Idiopathic systemic capillary leak syndrome in childhood : A Literature Review

Idiopathic systemic capillary leak syndrome in childhood: A Literature Review Tu-Anh Tran1*, Anne Filleron1, Mathieu Simonin2 and Pierre Corbeau3 1Department of Pediatrics, Nîmes University Hospital, INSERM U 1183, Montpellier-Nîmes University, Nîmes, France 2Institut Gustave Roussy, Department of Pediatric Oncology, 114 Rue Paul Vaillant, 94800 Villejuif, France 3Department of Immunology, Nîmes university hospital, Montpellier-Nîmes university, Nîmes, France


Introduction
Systemic capillary leak syndrome (SCLS), also known as Clarkson's disease 1 , is a rare and severe condition characterized by a recurrent stereotypical triad: hypovolemic shock, generalized edema, paradoxical hemoconcentration and hypoalbuminemia 2 .It is caused by massive fluid extravasation into the interstitial space.Mortality may result from hemodynamic failure in the acute phase or cardiac failure due to reflex circulatory overload in the subacute phase 3 .The physiopathology of this disease is still debated.Yet, studies clearly describe an inflammatory substratum 4,5 , and we have recently shown that interleukin-17 might be involved 6 .Approximately 170 idiopathic systemic capillary leak syndromes have been reported in the literature 7 .Here we review all the 21 published cases of pediatric idiopathic SCLS.

Review of the literature
We conducted a literature search to identify case reports of pediatric (<18 years) idiopathic SCLS.Briefly, PubMed was searched from January 1960 to October 2016 using the following keywords: "idiopathic capillary leak syndrome", "Clarkson's disease", "pediatric and gastrointestinal symptoms in nine patients (Table 1).Sixteen patients presented with edema (periorbital, facial, limbs, or generalized ascites) and among 16 patients who experienced hypotension, ten presented with hypovolemic shock.In addition, five patients had heart failure and a further six developed pulmonary edema during the recovery phase (Table 1).Two patients suffered from neurological complications (cerebellar edema or seizure) (Table 1).
The sex ratio (M/F) of pediatric cases was 0.32 with a median age at disease onset of 5.7 years (range: 17 days-17 years) and a median age at diagnosis of 6.0 years (range: 17 days-23 years).Three cases had a family history of SCLS.Individual characteristics and disease courses are summarized in Table 1.Four patients had only one attack, whereas the others experienced several ones with a median of three attacks (Table 1).A possible viral infection was suspected as a triggering factor for 11 patients (Table 1 esterase inhibitor was normal when analyzed, while the inflammatory marker tumor necrosis factor (TNF)-alpha was high in six cases 6,12,20 , and interleukin-17 in one case 6 .Surprisingly, none of the 15 children whose data were available showed evidence of the monoclonal gammopathy that is otherwise frequently seen in adult SCLS.
Therapy during the acute phase included massive intravenous fluid administration in all cases.Fluid administration led to severe complications during the repletion phase: seven patients suffered acute pulmonary edema and three patients presented with heart failure (Table 1).Inotropic drugs and/or mechanical ventilation were necessary in ten cases, intravenous or subcutaneous immunoglobulins and/or systemic steroids in eight cases, and anti-TNF therapy in one case 12 .After the attack, 12 patients received one or more prophylactic treatments: Gingko biloba alone (n=1) 8 or associated with terbutaline (n=1) 11 , theophylline with terbutaline (n=4) 9,12,18,21 , montelukast (n=1) 13 , verapamil and aminophylline (n=1) 17 and immunoglobulins (n=4) 20 .Two deaths were reported: one occurred 2.7 years after the first attack 15 , one in a 17-day-old baby during his first attack 13 .No one of the patients who died was on prophylactic treatment.

Discussion
The clinical and laboratory features of pediatric disease are highly similar to adult cases 13,15 , except for two important differences.Firstly, monoclonal gammopathy has not been reported in the pediatric setting, in striking contrast to the high incidence (89% 15 or 76% 13 ) observed in adult patients.The contribution of gammopathy to disease pathogenesis remains debated 23 .Also, we have found no evidence that gammopathy has any correlation with SCLS in children.Secondly, the occasional family history of SCLS in pediatric cases has not been reported in adults 13,15 , suggesting that an inherited predisposition confers a higher risk of earlier presentation.
Neurologic involvement has been reported in only three adults 24 and in two pediatric cases thus far.Sion-Sarid et al 14 .reported a case of SCLS with neurological complications.In their case, the clinical and the radiological findings were similar to those of reversible posterior leukoencephalopathy syndrome, an uncommon neurologic syndrome, after rapid onset of severe hypertension.In our case previously reported 6 , hyponatremia present during the acute phase could be partly responsible for a degree of brain edema and seizures.However, the origin of the CNS-abnormality remains unknown in our case.In both cases, the neurologic deficits and the MRI brain lesions completely resolved.
Therapy during the acute phase consists in fluid administration to stabilize hemodynamic instability.However, this fluid replacement should not be excessive because some patients affected with SCLS die due to complications of massive fluid repletion (acute pulmonary edema and/or heart failure).

Elevated inflammatory cytokines have been reported
in patient's sera 20 .Remission samples of our patient's leukocytes exhibited abnormal patterns of cytokine secretion as levels of Th17 pro-inflammatory factors in supernatants of cultured PBMC were elevated compared to healthy controls 6 .Strikingly, these differences were more marked following in vitro leukocyte stimulation, suggesting that intrinsic differences in cytokine responses to biological stimuli in vivo might contribute to disease pathogenesis.

Conclusion
SCLS remains a rare disease in children but with increasing number of cases recently reported.Due to the extremely low incidence of pediatric SCLS, recommendation for treatment and pathophysiology studies might be better undertaken within the framework of an international registry.

Table 1 .
). Prodromal symptoms occurred in 17 patients, including flu-like symptoms in nine patients Physical and biological features of the paediatric idiopathic SCLS cases.