[Veno-venous extracorporeal membrane oxygenation for capillary leak syndrome during induction chemotherapy in acute myeloid leukemia].

A 44-year-old woman was diagnosed with acute myeloid leukemia (RUNX1::RUNX1T1 translocation) and received induction chemotherapy with idarubicin hydrochloride and cytosine arabinoside. The pneumonia that had been present since admission worsened, and a drug-induced skin rash appeared. On day 17, she presented with respiratory failure and shock, complicated by hemoconcentration and hypoalbuminemia. This was considered capillary leak syndrome due to pneumonia and drug allergy, so she was started on pulse steroid therapy and IVIG, and was intubated on the same day. On day 18, venovenous-extracorporeal membrane oxygenation (VV-ECMO) was started due to worsening blood gas parameters despite ventilatory management. Bronchoalveolar lavage fluid was serous, and both blood and sputum cultures yielded negative. The patient was weaned from VV-ECMO on day 26 as the pneumonia improved with recovery of hematopoiesis. She was disoriented, and a CT scan on day 28 revealed cerebral hemorrhage. Her strength recovered with rehabilitation. After induction chemotherapy, RUNX1::RUNX1T1 mRNA was not detected in bone marrow. The patient received consolidation chemotherapy, and has maintained complete remission. Severe respiratory failure during induction chemotherapy for acute leukemia can be fatal, but VV-ECMO may be lifesaving.

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.

Ultrasound findings and specific intrinsic blood volume expansion therapy for neonatal capillary leak syndrome: report from a multicenter prospective self-control study.

OBJECTIVE: Capillary leak syndrome (CLS) is characterized by severe systemic edema without specific treatment, resulting in a high mortality rate. This study investigated whether there is organ edema in neonatal CLS patients and specific treatment strategies to improve patient prognosis. METHODS: Thirty-seven newborns diagnosed with CLS were included in this study. (1) Routine point-of-care ultrasound (POCUS) was used to identify whether the patients had visceral edema or fluid collection. (2) All patients were treated with 3% NaCl intravenously, and the clinical manifestations, laboratory indices and outcomes were compared before and after treatment. RESULTS: (1) Diffuse severe edema was found in 92.0% of the patients. (2) The POCUS examination revealed that CLS patients exhibited significant visceral edema in addition to diffuse severe edema, which included pulmonary edema in 67.6%, cerebral edema in 37.8%, severe intestinal edema in 24.3%, severe myocardial edema in 8.1%, pericardial effusion in 5.4%, pleural effusion in 29.7% and peritoneal effusion in 18.9%. Two patients (5.45%) had only myocardial edema without other manifestations. (3) Before and after the intravenous injection of 3% NaCl, there were no significant differences in the serum sodium or potassium levels of CLS patients, while the hemoglobin and hematocrit levels were significantly lower after treatment (p < 0.01). Her plasma ALB concentration and arterial pressure returned to normal levels after the treatment was completed. (4) All the patients survived, and no side effects or complications were observed during or after treatment with 3% NaCl. CONCLUSIONS: (1) In addition to diffuse severe edema, visceral edema and effusion are common and important clinical manifestations of neonatal CLS and need to be detected by routine POCUS. (2) The intravenous injection of 3% NaCl is a safe, effective and specific treatment strategy for neonatal CLS, with a survival rate of 100% and no adverse effects.

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.

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.

Periodic generalized edema following COVID-19 infection.

The unprecedented impact and sequelae of COVID-19 infection are not yet fully understood, and better understanding of the pathophysiology of these infections is needed. Endothelial dysfunction might be common sequelae associated with COVID-19, and increased inflammatory responses, oxidative stress, proinflammatory cytokines, and impaired mitochondrial function also contribute to the pathophysiology of post COVID-19 medical disorders. Systemic capillary leak syndrome following COVID-19 infection, both new onset and exacerbation of a prior disorder, has been reported. The pathophysiology of SCLS is uncertain; it likely develops during transient vascular endothelial dysfunction or endotheliopathy and inflammation resulting from circulating humoral factors. Here, we report a case of adult patient with 2 episodes of systemic capillary leak syndrome following prior COVID-19 infection. This patient had a transient response to intravenous IgG.

