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Thrombotic microangiopathies (TMA) are a group of clinical syndromes associated with haemolytic anaemia, thrombocytopenia and organ dysfunction, mainly renal or neurological. They are associated with significant morbidity and mortality, so early diagnosis and treatment are essential. In this article we report two cases of TMA; a patient with thrombotic thrombocytopenic purpura (TTP) and a patient with atypical haemolytic uraemic syndrome (aHUS).

An 8-year-old boy presented with fever, vomits, bloody diarrhoea, and blurred vision. The patient was diagnosed with Haemolytic Uraemic Syndrome (HUS) due to the symptoms and a positive Verotoxin stool test. Funduscopic examination showed retinal involvement in both eyes, peri-papillary paleness, retinal haemorrhages, and soft "Purtscher Fleckens" exudates. A favourable outcome was achieved after hospital admission and systemic treatment. Dialysis treatment was not needed due the preserved diuresis. Although Purtscher-like retinopathy is very uncommon, ocular examination is mandatory in patients with pancreatitis, autoimmune diseases, and thrombotic microangiopathies, such as HUS.

Studies of complement genetics have changed the landscape of thrombotic microangiopathies (TMAs), particularly atypical haemolytic uraemic syndrome (aHUS). Knowledge of complement genetics paved the way for the design of the first specific treatment for aHUS, eculizumab, and is increasingly being used to aid decisions regarding discontinuation of anti-complement treatment in this setting. Complement genetic studies have also been used to investigate the pathogenic mechanisms that underlie other forms of HUS and provided evidence that contributed to the reclassification of pregnancy- and postpartum-associated HUS within the spectrum of complement-mediated aHUS. By contrast, complement genetics has not provided definite evidence of a link between constitutional complement dysregulation and secondary forms of HUS. Therefore, the available data do not support systematic testing of complement genes in patients with typical HUS or secondary HUS. The potential relevance of complement genetics for distinguishing the underlying mechanisms of malignant hypertension-associated TMA should be assessed with caution owing to the overlap between aHUS and other causes of malignant hypertension. In all cases, the interpretation of complement genetics results remains complex, as even complement-mediated aHUS is not a classical monogenic disease. Such interpretation requires the input of trained geneticists and experts who have a comprehensive view of complement biology.

Atypical haemolytic uremic syndrome (aHUS) is a clinically and genetically heterogeneous condition caused by a complex interplay between genomic susceptibility factors and environmental influences. Pathogenic variants in the DGKE gene are recently identified in cases with infantile-onset autosomal recessive aHUS. The presence of low serum C3 levels, however, has rarely been described in cases of DGKE-associated aHUS. Molecular genetic testing was performed by a commercial next-generation sequencing (NGS) panel as well and by an in-house developed targeted NGS for DGKE gene. Copy number variations (CNVs) were computed from NGS data by calculating a normalised copy number ratio of aligned number of reads at targeted genomic regions against multiple reference regions of the same sample and multiple controls. We report here two such novel clinically relevant variants (c.727_730delTTGT and c.251_259delGCGCCTTC) in the DGKE gene, in two families of infantile aHUS with low serum C3 levels.

Atypical Haemolytic Uraemic Syndrome (aHUS) is considered an uncommon pathology that usually affects young adults and causes acute kidney injury which can further lead to End Stage Renal Disease (ESRD). Here we present the case of a previously healthy young boy who was diagnosed as a case of atypical HUS on renal biopsy in Sheikh Zayed Hospital Lahore. His C3 was low, while ANA and C-ANCA P-ANCA were in normal range; multiple sessions of plasmapheresis were conducted, whereas IV Methylprednisolone was also given during both admissions (the patient had to be readmitted six months later after having been discharged on improvement). After that, his GFR improved along with other laboratory parameters. Rituximab was also offered but the family refused due to affordability issue.

Thrombotic microangiopathy with renal dysfunction is a haematological and renal emergency warranting urgent diagnosis and intervention. As the potential underlying causes may be complex, assessment and management can be challenging for treating clinicians, and a timely and collaborative approach between general physicians, haematologists and nephrologists may be extremely helpful in order to optimise clinical outcomes. This paper will aim to build an understanding of different potential presentations of thrombotic microangiopathies and provide a practical framework for diagnosis and management, using a case-based discussion format, for acute and general physicians. Some aspects of subsequent specialist management are also discussed.

The purpose of this series is to highlight a range of rare health conditions: those that affect no more and usually fewer than 1 person in every 2000. Many healthcare assistants and nurses will encounter some of these conditions, given the high number of them. This 29th article will briefly explore four of these rare conditions.

