Systemic capillary leak syndrome: recognition preventsmorbidity and mortalityD. J. Rabbolini,1 N. Ange,2 G. D. Walters,3 M. Pidcock1 and K. L. Randall2

Departments of 1Haematology, 2Immunology and 3Renal Medicine, The Canberra Hospital, Canberra, Australian Capital Territory, Australia

Key wordssystemic capillary leak syndrome,

polycythaemia, intravenous immunoglobulin,

shock, oedema.

CorrespondenceKatrina Randall, Department of Immunology,

The Canberra Hospital, PO Box 11, Woden,

ACT 2606, Australia.

Email: katrina.randall@anu.edu.au

Received 13 December 2012; accepted 2

February 2013.

doi:10.1111/imj.12271

Abstract

Idiopathic systemic capillary leak syndrome (SCLS) is extremely rare but carries a high

morbidity and mortality. The diagnosis is made clinically by a classic triad of hypoten-

sion, hypoalbuminaemia and haemoconcentration. There have been recent advances in

understanding the pathophysiological basis for SCLS and in effective prophylaxis. We

report a case of SCLS to increase awareness of the condition and to highlight the benefits

of prophylactic intravenous immunoglobulin in this condition.

A 61-year-old man presented to the EmergencyDepartment at the Canberra Hospital following syncope.He had returned from an overseas trip 6 days prior andhad suffered general malaise in the preceding days. Whilein the Emergency Department, he experienced anothersyncopal episode associated with vomiting. Generalexamination found him to be hypotensive, with a bloodpressure of 87/54 mmHg, heart rate 92 b.p.m. with aregular rhythm and respiratory rate of 14 breaths/min,with oxygen saturation of 94–96% on a Hudson maskwith 6 L/min oxygen. His peripheries were cool andcyanosed, and there was marked tense pedal oedema tothe level of the thighs. A focussed systemic examinationdid not demonstrate any signs of cardiopulmonarydisease, carotid stenosis nor focal neurological signs. Inaddition, there were no signs of congestive cardiac failureor stigmata of chronic liver disease to account for theimpressive peripheral oedema. The electrocardiogramand chest X-ray were normal. Subsequent blood tests(Table 1) demonstrated polycythaemia and leucocytosiswith evidence of an acute kidney injury, hypo-proteinaemia and hypoalbuminaemia. Other significantresults included a raised anion gap metabolic acidosis, anelevated lactate and creatine kinase (CK). A computed

tomography (CT) brain did not demonstrate any acutefocal abnormalities and venous duplex Dopplers of hislegs revealed patent veins bilaterally.

Significantly, the patient had a history of two previousadmissions to hospital, the first in Sydney in 2001 requir-ing an intensive care unit (ICU) admission, and thesecond in Canberra in 2008. At this time, both were eitherpreceded by long haul travel or physical exertion andwere characterised by syncope, tense peripheral legoedema without evidence of thrombosis, persistent hypo-tension and acute kidney injury, hypoalbuminaemia,polycythaemia and following investigation, the pre-sence of a serum paraprotein. During both previousadmissions, he had been treated with intravenous fluidswith a good response. During the first admission, he hadbeen venesected for profound haemoconcentration(haemoglobin 220 g/L). He had been followed up inthe clinic after each admission and given a diagnosis ofmonoclonal gammopathy of undetermined significance(MGUS).

Due to poor response to fluid resuscitation (9 L ofcrystalloid in 16 h), our patient was transferred to theICU for further management. He remained hypotensivewith progressive drowsiness and oliguria, and wasthought to have pseudopolycythaemia secondary todehydration. However, an explanation for his tense pedaloedema and drowsiness was unclear.

Funding: None.Conflict of interest: None.

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The hypotension eventually responded to further crys-talloid and colloid fluid boluses. His legs remained tenselyswollen, and the orthopaedic team was consulted toexclude compartment syndrome. Further studies toexclude thrombosis were done by CT angiography as thelegs were so oedematous that ultrasound was unreliable.

The patient was discharged to the ward after 48 h inICU, but on the next day developed shortness of breathand hypoxia. He was found to have pulmonary oedemaand peripheral oedema now involving his abdomen, andwas treated with intravenous frusemide and other stand-ard supportive measures. Over the following days, slowresolution of his generalised oedema was noted and hiscondition slowly improved.

Further investigation revealed an erythropoietin levelabove reference range (RR) measuring 33 mIU/mL (RR4–19 mIU/mL) and no JAK-2 V617F mutation. Second-ary causes of polycythaemia including medications andhypoxia were excluded on history and arterial blood gasrespectively. A CT scan did not show lymphadenopathyor hepatosplenomegaly. A bone marrow biopsy con-firmed the presence of a plasmacytosis in keeping with anMGUS with a serum immunoglobulin G kappa monoclo-nal protein measuring 9 g/L.

The cause of the observed hypoalbuminaemia was alsoinvestigated. He was well nourished and did not have anyevidence of chronic inflammatory conditions nor infec-tions, and the measured proteinuria of 0.68 g/24 h wasunlikely to explain the degree of observed oedema.

Investigation of the hypotensive episode excludedadrenal mineralocorticoid and corticosteroid insufficien-cies. A normal serum tryptase excluded the possibilities ofsystemic mastocytosis and/or anaphylaxis and a normalC1 esterase level, hereditary angioedema.

Finally, following a renal consultation, the characteris-tic clinical presentation was recognised as systemic capil-lary leak syndrome (SCLS).

