Background
Systemic capillary leak syndrome (SCLS) (Clarkson’s disease) presents clinically with transient hemoconcentration, hypoalbuminemia, hypotension, and generalized edema, without known cause [ 1 ]. In 1960, Clarkson et al. first described an idiopathic form of this disorder characterized by repeated episodes of edema and hypotension associated with increased capillary permeability that resolved spontaneously [ 2 ]. Although triggers for acute episodes of SCLS have not yet been identified, they are frequently preceded by viral infections or intense physical exertion, suggesting a role for inflammatory mediators in acute SCLS [ 1 ].
Common complications of SCLS include hypotensive shock, acute kidney injury resulting from hypovolemia, and muscle compartment syndromes due to massive soft tissue edema, which can lead to mortality in untreated cases. Treatment for acute episodes of SCLS is supportive, including an intravenous infusion of crystalloids, colloids, and vasopressors to maintain adequate blood pressure, but with avoidance of excessive intravenous fluids that can exacerbate edema. Clinical observation and monitoring for the early signs and symptoms of an acute attack of SCLS, and treatment in a highly equipped intensive care unit (ICU) are all important measures to improve the chances of patient survival. A monoclonal gammopathy, typically IgG kappa, has been described in up to 90% of patients with acute SCLS [ 3 , 4 ]. From the published literature, most cases of SCLS present in middle-aged adults, and SCLS is equally reported in both sexes [ 5 , 6 ]. Although at least 300 cases of SCLS have been reported in the literature at this time, because the condition is rare and the diagnosis may be missed, it is likely that cases of SCLS are under-reported.
Findings from in vitro studies suggest that vascular endothelial hyperpermeability contributes to the clinical presentation of SCLS [ 7 , 8 ]. Also, serum samples from patients in the acute phase of SCLS, when added to normal microvascular endothelial cells in culture disrupted cell-cell contacts and induced morphological changes consistent with vascular barrier dysfunction [ 7 , 8 ]. Microvascular endothelial cells provide the foundation for the vasculature, and on their luminal side, the microvascular endothelial cells secrete endothelial surface glycocalyx (ESG), which is of critical importance for the stabilization of hemodynamic equilibrium [ 9 ]. The basal side of the endothelium, lined by a basement membrane, forms important contacts with the extracellular matrix. These microvasculature structures function as a barrier between the blood and the interstitial fluid. During acute episodes of SCLS, the microvascular endothelial barrier is highly permeable for fluid, plasma, and protein molecules of up to 900 kDa, which can enter into the interstitial space, causing edema [ 10 ]. The specific molecules that mediate endothelial hyperpermeability in SCLS are unknown.
Although a flu-like prodrome has been reported in up to 88% of cases of SCLS, specific infectious or other triggers for attacks can only be identified in approximately 60% of cases [ 3 , 5 ]. Common complications of acute attacks of SCLS include acute kidney failure (89%), muscle compartmental syndromes with rhabdomyolysis (43%), thromboses, pulmonary edema, and painful peripheral neuropathies. The five-year survival rate for SCLS has been reported to be between 73–78% [ 3 , 5 ].
This report is the second known case of SCLS in Norway [ 9 ]. In addition to reporting a rare condition, this report includes details of the medical history of the family members, in an attempt to identify predisposing factors for SCLS. In this case, a family history of lymphoproliferative disorders, cardiovascular disease, cancer, and diabetes was identified. A transient increase in the cell surface heparan sulfate proteoglycan, syndecan-1 (CD138) was identified during the acute presentation, which normalized during the recovery phase. These findings suggest that reduced ESG function could contribute to vascular endothelial hyperpermeability in SCLS.
Case Report
In 2009, a 49-year-old woman reported an upper respiratory tract infection with rhinorrhea, cough, and fever of between 38–39°C, for two days. The patient had experienced increasing lethargy, fatigue, and loss of appetite for several days and was confined to bed. She became dehydrated and noted reduced urine output. On the fifth day of her symptoms, she experienced a brief syncopal attack with subsequent nausea and vomiting, but she was awake with normal mentation, but this episode resulted in emergency admission to hospital by ambulance and given intravenous Ringer’s solution.
On hospital admission, the patient had no detectable pulse or measurable blood pressure in her extremities. She experienced brief, intermittent episodes of syncope but was fully awake and mentally coherent between these episodes. She initially presented with blueish extremities but had no peripheral edema or skin rashes. Her blood pressure was 60/40 mm Hg, her pulse was regular at between 85–105 beats per min, her temperature was 35.9ºC, her respiration rate was 42 breaths per min, and her weight to height ratio was 50 kg to 1.65 m. Serum glucose was 9,8 mmol/L, with dipstick urinalysis showing urine protein of 3+, and erythrocytes of 2+. Electrocardiogram (ECG) and echocardiography were normal. Analytical blood results before, during, and after the initial presentation are summarized in Table 1 .
