22q11.2 Deletion-Associated Blood-Brain Barrier Permeability Potentiates Systemic Capillary Leak Syndrome Neurologic Features.

We present a case study of a young male with a history of 22q11.2 deletion syndrome (22qDS), diagnosed with systemic capillary leak syndrome (SCLS) who presented with acute onset of diffuse anasarca and sub-comatose obtundation. We hypothesized that his co-presentation of neurological sequelae might be due to blood-brain barrier (BBB) susceptibility conferred by the 22q11.2 deletion, a phenotype that we have previously identified in 22qDS. Using pre- and post-intravenous immunoglobulins (IVIG) patient serum, we studied circulating biomarkers of inflammation and assessed the potential susceptibility of the 22qDS BBB. We employed in vitro cultures of differentiated BBB-like endothelial cells derived from a 22qDS patient and a healthy control. We found evidence of peripheral inflammation and increased serum lipopolysaccharide (LPS) alongside endothelial cells in circulation. We report that the patient's serum significantly impairs barrier function of the 22qDS BBB compared to control. Only two other cases of pediatric SCLS with neurologic symptoms have been reported, and genetic risk factors have been suggested in both instances. As the third case to be reported, our findings are consistent with the hypothesis that genetic susceptibility of the BBB conferred by genes such as claudin-5 deleted in the 22q11.2 region promoted neurologic involvement during SCLS in this patient.

Two cases of systemic capillary leak syndrome associated with COVID-19 in Japan.

Systemic Capillary Leak Syndrome (SCLS) is a rare disease that causes severe distributive shock provoked by infection or vaccination. SCLS is clinically diagnosed by a triad of distributive shock, paradoxical hemoconcentration, and hypoalbuminemia. SCLS associated with coronavirus disease (COVID-19) in adults has not been reported yet in Japan. Case 1: A 61-year-old woman with fever, sore throat, headache, and muscle pain was admitted to our emergency department with suspected COVID-19. She had been diagnosed with SCLS 3 years earlier. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen and polymerase chain reaction (PCR) tests were negative at admission. She went into shock in the emergency department and was treated for septic shock. The following day, the SARS-CoV-2 PCR test was positive. She did not respond to fluid resuscitation and catecholamine and finally died. Case 2: A 58-year-old man was admitted to our hospital for de-saturation due to COVID-19. He got into shock on day 3. SCLS was suspected, and 5 g of intravenous immunoglobulin and 5% albumin were administered for sepsis treatment. He responded to the aggressive fluid therapy within 48 h and was finally discharged. COVID-19 can trigger SCLS, and early recognition of SCLS is crucial for survival. Primary care physicians should consider SCLS when they observe distributive shock and paradoxical hemoconcentration deviations from the natural course of COVID-19.

[A case of brucellosis complicated with capillary leak syndrome and multiple organ dysfunction syndrome].

Brucellosis can lead to pathological changes of multiple systems. Capillary leak syndrome (CLS) is a clinical syndrome caused by different reasons, mainly characterized by hypotension, hypoproteinemia and systemic edema. The condition is critical and the clinical manifestations are complex, and multiple organ dysfunction syndrome (MODS) may occur in severe cases. CLS caused by brucellosis is extremely rare. The diagnosis and treatment of a patient with brucellosis complicated with CLS and MODS was analyzed in this paper, in order to improve the knowledge of clinicians about brucellosis and its complications.

Case report: Clinical experience of treating pembrolizumab-induced systemic capillary leak syndrome (SCLS) in one patient with metastatic gastroesophageal junction squamous cell carcinoma.

Systemic capillary leak syndrome (SCLS) is a rare and complex adverse effect of immune checkpoint inhibitors (ICIs). The diagnosis of drug-induced SCLS is based on diffuse infusions of exudative fluid into the interstitial areas and the exclusion of other causes. The best management of ICIs-induced SCLS is not settled, though proper supportive care and corticosteroids were commonly applied as the first-line treatment. In our patient with advanced gastroesophageal junction squamous cell carcinoma, although ICIs-induced SCLS was successfully controlled with corticosteroids, the patient soon experienced cancer progress and died of pulmonary infections. Based on our experience and the reported cases by other hospitals, different stages of SCLS might respond differently to the same treatment. Therefore, a grading of ICIs-induced SCLS might help to stratify the patient for different treatment strategies. Besides, corticosteroids-sensitive patients, though waived from deadly SCLS, might be at higher risk of cancer progress and subsequent infections due to the application of corticosteroids. Considering that the inflammatory factors should be closely involved in the development of ICIs-induced SCLS, targeted therapy against the driver inflammatory cytokine might offer treatment regimens that are more effective and safer.

[Research Progress on Capillary Leak Syndrome Associated with Hematopoietic Stem Cell Transplantation--Review].