Severe haemolytic anaemia is a rare complication of haemodialysis that is often difficult to recognize, especially when there are other potential differential diagnoses. Here, we present the case of 19-year-old man on haemodialysis who developed severe haemolytic anaemia while recovering from acute renal failure secondary to rhabdomyolysis. Other causes of haemolytic anaemia such as thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome were ruled out. As his blood counts were dropping on days following haemodialysis, haemolysis secondary to the mechanical sheering effect of the catheter was considered and his haemodialysis catheter was exchanged, which led to the resolution of anaemia. LEARNING POINTS: Haemodialysis-related haemolysis can be due to the mechanical sheering effect of the catheter/tubing, and overheating or contamination of the dialysate fluid. Most cases of catheter or faulty tubing-related haemolysis need a high level of suspicion for diagnosis and normally resolve with correction of the underlying mechanical issue. Due to the rarity of the phenomenon, it is very important to rule out other life-threatening causes of haemolytic anaemia, such as disseminated intravascular coagulation and thrombotic thrombocytopenic purpura.

A 19-year-old woman, previously fit and well, was admitted 4 days postpartum with a 2-day history of headache, abdominal pain and vomiting. She denied diarrhoea. Her family history was remarkable for her father having lupus and immune thrombocytopenia. This was her first pregnancy and she delivered

Dysregulation of the alternative complement pathway is a major pathogenic mechanism in two rare renal diseases: atypical haemolytic uraemic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN). We report on a 66-year-old male with chronic hepatitis C virus (HCV) infection and a combined liver–kidney transplant that was diagnosed with MPGN at the age of 63 years and a 5-year-old boy who presented with aHUS at the age of 21 months following a Streptococcus pneumoniae infection. Both patients carried similar frameshift variants in the complement CFHR5 gene that segregate with reduced levels of factor H–related 5 (FHR-5). We conclude that low FHR-5 levels may predispose to viral and bacterial infections that then trigger different renal phenotypes.

Consumption of foods, water, vegetables, fruits, undercooked/ground/raw meat, unpasteurized milk or milk products contaminated with the bacterium strain Escherichia coli 0157:H7 has become a serious public health concern. This strain naturally inhabits the digestive tract of healthy cattle, and is released into the environment through the faeces of the animal. This strain cause haemorrhagic enterocolitis or gastroenteritis, and then haemolytic uraemic syndrome (HUS). HUS is a disorder characterised by haemolytic anaemia, low platelet count and acute kidney failure, and this disorder is a consequence of the production and action of Shiga-like toxin produced mainly by this bacterial strain (accounting for 90 percent of all cases), and occurs mainly in children less than five (5) years of age, but also occurs in the elderly. After infection with this bacterial strain, the disorder begins with intestinal perforation and ulceration leading to bloody diarrhoea, and consequently acute kidney injury, thrombocytopenia and microangiopathic haemolytic anaemia. In conjunction with clinical manifestations, several laboratory investigations (haematological, biochemical and microbiological assays) are implicated in the diagnosis of HUS. There is currently no specific treatment for HUS; however, supportive care (such as treatment of hypertension, fluid and electrolyte imbalance, haemodialysis, blood transfusion, etc) happens to be the only ameliorative measure for this disorder.

The complement system plays a key role in pathogen immunosurveillance and tissue homeostasis. However, subversion of its tight regulatory control can fuel a vicious cycle of inflammatory damage that exacerbates pathology. The clinical merit of targeting the complement system has been established for rare clinical disorders such as paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome. Evidence from preclinical studies and human genome-wide analyses, supported by new molecular and structural insights, has revealed new pathomechanisms and unmet clinical needs that have thrust a new generation of complement inhibitors into clinical development for a variety of indications. This review critically discusses recent clinical milestones in complement drug discovery, providing an updated translational perspective that may guide optimal target selection and disease-tailored complement intervention.

Aim Atypical haemolytic uraemic syndrome (aHUS) is a debilitating condition that can cause significant morbidity and mortality in children if not adequately and promptly treated. This report shares real-world data on the use of eculizumab in children with aHUS. Methods We report our experience with the use of eculizumab in 14 children with aHUS. Results The median age at aHUS diagnosis was 12 months (range: 2-108 months), with six (42.9%) patients presenting in infancy and six (42.9%) being males. Eculizumab therapy was associated with haematological and thrombotic microangiopathy responses in 14 (100%) and 13 (92.9%) patients after a median of 9 days (range: 7-12 days) and 9.5 days (range: 7-14 days), respectively. None of the six patients who were previously treated with plasma therapy required any further infusions. Of the six patients who previously required dialysis, only one patient continued to do so and eventually received a renal transplant. The median time to ≥25% decrease in serum creatinine level in the remaining patients was 16 days (range: 14-21 days), and estimated glomerular filtration rate increased from a median of 17-101 mL/min/1.73 m2 . The safety profile was similar to that reported in the literature, and 10 patients continue to receive therapy, with 3 being on the drug for 4 or more years. Conclusion Our study adds to the growing body of evidence highlighting the efficacy and safety of eculizumab for the management of children with aHUS.