On admission, on the fifth day of her illness, high values were measured for hemoglobin (Hb) (24.6 g/dL), hematocrit (Hct) (73%), and erythrocytes (7.6×10 12 /L). White blood cells were increased (17×10 9 /L) and were mainly comprised of neutrophils (15×10 9 /L). Platelet levels were 298×10 9 /L, and total protein was 69 g/L, which were all within normal reference values. Albumin (37 g/L) was decreased compared to a previous baseline value of 50 g/L. Creatinine (142 mmol/L), serum glutamic oxaloacetic transaminase (SGOT), and creatinine kinase (CK) all were increased. C-reactive protein (CRP) was 8 mg/L, which was 3 mg/L above normal limits. On hospital admission, only small amounts of urinary protein (0.2–0.5 g/L) were detected.
Because of her hypotension and elevated white blood cell count, a diagnosis of afebrile sepsis was first suspected, and she was treated empirically with antibiotics; she was also anticoagulated with enoxaparin 40 mg because she was considered to be at increased risk for thrombosis; intravenous hydrocortisone 250 mg was given for presumed adrenal insufficiency. She received 20 liters of intravenous crystalloid to achieve hemodynamic stability, which resulted in rapid development of generalized peripheral edema.
Five hours after her hospital admission, she required fasciotomy in both lower extremities to treat acute compartment syndrome. The muscles of the legs appeared to be clinically normal, and a pressure gauge was inserted into the muscle to enable incision closure and wound monitoring. Although the diuretic furosemide was given, urine output remained minimal during the first 24–48 hours following hospital admission.
On the sixth day of her illness, pleural effusions and retropharyngeal edema were diagnosed radiologically. However, her leg pain and interstitial muscle pressure increased progressively, and a bilateral fasciotomy was again performed. Necrotic areas were now seen in the leg muscles.
Creatine kinase (CK) levels increased over the next two days, peaking on the ninth day of her illness (13,980 U/L). Sporadic increases in liver and muscle enzymes were detected. Following resuscitation with large amounts of intravenous fluids and plasma extravasation from the surgical fasciotomy sites, the patient developed anemia requiring transfusion on the tenth day of disease. A slight increase in fibrinogen was noted on admission while D-dimer was normal. Erythrocyte sedimentation rate (ESR), prothrombin time (PT), INR, and platelet counts were all within normal limits during her hospital course. On the ninth day of her disease, complement levels, C3 (0.46 g/L) and C4 (0.05 g/L) were decreased. More extensive complement analysis performed one year later revealed lack of mannose-binding lectin (MBL), as shown in Table 2 .
Based on clinical signs, symptoms, and laboratory tests, the differential diagnosis included sepsis, idiopathic anaphylaxis, hereditary angioedema, polycythemia vera, and cardiac insufficiency. However, these diagnoses were excluded because the combination of signs and symptoms of severe hemoconcentration, hypoalbuminemia, protracted hypotension, and generalized edema with accompanying compartment syndromes were pathognomonic of systemic capillary leak syndrome (SCLS).
In support of the diagnosis of SCLS, C1 esterase inhibitor levels and function were normal, and blood cultures were negative. There were no triggers found for an anaphylaxis reaction, and there were no typical allergic signs and symptoms of anaphylaxis, such as urticaria, stridor, or wheezing. Although small amounts of proteinuria were detected, urinary protein loss was unlikely to account for the acute drop in serum albumin. The urinary protein before the episode was equivalent to that obtained at the time of hospital admission, whereas serum albumin was initially normal on admission, and urine output was minimal during this time. Also, the urinary protein to creatinine ratio was only 0.4, which was well below levels required for the diagnosis of nephrotic syndrome. Serum immunoelectrophoresis showed a monoclonal IgG-kappa paraprotein (1–2 g/L); IgG paraprotein is frequently (80–90%) found in the serum of patients with SCLS (1). Free kappa or lambda light chains were within normal reference ranges, and the kappa to lambda ratio was normal. While IgG and IgA were in the lower reference range, IgM was in the high normal range. Serum levels of the cell surface heparan sulfate proteoglycan, syndecan-1 (CD138), a measure of endothelial surface glycocalyx (ESG) damage, were analyzed by enzyme-linked immunoassay (ELISA) (Diaclone, Besancon, France) and peaked at up to 500 ng/mL (reference range, 50–100 ng/mL), and normalized on disease remission ( Figure 1 ).
