{"paper_id":"42ad0d4f-490c-4fcc-b178-0ad5c906463b","body_text":"Use of complement C5-inhibitor eculizumab in patients with infection-associated hemolytic uremic syndrome – a case-series report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Use of complement C5-inhibitor eculizumab in patients with infection-associated hemolytic uremic syndrome – a case-series report Petra Varga, Erika Biró, Andrea Berkes, Erzsébet Lakatos, Edit Szikszay, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5389564/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Mar, 2025 Read the published version in BMC Pediatrics → Version 1 posted 4 You are reading this latest preprint version Abstract Background : Hemolytic uremic syndrome (HUS), characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury (AKI), remains a leading cause of pediatric AKI. The complement system has a crucial role in the pathogenesis of atypical hemolytic uremic syndrome (aHUS) and eculizumab (ECZ) was approved as standard of care for its treatment. The two widely characterized forms of infection-associated HUS are Shiga toxin-producing E. coli (STEC)-HUS and Streptococcus pneumoniae-associated (SP)- HUS. Extrarenal manifestations such as central nervous system (CNS) involvement occur approximately in 20% of the cases and are accompanied by higher mortality. Abnormalities of the alternative complement pathway may also contribute to the development of both STEC-HUS and SP-HUS, offering a potential treatment option for complement C5 inhibition. Beyond best supportive care as standard therapeutic approach, ECZ has been succesfully used in both STEC-HUS and SP-HUS patients. We provide further support that early use of ECZ for infection-associated HUS with severe clinical manifestation and abnormal complement-activation profile may be an effective therapeutic approach. Case presentation: We report on three children (median age: 2 years, range: 2-10 years) diagnosed with infection associated HUS treated with complement C5-inhibitor ECZ. All three patients were treated with ECZ and had excellent outcome. We retrospectively analyzed the clinical course, laboratory data and outcome of children with infection associated HUS treated with ECZ. Conclusion: In accordance with previous observations ECZ is an efficacious therapeutic choice in severe HUS patients with multiorgan involvement. A detailed complement activation profile, especially sC5b-9, is useful to indicate ECZ administration. Hemolytic uremic syndrome Infection-associated HUS STEC-HUS SP-HUS Eculizumab CNS involvement Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Hemolytic uremic syndrome (HUS) is charaterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury (AKI) 1 . Infection is the most common cause of HUS as Shiga-like toxin (verotoxin) producing bacteria, including Shiga toxin-producing enterohaemorrhagic Escherichia coli (STEC), mostly E. coli serotype 0157:H7 or Shigella dysenteriae type 1 are responsible for 90% of all HUS cases 23 . The acute phase of STEC-HUS is severe, with a mortality rate of up to 5% while it may reach up to 20% when presenting with neurological involvement. At least 50% of pediatric HUS patients require dialysis and 30% survive with long-term renal sequelae 3 4 5 6 . Streptococcus pneumoniae-associated HUS (SP-HUS) represents approximately 5–15% of all HUS cases, of which long-term kidney outcome seems to be similar to STEC-HUS 7 . Higher mortality rate has been reported in 11–16% of SP-HUS patients, where neuraminidase-induced endothel damage leads to the activation of the complement system and thrombotic microangiopathy (TMA) 8 9 . A recent publication reports that a working group of specialists in thrombotic microangiopathies was convened to reclassify TMA on the basis of the main mechanism/etiology of the underlying disease. Thus, infection-associated TMA is listed as a separate entity, with STEC, pneumococcus, viral infection and sepsis as its background. This approach was believed to best support potential treatment methods and utilization of more tailored therapies 10 . Current management of both STEC-HUS and SP-HUS is based on supportive care, including fluid resuscitation, fluid- and electrolyte balance control, blood pressure control, continuous kidney replacement therapy (CKRT) and hematological support. While there is no validated specific therapy, the role of complement dysregulation has been established in either STEC-HUS or other infection-related cases of HUS, suggesting that eculizumab (ECZ) (trade name Soliris; Alexion Pharmaceuticals) may be a useful therapy 4 8 . ECZ, a humanized monoclonal C5 antibody inhibits terminal complement complex formation. ECZ has been approved both by the European Medicines Agency (EMA) and by the US Food and Drug Administration (FDA) in September 2011 for the treatment of atypical hemolytic uremic syndrome (aHUS) as standard of care, found to be effective in preventing progression to end-stage renal disease 11 . The role of complement activation (AP) has been established in STEC-HUS, although the exact mechanism is still unclear 12 . Previous case reports and cohort studies as well as a current meta-analysis have demonstrated potential benefits of using ECZ, and described convincing clinical improvement after treatment with ECZ in severe STEC-HUS with progressive neurological involvement 13 . None of these studies was randomized or blinded 12 14 15 16 . A recent randomized, controlled study revealed no convincing benefit of ECZ used in the acute phase of all STEC-HUS cases, however significantly better long-term kidney outcome was observed in the treated group 17 . Still, decision about the potential use of ECZ requires a multidisciplinary background and judgement is often made on the basis of clinical parameters of disease progression. Conventional complement serology studies (C3, C4, CH50) may not be informative, as often only marginal changes can be detected and kidney biopsy is not performed when diagnosis is otherwise confirmed. An extended complement activation panel may provide further data about the activation profile and help guide clinical decision 18 19 . Genetic analysis of the complement regulation cascade is not part of the routine clinical investigation in infection-associated HUS types, even though it may provide additional information about long-term prognosis 19 . Herein, we are presenting a series of three children diagnosed with infection associated HUS treated with complement C5-inhibitor ECZ. Case presentations We retrospectively reviewed three infection-associated HUS cases treated with complement C5-inhibitor ECZ in our institute (Institute of Pediatrics, University of Debrecen, Hungary). HUS was defined as hemolytic