Renal Replacement Therapy in Idiopathic Systemic Capillary Leak Syndrome: A Case Report.

Idiopathic systemic capillary leak syndrome (ISCLS) is a rare disease characterized by hypotensive shock, anasarca, hemoconcentration, and hypoalbuminemia. Despite the life-threatening course of the disease, no treatment strategy has been established. A 68-year-old man presented with hypotensive shock following a prodrome. Based on the characteristic blood test findings, ISCLS was suspected. The patient was resuscitated by administering massive amounts of fluids and inotropic and vasopressor agents. After his blood pressure had stabilized, renal replacement therapy (RRT) was promptly initiated to facilitate the removal of excess fluid, despite the presence of urine output. Typically, ISCLS has three phases: prodromal, leak, and post-leak. Diuresis should be promptly induced during the transition from the leak phase to the post-leak phase to avoid fatal complications such as pulmonary edema. We propose that in patients with ISCLS, early introduction of RRT is recommended if indicated.

Unlocking endothelial barrier restoration: FX06 in systemic capillary leak syndrome and beyond.

Increased vascular permeability is a prevalent feature in a wide spectrum of clinical conditions, but no effective treatments to restore the endothelial barrier are available. Idiopathic systemic capillary leak syndrome (ISCLS) is a life-threatening Paroxysmal Permeability Disorder characterized by abrupt, massive plasma extravasation. This condition serves as a robust model for investigating therapeutic approaches targeting interendothelial junctions. We conducted a single-center, interventional in vitro study at the Referral Center for ISCLS in Italy, involving four diagnosed ISCLS patients, aiming at investigating the effects of FX06, a Bß15-42 fibrin-derived peptide binding to VE-Cadherin, on endothelial barrier exposed to intercritical and acute ISCLS sera. The Transwell Permeability Assay was used to assess the permeability of human umbilical vein endothelial cells (HUVECs) exposed to ISCLS sera with or without FX06 (50 µg/ml). Acute ISCLS serum was also tested in a three-dimensional microfluidic device. Nitric oxide (NO), VE-Cadherin localization, and cytoskeletal organization were also assessed. In two and three-dimensional systems, ISCLS sera increased endothelial permeability, with a more pronounced effect for acute sera. Furthermore, acute sera altered VE-Cadherin localization and cytoskeletal organization. NO levels remained unchanged. FX06 restored the endothelial barrier function by influencing cellular localization rather than VE-Cadherin levels. In conclusion, FX06 prevents and reverts the hyperpermeability induced by ISCLS sera. These preliminary yet promising results provide initial evidence of the in vitro efficacy of a drug targeting the underlying pathophysiological mechanisms of ISCLS. Moreover, this approach may hold potential for addressing hyperpermeability in a spectrum of clinical conditions beyond ISCLS.

Exacerbations of Idiopathic Systemic Capillary Leak Syndrome following BNT162b2 mRNA COVID-19 Vaccine (Pfizer-BioNTech).

A Japanese man experienced three episodes of hypovolemic shock and was diagnosed with systemic capillary leak syndrome (SCLS). He developed SCLS exacerbation 2 days after receiving a second dose of the Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine, 1 year after the third episode. After fluid therapy and albumin administration, we initiated terbutaline and theophylline prophylaxis for SCLS. A literature review revealed that SCLS attacks often occur 1-2 days after the second COVID-19 vaccination. Patients with a history of SCLS should avoid COVID-19 vaccination and be carefully monitored for 1-2 days if they receive the vaccine.

Bilateral choroidal effusions and angle closure in the setting of systemic capillary leak syndrome from HLA-directed vaccine and pembrolizumab therapy for squamous cell carcinoma.

Purpose: Immunotherapy has become an important addition to oncology treatment plans in recent years. As these therapies become more widely employed, many unique side effects have been reported. In ophthalmology the most well-documented side effects of immune checkpoint inhibitors (ICI) include uveitis, macular edema and dry eye syndrome. This manuscript describes a rare case of bilateral choroidal effusions and secondary angle narrowing in the setting of systemic capillary leak syndrome (SCLS) from an HLA-directed vaccine and an ICI, pembrolizumab, for the treatment of stage IV squamous cell carcinoma (SCC) of the lung. Observations: A 67-year-old male with a history of stage IV SCC of the lung status-post pneumonectomy presented to the emergency department due to functional decline, anasarca, and dyspnea after receiving an HLA-directed vaccine in combination with pembrolizumab. Extensive workup revealed that his symptoms were secondary to SCLS. Ophthalmology was consulted due bilateral choroidal detachments seen on magnetic resonance imaging. B-scan ultrasound and ultrasound biomicroscopy revealed large, non-appositional choroidal effusions with anterior rotation of the ciliary body. Given minimal response to oral steroid therapy, sub-Tenon's triamcinolone acetonide, atropine, and intraocular pressure-lowering eyedrops were initiated with a good response. Conclusions and Importance: Choroidal effusions and secondary angle closure can be rare complications of SCLS in the setting of ICIs. Clinicians must be aware of the potentials side effects of ICI therapy, as these medications become more commonly used.

