Fatal Systemic Capillary Leak Syndrome in a Patient with a COVID-19 Infection (2024)

Abstract

A 29-year-old Japanese woman was admitted to our hospital with a fever, cardiogenic shock, and cardiac arrest. Laboratory data indicated multiple organ failure in addition to hemoconcentration, hypoalbuminemia, and myocardial damage. The coronary angiography findings were normal, and fulminant myocarditis was suspected. Venoarterial peripheral extracorporeal membrane oxygenation and an Impella CP left ventricular assist device were initiated, along with the administration of positive inotropic agents. However, hypovolemic shock and hypoalbuminemia progressed along with severe anemia, and the patient died 18 hours after admission. The patient was diagnosed with systemic capillary leak syndrome associated with coronavirus disease 2019.

Keywords: infection, shock, multiple organ failure, arrest

Introduction

Systemic capillary leak syndrome (SCLS), also known as Clarkson syndrome, is a rare disorder with a potentially fatal outcome (1). It is characterized by endothelial dysfunction, which leads to extravasation of plasma and proteins into the interstitial space, resulting in acute episodes of hypovolemic shock, hemoconcentration, and hypoalbuminemia (2).

The diagnosis is clinically based on the presence of a triad of symptoms, including hypotension (systolic blood pressure <90 mmHg), hemoconcentration (hematocrit >49-50% in men and 43-45% in women), and hypoalbuminemia (<3.0 g/dL).

It can occur secondary to various conditions, such as blood malignancies, immune disorders, toxicity, medication, infections, or idiopathic (Clarkson disease) (1). We herein present the case of a patient with fatal SCLS associated with coronavirus disease 2019 (COVID-19).

Case Report

A 29-year-old Japanese woman was admitted to our hospital with a fever, cardiogenic shock, and cardiac arrest. Her medical history was unremarkable and she had no family history of note. She reported no history of smoking or alcohol consumption. The patient was transported to our hospital via ambulance. Cardiopulmonary resuscitation was continued, and ventilator and venoarterial peripheral extracorporeal membrane oxygenation (VA-ECMO) were initiated along with positive inotropic agents. Chest radiography revealed consolidation of the right lung field without cardiomegaly (Fig. 1A). Electrocardiography (ECG) revealed sinus rhythm and mild ST-segment elevation in all the leads (Fig. 1B). Transthoracic echocardiography (TTE) revealed diffuse hypokinesis of the left ventricle ejection fraction (LVEF, 20%) (Fig. 1C-G). Computed tomography (CT) revealed a ground-glass shadow as well as granular and patchy shadows in both lungs, suggesting COVID-19 pneumonia (Fig. 2A-C). Laboratory data indicated leukocytosis (white blood cell count, 21.7×10³/μL) and inflammation (C-reactive protein, 6.51 mg/dL), hemoconcentration (hemoglobin, 19.5 g/dL), hypoalbuminemia (2.9 g/dL), and myocardial damage (high-sensitivity troponin T, 0.615 ng/mL). Heart failure was evident (NT-proBNP>35,000 pg/mL), along with increased creatine kinase (7,555 IU/L), aspartate aminotransferase (453 IU/L), and lactate dehydrogenase (1,175 IU/L) levels, indicating rhabdomyolysis. An electrolyte imbalance was also observed, including hyperkalemia (sodium, 126 mEq/L; kalium, 8.6 mEq/L; chloride, 88 mEq/L) and lactic acidosis (20 mmol/L) (Table 1). A severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test of a nasal swab specimen was positive (255,147 copies).

Coronary angiography yielded normal results, and an endomyocardial biopsy was performed because fulminant myocarditis was suspected. An Impella CP left ventricular assist device was initiated, in addition to VA-ECMO. Additionally, 4,000 mL of an intravenous electrolyte solution was administered to the patient for over 3 h to maintain her blood pressure. Despite these interventions, the patient did not show any signs of recovery. Moreover, anemia perisisted (8.4 g/dL) and hypoalbuminemia progressed (1.4 g/dL) (Table 2). Computed tomography (CT) revealed rapid progression of lung consolidation and post-peritoneal fluid retention (Fig. 2D-F). Chest and abdominal CT revealed no hemorrhagic lesions. Unfortunately, the patient succumbed to hemodynamic deterioration 18 h after admission. The bacterial blood cultures were negative.

A histopathological evaluation revealed interstitial edema with no significant cell infiltration or myocyte necrosis, suggesting fulminant myocarditis (Fig. 3). Finally, the patient was diagnosed with SCLS associated with a COVID-19 infection.