Atypical haemolytic-uraemic syndrome (aHUS) is a rare cause of thrombotic microangiopathy (TMA). The typical form occurs most frequently in children following infection with Shiga-like toxin-producing bacteria, whereas in the atypical form genetic mutations affecting complement regulatory proteins involved in the alternative complement pathway may be identified. The clinical features of aHUS may mimic other causes of TMA such as thrombotic thrombocytopenic purpura and malignant hypertension. We present a case of a 67-year-old woman who presented with a TMA and discuss the diagnostic challenges that were confronted due to the many overlapping clinical and laboratory features of the different causes of this syndrome. Clinicians should be aware of the varied clinical manifestations of TMAs to ensure early diagnosis and initiation of appropriate treatment.

Microvascular injury, including thrombotic microangiopathy, has been widely reported as a hallmark pathological feature of organ injury in the setting of COVID-19. COVID-19 is also responsible for a wide variety of illnesses and presentations. Most people infected with the COVID-19 virus will experience mild to moderate respiratory illness and recover without requiring special treatment. Others, especially the elderly and those with comorbidities, are more likely to develop serious illness with multi-organ involvement. This paper highlights 2 patients who were infected with COVID-19 and developed HUS at the Couva Hospital, Trinidad.

8 p.-2 fig.-3 tab., Background: Kidney transplantation (KTx) is a strong trigger for the development of either recurrent or de novo atypical haemolytic uraemic syndrome (aHUS). According to previous studies, eculizumab (ECU) is effective for prophylaxis and for treatment of recurrence., Methods: We evaluated the experiences of Spanish patients with recurrent and de novo aHUS associated with KTx, treated or not treated with ECU. In the de novo group, we classified patients as having early de novo (during the first month) or late de novo aHUS (subsequent onset)., Results: We analysed 36 cases of aHUS associated with KTx. All of the 14 patients with pre-KTx diagnosis of aHUS were considered to have high or moderate risk of recurrence. Despite receiving grafts from suboptimal donors, prophylactic ECU was effective for avoiding recurrence. The drug was stopped only in two cases with low–moderate risk of recurrence and was maintained in high-risk patients with no single relapse. There were 22 de novo aHUS cases and 16 belonged to the early de novo group. The median time of onset in the late group was 3.4 years. The early group had a better response to ECU than the late group, probably due to earlier diagnosis and use of the drug. No genetic pathogenic variant was detected in de novo aHUS cases, suggesting a secondary profile of the disease. ECU was stopped in all de novo patients with no relapses. ECU was well tolerated in all cases., Conclusions: Both groups (pre-aHUS and de novo) presented different clinical profiles, management approaches and outcomes. One should consider aHUS regardless of time after KTx. Genetic studies are crucial to stratify risks of relapse and to determine necessary lengths of treatment. We suggest short ECU treatment for de novo cases without pathogenic mutation and that ECU treatment be considered pre-emptively for patients with moderate or high risk of recurrence., This project was co-founded by Public Research Network REDinREN ISCIII 16/009/009 and the SENTRA group. S.R.d.C. is supported by the Spanish Ministerio de Economía y Competitividad-FEDER (SAF2015-66287R) and the Autonomous Region of Madrid (S2017/BMD-3673).

