The vascular endothelial barrier maintains intravascular volume and metabolic homeostasis. Although plasma fluids and proteins extravasate continuously from tissue microvasculature (capillaries, post-capillary venules), systemic vascular leakage increases in critical illness associated with sepsis, burns and trauma, among others, or in association with certain drugs or toxin exposures. Systemically dysregulated fluid homeostasis, which can lead to hypovolaemia, hypotensive shock and widespread tissue oedema, has been termed systemic capillary leak syndrome (SCLS) when overt secondary causes (for example, heart or liver failure) are excluded. In severe forms, SCLS is complicated by compartment syndrome in the extremities and multi-organ dysfunction syndrome due to shock and systemic hypoperfusion. The different forms of SCLS include idiopathic SCLS (ISCLS) and secondary SCLS (SSCLS), which can be triggered by several conditions, including certain infections and haematological malignancies. A subgroup of patients with ISCLS have monoclonal gammopathy-associated SCLS (also known as Clarkson disease), which is an ultra-rare and extreme form of ISCLS. ISCLS can be managed effectively with monthly prophylactic immunoglobulin therapy whereas SSCLS frequently does not recur once the underlying condition resolves or the offending agent is discontinued. Thus, differentiation between ISCLS, SSCLS and other causes of oedema is crucial for quick Nature Reviews Disease Primers | (2024) 10:86 2 0123456789();:
Primerprophylactic therapy. A chronic form of SCLS consisting of persistent, non-paroxysmal peripheral oedema and hypoalbuminaemia has been described 6 ; however, because these patients do not experience acute flares meeting the clinical criteria for ISCLS or MG-CLS, we do not discuss this entity here.Although the precise molecular mechanisms underlying SCLS from all causes remain poorly understood, progress has been made in the past decade towards better disease recognition, prophylactic treatment and understanding of pathophysiology, particularly for MG-CLS, which include the identification of autonomous functional defects in the MG-CLS vascular endothelium 7-10 and a natural mouse model of disease 11 . In contrast to these vascular-centric mechanisms, many drugs or toxins implicated in SSCLS may exert their effects indirectly by modulating the immune system or eliciting release of pro-inflammatory cytokines 2 . Less frequently, drugs or infectious pathogens are directly toxic to endothelial cells, resulting in activation, injury, or cell death 12 and subsequent vascular leakage.Because there are no disease-specific biomarkers other than the monoclonal gammopathy present in some patients, ISCLS is diagnosed based on clinical characteristics: at least one episode in which hypotension (systolic blood pressure <100 mmHg), haemoconcentration (haemoglobin levels above the normal range for age and sex or ≥20% increase in haemoglobin or haematocrit (Hct) over the last reference value in each patient), and hypoalbuminaemia (seru...
