Background

Systemic capillary leak syndrome (SCLS), also known as Clarkson’s disease, is a rare disorder of unknown aetiology. Since SCLS was first described in 1960, fewer than 500 cases have been reported in the medical literature. SCLS is diagnosed by the classic triad of hypotension, haemoconcentration and hypoalbuminaemia resulting from fluid extravasation.1 This ‘leak’ phase lasts several days, and the ‘post-leak’ phase usually begins from 48 hours to 1 week after the onset of shock, in which fluids are mobilised from the peripheral tissues into the intravascular space, followed by normalisation of blood pressure and diuresis.2 Anasarca and compartment syndromes may develop as a result of excessive intravenous fluid administration during the ‘post-leak’ phase.3

Monoclonal gammopathy of uncertain significance (MGUS) is present in 68%–85% of patients with SCLS, but a pathogenic role of paraprotein remains unclear.4 Typically, SCLS can be triggered by upper respiratory infections such as influenza,5 6 West Nile virus7 and so on. Recently, five cases of SCLS triggered by COVID-19 were reported.8 9 SCLS is considered a cytokine-mediated disease, so the benefit of steroids presumably relates to their ability to reduce the expression of multiple cytokines10; however, the reason that steroids are ineffective in some cases of capillary leak syndrome is unknown.11 Currently, intravenous immunoglobulin (IVIg) is the most promising therapy for both acute treatment12 and long-term prevention.13

Case presentation

A woman in her 40s presented to the local emergency department with a 1-day history of generalised malaise, chest discomfort and anasarca. Four days earlier, she had received the second dose of the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine (Pfizer-BioNTech). She was not on any medications and had no known allergies, alcohol abuse, prior episodes of oedema, or family history of oedema or sudden death. When she received the first dose of the COVID-19 vaccine 3 weeks before the second one, she was aware of mild generalised malaise, which resolved spontaneously in a few days. She receives influenza vaccine every year and never had problems. She had hypotension (<60 mm Hg) and tachycardia (130 beats per minute). After receiving 5 L of intravenous fluid, she remained in shock and was transferred to our hospital. When she arrived at our hospital, her consciousness was lucid, and her body temperature was 37°C, blood pressure was 86/52 mm Hg, respiratory rate was 23 per minute, heart rate was 129 beats per minute and oxygen saturation was 99% (oxygen 2 L/min via nasal cannula). Chest X-ray and whole-body CT were unremarkable. Echocardiography showed normal myocardial function. Her serum haemoglobin level was elevated (241 g/L; normal 137–168 g/L) and her serum albumin level declined (18 g/L; normal 41–51 g/L) (table 1). Blood cultures and multiple nasal swab PCR tests for COVID-19 were all negative. We admitted her to the intensive care unit, treating her with 5 L of intravenous fluid over the next 24 hours and norepinephrine. The following day, monoclonal gammopathy of unknown significance (IgG λ) was detected. In view of these clinical features and results, we diagnosed her with SCLS. Therefore, treatment with methylprednisolone (mPSL) 1000 mg/day for 3 days and IVIg 50 g (1 g/kg) was commenced. Urine output increased to 5500 mL/day on day 4 and the intravenous fluid was withdrawn. Ultrasonography and contrast-enhanced CT revealed thrombi in the femoral vein and inferior vena cava (5 cm in length, 2 mm in diameter, homogeneous, low echo) on day 5. Anticoagulation therapy using intravenous unfractionated heparin was administered. D-dimer level declined (3200 µg/L; normal 1–1000 µg/L) on day 8 and follow-up ultrasonography showed a significant reduction in the thrombi on day 9, so anticoagulation therapy was withdrawn. D-dimer level declined further to 1000 on day 11. All symptoms resolved and laboratory abnormalities improved. The patient was discharged 12 days after admission. She is under regular follow-up without recurrence.

Investigations

SCLS is characterised by hypovolaemic shock as a result of fluid extravasation. Serum albumin level is low, and haemoglobin level and haematocrit are remarkably high. In several days, fluids rapidly return to the blood vessels and pulmonary oedema usually arises. As a result, death from SCLS typically occurs during this phase, and intravascular volume and chest X-ray should be monitored frequently. MGUS is observed in most of the patients with SCLS, so M-component tests (blood and urine) and bone marrow examination should be done.

Differential diagnosis

In the acute leak phase, other causes of hypovolaemic shock must be ruled out. Blood and urine culture is essential to exclude sepsis, and whole-body CT should be done. Serum tryptase levels and whether urticaria is present are useful to rule out anaphylaxis. Haemoglobin levels and haematocrit are remarkably high, so haemorrhagic shock can be ruled out. There are no specific diagnostic criteria for SCLS; however, the classic triad of hypotension, haemoconcentration and hypoalbuminaemia could support the diagnosis of SCLS if other causes of hypovolaemic shock have been ruled out.

Treatment

The patient received over 10 L of intravenous fluid per day. The following day, we started mPSL 1000 mg/day for 3 days and IVIg 50 g (1 g/kg). Anticoagulation therapy is also necessary if a thrombus formed in the deep veins. After acute therapy, we continued IVIg 0.6 g/kg/month as prophylaxis therapy.

Outcome and follow-up

Presently, 2 months have passed since she was discharged. She is under regular monthly follow-up and she is receiving IVIg 0.6 g/kg/month without recurrence. She has not yet received the third dose of the COVID-19 vaccine. We are planning to hospitalise her for monitoring before vaccination.