Treatment with intravenous immunoglobulin IgG (IVIG) commenced on the seventh and eighth day of illness, based on previous reports of its efficacy in acute SCLS [ 12 ]. Clinical improvement was found within the first two hours of IVIG treatment, with resorption of generalized edema and an increase in urine output, and no signs of pulmonary edema developed on the following days. Antibiotics were withdrawn.
Five weeks following hospital admission, the patient left the hospital and underwent a slow process of rehabilitation. However, at present, due to leg pains and muscular weakness, she currently requires orthopedic support for walking, remains weak, and her quality of life is reduced. The patient also suffers from frequent upper respiratory tract infections but has had no further episodes of SCLS in the past eight years. The M-component of her monoclonal gammopathy has progressively declined to almost undetectable levels, and Hb, Hct, creatinine, and CK have remained within normal limits ( Table 1 ). She has received prophylaxis with terbutaline and theophyl-line, as recommended in the literature for the treatment of SCLS. The patient has been informed of her medical condition and has been made aware of the early symptoms of SCLS with information regarding this condition, should she require further hospital admissions.
Relevant past medical history and family history
Examination of the patient’s prior medical history showed that she was born nine weeks before term, weighing 1,070 g. Pregnancy and delivery were complicated by toxemia, Rhesus incompatibility, and exchange transfusion. She had appendicitis at two-years-of-age, which was complicated by sepsis. From early childhood, she had repeated urinary tract infections with cystitis, and at least four episodes of cysto-pyelonephritis, but she had no permanent kidney damage. During her pregnancies an increased blood glucose was noted.
In her paternal family, there were several cases of premature death due to heart disease, cancer, and diabetes. Her mother had toxemia associated with all three pregnancies, and died at 76 years-of-age and had a weak serum IgM-lambda monoclonal gammopathy of undetermined significance (MGUS). Six of mother’s brothers and sisters died of cardiovascular disease, and one of the mother’s sisters died at 72-years-of-age of multiple myeloma after 12 years with a known IgA-kappa monoclonal gammopathy of undetermined significance (MGUS).
Discussion
The pathogenesis of systemic capillary leak syndrome (SCLS) (Clarkson’s disease) is not understood, and the site of the vascular endothelial hyperpermeability in SCLS remains unknown. Although transient increases in circulating vascular endothelial growth factor (VEGF), angiopoietin-2 (Angpt-2), and monocyte/macrophage-associated inflammatory mediators including C-X-C chemokine motif 10 (CXCL10), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 during acute episodes of SCLS suggest a role for these cytokines in the mechanism of vascular leak, the specific pathways resulting in vascular endothelial hyperpermeability in SCLS remain unknown. Preliminary study findings from our laboratory ( unpublished data ) suggest that individuals affected by SCLS have cutaneous hyper-responsiveness to inflammatory mediators that affect the microvasculature and that endothelial cells derived from patients with SCLS exhibit this behavior persistently in vitro .
The barrier function of the microvasculature is a complex physiological process in which adhesive cell-cell junction contacts prevent plasma and cell extravasation. Under normal homeostatic conditions, microvascular endothelial cells secrete endothelial surface glycocalyx (ESG), which fortifies the endothelial barrier via several mechanisms. ESG is a fibrous matrix rich in negatively-charged proteoglycans containing sialic and neuraminic acids, which prevent binding of circulating leukocytes and platelets. Vascular endothelial cells actively build and replenish the structural components of ESG, as well as blood group antigens and endothelial superoxide dismutase (eSOD). Components from plasma, including albumin, anti-thrombin, and calcium ions, are interspersed throughout the ESG meshwork, which helps to maintain intravascular osmotic pressure, coagulation, and platelet adhesion [ 13 , 14 ]. ESG also protects endothelial cells from shear stress induced by circulating blood, and ESG degradation due to endothelial cell damage may contribute to the severity of plasma leak in diverse clinical conditions including, dengue virus infection and heart failure [ 15 – 17 ].
