Extra-corporeal membrane oxygenation and Eculizumab: Atypical treatments for typical haemolytic uraemic syndrome

Abstract

A 19-year-old female with no medical history presented with bloody diarrhoea. Investigations revealed an acute kidney injury, thrombocytopenia and microangiopathic haemolysis. A diagnosis of haemolytic uraemic syndrome secondary to Shiga toxin-producing Escherichia coli 055 was confirmed and supportive therapy commenced in the intensive therapy unit. On day 11 of her admission, she rapidly deteriorated with evidence of refractory cardiogenic shock and neurological involvement, both features associated with a poor prognosis. Cross-specialty collaboration prompted a trial of veno-arterial extra-corporeal membrane oxygenation and Eculizumab, a complement inhibitor normally reserved for atypical haemolytic uraemic syndrome, as a bridge to organ recovery. To our knowledge, herein we present the first adult patient with haemolytic uraemic syndrome induced cardiogenic shock successfully supported to cardiac recovery with extra-corporeal membrane oxygenation. The potential role for Eculizumab in Shiga toxin-producing Escherichia coli/typical haemolytic uraemic syndrome is also discussed.

Introduction

Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy (TMA), the classical features of which are microangiopathic haemolysis, thrombocytopenia and acute kidney injury due to thrombi in the renal vasculature.¹ HUS is further subdivided into HUS associated with Shiga toxin-producing Escherichia coli infection (STEC-HUS), and atypical HUS (aHUS). Cases of STEC-HUS (i.e. typical HUS) normally present 48–96 h after gastroenteritis caused by STEC where the toxin is felt to trigger endothelial cell dysfunction, propagating a systemic microangiopathy. Standard of care for STEC-HUS is plasma exchange and supportive therapy including renal replacement. The development of extra-renal manifestations is associated with significant mortality in STEC-HUS. The rarer aHUS is usually caused by uncontrolled activation of the complement system, often as a result of a mutation in complement regulatory proteins. Eculizumab is a humanized monoclonal antibody that binds with high affinity to the human C5 complement protein blocking the generation of pro-inflammatory C5a and is licensed for the treatment of aHUS.²

Case series in children with STEC-HUS have raised the potential role of extra-corporeal support in those with cardiac involvement, and of Eculizumab in those with neurological involvement.^3–7 Herein, we present, to our knowledge, the first adult patient with cardiogenic shock and evidence of neurological involvement secondary to STEC-HUS successfully supported with extra-corporeal membrane oxygenation (ECMO) and Eculizumab.

Case report

A 19-year-old female with no medical history presented to a district general hospital with bloody diarrhoea. Investigations revealed acute kidney injury, thrombocytopenia and microangiopathic haemolysis. A diagnosis of STEC-HUS was confirmed by stool sample positive for Escherichia coli 055. Computed tomography (CT) scan of the abdomen demonstrated severe pancolitis and multiple renal infarcts. She was commenced on broad-spectrum antibiotics, haemofiltration and daily plasma exchange and transferred to the intensive therapy unit (ITU) of a specialist TMA centre. Transthoracic echocardiogram (TTE) performed on day 10, in response to a serum troponin T of >3000 ng/L, revealed normal biventricular function and a small pericardial effusion.

On day 11 she deteriorated rapidly, evidenced by tachycardia, drowsiness and a serum lactate of >8 mmol/L. Bedside TTE demonstrated cardiac tamponade. She was therefore transferred to a tertiary cardiac unit for pericardiocentesis. Despite draiage of 180mL of straw-coloured pericardial fluid, her haemodynamic status failed to improve. Repeat TTE demonstrated severe biventricular impairment with an ejection fraction (EF) of <15%. Pulmonary artery catheter data demonstrated a cardiac index of 1.8 L/min/m², consistent with a diagnosis of cardiogenic shock. Despite moderate doses of adrenaline (0.1 mcg/kg/min) and milrinone (0.3 mcg/kg/min) her serum lactate remained >5 mmol/L with persisting evidence of hypoperfusion. In view of progressive confusion, a CT scan of the brain was performed which demonstrated symmetrical changes in the basal ganglia likely secondary to microvascular thrombosis.