anemia, thrombocytopenia and acute kidney injury (AKI) caused by TMA. AKI was defined by KDIGO criteria 20 . The presence of confirmed infection (stool culture, blood culture and/or polymerase chain reaction (PCR) was necessary for the infection-associated HUS diagnosis. ECZ therapy was indicated in patients with signs of alternative complement pathway (AP) activation. We documented demographics (gender, age, body weight (BW), height, body mass index (BMI), microbiological data (primary site of infection, results of bacterial cultures, PCR studies), laboratory panel (haemoglobin, platelet, creatinine, urea, LDH, fragmentocytes, haptoglobin, CRP, direkt Coombs test) including complement factors and activation (ADAMTS13 metalloproteinase activity, CH50, APH50, C3, C4, CFH, CFI, CFB, CFC1q, sC5b-9), results of genetic analysis (mutation of CFH, CFI, CD46, C3, CFB, THBD, CFHR5, DGKE) (Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary). As well as major clinical data including duration and modality of kidney replacement therapy, radiological investigation and administration of ECZ and follow-up parameters (3–6 months) included estimated GFR (eGFR) using the Schwartz formula, proteinuria defined by protein-creatinine ratio from spot urine, presence of hematuria and arterial hypertension (defined as blood pressure values above the 95th percentile in at least three individual measurements 21 . Patient 1 A 2,5 year old female child, who was well previously, was admitted to our pediatric intensive care unit (PICU) with loss of appetite for 5 days, vomiting, loose stools (with no blood or mucus), abdominal pain, petechiae, orbital and limb oedema, without fever. Laboratory tests on admission were typical for TMA (Table 1 ). Direct Coombs test and virulence marker used to confirm EHEC from a stool sample were negative. Despite the adequate supportive therapy, significant progression was seen as the patient became oliguric over the next 4 days, developed general oedema, her kidney function deteriorated with worsening TMA related hemolysis. Based on the negative stool E.coli test (verotoxin negative) and the suspicion of aHUS due to an uncertain infectious and unknown family history, ECZ was administered on the 7th day. Consequently, within 3 days, the platelet count increased (from 38 G/L to 100 G/L without transfusion), the LDH activity significantly decreased (from 1959 U/L to 1100 U/L), diuresis improved and dialysis became unnecessary (Fig. 1 ). Given the favorable response to ECZ, it was repeated once 7 days later. In the following 2 weeks, her condition improved dramatically. Eventually, repeated stool bacteriological tests confirmed EHEC. Immunoserological tests (C3, C4, CH50) did not indicate dysregulation of the alternative pathway of the complement system, while the level of the activation complex of the terminal pathway increased markedly, indicating ongoing complement activation (Fig. 1 ). Subsequent genetic tests confirmed MCPggaac risk haplotype in homozygous form. After 7 days of intensive care treatment and a total of 14 days of hospitalization, the patient was discharged with an eGFR value of 63 ml/min/1,73m 2 and physiological blood count parameters. During subsequent control examinations, she was free of symptoms and complaints and the eGFR returned to normal (120 ml/min/1,73m 2 ) (Table 2 ). Table 1 Initial presentation, laboratory values and complement diagnostic on admission ​​of patients with infection associated hemolytic uraemic syndrome treated with Eculizumab. Abbreviations: F, female; M, male; LDH, lactate dehydrogenase; PCT, procalcitonin; HUS, hemolytic uremic syndrome; SP-HUS, Streptococcus pneumoniae-associated HUS; STEC-HUS, Shiga toxin-producing Escherichia coli-HUS; AP, complement activation; APH50, alternative payway total complement activity; CFB, complement factor B; CFH, complement factor H; CFI, complement factor I; CH50, total complement activity; SC5b-9, terminal complement complex; Patient Patient 1 Patient 2 Patient 3 Initial presentation Age (months) 31 28 125 Gender F F M Weight (kg) 15 11,6 29 Height (cm) 103 90 136 Presenting complaints vomiting, oedema pneumonia, DIC fever, watery diarrhea, abdominal pain Neurological symptoms No No Encephalopathy, seizure (tonic), hemiparesis Onset of neurological symptoms from illness No No Day 4 Haemoglobin (g/L) 87 62 98 Thrombocytes (G/L) 37 6 60 Creatinine (µmol/L) 211 152 730 Urea (mmol/L) 27,4 27,3 53,7 LDH (< 500 U/L) 1481 6938 3517 Fragmentocytes Yes Yes Yes C-reactive protein (< 2,2 mg/L) 5,5 201 23,6 PCT (< 0,5 ug/L) N.A. 108,19 70,63 Direkt Coombs test Negative Yes Negative Type of HUS STEC-HUS SP-HUS STEC-HUS Stool culture E.coli stx1/2 negative E.coli stx1/2 Blood culture Negative Pneumococcus Negative Complement diagnostic at admission ADAMTS13 metalloproteinase activity (67–151%) 90 11 27 CH50 (48–103 CH50/ml) 59 0 47 APH50 (70–125%) 113 48 82 C3 (0,9 − 1,8 g/L) 1,13 0,53 0,9 C4 (0,15 − 0,55 g/L 0,17 0,1 0,11 CFH (250-880mg/L) 366 175 246 CFI (70–130%) 102 38 90 CFB (70–130%) 97 72 10 CFC1q (60–180 mg/L) 38 88 113 SC5b-9 (110–252 ng/mL) 258 2459 845 Haptoglobin (0,3 − 2 g/L) 0,02 0,2 0,15 Table 2 Clinical parameters ​​and outcome data of patients with infection associated hemolytic uremic syndrome treated with Eculizumab. Abbreviations: HUS, Hemolytic uremic syndrome; CVVHDF, continuous venovenous hemo-diafiltration; PLT, platelet; LDH, lactate dehydrogenase; RBC, red blood cell; HFNC, high flow nasal cannule; MV, mechanical ventilation; ICU, intensive care unit; Patient Patient 1 Patient 2 Patient 3 Clinical parameters Time from HUS Dg to dialysis (days) N.A. 1 1 Type of dialysis N.A. CVVHDF CVVHDF Duration of dialysis (days) 0 10 13 Time to PLT normalization (days) 10 7 9 Time to LDH normalization (days) 14 13 14 Time from HUS Dg to Eculizumab treatment (days) 7 6 9 Eculizumab doses 2 2 2 Proven bacterial infection within 6 weeks of Eculizumab administration No No No Proven viral infection within 6 weeks of Eculizumab administration No Yes Yes Plasma exchange No No 4 Need for transfusion Yes Yes Yes No. of RBC transfusion (unit) 3 7 9 No. of PLT transfusion (unit) 4 20 16 Ventilation support No HFNC MV Catecholamines use No No Yes Antibiotic use No Yes Yes Pleural effusion No Yes Yes Effusion drainage No Yes Yes Throrascopy No Yes No Neurologic symptoms No No Yes Gastrointenstinal complications No No Yes Outcome Death No No No Length of ICU stay (days) 7 17 14 Length of stay total in hospital (days) 14 24 25 Renal function recovery (days) 3 10 13 eGFR at exmission (ml/min/1,73 m2) 63 67 81 Hypertension No No Yes Proteinuria Yes Yes Yes Neurologic symptoms at exmission No No Yes Patient 2 A 28 month old female child presented at our institute with a 4-day history