Idiopathic Systemic Capillary Leak Syndrome: A Rare Cause of Refractory Shock Following Influenza B Infection.

A 68-year-old man presented to the Emergency Department with undifferentiated shock. During the three days prior, he experienced a non-specific viral-like illness. On examination his blood pressure was 70/40 mm Hg with cool, clammy, and mottled extremities and flat neck veins. Laboratory investigations revealed a positive influenza B screen alongside elevated hemoglobin and hematocrit. Following aggressive fluid resuscitation his blood pressure had marginally improved and he was transferred to the intensive care unit (ICU). Vasopressor support with cautious fluid resuscitation continued and at 7- and 10-h following presentation, serum albumin levels were extremely low. Idiopathic systemic capillary leak syndrome triggered by influenza B infection was diagnosed. Following a 9-day ICU stay the patient made a complete recovery and remains stable on intravenous immunoglobulin therapy. This case highlights the importance judicious fluid resuscitation and serum albumin levels when confronted with refractory shock.

Massive vulvar edema revealing idiopathic systemic capillary leak syndrome.

Idiopathic systemic capillary leak syndrome is a rare disease characterized by recurrent episodes of hypotension, hypoalbuminemia and peripheral edema caused by capillary hyperpermeability with approximately 350 documented cases worldwide. We report herein the case of a 22-year-old primiparous patient with an unusual compartment syndrome represented with spontaneous massive vulvar edema. Treatment consisted of volume replacement and intravenous polyvalent immunoglobulins perfusions. Vulvar edema was treated surgically by incision and drainage with favorable outcome. The pregnancy follow-up did not show any fetal abnormalities. The childbirth at 35 weeks was natural and the newborn was healthy.

A deadly capillary leak attack. Clarkson's disease: a narrative review.

A previously 42-year-old healthy man was brought in by an ambulance to the emergency department with symptoms of a distributive shock. He experienced a rapid decline in his clinical state that evolved into a cardiac arrest. Despite all the performed measures and a prolonged resuscitation, the patient died a few hours later without an initial clear diagnosis. Lab results showed an extremely high haemoconcentration leading to further investigations which suggested the possibility of Clarkson's disease, although septic shock as an alternative diagnosis could not be excluded. Nevertheless, because of its presentation, especially emergency and intensive care physicians should be aware of the existence of this condition in the event of an unexplained refractory distributive shock in combination with haemoconcentration and hypoalbuminemia given its possible fatal outcome.

[Idiopathic systemic capillary leak syndrome: 2 cases with misleading presentation]. / Syndrome de fuite capillaire idiopathique : 2 cas cliniques de présentation trompeuse.

INTRODUCTION: Idiopathic systemic capillary leak syndrome (ISCLS) also known as Clarkson syndrome is a rare and sudden life-threatening entity. Three consecutive phases are described. A first non-specific prodromal phase often manifests as "flu-like" symptoms and precedes capillary leak phase with major hypovolemic and distributive shock leading to serious and frequent multiorgan dysfunction syndrome (MODS). Severe hypovolemia contrasts with edema, and hemoconcentration with hypoalbuminemia. ISCLS is characterized by these two clinical and biological paradoxes. Subsequent recovery phase exhibits organ function restoration along with interstitial/intravascular volumes normalization. The latter occurs spontaneously and systematically in patients surviving from leak phase. OBSERVATIONS: We report here two ISCLS cases admitted in intensive care unit (ICU) both enhancing initial misdiagnosis possibly lowering prognosis and outcome. Our first 28-year-old female patient was admitted for « polycythemia vera ¼ although hemoconcentration was attributable to hypovolemia. She presented circulatory arrest during the second bloodletting session and complicated with MODS. In and out ICU favorable outcome was noted on intravenous immunoglobulin therapy. A second 57-year-old male patient was admitted in ICU for severe "myositis" (myalgia and rhabdomyolysis) although rectified diagnosis retained compartment syndrome (muscular severe edema following capillary leak). Rapid and refractory hypovolemic shock appeared with subsequent MODS leading to death. CONCLUSION: ISCLS pathophysiology remains unknown but certainly implies transitory endothelial dysfunction. Impossibility of randomized controlled trial for this exceptional disease led to based-on-experience therapeutic guidelines implying symptomatic care (cardiac output surveillance, nephroprotection, prudent fluid intake, prudent vasoactive amine use) and specific therapies (intravenous aminophylline during severe flares). Although enhancing controversial and even deleterious effects during the acute phase, polyvalent immunoglobulins are effective for relapse prevention. Syndromic diagnosis is difficult, but its precocious finding constitutes a key-element in better outcome before organ failure.

