptic meningitis, and has all the potential problems of a large pool blood product. Hepatitis C is a real risk even though now it has been reduced through viral inactivation procedures (Yap, 1996). High-dose steroids cause psycopathy, carbohydrate intolerance, intracranial hypertension, and (most importantly) immunosuppression with a small but real risk of overwhelming varicella infection (Dowell & Bresee, 1993). So why rush into treatment of well children who just have bruising and purpura? Davis & Raffles (1997) eloquently put the paediatrician's view when they asked how you face grieving parents of a child who has died from ICH when you have given no treatment. Perhaps the answer is with as much difficulty as facing those grieving for a child lost through chicken pox, or telling a young adult with progressive liver disease how it came about. It is very difficult to balance risks and benefits when both are tiny. It is important to note that the only early death reported in all the 829 children in the 13 trials referred to above was that of an 11-year-old girl who perished with cerebral bleeding after three doses of IVIg (Imbach et al, 1985). She had a florid concomitant viral infection so may not have had simple immune thrombocytopenia as a sole bleeding tendency. Nevertheless this one tragic child is a beacon illustrating the rarity of early ICH and the fact that the risk of it is not eliminated by treatment. So the decision to treat at the time of diagnosis has to be an individual one taken at the bedside. If faced with a worryingly haemorrhagic child and a platelet count < 20 × 109/l, arguably short sharp high-dose steroid therapy is the least risky and most acceptable option from the patient's point of view. There is simply no evidence that IVIg offers any clinically important advantage in these circumstances. Steroids should not be continued, however, if there is no response or if there is a rapid relapse after withdrawal. The considerable risks of long-term side-effects outweigh the benefits of either too-frequent high-dose pulses or any attempt to titrate the platelet count against a regular lower steroid dose. No mention has been made of platelet transfusions because there is no place for their routine use in ITP, either at diagnosis or later if the disease becomes chronic. Despite this the practice depressingly continues (Bolton-Maggs & Moon, 1997). Conventional doses of platelets offer risk without benefit since the transfused platelets are rapidly cleared from the circulation. The only extraordinary circumstance where platelets are appropriate is true life-threatening haemorrhage (intracranial or elsewhere), and then the dose should be massive, analogous to the 'swamping' dosages of factor VIII used in haemophiliacs with inhibitors. Children who have ITP that persists for 6 months or more present a spectrum of problems varying from mild symptomless low platelet counts through intermittent relapsing symptomatic thrombocytopenia to the rare stubborn and persistent symptomatic and haemorrhagic disease (CSITP). It is the latter (smallest) category that presents the biggest challenge and to which the rest of this section refers. Children with less severe forms of chronic ITP need either no therapy at all or just an occasional therapeutic nudge with the least harmful treatment that is effective to tide them over a symptomatic relapse. Symptomless children can be left without therapy and merely kept under observation. They should not be considered for therapy unless they slide into the CSITP group, and should be given every opportunity to remit spontaneously as the majority will do so given time (Medeiros & Buchanan, 1996). Untreated and unremitting CSITP carries a small risk of ICH (see above) which approaches or exceeds 1% by 12 months from diagnosis and continues gradually to increase as a function of time of exposure. It is understandable that efforts to reduce this risk and to relieve other morbidity (mucosal bleeding, menorrhagia) have been made over the years, with the result that many candidate therapies have been tried. None has proved universally successful, and none (so far) has been assessed in the context of a randomized clinical trial. Before contemplating any therapy in CSITP it is important to revisit the diagnosis to ensure that the problem is not due to marrow failure or part of a wider autoimmune disorder or immune deficiency syndrome. That done, any candidate treatment should then ideally fulfil two criteria; first, it should be effective, and secondly it should be less hazardous than the untreated disease. The strategies for which there is the most recorded experience are splenectomy, intermittent IVIg (polyvalent or anti-D) and pulse steroid therapy. Other immuno-modulatory regimens, of which there is less recorded experience (in children), include danazol, vincristine, cyclophosphamide, azathioprine, α-interferon, dapsone, ascorbic acid and staphylococcal protein A immunoadsorption. These latter therapies are generally reserved for rare and difficult patients who have exhausted more conventional options. They are of limited use, and experience with them in children is only anecdotal. They have recently been reviewed in detail elsewhere (Blanchette et al, 1998). The most difficult decision to make in any child with CSITP is whether to opt for splenectomy, and if so at what stage. Despite the fact that no randomized trial has ever been carried out, experience of this treatment for childhood ITP has been accumulating for > 70 years, and there is little doubt that it can induce lasting remissions in the