Capillary leak syndrome: State of the art in 2021.

Capillary leak syndrome (CLS) is an increasingly acknowledged multifaceted and potentially lethal disease. Initial nonspecific symptoms are followed by the intriguing CLS hallmark: the double paradox associating diffuse severe edema and hypovolemia, along with hemoconcentration and hypoalbuminemia. Spontaneous resolutive phase is often associated with poor outcome due to iatrogenic fluid overload during leak phase. CLS is mainly triggered by drugs (anti-tumoral therapies), malignancy, infections (mostly viruses) and inflammatory diseases. Its idiopathic form is named after its eponymous finder: Clarkson's disease. CLS pathophysiology involves a severe, transient and multifactorial endothelial disruption which mechanisms are still unclear. Empirical and based-on-experience treatment implies symptomatic care during the acute phase (with the eventual addition of drugs amplifying cAMP levels in the severest cases), and the prophylactic use of monthly polyvalent immunoglobulins to prevent relapses. As CLS literature is scattered, we aimed to collect and summarize the current knowledge on CLS to facilitate its diagnosis, understanding and management.

Epidemiology, risk factors, and prognosis of capillary leak syndrome in pediatric recipients of stem cell transplants: a retrospective single-center cohort study.

CLS involves sudden loss of intravascular fluids into the interstitial spaces. CLS was described as a possible complication after SCT. Few studies report the incidence of CLS in pediatric populations. We aimed to assess CLS incidence, its risk factors, and impact on the survival. The clinical charts of patients <18 years of age transplanted at our institution between 2002 and 2012 were reviewed. CLS was defined by weight gain >3% in 24 hours and positive intake balance despite furosemide administration. In total, 234 patients underwent 275 allogeneic SCT procedures in the analyzed time frame. Fifteen patients developed CLS (5.4%). The probability of developing CLS was significantly increased in patients suffering from sepsis (14.3% vs 0.6%, P<.001). Patients with CLS exhibited an increased risk of acute GvHD in the first 30 days after SCT (10.8% vs 1.8%, P=.002). Ten of the patients with CLS required intensive care. CLS strongly impacts OS at day +100 after SCT and is a predictive factor of TRM at the same date (42.9% vs 5%, P<.0001). The biological relation among sepsis, GvHD, and CLS development in terms of cytokine release and endothelial damage warrants further studies.

[Clinical risk factors for capillary leak syndrome in children with sepsis].

OBJECTIVE: To investigate the clinical features of capillary leak syndrome (CLS) in children with sepsis, and to analyze its risk factors. METHODS: Clinical data of 384 children with sepsis was studied retrospectively. They included 304 cases of general sepsis, 54 cases of severe sepsis and 26 cases of septic shock, and were divided into non-CLS (n=356) and CLS groups (n=28). Univariate analysis was performed for each of the following variables: sex, age, malnutrition, anemia, coagulation disorders, white blood cell count, C-reactive protein (CRP), procalcitonin (PCT), tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, blood glucose, lactic acid, Pediatric Risk of Mortality (PRISM) III score, pediatric critical illness score (PICS), severe sepsis and number of failed organs≥3. The statistically significant variables (as independent variables) were subjected to multivariate logistic regression analysis. RESULTS: The incidence rate of CLS in children with septic shock, severe sepsis and general sepsis were 42.3%, 20.1% and 1.3%, respectively, with significant differences among them (P<0.01). There were significant differences in anemia, coagulation disorders, CRP, PCT>2 ng/mL, TNF, IL-1, IL-6, blood glucose, lactic acid, PRISM III score, PICS and number of failed organs≥3 between the non-CLS and CLS groups (P<0.05). Severe sepsis/shock and PRISM III score were the independent risk factors for CLS in children with sepsis. CONCLUSIONS: The severity of sepsis and PRISM III score are positively correlated with the incidence of CLS in children with sepsis. Early monitoring of such factors as infection markers and blood glucose in children with severe sepsis and high PRISM III score may contribute to early diagnosis and effective intervention, thus reducing the mortality from CLS in children with sepsis.