The patient was discharged with a letter to present to theEmergency Department in the event of recurrence andgiven a MedicAlert bracelet. The critical issue of prophy-lactic therapy was considered, and based on the evidenceavailable at the time,1 he was commenced on monthlyintravenous immunoglobulin (IVIg) at 2 g/kg given overtwo consecutive days. This strategy has resulted in aresolution of his chronic oedema and a good functionaloutcome. Eighteen months after the diagnosis, he has notexperienced any further recurrences and is now receivingIVIg under the new eligibility criteria published in 2012.2

The first description of idiopathic SCLS was byClarkson in 19603 (earning the eponym of Clarksondisease/syndrome). Only 100 cases were reported up to2006, but from 2006 to 2011 at least 50 more cases havebeen identified.4 This apparent increase in incidence ismore likely related to an increasing awareness of thedisease rather than actual increased incidence, butdespite this increased awareness, it is still estimated thatseveral patients die during their first attack when thecause goes unrecognised.5

Patients with idiopathic SCLS present with a classictriad of hypotension, hypoalbuminaemia and haemo-concentration with pseudopolycythaemia due to plasmaloss from the circulation into tissues, resulting in ana-sarca. Attacks may occur spontaneously or following aprodromal illness with flu-like symptoms and severalprecipitants, such as infection, sustained physical effortand menstruation have been identified.1 Although theypresent with profound hypotension (median systolicblood pressure 60 mmHg),1 this is often not associatedwith loss of consciousness.

Acute attacks usually demonstrate three phases: a pro-dromal phase, an acute extravasation phase and a recov-ery phase. Patients are taught to present to medical careearly if they recognise their prodromal symptoms. Theacute phase is managed in an intensive care setting

Table 1 Laboratory values

Test (unit, normal range) Day1 02h00 Day1 11h10 Day1 21h15 Day2 04h45 Day2 14h00 Day3 04h00 Day5 11h30

Haemoglobin (g/L, 135–180) 179 210 193 161 153 124 103

HCT (0.4–0.53) 0.54 0.63 0.59 0.48 0.45 0.37 0.30

White blood cells (×109/L, 4.0–11.0) 11.4 18.8 35.3 35.4 27.5 16.4 6.9

Platelets (×109/L, 150–400) 213 253 249 266 268 204 118

Sodium (mmol/L, 137–145) 137 137 135 132 129 130 139

Potassium (mmol/L, 3.2–5.0) 4.4 4.8 4.7 4.5 4.6 4.4 3.4

Urea (mmol/L, 2.5–7.5) 7.2 8.3 10.1 11.9 13.2 10.9 4.4

Creatinine (μmol/L, 60–110) 95 133 139 160 137 92 60

CK (U/L, 20–200) — 268 236 180 — — 227

Total protein (g/L, 60–80) 60 59 — — — — 58

Albumin (g/L, 33–50) 31 29 16 42 32 32 38

—, no result available for this time point. CK, creatine kinase; HCT, haematocrit.

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© 2013 The AuthorsInternal Medicine Journal © 2013 Royal Australasian College of Physicians1146

and requires central venous pressure (CVP) monitoring.Rather than aiming for normotension and a normal CVP,the aim is to use vasopressors and fluid boluses (ratherthan continuous infusions) to prevent shock, and somedegree of oliguria is expected. This judicious fluid use is totry to minimise the morbidity of the recovery phase,although this is anecdotal as no trials have been carriedout.5 Serial compartment pressure measurements, CK,lactate and early orthopaedic consultation to avoid limbdamage and loss are imperative. The resolution of capillaryhyperpermeability and transition into the recovery phasecan often be rapid; it is characterised by a marked decreasein the amount of fluid required to maintain intravascularvolume, and thus iatrogenic pulmonary oedema is fre-quently encountered.6

The high morbidity experienced during acute attacksis most often related to patients requiring fasciotomiesfor compartment syndrome and iatrogenic pulmonaryoedema. The 5-year survival is 73%, with 75% of deathsoccurring during an acute attack.1 A predominant factorappears to be myocardial oedema and lethal cardiacarrhythmia.1

Idiopathic SCLS characteristically affects Caucasians,with a median age of onset at 49.1 years with no appar-ent gender bias, although case reports of SCLS affectingAsians, Africans and children are documented. Seventy-six per cent of patients had an associated monoclonalgammopathy in one study,6 89% in another.1 The rate oftransformation to multiple myeloma is estimated to bethe same as patients with MGUS.6 The median diagnostic

delay in one cohort was 7 months,1 while in another itwas 1.1 years.6

IVIg has shown clinical efficacy in the acute andprophylactic treatment of SCLS.1,7–9 There remains someongoing discussion about whether IVIg is superior toterbutaline and aminophylline or theophylline, but hasrapidly become standard of care among physicians whomanage cohorts of these patients.8,9 No matter the choiceof prophylactic therapy, those who have prophylactictherapy have significant survival advantage over thosewho do not.1

The exact pathophysiology of idiopathic SCLS is notknown, but some recent advances have been made. Inthe original description of the syndrome, Clarksondescribed the results obtained by a colleague whoinjected plasma, drawn from his patient during an acuteepisode, into rats, inducing a shock-like state.3 Xie et al.4

recently showed that factors in SCLS serum induceendothelial permeability in vitro by disrupting endothelialadherens junctions and causing cell retraction withoutinducing cell death. This reaction occurred even whenthe immunoglobulin fraction of the serum was removedand was prevented in the presence of IVIg. They proposethat vascular endothelial growth factor and angiopoietin2 may be the factors, as both were found to be elevatedduring acute attacks.

While the pathogenesis remains unclear, what iscertain is that timely diagnosis and institution of prophy-lactic therapy reduces morbidity and mortality in thiscondition, as highlighted by this case.

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© 2013 The AuthorsInternal Medicine Journal © 2013 Royal Australasian College of Physicians 1147