Treatment of severe neurological defi cits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4-associated haemolytic uraemic syndrome: A prospective trial
Institut für Immunologie und Transfusionsmedizin, Ernst-Moritz-Arndt-Universität, Greifswald, Germany. The Lancet
(Impact Factor: 45.22).
09/2011; 378(9797):1166-73. DOI: 10.1016/S0140-6736(11)61253-1
In May 2011, an outbreak of Shiga toxin-producing enterohaemorrhagic E coli O104:H4 in northern Germany led to a high proportion of patients developing post-enteritis haemolytic uraemic syndrome and thrombotic microangiopathy that were unresponsive to therapeutic plasma exchange or complement-blocking antibody (eculizumab). Some patients needed ventilatory support due to severe neurological complications, which arose 1 week after onset of enteritis, suggesting an antibody-mediated mechanism. Therefore, we aimed to assess immunoadsorption as rescue therapy.
In our prospective non-controlled trial, we enrolled patients with severe neurological symptoms and confirmed recent E coli O104:H4 infection without other acute bacterial infection or raised procalcitonin concentrations. We did IgG immunoadsorption processing of 12 L plasma volumes on 2 consecutive days, followed by IgG replacement (0·5 g/kg intravenous IgG). We calculated a composite neurological symptom score (lowest score was best) every day and assessed changes before and after immunoadsorption.
We enrolled 12 patients who initially presented with enteritis and subsequent renal failure; 10 (83%) of 12 patients needed renal replacement therapy by a median of 8·0 days (range 5-12). Neurological complications (delirium, stimulus sensitive myoclonus, aphasia, and epileptic seizures in 50% of patients) occurred at a median of 8·0 days (range 5-15) and mandated mechanical ventilation in nine patients. Composite neurological symptom scores increased in the 3 days before immunoadsorption to 3·0 (SD 1·1, p=0·038), and improved to 1·0 (1·2, p=0·0006) 3 days after immunoadsorption. In non-intubated patients, improvement was apparent during immunoadsorption (eg, disappearance of aphasia). Five patients who were intubated were weaned within 48 h, two within 4 days, and two patients needed continued ventilation for respiratory problems. All 12 patients survived and ten had complete neurological and renal function recovery.
Antibodies are probably involved in the pathogenesis of severe neurological symptoms in patients with E coli O104:H4-induced haemolytic uraemic syndrome. Immunoadsorption can safely be used to rapidly ameliorate these severe neurological complications.
Greifswald University and Hannover Medical School.
Available from: Jan T Kielstein
- "The rapid onset of psychiatric symptoms, which occurred within 24 h after diagnosis of HUS in half of the patients, as well as their improvement over time correspond with recently published data from neurological examinations . Our observation that higher age could be a risk factor for development of psychiatric symptoms is in line with a reported significance between higher age and a low score in the Mini-Mental State Examination of affected patients with HUS . "
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ABSTRACT: BackgroundIn May 2011 an outbreak of Shiga toxin-producing enterohaemorrhagic E. coli (STEC) O104:H4 in Northern Germany led to a high number of in-patients, suffering from post-enteritis haemolytic-uraemic syndrome (HUS) and often severe affection of the central nervous system. To our knowledge so far only neurological manifestations have been described systematically in literature.AimTo examine psychiatric symptoms over time and search for specific symptom clusters in affected patients.Methods31 in-patients suffering from E. coli O104:H4 associated HUS, were examined and followed up a week during the acute hospital stay. Psychopathology was assessed by clinical interview based on the AMDP Scale, the Brief Symptom Inventory and the Clinical Global Impressions Scale.ResultsAt baseline mental disorder due to known physiological condition (ICD-10 F06.8) was present in 58% of the examined patients. Patients suffered from various manifestations of cognitive impairment (n = 27) and hallucinations (n = 4). Disturbances of affect (n = 28) included severe panic attacks (n = 9). Psychiatric disorder was significantly associated with higher age (p<0.0001), higher levels of C-reactive protein (p<0.05), and positive family history of heart disease (p<0.05). Even within the acute hospital stay with a median follow up of 7 days, symptoms improved markedly over time (p <0.0001).ConclusionsAside from severe neurological symptoms the pathology in E.coli O104:H4 associated HUS frequently includes particular psychiatric disturbances. Long term follow up has to clarify whether or not these symptoms subside.
Available from: Christian Combe
- "Immunoadsorption was performed as described [18, 31]. "
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ABSTRACT: An outbreak of haemolytic uraemic syndrome (HUS) due to Shiga toxin-secreting Escherichia coli (STEC) O104:H4 from contaminated fenugreek sprouts occurred in June 2011 near Bordeaux, France. In the context of this outbreak, all patients were treated with the monoclonal anti-C5 antibody, eculizumab.
The diagnosis of HUS was made based on haemolytic anaemia, low platelet count and acute kidney injury. Data were obtained from initial gastrointestinal symptoms to the end of follow-up 10 weeks after the start of eculizumab.
Among 24 cases of STEC gastroenteritis, HUS developed in nine patients (eight adults and one child), 6 (median; range 3-12) days after digestive symptoms begun. The median (range) highest or lowest biological values were platelet count 26 (range 14-93) G/L; haemoglobin 6.6 (range 5-10.7) g/dL; LDH 1520 (range 510-2568) IU/L; creatinine 152 (range 48-797) µmol/L. All patients had extra-renal complications (liver 9, pancreas 5, brain 3 and heart 3). Two patients were dialysed, and one was ventilated. After failure of plasma exchange to increase platelets in the first three patients, eculizumab was administered in all nine patients, 0-4 days after HUS diagnosis (median 1 day). One patient with very severe neurological HUS received immunoadsorption. Outcome was favourable in all patients, with rapid normalization of haemoglobin, platelets, LDH levels, renal function and neurological improvement. There were no deaths and no serious adverse events related to eculizumab.
Early treatment of O104:H4 STEC-HUS by eculizumab was associated with a rapid and efficient recovery. Controlled prospective evaluation of eculizumab in STEC-HUS is warranted.
Available from: Muhammad Yunus Amran
- "In the German outbreak, 30% of HUS patients showed signs and symptoms of encephalopathy, including delirium, stimulus-sensitive myoclonus, aphasia, and epileptic seizures requiring mechanical ventilation . These patients were treated with IgG, and IgG complexes were depleted by immunoadsorption . This treatment was effective in improving the severe neurological complications. "
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ABSTRACT: A large outbreak of Shiga toxin (Stx)-producing enteroaggregative Escherichia coli (EAEC) O104:H4 occurred in northern Germany. From this outbreak, at least 900 patients developed hemolytic uremic syndrome (HUS), resulting in more than 50 deaths. Thirty percent of the HUS patients showed encephalopathy. We previously established a mouse model with encephalopathy associated with blood brain barrier (BBB) damage after oral infection with the Shiga toxin (Stx) 2c-producing Escherichia coli O157: H- strain E32511 (E32511). In this model, we detected high expression of the Stx receptor synthase enzyme, glycosphingolipid globotriaosylceramide (Gb3) synthase, in endothelial cells (ECs) and neurons in the reticular formation of the medulla oblongata by in situ hybridization. Caspase-3 was activated in neurons in the reticular formation of the medulla oblongata and the anterior horn of the spinal cord. Astrocytes (ASTs) were activated in the medulla oblongata and spinal cord, and a decrease in aquaporin 4 around the ECs suggested that BBB integrity was compromised directly by Stx2c or through the activation of ASTs. We also report the effectiveness of azithromycin (AZM) in our model. Moreover, AZM strongly inhibited the release of Stx2c from E32511 in vitro.
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