of pneumonia-associated fever, vomiting, shortness of breath and oliguria in association with gross hematuria. Her previous history was uneventful, she received the mandatory vaccinations, including pneumococcal polysaccharide vaccine containing 13 serotypes. The admission lab tests were characteristic of TMA with elevated inflammatory markers and evidence of disseminated intravascular coagulation (DIC). Direct Coombs test was positive (Table 1 ). The radiological examinations confirmed right-sided pneumonia with pleural effusion. Overall, the results of the clinical, laboratory and radiological examinations corresponded with the diagnosis of invasive pneumococcus infection and an associated SP-HUS which was supported by hemoculture positivity for Streptococcus pneumoniae. Her management included combined antibiotic treament and supportive therapy (transfusion, intravenous immunoglobulin, respiratory support), which was supplemented from day 2 with continuous kidney replacement therapy (CKRT) due to oliguric AKI, significant fluid overload and metabolic acidosis. Due to worsening respiratory distress with increasing fibrinopurulent chest fluid, critical thrombocytopenia, and coagulopathy, primary video-assisted thoracic surgery (VATS) and chest drainage were performed. Due to onging significant hematological activity, uncontrolled complement activation (reduced C3, C4 and CH50 levels and alternative pathway activity, extremely elevated terminal pathway activation markers) (Table 1 ), administration of ECZ was initiated on Day 7 with excellent clinical response (Fig. 2 ). ECZ was discontinued after two doses of ECZ as kidney function improved, the child recovered without residual symptoms. As expected, no genetic abnormalities were detected. After 17 days of intensive care treatment and a total of 24 days of hospitalization, she was discharged home with an eGFR value of 67 ml/min/1,73m 2 and physiological blood count parameters. During the subsequent control examinations, she was free of symptoms, urinanalysis revealed only microscopic hematuria (no acanthocytes, no proteinuria) while eGFR returned to normal (130 ml/min/1,73m 2 ). A high normal eGFR value might have reflected a modest hyperfiltration which was not observed later (Table 2 ). Patient 3 The previously healthy 10-year-old boy was admitted with complaints of watery, non-bloody diarrhea, abdominal pain, and fever lasting for 4 days. The laboratory tests performed at the time of admission confirmed TMA with leukocytosis, markedly elevated inflammatory values (Table 1 ). In addition to the clinical picture, the EHEC positivity confirmed by the PCR test from stool sample suggested the diagnosis of STEC-HUS. The critically ill patient required antibiotic treatment (meropenem) for severe abdominal symptoms, presumed sepsis caused by bacterial enterocolitis. Despite the administration of intravenous fluids and diuretics, on the 2nd day after admission CKRT was started due to prolonged anuria, volume overload and polyserositis (mainly pleural effusions). Despite CKRT, progressive bilateral pleural effusion developed requiring bilateral pleural drainage, and non-invasive ventilation therapy. Due to severe hematological activity, regular transfusions were given. On the 4th day of treatment, fluctuating and later worsening consciousness was noticed. Despite plasma exchange (PLEX) treatment severe extrarenal symptoms (polyserositis, central nervous system involvement) including neurological symptoms progressed (tonic-clonic convulsion, aphasia, right-sided hemiparesis). Cranial MRI revealed a symmetric, hyperintense, banded abnormality on FLAIR and DWI images in the area of ​​the thalamus on both sides, which corresponded to Percheron arteriopathy (Fig. 3 ). Serological studies obtained earlier confirmed the global abnormal activation of the complement system with low level of complement factors (C3, C4, CH50) and a markedly elevated terminal pathway activation (sC5b-9) (Table 1 ). As a consequence of an unsatisfactory clinical response to supportive therapy and plasmapheresis the use of ECZ was indicated. ECZ was administered on the 9th day, after which sudden and dramatic improvement was seen in TMA related hematological activity with no further need for transfusions (Table 1 ). Dialysis was stopped after a total of 13 days of treatment (Fig. 4). A gradual improvement in neurological symptoms was observed. After 14 days of intensive care treatment and a total of 25 days of hospitalization, the patient was discharged home with an eGFR value of 81 ml/min/1,73m 2 and physiological hematological parameters. Urinanalysis revealed modest proteinuria (3 g/L) on admission. During complex rehabilitation, his neurological symptoms fully regressed. Low dose ACE-I treament managed to control systolic hypertension and proteinuria while eGFR returned to normal (120 ml/min/1,73m 2 ) (Table 2 ). Subsequent genetic tests confirmed that the patient carries the MCPggaac risk haplotype in homozygous form. Discussion and conclusions In the presented case series we report about the clinical course and outcome of three children with severe HUS. In all three cases the typical triad of TMA related hemolytic anemia, thrombocytopenia and AKI were observed with the activation of the complement system. The clinical presentation showed substantial differencies and variations among the cases (2 STEC-HUS and 1 SP-HUS) highlighting the difficulties of diagnosing and managing pediatric TMA cases. Initial management was provided on the basis of best supportive care in each case 20 22 (KDIGO). Eventually, all three patients received C5-complement inhibitor (ECZ), either due to the suspicion of aHUS case or due to the progressive course of the disease with prolonged CKRT requirement, persistent hematological activity, central nervous system (CNS)/multiorgan involvement and evidence of complement activation. In the first patient (Patient 1), in addition to the negativity of the first stool for verotoxin, based on the progression observed in the clinic (worsening kidney function, prolonged anuria and severe hematological activity), ECZ therapy was started with the suspicion of aHUS. Rapid improvement was observed within 72 hours including hematological parameters and diuresis returning to normal. Interestingly, repeated test (verotoxin PCR from stool) in a reference laboratory finally revealed STEC-HUS. The serum complement parameters showed only borderline activation with normal C3, C4, CH50 levels and mild elevation of sC5b-9. Atypical HUS requires an immediate intervention and decision to start ECZ is recommended at an early stage 23 24 . The other patient with STEC-HUS (Patient 3) had severe extrarenal manifestations including