Idiopathic systemic capillary leak syndrome (Clarkson disease)

Abstract

In 1960, Dr Bayard Clarkson described a woman experiencing sporadic recurrent episodes of shock and anasarca. Plasma from an acute attack induced a shock-like syndrome when injected into rats. The enigmatic systemic capillary leak syndrome (SCLS) named for Dr Clarkson is characterized by transient and severe but reversible hemoconcentration and hypoalbuminemia caused by leakage of fluids and macromolecules into tissues. Although less than 500 cases of SCLS have been reported in the literature since 1960, the condition is probably underdiagnosed because of a lack of awareness and a high mortality without treatment. Allergists should be vigilant of this diagnosis because its presentation can resemble more common plasma leakage syndromes, including angioedema or systemic anaphylaxis. Although the precise molecular cause of SCLS remains unknown, substantial advances over the last 5 years have increased our understanding of SCLS pathogenesis.

Keywords: Vascular leak; anaphylaxis; angioedema; intravenous immunoglobulin.

Figure 1. Acute SCLS sera induce junctional destabilization and contraction of endothelial cells

Application of same-subject SCLS patient sera from non-symptomatic period (Basal, left) v. that obtained during an acute attack (Episodic, right) to primary human dermal microvascular endothelial cells demonstrates disruption of junctional VE-cadherin (green), increased actin stress fibers (red), and development of gaps between adjacent cells (white arrows).

Figure 2. Angpt-Tie2 pathway mediates endothelial barrier function in response to inflammatory stressors

(A) Schematic of Tie2-dependent barrier defense pathway in endothelium. (B–C) Vascular permeability measurements from lungs of mice treated with LPS with and without Angpt-1 demonstrating enhanced susceptibility to vascular leakage arising from incomplete loss of expression of either Tie2 (receptor for Angpt-1) (B) or p47Phox (C). Results are normalized to respective genetic controls to illuminate differences in responses to LPS. ****p<0.0001, 2-way ANOVA. Adapted from References^{, ,} .

Figure 3. RNAseq of SCLS BOECs implicates persistent pro-migratory and pro-inflammatory responses

Ingenuity pathway analysis of RNAseq results from 6 SCLS BOECs v. 6 control BOECs organized by Benjamini-Hochberg corrected p-value. Dash p=0.05. Highlighted box indicates categories with particular functional relevance to SCLS.

Figure 4. Cardiovascular MRI suggests myocardial vascular leak in SCLS

(A) Pre-and post-contrast myocardial T1 maps in a patient with SCLS. Regions of interest drawn within the septum and blood pool are used to calculate the extracellular volume fraction (ECV). (B) Mid-ventricular short axis ECV map in the same patient. The color scale for displaying ECV values was chosen so that green colors represent the mean ± 3 s.d. of normal myocardium from age-matched controls. (C) CMRI demonstrates increased myocardial ECV in patients with active VEH compared to asymptomatic group. **p=0.003, Mann-Whitney. Adapted from References^, .

Figure 5. Proposed treatment algorithms for active SCLS (left) and prophylactic management (right)

MODS-multi-organ dysfunction syndrome; DVT-deep venous thrombosis; IVIG-intravenous immunoglobulins; SCIG-subcutaneous immunoglobulin; cAMP-cyclic adenosine monophosphate.