15 p.-8 fig.-3 tab., Haemolytic Uraemic Syndrome associated with Streptococcus pneumoniae infections (SP-HUS) is a clinically well-known entity that generally affects infants, and could have a worse prognosis than HUS associated to E. coli infections. It has been assumed that complement genetic variants associated with primary atypical HUS cases (aHUS) do not contribute to SP-HUS, which is solely attributed to the action of the pneumococcal neuraminidase on the host cellular surfaces. We previously identified complement pathogenic variants and risk polymorphisms in a few Hungarian SP-HUS patients, and have now extended these studies to a cohort of 13 Spanish SP-HUS patients. Five patients presented rare complement variants of unknown significance, but the frequency of the risk haplotypes in the CFH-CFHR3-CFHR1 region was similar to the observed in aHUS. Moreover, we observed desialylation of Factor H (FH) and the FH-Related proteins in plasma samples from 2 Spanish and 4 Hungarian SP-HUS patients. To analyze the functional relevance of this finding, we compared the ability of native and “in vitro” desialylated FH in: (a) binding to C3b-coated microtiter plates; (b) proteolysis of fluid-phase and surface-bound C3b by Factor I; (c) dissociation of surface bound-C3bBb convertase; (d) haemolytic assays on sheep erythrocytes. We found that desialylated FH had reduced capacity to control complement activation on sheep erythrocytes, suggesting a role for FH sialic acids on binding to cellular surfaces. We conclude that aHUS-risk variants in the CFH-CFHR3-CFHR1 region could also contribute to disease-predisposition to SP-HUS, and that transient desialylation of complement FH by the pneumococcal neuraminidase may have a role in disease pathogenesis., This study was funded by the Spanish Instituto de Salud Carlos III (ISCIII) and the European Regional Development Fund from the European Union (grants PI16/00723 and PI19/00970 to PS-C). IG and EA are supported by the Spanish Autonomous Region of Madrid (Complement II-CM network; S2017/BMD-3673). IG was also supported by the Spanish Fundación Senefro (http://www.senefro.org/). The study was also supported by the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the molecular biology thematic programme of the Semmelweis University, by the National Office for Innovation and Research (KH130355 to ZP), and by the MSCA-ITN (Horizon 2020) CORVOS (Grant 860044 to ZP). DC was supported by the Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences (PPD2018-016/2018).

Recurrent outbreaks of haemolytic uraemic syndrome (HUS) caused by Shiga toxin-producingEscherichia coli(STEC) serotype O55:H7 occurred in England between 2014 and 2018. We reviewed the epidemiological evidence to identify potential source(s) and transmission routes of the pathogen, and to assess the on-going risk to public health. Over the 5-year period, there were 43 confirmed and three probable cases of STEC O55:H7. The median age of cases was 4 years old (range 6 months to 69 years old) and over half of all cases were female (28/46, 61%). There were 36/46 (78.3%) symptomatic cases, and over half of all cases developed HUS (25/46, 54%), including two fatal cases. No common food or environmental exposures were identified, although the majority of cases lived in rural or semi-rural environments and reported contact with both wild and domestic animals. This investigation informed policy on the clinical and public health management of HUS caused by STEC other than serotype O157:H7 (non-O157 STEC) in England, including comprehensive testing of all household contacts and household pets and more widespread use of polymerase chain reaction assays for the rapid diagnosis of STEC-HUS.

Background Eculizumab modifies the course of disease in patients with atypical haemolytic uraemic syndrome (aHUS), but data evaluating whether eculizumab discontinuation is safe are limited. Methods Patients enrolled in the Global aHUS Registry who received ≥1 month of eculizumab before discontinuing, demonstrated haematologic or renal response prior to discontinuation and had ≥6 months of follow-up were analysed. The primary endpoint was the proportion of patients suffering from thrombotic microangiopathy (TMA) recurrence after eculizumab discontinuation. Additional endpoints included: estimated glomerular filtration rate changes following eculizumab discontinuation to last available follow-up; number of TMA recurrences; time to TMA recurrence; proportion of patients restarting eculizumab; and changes in renal function. Results We analysed 151 patients with clinically diagnosed aHUS who had evidence of haematologic or renal response to eculizumab, before discontinuing. Thirty-three (22%) experienced a TMA recurrence. Univariate analysis revealed that patients with an increased risk of TMA recurrence after discontinuing eculizumab were those with a history of extrarenal manifestations prior to initiating eculizumab, pathogenic variants or a family history of aHUS. Multivariate analysis showed an increased risk of TMA recurrence in patients with pathogenic variants and a family history of aHUS. Twelve (8%) patients progressed to end-stage renal disease after eculizumab discontinuation; seven (5%) patients eventually received a kidney transplant. Forty (27%) patients experienced an extrarenal manifestation of aHUS after eculizumab discontinuation. Conclusions Eculizumab discontinuation in patients with aHUS is not without risk, potentially leading to TMA recurrence and renal failure. A thorough assessment of risk factors prior to the decision to discontinue eculizumab is essential.

The article Ravulizumab: A Review in Atypical Haemolytic Uraemic Syndrome, written by Yahiya Y. Syed, was originally published electronically in SpringerLink on 18 March 2021 without open access.