Idiopathic systemic capillary leak syndrome (Clarkson's disease): the Mayo clinic experience.

OBJECTIVE: To determine clinical features, natural history, and outcome of a well-defined cohort of 25 consecutive patients with idiopathic systemic capillary leak syndrome (SCLS) evaluated at a tertiary care center. PATIENTS AND METHODS: Records of patients diagnosed as having SCLS from November 1, 1981, through April 30, 2008, were reviewed. Descriptive statistics were used to analyze patient demographics, clinical features, complications, and therapeutic interventions. RESULTS: Of the 34 patients whose records were reviewed, 25 fulfilled all diagnostic criteria for SCLS. The median age at diagnosis of SCLS was 44 years. Median follow-up of surviving patients was 4.9 years, and median time to diagnosis from symptom onset was 1.1 years (interquartile range, 0.5-4.1 years). Flulike illness or myalgia was reported by 14 patients (56%) at onset of an acute attack of SCLS, and rhabdomyolysis developed in 9 patients (36%). Patients with a greater decrease in albumin level had a higher likelihood of developing rhabdomyolysis (p=.03). Monoclonal gammopathy, predominantly of the IgG-κ type, was found in 19 patients (76%). The progression rate to multiple myeloma was 0.7% per person-year of follow-up. The overall response rate to the different therapies was 76%, and 24% of patients sustained durable (>2 years) complete remission. The estimated 5-year overall survival rate was 76% (95% confidence interval, 59%-97%). CONCLUSION: Systemic capillary leak syndrome, a rare disease that occurs in those of middle age, is usually diagnosed after a considerable delay from onset of symptoms. The degree of albumin decrement during an attack correlates with development of rhabdomyolysis. A reduction in the frequency and/or the severity of attacks was seen in nearly three-fourths of patients who were offered empirical therapies. The rate of progression to multiple myeloma appears to be comparable to that of monoclonal gammopathy of undetermined significance.

Risk factors for capillary leakage syndrome after bone marrow transplantation.

Age, hematopoietic growth factors, cyclosporin A, mode of bone marrow transplantation (BMT) (autologous, allogeneic-related, unrelated), and underlying disease were assessed as potential risk factors for capillary leakage syndrome (CLS) in 96 patients after BMT. CLS was defined as unexplained weight gain of > 3% within 24 h and nonresponsiveness to furosemide. CLS occurred in 9/21 patients after unrelated compared with 2/33 after allogeneic-related BMT (p = 0.0017) for hematopoietic disorders (n = 54) and in 6/7 patients after allogeneic-related compared with 3/35 after autologous BMT (p = 0.001) for solid tumors (n = 42). Hematopoietic growth factors and cyclosporin A were no significant risk factors on their own. We conclude that unrelated BMTs or high-intensity conditioning regimens used in combination with allogeneic-related BMT are the main risk factors for CLS.

Marrow engraftment and clinical manifestations of capillary leak syndrome.

A capillary leak syndrome occurs frequently in bone marrow transplant patients in addition to graft-versus-host-disease and infection. The underlying pathology is poorly understood but the clinical manifestations of excessive weight gain, ascites, and edema associated with kidney and liver abnormalities suggest a common injury to multiple organs. The clinical courses of 55 allogeneic and autologous marrow transplant recipients were retrospectively reviewed with regard to the presentation of a capillary leak syndrome (CLS). Twenty-nine patients (53%) developed non-cardiogenic pulmonary edema with or without concurrent pleural effusions; the incidence was comparable in allogeneic and autologous recipients. Pulmonary features were accompanied by hepatic dysfunction in 28, renal dysfunction in 22, and central nervous system abnormalities in 17. There was a strong correlation between time of engraftment and the first manifestations of CLS, both of which occurred earlier in allogeneic than in autologous transplant recipients. These data confirm that CLS occurs in both allogeneic and autologous transplant recipients and suggest a pivotal contribution by circulating leukocytes.