Syndecan-1 (CD138) is a transmembrane proteoglycan component of ESG that binds to hyaluronan on the luminal side of the endothelial cell membrane and cytoskeletal components on the cytosolic side. In conditions associated with ESG disruption, for example, sepsis, trauma, and ischemia, syndecan-1 (CD138) is shed and circulates in the serum, reflecting both damage to the ESG and weakening of the endothelial barrier [ 18 ]. Damage to ESG promotes white blood cell and platelet adherence to the endothelial wall, initiating thrombosis. Plasma fluid leaks into the interstitial space through trans-endothelial cell pores and through widened intercellular gaps, which partially depend on the availability of syndecan-1 (CD138) [ 9 ].
In the case of the patient in this report, fluctuating levels of syndecan-1 (CD138) were found during the presentation of SCLS. Serum syndecan-1 (CD138) levels were within the normal range for the first several days of the acute presentation, peaked at five times the upper limit of normal on the sixth day, and then returned to baseline after that. An upper respiratory infection preceded the attack of SCLS in this patient, and it has previously been reported that viral membrane components, including neuraminidase, may lead to ESG disruption through digestion of neuraminic acids [ 19 ]. Therefore, viremia may have resulted in disruption of ESG in this patient. Serum syndecan-1 (CD138) levels increased to nearly ten times the upper limit of normal on days 9–12, which could reflect reperfusion injury resulting from mobilization of extravasated fluid during the recovery phase and restoration of intravascular volume, a phenomenon that has been described by previous clinical studies [ 20 ]. Syndecan-1 (CD138) levels returned to baseline during the convalescent phase, indicating the resolution of the acute endothelial dysfunction.
In this patient, several additional laboratory abnormalities were found during the acute phase in our patient that have not been previously reported in association with SCLS. Low levels of C3 and C4 were detected on the ninth day of the disease, which could reflect extravasation due to increased microvascular permeability, rather than complement consumption. Mannose-binding lectin (MBL) was low or undetectable in our patient. MBL adheres to mannose on the surface of many pathogens forming the complex, MBL-associated serine protease (MASP). MASP leads to the cleavage of C4 into C4a and C4b; C4b fragments then bind to microbes, initiating formation of C3-convertase. The subsequent complement cascade catalyzed by C3-convertase creates a membrane attack complex, which causes lysis of the pathogen as well as apoptosis and cell necrosis. MBL binds to glycoprotein in viruses and is instrumental in the first-line defense against infection [ 21 ]. MBL deficiency has been reported to be associated with recurrent infections in humans but has not previously been reported in SCLS. In the case of the patient in this report, MBL deficiency may have accounted for her history of frequent infections, including cystitis and pyelonephritis, as well as the frequent upper respiratory tract viral infections, such as the episode that triggered her attack of SCLS. Low levels of IgG and IgA, with normal levels of IgM, are findings that have previously been reported in cases of SCLS [ 22 , 23 ].
Finally, an important aspect of this case report was the discovery that several family members also had a history of monoclonal gammopathy of undetermined significance (MGUS). Although none of this patient’s relatives had a history of episodes of SCLS, to our knowledge, such familial clustering of paraproteinemia has not been previously reported in SCLS, and the pathophysiological significance of this finding requires further study [ 24 ].
Conclusions
This case report supports the view that damage to the microvascular endothelium and its ESG have a role in the pathogenesis of acute systemic capillary leak syndrome (SCLS) (Clarkson’s disease). This case also indicated that monitoring serum levels of syndecan-1 (CD138) might be used to monitor progression and resolution of episodes of SCLS. Further studies are needed to determine the mechanisms underlying the degradation of endothelial surface glycocalyx (ESG) and vascular damage in SCLS.