Capillary leak syndrome (CLS) is a clinical syndrome characterized by impairment of vascular endothelial barrier function, increased vascular permeability, and reversible systemic edema. It is one of the early fatal complications after hematopoietic stem cell transplantation. So far, the exact pathogenesis of CLS has not been elucidated, and the diagnostic criteria and treatment methods have not been unified. At present, it is believed that the fundamental cause of CLS is hypercytokinemia, and the core factor is high permeability of vascular endothelial cells. According to the clinical manifestations, the natural course of CLS can be divided into prodrome, leakage and recovery stages. As far as treatment is concerned, symptomatic and supportive treatment is dominant according to different characteristics of each stage. In this review, the pathogenesis, clinical manifestations, diagnosis and treatment of hematopoietic stem cell transplant-associated CLS were briefly summarized.

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.

Idiopathic systemic capillary leak syndrome: a case report.

BACKGROUND: Idiopathic systemic capillary leak syndrome (ISCLS) is a rare disease characterized by recurrent episodes of acute life-threatening attacks of shock, hemoconcentration, and hypoalbuminemia. Increase in capillary permeability results in reversible plasma movement into the interstitial spaces followed by appearance of related symptoms or complications, including renal failure. This condition can be potentially life-threatening; however, it is easily misdiagnosed. CASE PRESENTATION: A 47-year-old man with no previous medical history presented to the emergency department after experiencing general weakness and abdominal pain. He developed hypovolemic shock within 3 h of presentation and initial laboratory tests showed hemoconcentration, hypoalbuminemia and acute kidney injury. Following vigorous fluid therapy and supportive care, the patient recovered, but a similar episode recurred after 4 months without any specific trigger. Based on the combined clinical manifestations and laboratory findings of both the attacks, he was diagnosed with ISCLS. Symptomatic relief was achieved via oxygen supplementation and massive volume replacement using normal saline and the patient was prescribed bambuterol 10 mg and theophylline 400 mg once-a-day. He was discharged from the hospital on day 5 of hospitalization. Thereafter, the patient has been followed for 5 years without any symptoms or recurrence of ISCLS even in the situation of COVID-19 infection. CONCLUSIONS: ISCLS is an extremely infrequent and commonly misdiagnosed disease. However, early diagnosis, treatment and prophylaxis through accumulated clinical data can prevent ISCLS recurrence and the development of related fatal complications. Therefore, clinicians need to be well aware of the variety of clinical characteristics and treatment options of this disease.

Denileukin diftitox-induced systemic capillary leak syndrome with acute kidney injury.

Systemic capillary leak syndrome is a rare and life-threatening disorder, characterized by recurrent episodes of unexplained hypotension, hemoconcentration, and hypoalbuminemia. This condition is caused by leakage of plasma and proteins into the extravascular space and can be classified as either idiopathic or secondary. Secondary systemic capillary leak syndrome can result from cancer, infections, medications, or surgery. Systemic capillary leak syndrome frequently develops as a side effect of denileukin diftitox treatment of refractory cutaneous T-cell lymphoma. However, the pathophysiology of this disease is not well understood. Herein, we report a case of denileukin diftitox-induced systemic capillary leak syndrome.

Immune checkpoint inhibitors-induced systemic capillary leak syndrome: A report of two cases.

INTRODUCTION: The occurrence of systemic capillary leak syndrome under immune checkpoint inhibitors has seldom been reported in the literature. OBSERVATION: We report two cases of systemic capillary leak syndrome that occurred with nivolumab (anti-PD-1 antibody) for one, and with an anti-PD-1/CTLA-4 bi-specific antibody for the other. Patients presented with anasarca, hypoalbuminemia, acute kidney injury and, in one case, circulatory collapse. Immune checkpoint inhibitor causality was retained in the lack of evidence for other causes of secondary capillary leak syndrome or for an idiopathic form. The symptoms resolved after a few days of supportive measures (associated with glucocorticoids in one case). DISCUSSION: A high index of suspicion is required for the diagnosis of immune checkpoint inhibitors-induced systemic capillary leak syndrome because its presentation may differ from that of the idiopathic form. Activated CD8+ T-cells play a prominent role in the occurrence of immune checkpoint inhibitors-induced capillary leakage via their cytolytic action on the vascular endothelium. Treatment relies on supportive measures and discontinuation of the immune checkpoint inhibitor while the place of immunomodulatory drugs remains to be defined.

Idiopathic systemic capillary leak syndrome, a unique complement and interferon mediated endotheliopathy syndrome: The role of the normal skin biopsy in establishing the diagnosis and elucidating pathogenetic mechanisms.

