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


 Systemic capillary leak syndrome (SCLS), is a rare condition characterized by a recurrent stereotypical triad: hypovolemic shock, generalized edema, paradoxical hemoconcentration and hypoalbuminemia. 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 sub-acute phase. To date, twenty-one pediatric cases were reported in the literature. Sex ratio (M/F) was 0.32 with a median age at disease onset of 5.7 years and at diagnosis of 6 years. The disease was recurrent in 81% of patients with a median of three attacks. Severe complications were possible involving central nervous system (n=2) or rhabdomyolysis, with a compartment syndrome needing fasciotomy (n=5). The median time to clinical recovery was five days. Although the clinical manifestations of pediatric and adult SCLS were similar; in the opposite of adult SCLS, none of the children showed evidence of monoclonal gammopathy and three pediatric cases had a family history of SCLS. Seventy five percent of the patients were treated with prophylactic treatment (mainly immunoglobulins, theophylline plus verapamil). Several inflammatory cytokines were suspected to be involved in the pathophysiology of SCLS, especially interleukin-17 and tumor necrosis factor -alpha.


 

Systemic capillary leak syndrome (SCLS), also known as Clarkson’s disease1, is a rare and severe condition characterized by a recurrent stereotypical triad: hypovolemic shock, generalized edema, paradoxical hemoconcentration and hypoalbuminemia2. 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 sub-acute phase3. The physiopathology of this disease is still debated. Yet, studies clearly describe an inflammatory substratum4,5, and we have recently shown that interleukin-17 might be involved6. Approximately 170 idiopathic systemic capillary leak syndromes have been reported in the literature7. Here we review all the 21 published cases of pediatric idiopathic SCLS.

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 idiopathic capillary leak syndrome”, “pediatric Clarkson’s disease". Among the 178 eligible articles, we finally selected 21 cases for further analysis6,8-22 after exclusion of the adult patients.

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). Prodromal symptoms occurred in 17 patients, including flu-like symptoms in nine patients 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).

  Reference Sex Age at onset Age at diagnosis Attacks (n) Prodroma Trigger Complications Biological features SCLS family history Time to recovery
1 Luquel8 M 17 y 23 y 3 No Season APE NA Sister 24 hours
2 Foeldvari9 F 3 y 9 y 5 AbP URTI No NAa No 2 d
3 Karatzios10 F 6 y 6.8 y 2 AbP Influenzae (H3N2) Cpt Sd NA No 24 hours
4 Onal11 F 3 w 5 m 3 Diarrhoea Diarrhoea No ARI No 27 d
5 Dowden12 M 6 y 6 y 1 Fever, Nausea, Vomiting No Cpt Sd ARI, RM, IL-6/TNF No 5 d
6 Kapoor13 NA NA 4 y NA NA NA NA NA No NA
7 Kapoor13 NA 17 d 17 d NA NA NA NA NA Mother NA
8 Sion-Sarid14 M 5 m 8 y 5 AbP, Vomiting No APE, Heart failure, PRES Sd ARI, RM 8 family cases 7 d
9 Gousseff15 F 5.4 y 5.7 y 4 NA NA NA NA No NA
10 Piastra16 F 6 y 6 y 2 Fever No No ARI, RM No 7 d
11 Milani17 F 34 m 48 m 4 Fever, Cough URTI Cpt Sd ARI, RM No NA
12 Iwasa18 F 10 y 10 y 2 AbP, diarrhea No Cpt Sd ARI, RM,G-CSF/IL-6 No 3 d
13 Perme19 M 8y 9y 2 Coryzal symptoms, Cough, Fever Influenzae A Heart failure ARI, RM No 7d
14 Hsu20 M 8y 8 y 1 Coryzal symptoms, Vomiting Rhinovirus, Para-influenza 3 APE NAa No 4 d
15 Hsu20 F 22 m 22 m 3 Coryzal symptoms Respiratory Syncitial Virus APE RMa No NA
16 Hsu20 F 6 y 10 y 2 Coryzal symptoms Influenzae A Cpt Sd RMa No NA
17 Hsu20 F 3 y 6 y 3 Coryzal symptoms, Diarrhea Streptococcus A APE NAa No NA
18 Hsu20 M 4 y 4 y 3 Coryzal symptoms, Vomiting, Diarrhea Influenzae A Heart failure NAa No NA
19 Kerketta21 F 6 y 6 y 3 No No No NA No 8 d
20 Simonin6 F 11.5 y 11.5 y 1 Myalgia, Arthralgia, Fever URTI APE, Seizure ARI, TNF/IL-17 No 5 d
21 Moreira22 F 5 y 5 y 1 Vomiting No APE NA No NA
Table 1.Physical and biological features of the paediatric idiopathic SCLS cases.

Abbreviations: y: years, m: months, w: weeks, d: days; AbP: Abdominal pain, APE: acute pulmonary edema, ARI: acute renal impairment, Cpt Sd: compartment syndrome, NA: not available, PRES syndrome: Posterior Reversible Encephalopathy syndrome, RM: Rhabdomyolysis, SCLS: Systemic Capillary Leak Syndrome, Sd: syndrome, URTI: Upper Respiratory Tract Infection. a4 of this 6 cases have an increase of TNF.

Rhabdomyolysis was found in eight patients (Table 1). Five of them presented with a compartment syndrome and fasciotomy was necessary in five patients (Table 1). The median time to clinical recovery was five days (range: 1-27 days). Three patients6,14,19 had biopsies (muscular or cutaneous), both showing non-specific abnormalities. C1 esterase inhibitor was normal when analyzed, while the inflammatory marker tumor necrosis factor (TNF)-alpha was high in six cases6,12,20, and interleukin-17 in one case6. 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 case12. 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 attack15, one in a 17-day-old baby during his first attack13. No one of the patients who died was on prophylactic treatment.

The clinical and laboratory features of pediatric disease are highly similar to adult cases13,15, 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 debated23. 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 adults13,15, suggesting that an inherited predisposition confers a higher risk of earlier presentation.

Neurologic involvement has been reported in only three adults24 and in two pediatric cases thus far. Sion-Sarid et al14. 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 reported6, 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 sera20. 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 controls6. 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.

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.

Thanks are extended to Drs Mariella Lomma and Carey Suehs for editing the manuscript.

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Article Info

Article Notes

  • Published on: January 14, 2016

Keywords

  • Systemic capillary leak syndrome

  • Children
  • Clarkson's disease
  • Review
  • Pediatric
  • Physiopathology
  • Cytokines

*Correspondence:

Tu-Anh Tran
Department of Pediatrics, Nîmes University Hospital, 1 place Robert Debré, 30029 Nîmes, France. Tel: +33 4 66 68 32 84
Email: tu.anh.tran@chu-nimes.fr.
Copyright: ©2017 Tran TA. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License.
Citation: Tran TA, Filleron A, Simonin M, Corbeau P. Idiopathic systemic capillary leak syndrome in childhood: A Literature Review. J Rare Dis Res Treat. (2017) 2(1): 52-55