Extensive leukoencephalopathy associated with idiopathic capillary leak syndrome: report of a case with neuropathology.

INTRODUCTION: Idiopathic systemic capillary leak syndrome (ISCLS) is a rare cryptogenic disorder characterized by recurrent hemoconcentration, hypoalbuminemia, edema, and hypotension due to extravascular fluid leakage. This is the first report that details uncommon extensive leukoencephalopathy caused by ISCLS upon a neuropathological investigation. CASE REPORT: A 68-year-old female had recurrent episodes of hemoconcentration, hypoalbuminemia, and generalized edema and was diagnosed with ISCLS. After 9 years, brain magnetic resonance imaging (MRI) incidentally revealed extensive leukoencephalopathy without neurological deficits. Thorough examinations ruled out other disorders, and the cerebral involvement due to ISCLS was finally diagnosed. Three years later, she developed an acute-onset coma and status epilepticus together with hypotension and hemoconcentration, which were compatible with ISCLS recurrence. Electroencephalogram and MRI were correlated with a seizure arising from the left hemisphere. Extensive leukoencephalopathy did not show notable changes for 3 years. Although treatment for ISCLS recurrence temporally improved hemoconcentration and consciousness, consciousness worsened again by marked edema of the left hemisphere, and she died of cerebral herniation. A brain autopsy revealed straggly perivascular plasma leakage around the small vessels of the deep white matter, which supported that the leukoencephalopathy was caused by ISCLS. Widespread myelin pallor and decreased axonal density with sparse astrogliosis and microgliosis were observed in the cerebral white matter and corresponded with a chronic change in the MRI. CONCLUSION: Current radiological and pathological observations revealed that frequent perivascular leakages could cause chronic leukoencephalopathy, were linked with the development of systemic capillary leakage in ISCLS, and provided insights into the mysterious pathophysiology.

Choroidal Effusion Mimicking Uveal Melanoma: A Novel Presentation of Idiopathic Systemic Capillary Leak Syndrome.

BACKGROUND: Idiopathic systemic capillary leak syndrome (ISCLS, also known as Clarkson's disease) is a rare medical condition characterized by episodes of capillary endothelial cell dysfunction with leakage of fluid into the interstitial space resulting in severe hypotension, hemoconcentration, hypoalbuminemia, and generalized edema. Each episode can result in multiorgan failure due to systemic hypoperfusion. CASE PRESENTATION: We report a case of uveal effusion, mimicking uveal melanoma, associated with ISCLS following viral infection. A 74-year-old white male was evaluated in our ocular tumor clinic for a large intraocular mass in the right eye concerning for choroidal melanoma. We completed a review of the literature and list clinical recommendations for these cases. ISCLS, although rare, was a significant diagnostic consideration in this patient. Due to the high mortality rate of this condition, accurate diagnosis and prompt treatment was critical. We hypothesize that the mechanism of choroidal effusion development was due to reduced oncotic pressure from rapid decrease in serum albumin. Increased permeability of choroidal capillaries may be an additional mechanism leading to uveal effusion. CONCLUSION: With treatment, the patient had complete resolution of his choroidal effusion with no recurrence of his ISCLS. Further research should be considered on the role of viral infections in the pathogenesis of ISCLS.

The effects of severe hemoconcentration on acid-base equilibrium in critically ill patients: the forgotten role of buffers in whole blood.