In the context of refractory cardiogenic shock coupled with multi-system disease (renal, neurological, gastrointestinal and cardiac) associated with significant mortality, a multi-disciplinary discussion was undertaken between intensivists, haematology, cardiology and mechanical support specialists to discuss the merits of a trial of veno-arterial ECMO (VA-ECMO) to facilitate further plasma exchange and a trial of Eculizumab. She was cannulated for VA-ECMO percutaneously and was subsequently intubated due to obtundation and agitation. Repeat TTE on day 1 of VA-ECMO support demonstrated re-accumulation of the pericardial effusion, for which a pericardial drain was placed, draining 500 mL of blood stained fluid. Plasma exchange was continued daily and treatment with Eculizumab was initiated on day 2 of VA-ECMO owing to the multi-system involvement consistent with progressive thrombotic microangiopathy. Over the course of 96 h, her cardiac function improved with an EF of 45% on minimal ECMO support and she was decannulated from VA-ECMO, and the pericardial drain removed.

She spent a further eight weeks on ITU, the predominant issues being agitation, a prolonged tracheostomy wean and refractory hypertension. She received three further doses of Eculizumab at weekly intervals. Genetic testing subsequently excluded known mutations associated with complement activation regulation. She was discharged home after 13 weeks with an ejection fraction of 60%, normalisation of her renal function and resolution of the basal ganglia changes on MRI. Unfortunately, she suffered bilateral visual loss secondary to central retinal vein occlusion. Despite this she is now able to pursue her hobby of horse-riding.

Discussion

Based on registry data mortality in STEC-HUS is 5%, with increased age and multi-system involvement associated with higher mortality.^1,8 Heart failure secondary to HUS is rare, with only 19 documented cases amongst children.⁹ The aetiology is thought to be due to a combination of thrombotic micro-angiopathy of the coronary microvasculature, pericarditis with associated pericardial tamponade, and myocarditis.⁹ The true incidence is, however, difficult to ascertain in the absence of routine testing of troponin and echocardiography. There may well be cardiac involvement in both cases where there is no apparent haemodynamic compromise or in cases of sudden death.

The successful use of ECMO in HUS-associated refractory cardiogenic shock has been reported in three paediatric patients with STEC-HUS.^3–5 Of note all had mechanical support established (two on ECMO and one on cardiopulmonary bypass) subsequent to cardiac arrest; however, all progressed to cardiac recovery allowing decannulation after 7–10 days. None received Eculizumab.

Despite the absence of a reported adult case supported with ECMO and the presence of severe multi-organ dysfunction, the availability of potentially disease modifying therapies (Eculizumab and plasma exchange) and potential for cardiac and other organ recovery supported the decision to deploy VA-ECMO as both a bridge to supportive therapy and potential recovery. Indeed, using the survival after VA-ECMO (SAVE) score, to identify the pre-ECMO risk of poor outcome, this patient had a predicted mortality of >50% despite her young age and an aetiology of cardiogenic shock (myocarditis) associated with optimal outcomes (survival > 60%) according to Extracorporeal Life Support Organisation (ELSO) registry data.^10,11 This case highlights the notion that our understanding of the benefit of mechanical circulatory support in rarer aetiologies of cardiogenic shock remains limited and that whilst available risk scoring systems predict outcome, they do not predict benefit of ECMO. Despite the uncertain role of ECMO, discussion of such challenging cases with centres with expertise in cardiogenic shock and the capability to deploy VA-ECMO should be considered, specifically when disease modifying therapies to support cardiac recovery remain an option.

A detailed review of the possible contribution of complement activation to the pathogenesis of STEC-HUS, and thus the mechanism of any benefit of treatment with Eculizumab, is beyond the scope of this article and is discussed elsewhere.¹ However, small paediatric case series have suggested a beneficial role for Eculizumab in select patients.^6,7 Three patients with severe STEC-HUS and progressive neurological involvement despite plasma exchange demonstrated rapid clinical and biochemical improvement following a trial of Eculizumab.⁶ A case series of 11 children with typical HUS complicated by neurological involvement suggested that the early administration of Eculizumab improved outcomes.⁷ None of these patients received plasma exchange and one child died of refractory cardiogenic shock despite ECMO support. Nonetheless, registry data from a STEC-HUS outbreak affecting 491 adults did not support a benefit of Eculizumab compared to plasma exchange.⁸ Eculizumab should therefore be considered on a case-by-case basis.

Conclusion

Although rare, HUS can have catastrophic multi-system involvement requiring multi-organ support and requires a high index of suspicion and early intervention from generalists and specialists alike. This case highlights the role of cross-specialty collaboration and discussion regarding advanced organ support modalities, specifically ECMO, in cases where the prognosis in the context of multi-organ failure may be poor but where disease modifying therapies are available and organ and functional recovery achievable.

Consent

Signed consent for publication was obtained.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MS has received speakers' fees and advisory board for Alexion.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.