Introduction Acute bloody diarrhoea is associated with E.Coli enterocolitis, progressing to haemolytic uraemic syndrome (STEC-HUS) in 10–15% of cases. Health Protection Scotland (HPS) guidelines recommend commencing pre-emptive IV fluids in children with acute bloody diarrhoea and high risk features until an E.Coli result is known to reduce progression and severity of STEC-HUS. The service impact of this change is unknown. Aims Establish baseline annual presentation rate of children with acute bloody diarrhoea to RHC, Glasgow Evaluate management of children eligible for pre–emptive IV fluids prior to guideline implementation Estimate service impact of guideline implementation Methods A microbiology search identified all stools sent from RHC (ED/CDU) between 1/3/18–1/3/19. Children with acute bloody diarrhoea and high risk features were identified by screening records of patients with bloody/diarrhoeal samples. Data regarding management/diagnosis was extracted. CMPI and IBD cases were excluded. Results 55 patients had acute bloody diarrhoea (9% of 577 stool samples). 8 CMPI and 7 IBD cases were excluded. Of the remaining 40, 29 had high risk features meeting criteria for pre-emptive IV fluids. 32 had blood tests and 24 had urinalysis. Of 29 high risk patients, 22 (76%) were admitted for an average of 2 days (excluding HUS) and 7 (24%) were not admitted. 14 (47%) received IV fluids >24 hours and 8 (28%) were discharged before 24 hours. 22 (76%) grew a bacterial pathogen (E.Coli (n=4), Campylobacter (n=15), Salmonella (n=3)) and 3 (10%) developed STEC-HUS. Mean time to stool culture result was 47.8 hours. Of 11 without high risk features, 1 grew a bacterial pathogen (Campylobacter). Conclusion In this cohort, implementing HPS guidelines would necessitate 22 additional inpatient hospital days for IV fluids, 8 additional blood tests and 16 additional urinalysis tests. High risk features appear sensitive for pathogenic bloody diarrhoea and captured all STEC-HUS/E.Coli cases.

Introduction Presence of schistocytes in peripheral blood smear supporting haemolysis is important for diagnosis and decision-making in paediatric haemolytic uraemic syndrome (HUS). High observer dependency and requirement of expertise for peripheral smear evaluation propels us to think of other modalities to overcome these issues. We envisage that newer techniques like automated fragmented red blood cell percentage (FRC %), whose role has been described in transplant associated HUS and thrombotic thrombocytopenic purpura, can serve the purpose. Methods Twenty-eight children with HUS after excluding secondary causes were enrolled in this study. Blood samples were analysed for FRC% at admission, using SYSMEX XN-1000 (Japan) haematology analyser, and simultaneously, schistocytes in peripheral smear were reported by a single expert haematopathologist. Results Median age was 56 months ranging from 2 to 140 months. FRC% was elevated in 85.8% (n-24/28) with a mean of 4.56 ± 3.1%. FRC% had a sensitivity of 95.4% (C.I: 77.16% to 99.88%) in children who had FRC% >1.49% with an accuracy of 85.71% (C.I: 67.33% to 95.97%). However, specificity was only 50% (C.I: 11.81% to 88.19%) with a positive likelihood ratio of 1.91. Receiver-operator curve showed an AUC value of 0.841. Conclusion We suggest automated FRC% as a rapid and highly sensitive index for screening of paediatric HUS; however, a peripheral blood film examination is a must in cases with count >2% to avoid false positives as the index has low specificity.

Background and Aims Ravulizumab is a long-acting C5 inhibitor, derived from eculizumab, that is dosed every 8 weeks. Ravulizumab was approved in the United States for patients with atypical haemolytic uraemic syndrome (aHUS) and it is currently under evaluation in the EU based on the phase 3 trial (NCT02949128) efficacy and safety results at 26 weeks in patients with aHUS. Here, we report longer term efficacy and safety of ravulizumab obtained from the trial during the ongoing extension period. Method This phase 3 trial was a single arm, global, open label study in adults (≥18 years of age) with aHUS naïve to complement-inhibitor therapy. Ravulizumab was administered by intravenous infusion (IV) every 8 weeks during the maintenance phase. Patients fulfilling laboratory criteria for active TMA, ADAMTS13>5%, and negative STEC-HUS testing were eligible. Patients that completed the 26-week initial evaluation period could enter the extension period. The primary endpoint was complete TMA response (normalisation of platelet count and lactate dehydrogenase [LDH], and ≥ 25% improvement in serum creatinine from baseline, measured at 2 separate assessments obtained at least 28 days apart). Secondary endpoints included changes from baseline in haematological parameters, kidney function, and FACIT-fatigue scores. Treatment emergent adverse events were also evaluated. Here, interim cumulative data on primary and secondary endpoints through at least 52 weeks are reported. Results Forty-seven of 56 enrolled patients completed the initial evaluation period and received at least one dose of ravulizumab in the extension period. All patients achieved complete inhibition of terminal complement as demonstrated by sustained suppression of free-C5 ( Although three new SAEs were reported during the extension period, there were no further fatal adverse events. As in the primary analysis period, no meningococcal infections occurred through the last patient follow-up. Conclusion In the extension period of the phase 3 trial, ravulizumab continued to have a good benefit: risk profile. At last follow-up, the cumulative efficacy of ravulizumab to treat complement mediated TMA in patients with aHUS improved to 61% from 54% in the initial evaluation period. Most AEs occurred in the first 26 weeks, and there were no meningococcal infections identified in the study. These results suggest that with ravulizumab further improvement in efficacy is possible with longer treatment with no compromise in safety and improved convenience of 8-week dosing intervals.