PURPOSE: Idiopathic Systemic Capillary Leak Syndrome (ISCLS) is a paroxysmal permeability disorder characterized by abrupt onset of shock and hemoconcentration due to massive shift of fluids and proteins from the intravascular to the interstitial compartment. We hypothesize that increased hemoglobin concentration has a pivotal role in the acid-base imbalance during life-threatening crises. MATERIALS AND METHODS: Analysis of the acid-base balance fluctuations during six severe ISCLS flares admitted to ICU of a referral center for ISCLS. RESULTS: Acid-base equilibrium was assessed for plasma and the whole blood by single and multicompartmental models. The acute phase of ISCLS was characterized by shock, hypoalbuminemia, severe hemoconcentration, and acidosis. The physical-chemical approach for plasma found a remarkable component of unmeasured anions (SIG) during the acute phase. After correction of the physical-chemical model for the whole blood, the SIG variations disappeared because the buffer role of hemoglobin was relevant. CONCLUSION: Hemoglobin has a remarkable role in buffering metabolic acidosis during the shock phase of ISCLS. In these circumstances, the assessment of acid-base equilibrium in plasma alone may overestimate unmeasured anions. On the contrary, the physical-chemical model corrected for whole blood better explains the metabolic component of acid-base imbalance when marked shift of hemoglobin concentration occurs.

Myocardial edema in paroxysmal permeability disorders: The paradigm of Clarkson's disease.

PURPOSE: Paroxysmal Permeability Disorders (PPDs) comprise a variety of diseases characterized by recurrent and transitory increase of endothelial permeability. Idiopathic Systemic Capillary Leak Syndrome (ISCLS) is a rare PPD that leads to an abrupt massive shift of fluids and proteins from the intravascular to the interstitial compartment. In some cases, tissue edema may involve the myocardium, but its role in the development of shock has not been elucidated so far. MATERIALS AND METHODS: Assessment of cardiac involvement during ten life-threatening ISCLS episodes admitted to ICU. RESULTS: Transthoracic echocardiographic examination was performed in eight episodes, whereas a poor acoustic window prevented cardiac ultrasound assessment in two episodes. Myocardial edema was detected by echocardiography in eight episodes and marked pericardial effusion in one-episode. Cardiac magnetic resonance showed diffuse myocardial edema in another episode. In one case, myocardial edema caused fulminant left ventricular dysfunction, which required extracorporeal life support. The mean septum thickness was higher during the shock phase compared to the recovery phase [15.5 mm (13.1-21 mm) vs. 9.9 mm (9-11.3 mm), p = .0003]. Myocardial edema resolved within 72 h. CONCLUSIONS: During early phases of ISCLS, myocardial edema commonly occurs and can induce transient myocardial dysfunction, potentially contributing to the pathogenesis of shock.

Non-occlusive Mesenteric Ischaemia and Acute Kidney Injury: A Case Report of Severe Idiopathic Systemic Capillary Leak Syndrome.

Systemic capillary leak syndrome is a rare, underdiagnosed and life-threatening disease characterized by periodic episodes of hypovolaemic shock due to leakage of plasma from the intravascular to the extravascular space. It is associated with haemoconcentration, hypoalbuminaemia and generalized oedema. We report the case of a patient with a history of emergent extensive small and large bowel resection and several episodes of hypovolaemic shock with acute renal injury, who presented with abdominal pain, headache and generalized oedema. Severe systemic capillary leak syndrome was diagnosed after a complex diagnostic approach. This case report describes the acute and prophylactic treatment administered to the patient and the 4-year follow-up. We highlight the importance of timely recognition and prompt treatment, as well as the need for new investigations to prevent the serious and unusual complications seen in this case. LEARNING POINTS: Idiopathic systemic capillary leak syndrome (ISCLS) should be suspected in the presence of the triad of hypotension, haemoconcentration and hypoalbuminaemia; the diagnostic work-up is challenging and requires exclusion of several causes of hypotension and shock of uncertain aetiology.Acute mesenteric ischaemia leading to extensive and emergent bowel resection is an irreversible but atypical complication of ISCLS; other complications include myocardial oedema and deep vein thrombosis.ISCLS is characterized by three phases; supportive as well as prophylactic treatment adapted to each phase is crucial for prognosis and to avoid end-organ damage.

Handling shock in idiopathic systemic capillary leak syndrome (Clarkson's disease): less is more.