CNS involvement and polyserositis. The Percheron artery is a rare anatomical variant, in which both side vessels originate from the same main trunk, and its injury (vasculitis, thromboembolism) causes a symmetrical deviation. Symptoms such as fluctuating cognitive impairment, aphasia, and memory impairment were detectable in our patient with hemiparetic symptoms on the right side corresponding to the deviation seen in the MR image 25 26 (Fig. 4). In agreement with our current institutional protocol we performed a series of plasma exchange (PLEX) with fresh frozen plasma (FFP) (4 sessions) without detectable clinical improvement. Global activation of the complement system with markedly decreased C3, C4, CH50 levels and highly elevated sC5b-9 value was observed. Worsening CNS symptoms triggered the use of ECZ treatment. ECZ treatment resulted in remarkable improvement in the kidney function parameters (Fig. 3 ) as well as in CNS complications and hematological activity (Table 2 ). Cognitive dysfunctions, hemiparetic symptoms and aphasia were quickly resolved. A rapid improvement in both clinical and laboratory parameters correlate well with outcome of similar cases reported by others with ECZ treatment of STEC-HUS associated with severe CNS complications 27 12 16 28 29 . Our SP-HUS patient’s (Patient 2) clinical and laboratory findings corresponded with sepsis, bilateral pleuropneumonia, MOF, DIC and parallel TMA with unusually high level of LDH, deep thrombocytopenia (PLT: 7 G/L) and severe AKI. Severe global activation of the complement system and an extended endothelial damage was detected with charactheristic alterations in TMA related values (ADAMST13, C3, C4, CH50, MAC) (Table 1 ). In the management of SP-HUS both the drainage of the pleural effusion and intravenous immunoglobulin (blocking autoantibodies and neutralizing neuramidase) are important therapeutic steps which may explain the partial early improvement observed with LDH decrease and modest elevation of PLT count (from 7 G/L to about 30 G/L) (Fig. 2 ). However, prolonged need of CKRT, oligoanuria and severe AKI corresponded with a progressive clinical course of TMA/HUS. ECZ administration resulted in an impressive clinical improvement. Literature data about the use of C5-inhibitor in pediatric SP-HUS patients ECZ is scarce. Only few case reports and case series reports recount successful use of ECZ particularly in desperate clinical situations (severe CNS involvement or progressive and therapeutic refracter cases) where dysregulation of the complement pathway was presumed to play a central role in the disease pathomechanism 30 19 21 31 . A Czech study published in 2023 reported the use of ECZ in 4 cases out of 7 SP-HUS patients, with no evident advantage of ECZ in their cohort 31 . Beyond TMA related microangiopathic cell damage, in all three cases the core element of the pathomechanism was the predominant activation of the complement alternative pathway with consumptive decrease in complement factor C3 and C4 (Patient 2 and 3) and increased MAC levels (Patient 1, 2, 3) (Table 1 ). The first patient had normal C3 and C4 levels measured during admission. It was common in all three cases that regardless of standard „best supportive care” we observed either progression or at least unchanged clinical state regarding many important aspects of TMA-HUS such as oligoanuria, deteriorated kidney function, severe hematological activity, CNS involvement (Patient 2), polyserositis (Patient 2 and 3) and CKRT dependency (Patient 2 and 3). Both detailed complement activation profile and genetical analysis were obtained in all three cases in line with the institutional recommendation. Previous experimental and clinical observations proved that dysregulation of the complement alternative pathway could be a major pathogenetic event in both STEC-HUS and SP-HUS 18 19 32 . Even though ECZ received both FDA and EMA approval for the treatment of aHUS 33 34 , its use in STEC-HUS or SP-HUS remained elusive 17 27 35 . A recently published randomized controlled trial (RCT) about C5 inhibitor (ECZ) treatment in STEC-HUS found no convincing evidence in the short-term outcome as measured in time of CKRT need and eGFR in the acute phase, however convincing evidence was shown for the long-term benefit (significantly better eGFR in the treated group) of ECZ treatment in STEC-HUS 17 . Surprisingly good outcome was reported in case series of STEC-HUS associated with CNS complications, where ECZ indication was solely based on the clinical situation (TMA activity and severity of CNS invovement) 29 27 12 . One of the important issues is timing of ECZ administration. On the basis of previous experience with aHUS, early administration of ECZ has been associated with better long-term kidney outcome 11 23 24 . In our cases evaluation of complement activation markers was helpful, even though the disease course and clinical presentation were the major determinants in decision making, of which a multidisciplinary approach (ICU specialist and pediatric nephrologist) was preferred. Both parental consent and the Hungarian National Drug Administration license was obtained before the administration of ECZ. In agreement with available guidelines patients received antibiotic treatment or prophylaxis for the safe administration of ECZ and vaccination against all Neisseria strains in the earliest possible time 36 37 . We believe that all three patients responded impressively well to ECZ. Global activation of the complement system (Patient 2 and 3) may correspond with more extensive activation process that is not limited to the alternative pathway. In case 2 with SP-HUS, sepsis, DIC and neuraminidase-induced extensive endothelial damage while in case 3 STEC-related cell destruction augmented by inevitable antibiotic treatment may explain enhanced and global activation of the complement system. Consequently, inhibition of C5 may have been a valid strategy to blunt ongoing complement-mediated pathological events 12 32 38 . Previous publications did not present convincing data about the advantage of ECZ use in STEC-HUS, however some benefits of long-term outcome were reported 17 27 35 . In our cases both quick recovery and excellent outcome after ECZ treament convinced us that in similar clinical situtations (CNS involvement and/or severe multiorgan dysfunction) we would consider using ECZ again. We emphasize that complement activation data in hand may help clinical decision. Upon dismission modestly decreased kidney function was detected in all the patients (Table 2 ). However, in the early follow-up (6–12 weeks) tests only modest proteinuria requiring low dose ACE-I treatment and borderline systolic hypertension were seen in one of our