Background and Aims Atypical haemolytic uraemic syndrome (aHUS) triggered by pregnancy is a rare and under-recognised disease caused by dysregulation of the alternative complement pathway that occurs in approximately 1 in 25,000 pregnancies. The 311 phase 3 trial (NCT02949128) showed that ravulizumab, a long-acting C5 inhibitor built on eculizumab, with a maintenance dosing interval of 8 weeks, is efficacious in treating aHUS. In this analysis, we report outcomes in a subgroup of patients with postpartum-aHUS enrolled in the 311 study. Method This was a global, phase 3, single-arm, multicentre trial evaluating the efficacy and safety of ravulizumab in adults (≥18 years of age) with aHUS naïve to complement inhibitor treatment. The primary endpoint was complete thrombotic microangiopathy (TMA) response (simultaneous platelet count normalisation [≥150 x 109/L], lactate dehydrogenase [LDH] normalisation [≤246 U/L] and ≥25% improvement in serum creatinine at 2 separate assessments ≥28 days apart) through the 183-day initial evaluation period. Additional efficacy endpoints were: time to complete TMA response, haematological normalisation (platelet count and LDH), dialysis requirement status, and change in eGFR. Results Eight patients with postpartum-aHUS (mean age 36 [±8] years) were diagnosed within 12 days of delivery. Seven patients were white and one was Asian. Six patients (75%) had received plasma exchange/infusion before ravulizumab therapy; five (63%) were on dialysis. Complete TMA response was achieved in 7/8 patients (87.5%) in a median time of 32 days. Haematological normalisation was observed in all patients. By Day 29, all five patients on dialysis at baseline had discontinued dialysis, and by Day 183 all eight patients had improved CKD stage (defined based on eGFR value) by ≥1 category. Three possible treatment-related adverse events (non-serious) were noted in two patients (arthralgia and nasopharyngitis; urinary tract infection). All patients survived and no meningococcal infections occurred. Conclusion This is the first prospective analysis of a C5 inhibitor in postpartum-aHUS. Treatment with ravulizumab resulted in rapidly improved haematological and renal outcomes with no unexpected adverse events identified when administered at 8-weekly dosing intervals through intravenous infusion.

In November 2017, Public Health England identified an outbreak of Shiga toxin-producing Escherichia coli O157:H7 in England where whole genome sequencing results indicated cases were likely to be linked to a common source, and began investigations. Hypothesis generation included a review of enhanced surveillance data, a case-case study and trawling interviews. The hypothesis of interest was tested through the administration of focussed questionnaires and review of shopping history using loyalty card data. Twelve outbreak cases were detected, eight were hospitalised and four developed haemolytic uraemic syndrome. Frozen beef burgers supplied by a national retailer were identified as the vehicle of the outbreak. Testing of two left-over burger samples obtained from the freezers of two separate (unlinked) cases and a retained sample from the production premises were tested and found to be positive for the outbreak strain. A voluntary recall of the burgers was implemented by the retailer. Investigations at the production premises identified no contraventions of food safety legislation. Cooking guidance on the product packaging was deemed to be adequate and interviews with the cases/carers who prepared the burgers revealed no deficiencies in cooking practices at home. Given the long-shelf life of frozen burgers, the product recall likely prevented more cases.