Idiopathic systemic capillary leak syndrome (ISCLS) presents with recurrent potentially life-threatening episodes of hypovolemic shock associated with severe hemoconcentration and hypoproteinemia. Timely recognition is of paramount importance because ISCLS, despite resembling other kinds of hypovolemic shock, requires a peculiar approach, to prevent life-threatening iatrogenic damage. Due to the rarity of this condition with only scattered cases described worldwide, evidence-based recommendations are still lacking. Here, we summarize our 40 years' experience in treating shock in ISCLS patients to derive a therapeutic algorithm. Records from 12 ISCLS patients (mean follow-up is 6 years, with a mean age at symptoms' onset of 51.5 years) were informative for treatment modalities and outcome of 66 episodes of shock. Episodes are divided in three phases and treatment recommendations are the following: prodromal symptoms-signs (growing malaise, oligo-anuria, orthostatic dizziness) last 6-12 h and patients should maintain rigorous bed rest. The acute shock phase lasts 24-36 h. Patients should be admitted to ICU, placed on restrictive infusion of fluids favoring cautious boluses of high-molecular-weight plasma expanders when SAP < 70 mmHg; monitored for cerebral/cardiac perfusion, myocardial edema and signs of compartment syndrome. The post-acute (recovery) phase may last from 48 h to 1 week. Monitor for cardiac overload to prevent cardiac failure; in case of persistent renal failure, hemodialysis may be necessary; consider albumin infusion. Complications listed by frequency in our patients were acute renal failure, compartment syndrome and neuropathy, rhabdomyolysis, myocardial edema, pericardial-pleural-abdominal effusion, cerebral involvement, acute pulmonary edema and deep vein thrombosis.

Paroxysmal Permeability Disorders: Development of a Microfluidic Device to Assess Endothelial Barrier Function.

Background: Paroxysmal Permeability Disorders (PPDs) are pathological conditions caused by periodic short lasting increase of endothelial permeability, in the absence of inflammatory, degenerative, ischemic vascular injury. PPDs include primary angioedema, idiopathic systemic capillary leak syndrome and some rare forms of localized retroperitoneal-mediastinal edema. Aim: to validate a microfluidic device to study endothelial permeability in flow conditions. Materials and Methods: we designed a microchannel network (the smallest channel is 30µm square section). Human Umbilical Vein Endothelial Cells (HUVECs) were cultured under constant shear stress in the networks. Endothelial permeability assessment was based on interaction of biotinylated fibronectin used as a matrix for HUVECs and FITC-conjugated avidin. The increase in endothelial permeability was identified as changes in fluorescence intensity detected by confocal fluorescent microscopy. Results: The microchannels were constantly perfused with a steady flow of culture medium, ensuring a physiologically relevant level of shear stress at the wall of ~0.2 Pa. Our preliminary results demonstrated that circulation of culture medium or plasma from healthy volunteers was associated with low fluorescence of fibronectin matrix. When bradykinin diluted in culture medium was perfused, an increase in average fluorescence was detected. Conclusion: Our microvasculature model is suitable to study endothelial functions in physiological flow conditions and in the presence of factors like bradykinin known as mediator of several PPDs. Therefore, it can be a promising tool to better understand the mechanisms underlying disorders of endothelial permeability.

Idiopathic Systemic Capillary Leak Syndrome.

Idiopathic systemic capillary leak syndrome (ISCLS) is a very rare life-threatening disorder characterized by recurrent episodes of hypotension, hemoconcentration, and hypoalbuminemia. It is caused by transient endothelial dysfunction, leading to plasma leakage from intravascular to interstitial space. Here, we report a case of ISCLS with recurrent episodes of capillary leak which required a long-term prophylaxis with beta-2 adrenergic receptor agonist and theophylline. Although ISCLS is the rare entity, associated morbidity and mortality require physician's awareness to provide timely therapy. Under-recognition in the medical community and rarity of this syndrome has precluded analysis in rational clinical trial designs that are necessary to determine targeted and adequate therapy. This report is meant to enhance awareness of ISCLS among physician's community.

A case report of idiopathic systemic capillary leak syndrome that occurred during the postoperative period of abdominoperineal resection for colorectal cancer.

A 57-year-old woman without any past medical history underwent abdominoperineal resection for rectal cancer in our department. On postoperative day 15, the patient complained of sudden abdominal pain, and high fever was noted in addition to the appearance of erythema around the stoma. The diagnosis of phlegmon was made, and antibiotic infusion was started. However, a few days later, the patient developed hypovolemic shock with hypoalbuminemia and hemoconcentration. Fasciotomy was performed to exclude the necrotizing fasciitis, though all cultures were negative. Upon exclusion of the differential diagnoses, idiopathic systemic capillary leak syndrome (ISCLS) was diagnosed. She was successfully treated with massive fluid infusion under ventilation and continuous hemodiafiltration. Here, we report the first case of ISCLS that occurred during the postoperative period of colorectal surgery.

Episodic idiopathic systemic capillary leak syndrome in a girl.

Episodic idiopathic systemic capillary leak syndrome is a rare disorder that presents with attacks of circulatory shock due to plasma leakage into the extravascular space. Reported here is the case of a girl who had recurrent circulatory shock. The diagnosis of episodic idiopathic systemic capillary leak syndrome was made following the fourth episode. The course was favorable following acute i.v. cristalloids and methylprednisolone.