References:
1. Druey KM Parikh SM Idiopathic systemic capillary leak syndrome (Clarkson disease) J Allergy Clin Immunol 2017 140 3 663 70 28012935 10.1016/j.jaci.2016.10.042 PMC5481509
2. Clarkson B Thompson D Horwith M Luckey EH Cyclical edema and shock due to increased capillary permeability Trans Assoc Am Physicians 1960 73 272 82 13693910
3. de Chambrun MP Gousseff M Mauhin W Intravenous immunoglobulins improve survival in monoclonal gammopathy-associated systemic capillary-leak syndrome Am J Med 2017 130 10 1219.e19 e27 10.1016/j.amjmed.2017.05.023 28602874
4. Kapoor P Greipp PT Schaefer EW Idiopathic systemic capillary leak syndrome (Clarkson’s disease): The Mayo clinic experience Mayo Clin Proc 2010 85 10 905 12 20634497 10.4065/mcp.2010.0159 PMC2947962
5. Gousseff M Arnaud L Lambert M The systemic capillary leak syndrome: A case series of 28 patients from a European registry Ann Intern Med 2011 154 7 464 71 21464348 10.7326/0003-4819-154-7-201104050-00004
6. Dhir V Arya V Malav IC Idiopathic systemic capillary leak syndrome (SCLS): case report and systematic review of cases reported in the last 16 years Intern Med 2007 46 12 899 904 17575386 10.2169/internalmedicine.46.6129
7. Xie Z Ghosh CC Patel R Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome) Blood 2012 119 18 4321 32 22411873 10.1182/blood-2011-08-375816 PMC3359743
8. Xie Z Ghosh CC Parikh SM Druey KM Mechanistic classification of the systemic capillary leak syndrome: Clarkson disease Am J Respir Crit Care Med 2014 189 9 1145 47 24787070 10.1164/rccm.201310-1746LE PMC4098109
9. Radeva MY Waschke J Mind the gap: Mechanisms regulating the endothelial barrier. Acta Physiol (Oxf) 2017 [Epub ahead of print] 10.1111/apha.12860 28231640
10. Atkinson JP Waldmann TA Stein SF Systemic capillary leak syndrome and monoclonal IgG gammopathy; Studies in a sixth patient and a review of the literature Medicine (Baltimore) 1977 56 3 225 39 870792 10.1097/00005792-197705000-00004
11. de Chambrun MP Luyt CE Beloncle F The clinical picture of severe systemic capillary-leak syndrome episodes requiring ICU admission Crit Care Med 2017 45 7 1216 23 28622216 10.1097/CCM.0000000000002496
12. Lambert M Launay D Hachulla E High-dose intravenous immunoglobulins dramatically reverse systemic capillary leak syndrome Crit Care Med 2008 36 7 2184 87 18552679 10.1097/CCM.0b013e31817d7c71
13. Chappell D Westphal M Jacob M The impact of the glycocalyx on micro-circulatory oxygen distribution in critical illness Curr Opin Anaesthesiol 2009 22 2 155 62 19307890 10.1097/ACO.0b013e328328d1b6
14. Nieuwdorp M van Haeften TW Gouverneur MC Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo Diabetes 2006 55 2 480 86 16443784 10.2337/diabetes.55.02.06.db05-1103
15. Suwarto S Sasmono RT Sinto R Association of endothelial glycocalyx and tight and adherens junctions with severity of plasma leakage in Dengue infection J Infect Dis 2017 215 6 992 99 28453844 10.1093/infdis/jix041 PMC5407050
16. Nguyen TH Liu S Ong GJ Glycocalyx shedding is markedly increased during the acute phase of Takotsubo cardiomyopathy Int J Cardiol 2017 243 296 99 28528983 10.1016/j.ijcard.2017.04.085
17. Kim YH Nijst P Kiefer K Tang WH Endothelial glycocalyx as biomarker for cardiovascular diseases: Mechanistic and clinical implications Curr Heart Fail Rep 2017 14 2 117 26 28233259 10.1007/s11897-017-0320-5 PMC5386320
18. Rahbar E Cardenas JC Baimukanova G Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients J Transl Med 2015 13 117 25889764 10.1186/s12967-015-0481-5 PMC4397670
19. Puerta-Guardo H Glasner DR Harris E Dengue virus NS1 disrupts the endothelial glycocalyx, leading to hyperpermeability PLoS Pathog 2016 12 7 e1005738 27416066 10.1371/journal.ppat.1005738 PMC4944995
20. Rehm M Bruegger D Christ F Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia Circulation 2007 116 17 1896 906 17923576 10.1161/CIRCULATIONAHA.106.684852
21. Ji X Olinger GG Aris S Mannose-binding lectin binds to Ebola and Marburg envelope glycoproteins, resulting in blocking of virus interaction with DC-SIGN and complement-mediated virus neutralization J Gen Virol 2005 86 Pt 9 2535 42 16099912 10.1099/vir.0.81199-0
22. Kang PM Lawrence C Khan GA Hays RM Fulminating systemic capillary leak syndrome with lymphocytosis and hypogammaglobulinemia Ren Fail 1995 17 5 615 17 8570875 10.3109/08860229509037627
23. Lassoued K Clauvel JP Similowski T Pulmonary infections associated with systemic capillary leak syndrome attacks in a patient with hypogammaglobulinemia Intensive Care Med 1998 24 9 981 83 9803337 10.1007/s001340050700
24. Zhang W Ewan PW Lachmann PJ The paraproteins in systemic capillary leak syndrome Clin Exp Immunol 1993 93 3 424 29 8370170 10.1111/j.1365-2249.1993.tb08195.x PMC1554918