2.4.1 Main drugs involved
Drugs that can increase capillary permeability to proteins lead to the loss of protein-rich fluid from the intravascular to the interstitial space. The main drugs causing permeability edema include anticancer drugs (Azzoli et al., 2003; D’Angelo et al., 2011; Giles, O’Dwyer, & Swords, 2009; Hack, Bruey, & Koeppen, 2014; Izzedine, El-Fekih, & Perazella, 2016; Mertz, Lebrun-Vignes, Salem, & Arnaud, 2019; Rizzo, Aman, van Nieuw Amerongen, & Dudek, 2015; Sibaud et al., 2016; Siddall, Khatri, & Radhakrishnan, 2017), cytokines (Mertz et al., 2019), ambrisentan (Vercauteren et al., 2017) and calcineurin inhibitors (Mertz et al., 2019) (Figure 2 ). This mechanism of edema is becoming an increasingly common clinical picture with the advent of multikinase inhibitors that interfere with the signaling pathways involved in endothelial permeability (e.g., BCR-Abl inhibitors (García-Gutiérrez & Hernández-Boluda, 2019), ALK inhibitors (Hack et al., 2014; Izzedine et al., 2016)). Capillary leak syndrome (CLS) represents the paroxysmal picture of permeability edema. As in idiopathic CLS (i.e., Clarkson disease) (Druey & Parikh, 2017), drug-induced CLS is characterized by fluid-refractory hypotension, pathognomonic profile of hemoconcentration with rising hematocrit and paradoxical hypoalbuminemia in the absence of secondary causes for such abnormalities, and systemic pitting edema (Siddall et al., 2017). Cytokines (e.g., interleukin-2, granulocyte colony stimulating factor), and antineoplastic agents, especially gemcitabine and clofarabine, are the main drugs involved in secondary CLS (Jeong et al., 2019; Mertz et al., 2019)