patients (Patient 2). In association with proteinuric state, relatively higher eGFR values (> 95% for age and BSA) were temporarily seen at a later check-up (3–6 month) in patients 2 and 3 that may be accounted for hyperfiltration. Adverse events with the administration of ECZ Administration of ECZ is known to increase the risk of infections 37 . Therefore, antibiotic prophylaxis and vaccination against Neisseria species are recommended before the administration of the drug (see Solaris (eculizumab) package insert). Less is known about the incidence of other potential infective agents 39 . In two patients symptomatic cytomegalovirus (CMV) infection was detected with relatively higher copy number (Patient 2 and 3) after the 2nd dose of ECZ. In both cases specific antiviral therapy was indicated. The incidence of CMV infection is unknown in ECZ treated pediatric patients. Our cases highlight the importance of checking on CMV status upon ECZ treatment since C5-inhibiton in a sense is an immunocompromised state and an ongoing CMV-disease may compromise clinical improvement 40 41 . To our best knowledge, genetical analysis is not part of the routine diagnostics in infective HUS 36 . Even though infection is the major trigger of disease manifestations, current literature data suggest that risk haplotypes of complement regulatory genes are ocassionally detected in cases of HUS. Indeed, in two patients (Patient 1 and 3) we detected MCPggaac risk haplotype in homozygous form, which may increase the chance of a more severe HUS/TMA manifestation 42 . We did not consider long-term ECZ treament in these cases, and we do not expect and have not experienced recurrence as yet. Timing of ECZ treatment inititation seems to be an important issue, even though there is no consensus on the optimal time or indication for the administration of ECZ in infection-associated HUS. We strongly believe that detailed complement activation data, when it is available in a short turnaround time, is helpful in deciding about the use of ECZ and may in the future be an important part of the diagnostic panel. Timing of ECZ administration depended on many variable factors including parental consent or institutional and other official approvals. In our cases we managed to get all the necessary documents in 7 days for the off-label use of the drug. We report excellent outcome of our patients suggesting that the time-window for ECZ treatment is not yet defined 40 43 . Summary The use of complement C5 inhibition is still controversal in the treatment of infection-associated HUS types. Currently, the standard of care in infection-associated HUS types is mainly supportive. In selected HUS cases with CNS involvement and other severe extrarenal manifestations C5-inhibitor treatment (ECZ) may be used. Parental consent and/or institutional and other official approvals are all necessary for off-label use of ECZ. Early use of ECZ may improve both short-term and definitely long-term outcome especially in cases where complement system (AP) is overactivated. Detailed complement activation profile, particularly sC5b-9 is helpful to indicate ECZ administration. Proper antibiotic profilaxis/treament and vaccination against Neisseria species are recommended for safer use of ECZ. Monitoring of bacterial, viral infection including CMV is neccessary for patient’s assessment. Well-designed multicenter RCTs should be done to gain further evidence to support the benefit of complement inhibition in the treament of severe pediatric HUS with multiorgan involvement. Abbreviations aHUS atypical Hemolytic Uremic Syndrome AKI Acute Renal Injury AP complement activation APH50 alternative payway total complement activity BMI body mass index BW body weight CFB complement factor B CFH complement factor H CFHR5 complement factor H-related protein-5 CFI complement factor I CH50 total complement activity CKRT Continuous Kidney Replacement Therapy CMV Cytomegalovirus CNS Central Nervous System DGKE diacylglycerol kinase epsilon DIC Disseminated Intravascular Coagulation ECZ Eculizumab EMA European Medicines Agency FDA US Food and Drug Administration FFP Fresh Frozen Plasma HUS Hemolytic Uremic Syndrome PICU Pediatric Intensive Care Unit PLEX Plasma Exchange Therapy RCT Randomized Controlled Trial sC5b-9 solubilis terminal complement complex SP-HUS Streptococcus pneumoniae-associated HUS STEC-HUS Shiga toxin-producing Escherichia coli-HUS THBD thrombomodulin TMA Thrombotic Microangopathy VATS video-assisted thoracic surgery Declarations Ethics approval and consent to participate: The study was approved by the Scientific and Research Ethics Committee of the University of Debrecen under the registration number of 6879-2024 (DE KK RKEB/IKEB). Patients were enrolled in accordance with the Declaration of Helsinki. During anonymous data management, a general patient information sheet and an informed consent form were used. No additional intervention was performed, only the necessary and usual therapeutic and diagnostic methods were used. Informed Consent Statement: Written informed consent was obtained from the parent(s) or legal guardian of each child before the study. Consent for publication: not applicable Availability of data and materials: Dataset analyzed during the study represent patient’s data available in their medical documentation and the electronic patients’ database (MedSolution, UDMed) of the University of Debrecen for authorized personnel. Petra Varga, the first author can be contacted for additional data request ( [email protected] ) Competing interests: The authors declare no conflict of interest. Funding: This research received no external funding. Authors' contributions: All of the listed authors contributed significantly to the publication. TSZ indicated laboratory tests. PV, EB performed data collection. In addition, PV analyzed and interpreted data from pediatric patients with HUS. ZP performed complement diagnostic data, TSZ played a significant role in writing the manuscript. All authors read and approved the final manuscript. Acknowledgements: N/A Authors' information (optional) References Noris, M.; Remuzzi, G. Hemolytic Uremic Syndrome. Journal of the American Society of Nephrology. 2005;16 (4), 1035–1050. Sheerin, N. S.; Glover, E. Haemolytic Uremic Syndrome: Diagnosis and Management. 2019;F1000Res 8, F1000 Faculty Rev-1690. https://doi.org/10.12688/f1000research.19957.1. Gould, L. H.; Demma, L.; Jones, T. F.; Hurd, S.; Vugia, D. J.; Smith, K.; Shiferaw, B.; Segler, S.; Palmer, A.; Zansky, S.; Griffin, P. M. Hemolytic Uremic Syndrome and Death in Persons with Escherichia Coli O157:H7 Infection, Foodborne Diseases Active Surveillance Network Sites, 2000-2006. Clin Infect Dis. 2009;49(10), 1480–1485. https://doi.org/10.1086/644621. Trachtman, H.; Austin, C.; Lewinski, M.; Stahl, R. A. K. Renal and Neurological Involvement in Typical Shiga Toxin-Associated HUS. Nat Rev Nephrol. 