ObjectivesHaemolytic uraemic syndrome (HUS) following Shiga toxin-producingEscherichia coli(STEC) infection is the the most common cause of acute renal failure among children in the UK. This study explored differential progression from STEC to HUS by social, demographic and clinical risk factors.MethodsWe undertook a retrospective cohort study linking two datasets. We extracted data on paediatric STEC and HUS cases identified in the Public Health England National Enhanced Surveillance System for STEC and British Paediatric Surveillance Unit HUS surveillance from 1 October 2011 to 31 October 2014. Using logistic regression, we estimated the odds of HUS progression by risk factors.Results1059 paediatric STEC cases were included in the study, of which 207 (19.55%, 95% CI 17% to 22%) developed HUS. In the fully adjusted model, the odds of progression to HUS were highest in those aged 1–4 years (OR 4.93, 95% CI 2.30 to 10.56, compared with 10–15 years), were infected with an Shiga toxin (stx)2-only strain (OR 5.92, 95% CI 2.49 to 14.10), were prescribed antibiotics (OR 8.46, 95% CI 4.71 to 15.18) and had bloody diarrhoea (OR 3.56, 95% CI 2.04 to 6.24) or vomiting (OR 4.47, 95% CI 2.62 to 7.63), but there was no association with progression to HUS by socioeconomic circumstances or rurality.ConclusionCombining data from an active clinical surveillance system for HUS with the national enhanced STEC surveillance system suggests that 20% of diagnosed paediatric STEC infections in England resulted in HUS. No relationship was found with socioeconomic status or rurality of cases, but differences were demonstrated by age,stxtype and presenting symptoms.

Dengue disease is an inflammatory-driven pathology, and complement overactivation is linked to disease severity and vascular leakage. Additionally, dysregulation of complement alternative pathway (AP) components has been described, such as upregulation of complement factor D and downregulation of complement factor H (FH), which activate and inhibit the AP, respectively. Thus, the pathology of severe dengue could in part result from AP dysfunction, even though complement and AP activation usually provide protection against viral infections. In dengue virus-infected macrophages and endothelial cells (ECs), the site of replication and target for vascular pathology, respectively, the AP is activated. The AP activation, reduced FH and vascular leakage seen in dengue disease in part parallels other complement AP pathologies associated with FH deficiency, such as atypical haemolytic uraemic syndrome (aHUS). aHUS can be therapeutically targeted with inhibitors of complement terminal activity, raising the idea that strategies such as inhibition of complement or delivery of FH or other complement regulatory components to EC may be beneficial to combat the vascular leakage seen in severe dengue.

Several recent outbreaks of Shiga toxin-producing Escherichia coli (STEC) have highlighted the threat this group of organisms pose to public health. E. coli 0157:H7 has been identified as a major cause of STEC related foodborne disease worldwide but there is an increasing number of bloody diarrhoea and haemolytic uraemic syndrome cases associated with non-0157 STEC. The risk of foodborne disease associated with STEC cannot be eliminated at any one stage in the meat foodchain and control must be applied at multiple points. However, litde is known about STEC at the pre-slaughter and slaughter end of the beef food chain. The specific behaviour and characteristics of the STEC group of organisms that are associated with potential public health significance need to be investigated in this sector of the beef industry. This can be achieved by assessing the factors associated with the animal host and the farm environment during pre-slaughter and slaughter that may influence the risk of beef carcass contamination, and by studying the behaviour of STEC in selected environmental and meat ecosystems. The prevalence of E. coli, including 0157 and non-0157 STEC was monitored in multiple consignments of feedlot cattie at various stages during pre-slaughter at a feedlot and at an abattoir. A range of samples collected from the cattle and the environment were enriched and screened with polymerase chain reactions specific for Shiga toxin (stx) and E. coli 0157. E. coli 0157 were obtained using immunomagnetic separation and STEC were isolated following colony hybridisation on hydrophobic grid membrane filters. STEC were characterised by serology and genotyping. Pulsed-field gel electrophoresis was used to determine relationships among STEC isolated within the cattle populations and their environments. The prevalence of E. coli and STEC was monitored in a consignment of cattle during fattening at a feedlot. The prevalence of STEC initially decreased after the diet shift from pasture to grain at the feedlot. Throughout the 71 days of fattening, there were intermittent peaks in the number of catde shedding STEC and E. coli 0157. If animals were taken to slaughter at the time of such peaks, the risk of contamination would be greater. Both sorbitol-fermenting, non-shiga toxin-producing, and non-sorbitol fermenting shiga toxin-producing E. coli 0157 were intermittendy excreted by the catde during fattening and were recovered from the feedlot environment. The presence of E. coli 0157:H7, of different genotype, and 026:H11 on cattle hides at slaughter indicated the introduction of contamination from sources other than the feedlot at this point. In a second study, the presence of STEC was mapped in two consignments of cattle from the same pastures, during loading and transport to the same feedlot, then on to the abattoir and finally as carcasses in the chillers. In both consignments, the proportion of carcasses with evidence of stx by PCR was significantly lower than either faecal or hide samples. In one consignment, the number of cattle with evidence of STEC in faeces before loading on to trucks was significantly higher than when they were tested in the abattoir holding pens and in the faeces after evisceration.

