Capillary leak syndromes consist of conditions where fluid and protein leak across capillaries and lead to an accumulation of interstitial fluids and intravascular volume depletion. While sepsis is by far the most common of these syndromes, a large variety of poorly understood, relatively unusual syndromes of capillary leak exist [1]. Among these is Idiopathic Systemic Capillary Leak Syndrome (ISCLS), first described in 1960 and eponymously named Clarkson's disease [2]. Dr. Clarkson reported a case that would become the classic clinical presentation of this rare syndromic complex. He described a 34-year-old woman with an abrupt onset of fevers that were low-grade with a progressive decrement in blood pressure followed by rapid swelling of the face and extremities. The hematocrit increased despite intravenous fluid resuscitation. Anasarca and unexplained shock were followed several days later by a period of diuresis and a diminution in peripheral edema. The patient ultimately died of pulmonary edema and cardiac failure.

Since this distinctive clinical presentation was first described in 1960, there have been roughly 260 new cases of ISCLS reported in the literature. Most of these patients are adults, median age of 48 years, and of Caucasian extraction. Nevertheless, Clarkson's disease has been reported in newborns, children and individuals in their 80's, and patients of all ethnicities [3], [4].

The classic scenario includes acute episodes of plasma extravasation into the interstitial space resulting in shock, elevated hemoglobin (Hgb), and diminished serum albumin. This “leak” phase typically resolves spontaneously and is followed by a “recruitment” phase where fluid leaves the interstitial phase and enters the circulation, which can result in marked volume expansion with pulmonary edema and accumulation of fluid in serosal cavities. During the “leak” phase, the extravasation primarily occurs in skin and muscle tissues, especially skeletal muscle but at times the heart [5].

The “leak” phase is accompanied by hypotension and intravascular volume depletion that is resistant to infusion of crystalloid or albumin infusion. The resulting shock can lead to acute renal failure as well as other consequences of poor tissue perfusion. Hemoconcentration with increased viscosity can result in deep venous thrombosis. The fluid accumulation in muscle beds commonly results in compartment syndromes with consequences of ischemic neuropathy and rhabdomyolysis [1], [2], [3], [4], [5]. While many attacks of ISCLS are severe with features of multi-organ dysfunction, milder episodes with only slight edema of the extremities and muscle tightness or discomfort also occur. The same patient may have attacks that vary in intensity from being severe to mild attacks at different times [6]. Some patients are thought to have a chronic form manifesting as noncyclical persistent peripheral edema [7].

An association is the presence of a monoclonal gammopathy (MGUS), most commonly of the IgG kappa isotype, is observed in about two thirds of cases [8]. There does not appear to be any pathophysiologic link with hereditary forms of angioedema.

An exogenous trigger most commonly in the context of a viral prodrome linked with influenza, respiratory syncytial virus, West Nile virus, and most recently, COVID-19 has been reported [9], [10], [11], [12].. The pathogenesis of vasopermeability leading to the massive extravasation of plasma remains elusive, although the presence of humoral factors including vascular endothelial cell growth factor and angiopoietin that promote vascular endothelial cell hyperpermeability [13], transient spikes in monocyte inflammatory mediators such as CXCL10 [14], and impairment of microvascular endothelial cell barrier function provoked by sera from patients with an acute episode have all been documented [15]. In regards to the latter, a pediatric patient with fatal systemic capillary leak syndrome had a mutation in the function of p190ARhoGAP regulating endothelial permeability, a protein encoded by the gene ARHGAP35. Of importance and interest, episodes can be prevented and treated with high doses of intravenous immunoglobulin (IVIG) [16].

Normal skin was procured from the deltoid area as a diagnostic adjunct in establishing the diagnosis of capillary leak syndrome and as a clue to pathogenetic mechanisms that may underlie systemic capillary leak syndrome. The deltoid skin was chosen as this particular anatomic site is used to assess certain microvascular injury syndromes, namely atypical hemolytic uremic syndrome and severe COVID-19. The extent of microvascular complement deposition observed in normal deltoid skin in the setting of severe COVID-19 emphasized the role of systemic complement pathway activation in the disease [17], [18]. We report the biopsy results of “normal” skin obtained during five acute episodes of ISCLS in three patients, along with a sub-acute presentation of capillary leak syndrome in a fourth. The latter case includes a biopsy taken after the patient recovered.