2012;8(11),658–669. https://doi.org/10.1038/nrneph.2012.196. Loos, S.; Aulbert, W.; Hoppe, B.; Ahlenstiel-Grunow, T.; Kranz, B.; Wahl, C.; Staude, H.; Humberg, A.; Benz, K.; Krause, M.; Pohl, M.; Liebau, M. C.; Schild, R.; Lemke, J.; Beringer, O.; Müller, D.; Härtel, C.; Wigger, M.; Vester, U.; Konrad, M.; Haffner, D.; Pape, L.; Oh, J.; Kemper, M. J. Intermediate Follow-up of Pediatric Patients With Hemolytic Uremic Syndrome During the 2011 Outbreak Caused by E. Coli O104:H4. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2017;64(12),1637–1643. https://doi.org/10.1093/cid/cix218. Rosales, A.; Hofer, J.; Zimmerhackl, L.-B.; Jungraithmayr, T. C.; Riedl, M.; Giner, T.; Strasak, A. Orth-Höller, D.; Würzner, R.; Karch, H.; German-Austrian HUS Study Group. Need for Long-Term Follow-up in Enterohemorrhagic Escherichia Coli-Associated Hemolytic Uremic Syndrome Due to Late-Emerging Sequelae. Clin Infect Dis. 2012;54(10),1413–1421. https://doi.org/10.1093/cid/cis196. Scobell, R. R.; Kaplan, B. S.; Copelovitch, L. New Insights into the Pathogenesis of Streptococcus Pneumoniae-Associated Hemolytic Uremic Syndrome. Pediatr Nephrol. 2020;35(9),1585–1591. https://doi.org/10.1007/s00467-019-04342-3. Copelovitch, L.; Kaplan, B. S. Streptococcus Pneumoniae-Associated Hemolytic Uremic Syndrome. Pediatr Nephrol. 2008;23 (11),1951–1956. https://doi.org/10.1007/s00467-007-0518-y. Prestidge, C.; Wong, W. Ten Years of Pneumococcal-Associated Haemolytic Uraemic Syndrome in New Zealand Children. J Paediatr Child Health. 2009;45(12),731–735. https://doi.org/10.1111/j.1440-1754.2009.01603.x. Nester, C. M.; Feldman, D. L.; Burwick, R.; Cataland, S.; Chaturvedi, S.; Cook, H. T.; Cuker, A.; Dixon, B. P.; Fakhouri, F.; Hingorani, S. R.; Java, A.; Van De Kar, N. C. A. J.; Kavanagh, D.; Leung, N.; Licht, C.; Noris, M.; O’Shaughnessy, M. M.; Parikh, S. V.; Peyandi, F.; Remuzzi, G.; Smith, R. J. H.; Sperati, C. J.; Waldman, M.; Walker, P.; Vivarelli, M. An Expert Discussion on the Atypical Hemolytic Uremic Syndrome Nomenclature—Identifying a Road Map to Precision: A Report of a National Kidney Foundation Working Group. Kidney International. 2024;106(3),326–336. https://doi.org/10.1016/j.kint.2024.05.021. Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, Bingham C, Cohen DJ, Delmas Y, Douglas K, Eitner F, Feldkamp T, Fouque D, Furman RR, Gaber O, Herthelius M, Hourmant M, Karpman D, Lebranchu Y, Mariat C, Menne J, Moulin B, Nürnberger J, Ogawa M, Remuzzi G, Richard T, Sberro-Soussan R, Severino B, Sheerin NS, Trivelli A, Zimmerhackl LB, Goodship T, Loirat C. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368(23):2169-81. doi: 10.1056/NEJMoa1208981. PMID: 23738544.Licht C. Walsh, P. R.; Johnson, S. Eculizumab in the Treatment of Shiga Toxin Haemolytic Uraemic Syndrome. Pediatr Nephrol. 2019;34(9),1485–1492. https://doi.org/10.1007/s00467-018-4025-0. Mahat, U.; Matar, R. B.; Rotz, S. J. Use of Complement Monoclonal Antibody Eculizumab in Shiga Toxin Producing Escherichia Coli Associated Hemolytic Uremic Syndrome: A Review of Current Evidence. Pediatr Blood Cancer. 2019;66(11), e27913. https://doi.org/10.1002/pbc.27913. Weber, B.; Chan, D.; Hammer, S. Eculizumab Use in a Temporarily Dialysis-Dependent Patient With Shiga Toxin–Producing Escherichia Coli Hemolytic Uremic Syndrome With Neurological Complications. J Pediatr Pharmacol Ther. 2022;27(1), 90–95. https://doi.org/10.5863/1551-6776-27.1.90. Monet-Didailler, C.; Chevallier, A.; Godron-Dubrasquet, A.; Allard, L.; Delmas, Y.; Contin-Bordes, C.; Brissaud, O.; Llanas, B.; Harambat, J. Outcome of Children with Shiga Toxin-Associated Haemolytic Uraemic Syndrome Treated with Eculizumab: A Matched Cohort Study. Nephrol Dial Transplant. 2020;35 (12),2147–2153. https://doi.org/10.1093/ndt/gfz158. Lapeyraque, A.-L.; Malina, M.; Fremeaux-Bacchi, V.; Boppel, T.; Kirschfink, M.; Oualha, M.; Proulx, F.; Clermont, M.-J.; Le Deist, F.; Niaudet, P.; Schaefer, F. Eculizumab in Severe Shiga-Toxin-Associated HUS. N Engl J Med. 2011;364(26),2561–2563. https://doi.org/10.1056/NEJMc1100859. Garnier, A.; Brochard, K.; Kwon, T.; Sellier-Leclerc, A.-L.; Lahoche, A.; Launay, E. A.; Nobili, F.; Caillez, M.; Taque, S.; Harambat, J.; Michel-Bourdat, G.; Guigonis, V.; Fila, M.; Cloarec, S.; Djamal-Dine, D.; de Parscaux, L.; Allard, L.; Salomon, R.; Ulinski, T.; Frémeaux-Bacchi, V.; Morin, C.; Olivier-Abbal, P.; Colineaux, H.; Auriol, F.; Arnaud, C.; Kieffer, I.; Brusq, C. Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial. J Am Soc Nephrol. 2023;34(9),1561–1573. https://doi.org/10.1681/ASN.0000000000000182. Sinkovits, G.; Prohászka, Z. Update on the Role of the Complement System in the Pathogenesis of Thrombotic Microangiopathies. Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2014;35(1),115–122. Szilágyi, A.; Kiss, N.; Bereczki, C.; Tálosi, G.; Rácz, K.; Túri, S.; Györke, Z.; Simon, E.; Horváth, E.; Kelen, K.; Reusz, G. S.; Szabó, A. J.; Tulassay, T.; Prohászka, Z. The Role of Complement in Streptococcus Pneumoniae-Associated Haemolytic Uraemic Syndrome. Nephrol Dial Transplant. 2013;28(9),2237–2245. https://doi.org/10.1093/ndt/gft198. Khwaja, A. KDIGO Clinical Practice Guidelines for Acute Kidney Injury. Nephron Clinical Practice. 2012;120(4),c179–c184. https://doi.org/10.1159/000339789. Holle, J.; Habbig, S.; Gratopp, A.; Mauritsch, A.; Müller, D.; Thumfart, J. Complement Activation in Children with Streptococcus Pneumoniae Associated Hemolytic Uremic Syndrome. Pediatr Nephrol. 2021;36(5),1311–1315. https://doi.org/10.1007/s00467-021-04952-w. Igarashi, T.; Ito, S.; Sako, M.; Saitoh, A.; Hataya, H.; Mizuguchi, M.; Morishima, T.; Ohnishi, K.; Kawamura, N.; Kitayama, H.; Ashida, A.; Kaname, S.; Taneichi, H.; Tang, J.; Ohnishi, M. Study group for establishing guidelines for the diagnosis and therapy of hemolytic uremic syndrome. Guidelines for the Management and Investigation of Hemolytic Uremic Syndrome. Clin Exp Nephrol. 2014;18(4),525–557. https://doi.org/10.1007/s10157-014-0995-9. Nester, C. M.; Thomas, C. P. Atypical Hemolytic Uremic Syndrome: What Is It, How Is It Diagnosed, and How Is It Treated? Hematology. 2012;(1),617–625. https://doi.org/10.1182/asheducation.V2012.1.617.3798924. Noris, M.; Remuzzi, G. Atypical Hemolytic–Uremic Syndrome. New England Journal of Medicine. 2009;361 (17),1676–1687. https://doi.org/10.1056/NEJMra0902814. Musa, J.; Rahman, M.; Guy, A.; Kola, E.; Guy, A.; Hyseni, F.; Cobo, A.; Saliaj, K.; Bushati, F.; Ahmetgjekaj, I. Artery of Percheron Infarction: A Case Report and Literature Review. Radiol Case Rep. 2021;16(6),1271–1275. https://doi.org/10.1016/j.radcr.2021.02.059. Bain, S. E.; Hsieh, D. T.; Vezina, L. G.; Chang, T. Bilateral Paramedian Thalamic and Mesencephalic Infarcts in a Newborn Due to Occlusion of the Artery of Percheron. J Child Neurol. 