Idiopathic Systemic Capillary Leak Syndrome (ISCLS), also known as Clarkson's Syndrome, is due to primary fluid and protein leak across capillaries that leads to an accumulation of interstitial fluids and cardiovascular collapse from intravascular hypovolemia. Viral infections are a putative trigger of these episodes. ISCLS is typically associated with a monoclonal gammopathy. Here we present four patients with idiopathic systemic capillary leak syndrome. The cohort consists of three men and one woman who range in age from 55 to 72 years old. All of the patients had a monoclonal gammopathy. Two patients had viral triggers. Biopsies of normal skin were examined throughout all phases of the disease. During an acute attack, we identified perivascular mixed CD4+ and CD8+ T cell lymphocytic infiltrates in the superficial dermis. We observed significant microvascular deposits of C5b-9 and upregulation of type I interferon signaling in endothelium along with reduced serum levels of complement during very active disease. We also identified deposits of immunoglobulin along the dermal epidermal junction mirroring the monoclonal immunoglobulin isotype implicated in each patient. During a post treatment recovery or mild disease phase there was reduced inflammation and decreased amounts of C5b-9 and type I interferon expression. Sudden onset capillary leak syndrome reflects enhanced endothelial cell permeability as a unique form of endothelial injury mediated by the combined effects of complement pathway activation and upregulation of type I interferon signaling on endothelium.

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.

Markers of endothelial glycocalyx dysfunction in Clarkson disease.

BACKGROUND: Clarkson disease (monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome, ISCLS) is a rare idiopathic condition marked by transient, relapsing-remitting episodes of systemic microvascular hyper-permeability, which liberates plasma fluid and macromolecules into the peripheral tissues. This pathology manifests clinically as the abrupt onset of hypotensive shock, hemoconcentration, and hypoalbuminemia. METHODS: We analysed endothelial glycocalyx (eGCX)-related markers in plasma from patients with ISCLS during acute disease flares and convalescence by ELISA and comprehensive proteomic profiling. We evaluated eGCX-related components and gene expression in cultured endothelial cells using RNA-sequencing, real-time PCR, and fluorescence staining. RESULTS: Serum levels of eGCX-related core components including hyaluronic acid (HA) and the core proteoglycan soluble syndecan-1 (sCD138) were elevated at baseline and during acute ISCLS flares. Serial measurements demonstrated that sCD138 levels peaked during the recovery (post-leak) phase of the illness. Proteomic analysis of matched acute and convalescent ISCLS plasma revealed increased abundance of eGCX-related proteins, including glypicans, thrombospondin-1 (TSP-1), and eGCX-degrading enzymes in acute compared to remission plasma. Abundance of endothelial cell damage markers did not differ in acute and baseline plasma. Expression of several eGCX-related genes and surface carbohydrate content in endothelial cells from patients with ISCLS did not differ significantly from that observed in healthy control cells. CONCLUSIONS: eGCX dysfunction, but not endothelial injury, may contribute to clinical symptoms of acute ISCLS. Serum levels of of eGCX components including sCD138 may be measured during acute episodes of ISCLS to monitor clinical status and therapeutic responses.

Capillary leak syndrome in a patient with cancer-associated anti-transcriptional intermediary factor 1γ dermatomyositis treated with rituximab.

Capillary leak syndrome (CLS) is a rare condition characterised by increased capillary permeability, with subsequent hypoalbuminemia and hypotension, leading to an increased risk of shock and death. We present the case of a patient with anti-transcriptional intermediary factor 1γ dermatomyositis that developed CLS one week after starting treatment with rituximab and prophylactic co-trimoxazole. The patient was admitted to the Intensive Care Unit (ICU), recovered after treatment with intravenous immunoglobulin, albumin, and Ringer lactate, but died a month after the discharge due to a poorly differentiated hepatocarcinoma diagnosed in the ICU.

Drug-induced Capillary Leak Syndrome.

Capillary leak syndrome is a disease with a high mortality rate. Its signs and symptoms are nonspecific. Generalized edema, hypotension, hypoproteinemia, and hemoconcentration are the characteristics of capillary leak syndrome. Here we report three cases of capillary leak syndrome developed after being treated with gemcitabine and paclitaxel. Immediate treatment with corticosteroids may be life-saving.

Flare-up of generalized pustular psoriasis combined with systemic capillary leak syndrome after coronavirus disease 2019 mRNA vaccination.

Generalized pustular psoriasis (GPP) is characterized by acute flare-ups induced by various factors, but few reports have described GPP onset or flare-up induced by vaccination. To our knowledge, only three such cases following coronavirus disease 2019 (COVID-19) vaccination have been reported. We herein report a case of GPP flare-up after COVID-19 mRNA vaccination. A 65-year-old man with GPP controlled by infliximab presented with widespread pustular erythema, fever, and malaise following his second COVID-19 mRNA vaccination. A skin eruption was apparent at the injection site. He also exhibited systemic capillary leak syndrome (SCLS), which responded rapidly to secukinumab and systemic corticosteroids. Two biopsies, one of which was of the injection site, revealed not only findings typical of GPP, but also a dermal mixed-cell infiltration with eosinophils, and microthrombi in the small dermal vessels. The latter findings have been observed in cutaneous lesions induced by both COVID-19 infection and vaccination. This is the first case of a GPP flare-up accompanied by SCLS induced by a COVID-19 mRNA vaccine. Also, this is the first flare-up induced by the second vaccine dose, and the first such report including detailed histological data, including for the injection site.