majority of patients. The ASH panel carefully reviewed the evidence for this when constructing their guidelines. They reviewed 16 case series where the outcome of splenectomy was reported and noted that 72% of the 271 children described achieved a complete remission (George et al, 1996). This figure has to be interpreted with caution, though, because some of these children may have subsequently relapsed and many may merely have had a spontaneous remission brought forward by the operation. It is the background spontaneous remission rate that makes it so difficult to assess the value of any therapy in chronic ITP, and it should always be remembered that the majority of children will recover despite treatment rather than because of it. Splenectomy thus may be effective, but whether it is safer than the untreated disease is not so clear. Apart from the risks of any abdominal surgery, there is the hazard of overwhelming post-splenectomy sepsis. This was given a mortality of >1% for children with ITP by Singer (1973) in his seminal review 25 years ago, a figure which up to 8 years ago had apparently not changed (Holdsworth et al, 1991). Whether the size of the risk has subsequently been reduced by routine preoperative immunization against H. influenzae, S. pneumoniae and N. meningitidis and the use of post-operative long-term prophylactic antibiotics is not clear. Perhaps this is so, but it is unlikely to have been eliminated. And it may remain for life. So, those contemplating splenectomy must carefully weigh up whether the mortality of the treatment might exceed that of the untreated disease. They should remember that at least one in four children will not remit afterwards and will thus be left with a compounded risk. Predicting the outcome of splenectomy by responsiveness to IVIg (Law et al, 1997) or radioisotope studies (Najean et al, 1997) may improve this figure, but there will still be non-remitters, or those who subsequently relapse. The ASH panel were cautious and placed conditions on their tentative recommendation that persistence of disease after 12 months with bleeding symptoms and a platelet count of < 10 × 109/l may be an indication to proceed with the operation. They noted that patients should also have had no or only transient success with intermittent IVIg, anti-D or pulse steroids and have no contra-indications tosurgery. Children with CSITP who have not reached the stage where splenectomy is being considered and who genuinely need treatment for the relief of symptoms can be given pulses of IVIg, anti-D or steroids. There is no evidence that any of these strategies offers more than temporary relief and the duration and extent of response is variable, depending more on the patient than on the treatment. They are therefore probably more or less alternatives and can be considered together. Polyvalent IVIg may be the least attractive because of the need for slow i.v. infusion and the relatively high incidence of immediate unpleasant side-effects. Anti-D (25–55 μg/kg) in those who are Rh D positive appears to be no less effective, cheaper, easier to give and better tolerated (Andrew et al, 1992). Pulse steroids can be high-dose prednisolone, methyl prednisolone, or dexamethasone. They can be given by mouth or parenterally, and there is no evidence that any particular schedule is more or less effective than any other. There was some excitement a few years ago following a description of lasting remissions in adults with refractory CSITP given 5 d courses of 40 mg/d of dexamethasone monthly for 6 months (Andersen, 1994). The experience in children has been that only a proportion of them respond in much the same way as any other pulse steroid regimen, however (Borgna-Pignatti et al, 1997). Care must be taken with any pulse steroid strategy to avoid such frequent treatment that clinically obvious steroid side-effects arise, and there is no justification under any circumstances for long-term continuous steroids. Parents of children being treated with steroids should be warned of the dangers of immunosuppression. Children with CSITP who relapse or fail to remit after splenectomy are a rare but difficult problem. The ASH guideline offers no recommendations. For patients with troublesome symptoms, something from the catalogue of experimental therapies listed above might be considered. It cannot be over-emphasized, however, that symptomless patients are best left alone and a minimalist approach to all such children is the least potentially harmful. Spontaneous remission can still occur, given time. Childhood ITP is usually an uneventful self-limiting disorder. Its mortality has been over-estimated in the past and this has probably led to over-treatment of some patients. There is continuing and legitimate debate about the need for therapy immediately following diagnosis, though consensus exists for some intervention in the overtly haemorrhagic child with < 20 × 109/l platelets. Short-course high-dose steroids may be the least risky strategy. Chronic ITP is rare and should be given every opportunity to remit spontaneously. Splenectomy should be approached with extreme caution, though it still may have a place in the very infrequent children who are profoundly thrombocytopenic and overtly symptomatic for 12–24 months. Presently there are insufficient trial data on morbidity and mortality to support evidence-based treatment guidelines in childhood ITP and therefore there is every reason to encourage future multi-centre collaboration. Patients with CSITP are particularly difficult to treat and arguably should be referred to specialist centres.