2009;24(2),219–223. https://doi.org/10.1177/0883073808322672. Percheron, L.; Gramada, R.; Tellier, S.; Salomon, R.; Harambat, J.; Llanas, B.; Fila, M.; Allain-Launay, E.; Lapeyraque, A.-L.; Leroy, V.; Adra, A.-L.; Bérard, E.; Bourdat-Michel, G.; Chehade, H.; Eckart, P.; Merieau, E.; Piètrement, C.; Sellier-Leclerc, A.-L.; Frémeaux-Bacchi, V.; Dimeglio, C.; Garnier, A. Eculizumab Treatment in Severe Pediatric STEC-HUS: A Multicenter Retrospective Study. Pediatr Nephrol. 2018;33(8),1385–1394. https://doi.org/10.1007/s00467-018-3903-9. Pape, L.; Hartmann, H.; Bange, F. C.; Suerbaum, S.; Bueltmann, E.; Ahlenstiel-Grunow, T. Eculizumab in Typical Hemolytic Uremic Syndrome (HUS) With Neurological Involvement. Medicine (Baltimore). 2016;94(24),e1000. https://doi.org/10.1097/MD.0000000000001000. Wildes, D. M.; Harvey, S.; Costigan, C. S.; Sweeney, C.; Twomey, É.; Awan, A.; Gorman, K. M. Eculizumab in STEC-HUS: A Paradigm Shift in the Management of Pediatric Patients with Neurological Involvement. Pediatr Nephrol. 2024;39(1),315–324. https://doi.org/10.1007/s00467-023-06102-w. Gilbert, R. D.; Nagra, A.; Haq, M. R. Does Dysregulated Complement Activation Contribute to Haemolytic Uraemic Syndrome Secondary to Streptococcus Pneumoniae? Med Hypotheses. 2013;81(3),400–403. https://doi.org/10.1016/j.mehy.2013.05.030. Konopásek, P.; Zieg, J. Eculizumab Use in Patients with Pneumococcal-Associated Hemolytic Uremic Syndrome and Kidney Outcomes. Pediatr Nephrol. 2023;38(12),4209–4215. https://doi.org/10.1007/s00467-023-06037-2. Agarwal, H. S.; Latifi, S. Q. Streptococcus Pneumoniae-Associated Hemolytic Uremic Syndrome in the Era of Pneumococcal Vaccine. Pathogens. 2021;10(6),727. https://doi.org/10.3390/pathogens10060727. Soliris (eculizumab) Approved by FDA for All Patients with Atypical Hemolytic Uremic Syndrome (aHUS). Drugs.com. https://www.drugs.com/newdrugs/soliris-eculizumab-approved-fda-all-patients-atypical-hemolytic-uremic-syndrome-ahus-2872.html (accessed 2024-08-17). European Medicines Agency - Human medicines - EU/3/09/653. https://web.archive.org/web/20170923013346/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Forphans%2F2009%2F11%2Fhuman_orphan_000657.jsp&mid=WC0b01ac058001d12b (accessed 2024-08-17). Costigan, C.; Raftery, T.; Carroll, A. G.; Wildes, D.; Reynolds, C.; Cunney, R.; Dolan, N.; Drew, R. J.; Lynch, B. J.; O’Rourke, D. J.; Stack, M.; Sweeney, C.; Shahwan, A.; Twomey, E.; Waldron, M.; Riordan, M.; Awan, A.; Gorman, K. M. Neurological Involvement in Children with Hemolytic Uremic Syndrome. Eur J Pediatr. 2022;181(2),501–512. https://doi.org/10.1007/s00431-021-04200-1. Rovin, B. H.; Adler, S. G.; Barratt, J.; Bridoux, F.; Burdge, K. A.; Chan, T. M.; Cook, H. T.; Fervenza, F. C.; Gibson, K. L.; Glassock, R. J.; Jayne, D. R. W.; Jha, V.; Liew, A.; Liu, Z.-H.; Mejía-Vilet, J. M.; Nester, C. M.; Radhakrishnan, J.; Rave, E. M.; Reich, H. N.; Ronco, P.; Sanders, J.-S. F.; Sethi, S.; Suzuki, Y.; Tang, S. C. W.; Tesar, V.; Vivarelli, M.; Wetzels, J. F. M.; Floege, J. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney International. 2021;100(4),S1–S276. https://doi.org/10.1016/j.kint.2021.05.021. Ram S, Lewis LA, Rice PA. Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin Microbiol Rev. 2010;Oct;23(4):740-80. doi: 10.1128/CMR.00048-09. PMID: 20930072; PMCID: PMC2952982. Keenswijk, W.; Raes, A.; Vande Walle, J. Is Eculizumab Efficacious in Shigatoxin-Associated Hemolytic Uremic Syndrome? A Narrative Review of Current Evidence. Eur J Pediatr. 2018;177(3),311–318. https://doi.org/10.1007/s00431-017-3077-7. Benamu, E.; Montoya, J. G. Infections Associated with the Use of Eculizumab: Recommendations for Prevention and Prophylaxis. Curr Opin Infect Dis. 2016;29(4),319–329. https://doi.org/10.1097/QCO.0000000000000279. Sonata Jodele, Christopher E. Dandoy, Adam Lane, Benjamin L. Laskin, Ashley Teusink-Cross, Kasiani C. Myers, Gregory Wallace, Adam Nelson, Jack Bleesing, Ranjit S. Chima, Russel Hirsch, Thomas D. Ryan, Stefanie Benoit, Kana Mizuno, Mikako Warren, Stella M. Davies; Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood. 2020;135(13):1049–1057. doi: https://doi.org/10.1182/blood.2019004218 Osawa, R., Singh, N. Cytomegalovirus infection in critically ill patients: a systematic review. Crit Care. 2009;13,R68 https://doi.org/10.1186/cc7875 Turudic, D.; Pokrajac, D.; Tasic, V.; Kasumovic, D.; Prohaszka, Z.; Milosevic, D. The Rationale of Complement Blockade of the MCPggaac Haplotype Following Atypical Hemolytic Uremic Syndrome of Three Southeastern European Countries with a Literature Review. International Journal of Molecular Sciences. 2023;24(17),13041. https://doi.org/10.3390/ijms241713041. Wehling, C.; Amon, O.; Bommer, M.; Hoppe, B.; Kentouche, K.; Schalk, G.; Weimer, R.; Wiesener, M.; Hohenstein, B.; Tönshoff, B.; Büscher, R.; Fehrenbach, H.; Gök, Ö.-N.; Kirschfink, M. Monitoring of Complement Activation Biomarkers and Eculizumab in Complement-Mediated Renal Disorders. Clinical and Experimental Immunology. 2017;187(2),304–315. https://doi.org/10.1111/cei.12890. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 11 Mar, 2025 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Revision requested 12 Nov, 2024 Editor assigned by journal 10 Nov, 2024 Submission checks completed at journal 10 Nov, 2024 First submitted to journal 04 Nov, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-5389564\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Case Report\",\"associatedPublications\":[],\"authors\":[{\"id\":377017430,\"identity\":\"15659ce0-a57c-4307-992d-bc66685ce91f\",\"order_by\":0,\"name\":\"Petra Varga\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Debrecen\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Petra\",\"middleName\":\"\",\"lastName\":\"Varga\",\"suffix\":\"\"},{\"id\":377017431,\"identity\":\"63e5666b-3504-41e3-815c-2c4e992dbcc8\",\"order_by\":1,\"name\":\"Erika Biró\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Debrecen\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Erika\",\"middleName\":\"\",\"lastName\":\"Biró\",\"suffix\":\"\"},{\"id\":377017432,\"identity\":\"efeb27f1-efc2-408c-8936-3c3c3e6e3a61\",\"order_by\":2,\"name\":\"Andrea Berkes\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Debrecen\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Andrea\",\"middleName\":\"\",\"lastName\":\"Berkes\",\"suffix\":\"\"},{\"id\":377017433,\"identity\":\"0696cb01-bf13-42b3-927f-1230770a9fc9\",\"order_by\":3,\"name\":\"Erzsébet