A ligand-independent Tie2-activating antibody reduces vascular leakage in models of Clarkson disease.

Vascular dysfunction resulting from endothelial hyperpermeability is a common and important feature of critical illness due to sepsis, trauma, and other conditions associated with acute systemic inflammation. Clarkson disease [monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome (ISCLS)] is a rare, orphan disorder marked by spontaneous and recurrent episodes of hypotensive shock and peripheral edema due to widespread vascular leakage in peripheral tissues. Mortality from acute flares approaches 30% due to lack of effective therapies. We evaluated a monoclonal antibody (4E2) specific for the endothelial receptor tyrosine kinase Tie2 in ISCLS models. 4E2 activated Tie2 in ISCLS patient-derived endothelial cells and reduced baseline and proinflammatory mediator-induced barrier dysfunction. 4E2 also reduced mortality and/or vascular leakage associated with systemic histamine challenge or influenza infection in the SJL/J mouse model of ISCLS. These findings support a critical role for Tie2 dysregulation in ISCLS and highlight a viable therapeutic approach to this catastrophic disorder.

Pericardial effusion and systemic capillary leak syndrome late post-SARS-CoV-2 vaccination.

We report an interesting case of pericardial effusion associated with idiopathic systemic capillary leak syndrome (ISCLS) following administration of SARS-CoV-2 vaccine. This patient initially presented with dyspnoea and chest pain, with non-pitting oedema and clear lung fields. The diagnosis of ISCLS was made based on the clinical syndrome and laboratory evidence of polycythaemia and hypoalbuminaemia. An enlarging pericardial effusion was diagnosed on transthoracic echocardiogram. Daily point-of-care ultrasound (POCUS)-guided volume management and serial transthoracic echocardiograms contributed to avoidance of refractory shock, cardiac tamponade and critical care admission.

[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.

Rare variants in complement system genes associate with endothelial damage after pediatric allogeneic hematopoietic stem cell transplantation.

Introduction: Complement system has a postulated role in endothelial problems after hematopoietic stem cell transplantation (HSCT). In this retrospective, singlecenter study we studied genetic complement system variants in patients with documented endotheliopathy. In our previous study among pediatric patients with an allogeneic HSCT (2001-2013) at the Helsinki University Children´s Hospital, Finland, we identified a total of 19/122 (15.6%) patients with vascular complications, fulfilling the criteria of capillary leak syndrome (CLS), venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS) or thrombotic microangiopathy (TMA). Methods: We performed whole exome sequencing (WES) on 109 patients having an adequate pre-transplantation DNA for the analysis to define possible variations and mutations potentially predisposing to functional abnormalities of the complement system. In our data analysis, we focused on 41 genes coding for complement components. Results: 50 patients (45.9%) had one or several, nonsynonymous, rare germline variants in complement genes. 21/66 (31.8%) of the variants were in the terminal pathway. Patients with endotheliopathy had variants in different complement genes: in the terminal pathway (C6 and C9), lectin pathway (MASP1) and receptor ITGAM (CD11b, part of CR3). Four had the same rare missense variant (rs183125896; Thr279Ala) in the C9 gene. Two of these patients were diagnosed with endotheliopathy and one with capillary leak syndrome-like problems. The C9 variant Thr279Ala has no previously known disease associations and is classified by the ACMG guidelines as a variant of uncertain significance (VUS). We conducted a gene burden test with gnomAD Finnish (fin) as the reference population. Complement gene variants seen in our patient population were investigated and Total Frequency Testing (TFT) was used for execution of burden tests. The gene variants seen in our patients with endotheliopathy were all significantly (FDR < 0.05) enriched compared to gnomAD. Overall, 14/25 genes coding for components of the complement system had an increased burden of missense variants among the patients when compared to the gnomAD Finnish population (N=10 816). Discussion: Injury to the vascular endothelium is relatively common after HSCT with different phenotypic appearances suggesting yet unidentified underlying mechanisms. Variants in complement components may be related to endotheliopathy and poor prognosis in these patients.