Haemolytic uraemic syndrome (HUS) remains a leading cause of paediatric acute kidney injury (AKI). Haemolytic uraemic syndrome is characterised by the triad of microangiopathic haemolytic anaemia, thrombocytopenia and AKI. In ~ 90% of cases, HUS is a consequence of infection with Shiga toxin-producing E. coli (STEC), most commonly serotype O157:H7. Acute mortality from STEC-HUS is now less than 5%; however, there is significant long-term renal morbidity in one third of survivors. Currently, no specific treatment exists for STEC-HUS. There is growing interest in the role of complement in the pathogenesis of STEC-HUS due to the discovery of inherited and acquired dysregulation of the alternative complement system in the closely related disorder, atypical HUS (aHUS). The treatment of aHUS has been revolutionised by the introduction of the anti-C5 monoclonal antibody, eculizumab. However, the role of complement and anti-complement therapy in STEC-HUS remains unclear. Herein, we review the current evidence of the role of complement in STEC-HUS focusing on the use of eculizumab in this disease.

Aim Recently eculizumab, a monoclonal antibody to C5, was found to improve the disease course of atypical haemolytic uraemic syndrome (aHUS) and has been recommended as the first line treatment by an international consensus guideline. However, several practical issues in the use of eculizumab for the acute phase of aHUS have yet to be resolved. Methods Children who received eculizumab with diagnosis of aHUS between March 2010 and December 2015 at Tokyo Metropolitan Children's Medical Center were enrolled. aHUS was diagnosed according to the haemolytic uraemic syndrome (HUS) criteria after excluding Shiga toxin-inducing Escherichia coli (STEC) -associated HUS and thrombocytopaenic purpura. We retrieved and analyzed data from the electronic medical records at our institution. Results We reviewed four patients with suspected aHUS. Eculizumab was discontinued in one patient in whom STEC-HUS was later diagnosed. Treatment was continued in the remaining three patients without recurrence. Practical issues included difficulty in diagnosing aHUS, particularly in the acute phase, risk of infection by encapsulated organisms, especially Neisseria meningitis, and infusion reaction. In addition to issues relating to the acute phase, discontinuing eculizumab in stable patients in the chronic phase must be considered. Conclusion Eculizumab, the first line treatment for children with aHUS, is usually effective. However, certain problems associated with its use require caution to be exercised. As clinical information on eculizumab are still very limited, and the rationale for its long-term use has yet to be established, physicians are advised to exercise care when using eculizumab to manage aHUS.

We previously reported that Indian paediatric patients with atypical haemolytic–uraemic syndrome (aHUS) showed high frequencies of anti‐complement factor H (FH) autoantibodies that are correlated with homozygous deletion of the genes for FH‐related proteins 1 and 3 (FHR1 and FHR3) (FHR1/3 (–/–)). We now report that Indian paediatric aHUS patients without anti‐FH autoantibodies also showed modestly higher frequencies of the FHR1/3 (–/–) genotype. Further, when we characterized epitope specificities and binding avidities of anti‐FH autoantibodies in aHUS patients, most anti‐FH autoantibodies were directed towards the FH cell‐surface anchoring polyanionic binding site‐containing C‐terminal short conservative regions (SCRs) 17–20 with higher binding avidities than for native FH. FH SCR17–20‐binding anti‐FH autoantibodies also bound the other cell‐surface anchoring polyanionic binding site‐containing region FH SCR5–8, at lower binding avidities. Anti‐FH autoantibody avidities correlated with antibody titres. These anti‐FH autoantibody characteristics did not differ between aHUS patients with or without the FHR1/3 (–/–) genotype. Our data suggest a complex matrix of interactions between FHR1‐FHR3 deletion, immunomodulation and anti‐FH autoantibodies in the aetiopathogenesis of aHUS.

International audience; Haemolytic uraemic syndrome (HUS) is a rare complication of invasive infection by Streptococcus pneumoniae (SP-HUS), especially in adults. Here we report an unusual case of a 53-year-old man presenting SP-HUS with severe multivisceral involvement. After failure of supportive care and plasma exchanges, eculizumab (anti-C5 antibody) resulted in a favourable outcome.