ArticlesTreatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4-associated haemolytic uraemic syndrome: a prospective trial
Introduction
An outbreak of Shiga toxin-producing enterohaemorrhagic Escherichia coli O104:H4 infections in northern Germany in 2011 was associated with haemolytic uraemic syndrome in more than 800 patients,1 with about 30% of patients developing neurological complications ranging from delirium to status epilepticus.2, 3
The two most common forms of thrombotic microangiopathies, haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura, present with thrombocytopenia, intravascular haemolysis, fragmented red cells, and organ dysfunction. However, these forms have distinct pathogeneses.4 Haemolytic uraemic syndrome is a heterogeneous disease associated with infection with Shiga toxin-producing organisms in more than 90% of cases in children, and alternative complement pathway dysregulation accounts for a further 6% of cases.5 Thus, treatment with the complement cascade-blocking antibody eculizumab has been proposed as treatment in severe haemolytic uraemic syndrome.1 Thrombotic thrombocytopenic purpura is characterised by thrombocytopenia and microangiopathic haemolytic anaemia.6, 7 Thrombotic thrombocytopenic purpura is caused by deficiency or dysfunction of the von Willebrand factor-cleaving metalloproteinase, ADAMTS13,8, 9 usually due to autoantibodies. This results in formation of ultralarge von Willebrand factor multimers, which are no longer cleaved by the protease. Accumulation of these multimers within the microcirculation causes shear stress-dependent platelet aggregation and damage to red blood cells. This damage results in thrombi formation in the microvasculature, thrombocytopenia, microangiopathic haemolysis (fragmented red cells), and neurological symptoms.10 Kidneys are usually not affected in thrombotic thrombocytopenic purpura.11, 12 Plasma exchange is the treatment of choice in severe thrombotic thrombocytopenic purpura.11
By contrast, in haemolytic uraemic syndrome, renal failure is the predominant organ manifestation, with neurological symptoms and signs less common.13 Differentiation between thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome is often difficult and a wide range of ADAMTS13 activity has been reported in various disease states; for example, there is a notable reduction in ADAMTS13 activity in sepsis.5 Furthermore, Nolasco and colleagues14 reported that von Willebrand factor concentrations are also altered in the haemolytic uraemic syndrome. Shiga toxin stimulates release of ultralarge von Willebrand factor multimers from endothelial cells, which activate platelets. The toxin also inhibits function of ADAMTS13, further promoting accumulation of large von Willebrand factor multimers.
During the E coli O104:H4 outbreak, 12 of 63 affected patients with haemorrhagic enteritis who were treated at the Greifswald University and Hannover Medical School hospitals developed severe neurological complications necessitating management in intensive care units. Patients with these neurological complications did not respond to therapeutic plasma exchange or eculizumab, which has been reported to be effective in haemolytic uraemic syndrome in children.15 However, the delayed onset of neurological complications that occurred during the second week after onset of diarrhoea suggested an immune-mediated mechanism. This suggestion prompted us to use IgG immunodepletion as a rescue therapy in this life-threatening situation. Immunoadsorption provides a rapid and efficient method of antibody removal and has been used successfully in diseases associated with autoantibodies.16, 17
In this report, we describe the clinical presentation and response of neurological symptoms in 12 patients treated by IgG immunodepletion through immunoadsorption. We aimed to indirectly assess whether, in addition to Shiga toxin, antibodies produced in response to enterohaemorrhagic E coli infection might be an important cofactor in the pathogenesis of the severe neurological complications of haemolytic uraemic syndrome. We also aimed to assess whether immunoadsorption acts as an appropriate rescue therapy for patients with severe neurological complications.
Section snippets
Study design and patients
We did a prospective, interventional, non-controlled compassionate use trial at two medical centres in Germany (Greifswald University and Hannover Medical School), in which we provided immunoadsorption as rescue treatment for patients with severe neurological complications during the Escherichia coli O104:H4 outbreak in northern Germany. Our approach was approved by the Greifswald University's institutional review board (BB 64/11).
During June 2011, consecutive patients treated at the intensive
Results
Of 63 patients with enteroinvasive colitis due to E coli O104:H4 infection at Greifswald University and Hannover Medical School, 12 needed intensive-care treatment (11 female; mean age 51 years [range 38–63]). All patients presented with thrombotic microangiopathy (thrombocytopenia and fragmentation haemolysis) and renal impairment according to acute kidney injury network (AKIN) criteria. Ten patients met the criteria of acute kidney injury stage 3 and two met criteria of acute kidney injury
Discussion
We showed that IgG immunodepletion by immunoadsorption can strikingly improve neurological complications in patients with E coli O104:H4-associated haemolytic uraemic syndrome. The benefit of immunodepletion, together with the characteristic timeline of neurological complications occurring about 1 week after onset of enteritis, suggest that antibodies generated as a response to preceding E coli O104:H4 infection might be crucially involved in the pathogenesis of neurological complications seen
References (32)
- et al.
A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders
Kidney Int
(2006) - et al.
Abnormal VIII: von Willebrand factor patterns in the plasma of patients with the hemolytic-uremic syndrome
Blood
(1984) The thrombotic thrombocytopenic purpura and hemolytic uremic syndromes: overview of pathogenesis (Experience of The Oklahoma TTP-HUS Registry, 1989–2007)
Kidney Int
(2009)- et al.
Thrombotic thrombocytopenic purpura
J Thromb Haemost
(2005) - et al.
Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers
Blood
(2005) - et al.
Plasma exchange and immunoadsorption for autoimmune neurologic diseases—current guidelines and future perspectives
Atheroscler Suppl
(2009) Heparin-induced thrombocytopenia
J Thromb Haemost
(2009)- et al.
The temporal profile of the anti-PF4/heparin immune response
Blood
(2009) - et al.
Studies of the immune response in heparin-induced thrombocytopenia
Blood
(2009) - et al.
Effectiveness of therapeutic plasma exchange in the 1996 Lanarkshire Escherichia coli O157:H7 outbreak
Lancet
(1999)