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)