Polycythemia as an Uncommon Finding in 2 Children, One With Systemic Capillary Leak Syndrome and the Other With Protein-losing Enteropathy Caused by CD55 Deficiency.

We report 2 children with distinct causes of polycythemia, 1 from systemic capillary leak syndrome (SCLS) and the other from protein-losing enteropathy (PLE) caused by CD55 deficiency. There is only a single case series about polycythemia in children with SCLS, but none on polycythemia in children with PLE. We present a 10-year-old girl with hypoalbuminemia, polycythemia, and edema who died as a result of an SCLS attack and a 1-year-old girl with PLE who was successfully treated with eculizumab. Our experience suggests that hematologists should be alert for SCLS and PLE in children with relative polycythemia.

[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.

Systemic capillary leak syndrome secondary to decompression sickness.

Systemic capillary leak syndrome is a rare derangement of endothelial function characterised by extravasation of plasma and proteins into the interstitial space. Primary capillary leak syndrome is a rare, episodic medical illness of unknown molecular pathology while secondary capillary leak syndrome may be precipitated by any number of inflammatory and infectious syndromes. Decompression sickness, a disorder of depressurisation, has been identified as a very rare trigger. We present a structured case report of systemic capillary leak syndrome secondary to decompression sickness following deep diving, informing physicians of this potential complication. No pharmacological therapy has substantial evidence in the treatment of acute systemic capillary leak syndrome. By review of current recommendations for acute management, we also emphasise an observed positive response to judicious fluid resuscitation and an oral cyclic AMP-elevating agent (ie, terbutaline).

Capillary leak syndrome presenting as refractory ascites in a patient with lymphoma: A rare case report.

Capillary leak syndrome (CLS) is a serious disorder characterized by hypotension and refractory systemic oedema. CLS with marked ascites rather than systemic oedema is rare and prone to misdiagnosis and delayed treatment. We report here a case of marked ascites in an elderly male patient with hepatitis B virus reactivation. Following investigations to exclude common diseases that may have accounted for diffuse oedema and hypercoagulable state, anti-cirrhosis therapy failed and severe refractory shock developed 48 hours after admission. The patient developed mild pleural effusions followed by swelling of the face, neck, and extremities. A high cytokine concentration gradient was detected between serum and ascites. Peritoneal biopsy showed lymphoma cells. The final diagnosis was lymphoma recurrence complicated with CLS. Our case suggests that cytokine detection in serum and ascitic fluid may be helpful in the differential diagnosis of CLS. In similar cases, decisive intervention, such as, hemodiafiltration, should be implemented to lessen the likelihood of serious complications.

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.

Immune checkpoint inhibitor-associated capillary leak syndrome: A systematic review and a worldwide pharmacovigilance study.

BACKGROUND: Although a few case reports have shown that immune checkpoint inhibitors (ICIs) are potential inducers of capillary leak syndrome (CLS), an incidental finding cannot be ruled out. The aim of this study was to describe the clinical characteristics of ICI-induced CLS through a systematic review and to assess a potential safety signal. METHODS: Medline/PubMed, Embase, and Reactions Weekly were screened, and a global disproportionality study was performed using the World Health Organization pharmacovigilance database through January 15, 2023. A signal of disproportionate reporting was defined as a Bayesian information component (IC) with a 95% credibility interval (CrI) lower boundary that exceeds 0. RESULTS: A total of 47 cases of ICI-associated CLS were included, 14 from the systematic review (of 61 screened articles) and 33 from VigiBase (of 34,058,481 reports of adverse drug reactions). The median time to CLS onset from the start of ICI was 12 weeks (interquartile range 8-49, n = 24). A total of 57% (8/14) of patients experienced an immune-related adverse event (irAE) before CLS. A fatal outcome was reported in 23% (7/31) of patients. A significant overreporting of CLS was found with ICIs compared with all other drugs (IC 2.4, 95% CrI from 1.8 to 2.8). CONCLUSION: This study showed a significant signal of disproportionality reporting for ICI-induced CLS, characterized by a long time to onset, and compared with the idiopathic form of the disease with a less abrupt onset and a less consistent hemoconcentration pattern.

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.