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Pericardial effusion in pediatric SCT recipients with thrombotic microangiopathy

Pericardial effusion (PEF) is a known complication of hematopoietic SCT (HSCT) that can result in significant morbidity and even death by causing acute cardiac tamponade.1,2 The exact incidence and risk factors are not well described, but retrospective reviews report PEF occurring in 0.2–19% of HSCT patients.1,3,4 Age, gender, preparative conditioning regimen, GVHD and CMV or EBV viremias have been suggested as potential risk factors.1 The initial symptoms of PEF can be nonspecific, thus early detection and identification may improve patient outcomes.

In our clinical practice, we observed that patients with transplant-associated thrombotic microangiopathy (TA-TMA) tend to have clinically significant PEFs requiring medical or surgical interventions. TA-TMA occurs in ~25–30% of HSCT patients and is characterized by vascular endothelial damage leading to microangiopathic hemolytic anemia, thrombocytopenia and renal injury with multiorgan involvement and polyserositis in severe cases.5,6 Mortality in patients with severe multiorgan TA-TMA is as high as 90%.

Our goal was to determine the incidence and clinical significance of PEFs in patients diagnosed with TA-TMA. Our study cohort included 39 pediatric HSCT patients diagnosed with TA-TMA out of 100 patients who were prospectively enrolled in a study examining clinical and laboratory biomarkers of TMA occurring after HSCT from 2010 to 2012. TA-TMA was diagnosed using currently accepted diagnostic criteria including de novo anemia, thrombocytopenia, elevated dehydrogenase (LDH), low haptoglobin and presence of schistocytes on peripheral blood smear.5

We included patients diagnosed with TA-TMA who had at least one echocardiographic evaluation during the first year after HSCT. All patients had pre-HSCT echocardiography available for comparison that had been performed within 30 days before starting conditioning chemotherapy. The 2D transthoracic echocardiography studies were reviewed and interpreted by pediatric cardiologists. PEF was diagnosed if post-transplant echocardiography showed a new or increased presence of clear space between the visceral and parietal pericardium, reflecting an accumulation of fluid.7 PEF was defined as clinically significant if medical or surgical interventions were required.

In all, 33 of the 39 patients diagnosed with TA-TMA (85%) had echocardiographic studies performed for clinical indication. A total of 148 echocardiographs (median three studies per patient, range 2–22) were available. Of the 33 evaluated patients, 15 (45.4%) were diagnosed with PEF with the median time to diagnosis of 68 days after HSCT (interquartile range 58–259 days after HSCT). Of the 15 patients diagnosed with PEF, 5 (33%) had moderate-to-large effusion requiring medical management with diuretics and/or withdrawal of calcineurin inhibitors to control TA-TMA. Two patients (13.3%) with PEF had cardiac tamponade requiring surgical interventions. These two patients had persistent re-accumulation of pericardial fluid requiring repeated pericardiocentesis procedures until TA-TMA was controlled by discontinuation of calcineurin inhibitors in both the patients and eculizumab therapy in one patient. There were no infectious agents identified in pericardiocentesis fluid and these two patients did not have any evidence of GVHD.

There was a temporal relationship in the development of PEF and TA-TMA, as 13 of the 15 patients (87%) were diagnosed with PEF at a median of 54 days after TA-TMA diagnosis (interquartile range 22–120 days). Seven patients (47%) who were diagnosed with both TA-TMA and PEF died by 1 year post transplant with active signs of TMA. There were no significant differences in demographic and transplant characteristic between TA-TMA patients with PEF (n=15) and without PEF (n=18) (Table 1). The incidence of acute GVHD was similar in patients with and those without PEFs (6/15, 40% vs 8/18, 44%). The incidence of CMV viremia (7/15, 47% vs 6/18, 33%) and EBV viremia (5/15, 33% vs 6/18, 33%) was also similar in patients with and without PEFs, respectively.

Table 1 Demographic and transplant characteristics of pediatric patients with transplant-associated TMA (n=33)

Our study indicates that patients with TA-TMA have a much higher risk of developing clinically significant PEFs requiring medical or surgical interventions than is currently reported in the general HSCT population. We observed a similar incidence of acute GVHD and viral infections between patients with TA-TMA who had PEFs and those who did not. Even though the exact pathogenesis of PEFs in patients with TA-TMA is not completely understood, development of serositis most likely represents systemic inflammation in patients with TMA where vascular injury involves other organs besides the kidneys. In patients with other TMAs like atypical hemolytic uremic syndrome, it is speculated that myocardial injury from microangiopathy leads to inflammation and a reactive exudative process in the pericardial sac.8 TMA after HSCT has been shown to involve the vasculature of multiple organs including the lungs, bowel and the kidney, and it is possible that in certain cases, it can present as polyserositis. In severely affected patients, symptoms can progress rapidly and PEF may be refractory to symptomatic therapy until the underlying cause, such as TA-TMA, is controlled.9

By presenting our observations we would like to raise awareness of a potential association between TA-TMA and clinically significant PEF that can contribute to morbidity and prolonged hospital stay. We suggest that any patient who develops chest pain, tachycardia, cardiomegaly on chest X-ray or has signs of hypoxemia should be evaluated for PEF through echocardiography and tested for laboratory signs of TA-TMA.10 Patients diagnosed with a moderate-to-large PEF or impending tamponade should be promptly evaluated by a cardiologist.

We acknowledge that our study is limited to cardiac evaluations in patients with TA-TMA without comparison with HSCT patients without TA-TMA who had no clinically indicated radiologic evaluations. Future prospective controlled studies should further delineate the etiology and risk factors of PEFs after HSCT to propose clinical monitoring and intervention algorithms.

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Lerner, D., Dandoy, C., Hirsch, R. et al. Pericardial effusion in pediatric SCT recipients with thrombotic microangiopathy. Bone Marrow Transplant 49, 862–863 (2014). https://doi.org/10.1038/bmt.2014.40

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