The markedly elevated serum interleukin-6 (IL-6) levels prompted the utilization of a cytokine multiplex array. An analysis of the patient's serum revealed increased levels of proinflammatory cytokines, including IL-8, IL-10, IL-12p40, IL-15, IL-18, and tumor necrosis factor ALPHA (TNFα). Additionally, increased concentrations of fibroblast growth factor-2 (FGF-2), granulocyte colony-stimulating factor (G-CSF), and monocyte chemoattractant protein-1 (MCP-1) were observed. Notably, vascular endothelial growth factor (VEGF) remained undetectable in the patient's serum, as detailed in Table 2 when compared to healthy controls. We also performed genetic analyses of 31 autoinflammatory disease-related genes using targeted next-generation sequencing, as previously reported (3), and identified E84K and E148Q compound heterozygous variants of the MEFV gene as identifiable pathogenic factors. However, the patient had no signs or symptoms of familial Mediterranean fever (FMF). Moreover, we checked the serum level of histamine that can increase vascular permeability and found it within the normal range (0.25 ng/mL; normal range, 0.15-1.23 ng/mL).

Discussion

We herein report the case of a patient with SCLS associated with COVID-19 who presented with cardiac dysfunction and rhabdomyolysis.

Only 11 previous reports (13 patients) exist on SCLS in patients with a COVID-19 infection (4-14) (Table 3).

Among the reported cases and the present case (14 patients; age range, 10 months to 59 years; mean age, 47±17 years; 9 men and 5 women), 8 of 14 (57%) patients died, at least 6 of these 8 patients died within 24 h after admission, and none of the 5 patients with cardiac arrest survived (Table 3). Only nine of the 14 patients underwent TTE because COVID-19 infection made it difficult to perform TTE. Among these nine patients, only our patient had severe myocardial dysfunction, with an LVEF of 20%.

Four of the 14 patients had a history of previous SCLS, and 6 (43%) patients had monoclonal gammopathy of undetermined significance (MGUS) or monoclonal gammopathy. Five (36%) patients had rhabdomyolysis and 2 (14%) had compartment syndrome.

The mortality rate of SCLS associated with COVID-19 in these 14 patients was higher than that described in a previous report, which indicated a mortality rate of 20-30% in acute SCLS (11). The higher rate might be associated with the COVID-19 infection itself.

The mechanisms underlying myocardial dysfunction in patients with SCLS and COVID-19 have not been determined. Myocardial edema resulting from capillary leakage in the myocardium could be a cause of cardiac dysfunction in patients with COVID-19.

Our patient had extremely high serum IL-6 levels, which suggested a cytokine storm caused by COVID-19. Cytokines, which have negative inotropic effects, may be associated with cardiac dysfunction.

The precise mechanisms underlying SCLS have not yet been determined. MGUS has been detected in >80% of SCLS cases (6). However, monoclonal gammopathy-negative patients also present with typical severe SCLS, and no studies have established the functional role of monoclonal paraproteins in SCLS (6). Among the 14 SCLS cases associated with COVID-19, only six patients had MGUS or monoclonal gammopathy. However, one previous patient had Sjögren's disease (10).

The observed elevation of various cytokines, including IL-6, IL-12, IL-8, TNFα, and IL-10, aligns with the reported patterns in SCLS. The absence of heightened VEGF in this case is consistent with a report in which the VEGF elevation varied (15). Identification of MEFV variants adds a distinctive genetic aspect to this case. Our previous serum analysis revealed the discriminatory potential of IL-6 and IL-18 for distinguishing patients with FMF from controls during attacks. Furthermore, IL-6, G-CSF, IL-10, and IL-12p40 have demonstrated discriminatory capabilities within the FMF patient group between the febrile attack period and remission (16). The intricate interplay between IL-6, IL-10, G-CSF, IP-10, TNFα, and MCP-1 has emerged as a crucial player in the intricate pathogenesis of COVID-19 (17). Based on our patient's immunological profile and insights from previous reports, we hypothesized that the IL-6-centered cytokine storm triggered by COVID-19 may be linked to the activation of immune cells associated with innate immunity, driven by the presence of MEFV variants. This intricate interplay suggests a potential mechanism leading to the fatal manifestation of SCLS.

Further studies are needed to elucidate the specific mechanisms of SCLS in patients presenting with a COVID-19 infection.

In conclusion, SCLS and fulminant myocarditis should be considered in patients with COVID-19 associated with cardiac dysfunction and shock.

The authors state that they have no Conflict of Interest (COI).

References