Lakatos\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Debrecen\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Erzsébet\",\"middleName\":\"\",\"lastName\":\"Lakatos\",\"suffix\":\"\"},{\"id\":377017434,\"identity\":\"ba9d85f2-d1db-49ea-903c-b386c9c18ceb\",\"order_by\":4,\"name\":\"Edit Szikszay\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Debrecen\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Edit\",\"middleName\":\"\",\"lastName\":\"Szikszay\",\"suffix\":\"\"},{\"id\":377017435,\"identity\":\"a9f81bab-23da-4c04-8084-8145601cce36\",\"order_by\":5,\"name\":\"Zoltán Prohászka\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Semmelweis University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Zoltán\",\"middleName\":\"\",\"lastName\":\"Prohászka\",\"suffix\":\"\"},{\"id\":377017436,\"identity\":\"f60135a0-53c2-4be7-93d8-a8f36b082fac\",\"order_by\":6,\"name\":\"Tamás Szabó\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYHACNijNfADCZmYwYGZgOEBASwKYTiBZC48BzEb8WuT7Dz978PGHXTR//5mvGz6UMSRuZ2fe+LiA4U5iAw4tBgeOmRvOSEjOnXEjd9vNGecYEnc2sxUbz2B4hlsLY4OZNE8Cc27DDd5tt3nbGBI3HOYBijAcxqlFvpn9G1BLfe7882ee3f4L0WL+G58WhmMgMxMO5244kMN2mxFqCzM+LQZneMoNZ6Qdz914I83sZs85CeMNh9mKpWcYHDbG6bD+49sefLCpzp13/vCzGz/KbGQ3nD+88XNBxWFZnA5DAxIw24lUPwpGwSgYBaMAKwAAkMxgFDAY/h0AAAAASUVORK5CYII=\",\"orcid\":\"\",\"institution\":\"University of Debrecen\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Tamás\",\"middleName\":\"\",\"lastName\":\"Szabó\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-11-04 16:08:15\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-5389564/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-5389564/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1186/s12887-025-05546-3\",\"type\":\"published\",\"date\":\"2025-03-11T15:57:54+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":71512816,\"identity\":\"ee6665d1-40a5-4462-83b6-f6deed099854\",\"added_by\":\"auto\",\"created_at\":\"2024-12-16 10:39:37\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":220711,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eTimeline of patient 1 treated with ECZ. The first dose of ECZ was given on Day 7. 3 days after the first administration of ECZ, the platelet count increased (from 38 G/L to 100 G/L without transfusion), the LDH activity significantly decreased (from 1959 U/L to 1100 U/L), diuresis increased, and dialysis was unnecessary. Abbreviations: Hgb, hemoglobin; Thr, thrombocyte; LDH, lactate dehydrogenase; ECZ, Eculizumab;\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5389564/v1/012c7e08ce886cb02df92299.png\"},{\"id\":71512744,\"identity\":\"9ce95966-3476-47cf-9caa-52ad913a7b6b\",\"added_by\":\"auto\",\"created_at\":\"2024-12-16 10:39:28\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":248750,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eTimeline of patient 2 treated with ECZ. The first dose of ECZ was given on Day 7. 3 days after the first administration of ECZ, the platelet count increased (from 73 G/L to 182 G/L without transfusion), LDH activity significantly decreased (from 1946 U/L to 918 U/L), diuresis increased, dialysis was stopped after a total of 10 days of treatment. Abbreviations: Hgb, hemoglobin; Thr, thrombocyte; LDH, lactate dehydrogenase; CKRT, continuous kidney replacement therapy; CVVHDF, continuous veno-venous hemodiafiltration; ECZ, Eculizumab;\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5389564/v1/160cb923c2472666d279861a.png\"},{\"id\":71512807,\"identity\":\"ac5e6007-a2ea-4bff-b5e5-7a0349ec8d65\",\"added_by\":\"auto\",\"created_at\":\"2024-12-16 10:39:31\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":231831,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eMRI of patient 3. On the MRI (FLAIR and DWI) images, a symmetric, hyperintense, banded abnormality can be seen in the area of ​​both thalamus, on the basis of which the abnormality may correspond to Percheron arteriopathy (arrow). The Percheron artery is a rare anatomical variant, in which both lateral vessels originate from the same main trunk, and its injury (vasculitis, thromboembolism) causes a symmetrical deviation. The symptoms, such as fluctuating cognitive impairment, aphasia, memory impairment, and right-sided motor symptoms were all detectable in our 3rd patient and corresponded to the abnormality seen on the MR image.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5389564/v1/127de5f3a4dbfa5b7f98dd5c.png\"},{\"id\":71512808,\"identity\":\"a722bc33-4803-4fb8-aa01-c7ad0eb4e183\",\"added_by\":\"auto\",\"created_at\":\"2024-12-16 10:39:31\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":291954,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eTimeline of patient 3 treated with ECZ. The first dose of ECZ was given on Day 9, after which sudden and dramatic improvement was seen in hematological activity resulting in no need for further transfusions and quick normalization of hematological parameters. 3 days after the first administration of ECZ, the platelet increased (from 54 G/L to 180 G/L without transfusion) and LDH activity decreased (from 803 U/L to 581 U/L). Dialysis was stopped after a total of 13 days of treatment. Abbreviations: Hgb, hemoglobin; Thr, thrombocyte; LDH, lactate dehydrogenase; CKRT, continuous kidney replacement therapy; CVVHDF, continuous veno-venous hemodiafiltration; ECZ, Eculizumab;\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5389564/v1/2f8a3b1899552e991b59a977.png\"},{\"id\":78689157,\"identity\":\"7e9c1e9f-1d33-48bc-b869-ad951071673a\",\"added_by\":\"auto\",\"created_at\":\"2025-03-17 16:12:02\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1801067,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5389564/v1/cb6de2ee-5c1c-440c-9785-ccb1104c30e7.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Use of complement C5-inhibitor eculizumab in patients with infection-associated hemolytic uremic syndrome – a case-series report\",\"fulltext\":[{\"header\":\"Background\",\"content\":\"\\u003cp\\u003eHemolytic uremic syndrome (HUS) is charaterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury (AKI) \\u003csup\\u003e\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u003c/sup\\u003e. Infection is the most common cause of HUS as Shiga-like toxin (verotoxin) producing bacteria, including Shiga toxin-producing enterohaemorrhagic Escherichia coli (STEC), mostly E. coli serotype 0157:H7 or Shigella dysenteriae type 1 are responsible for 90% of all HUS cases \\u003csup\\u003e\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e\\u003c/sup\\u003e. The acute phase of STEC-HUS is severe, with a mortality rate of up to 5% while it may reach up to 20% when presenting with neurological involvement. At least 50% of pediatric HUS patients require dialysis and 30% survive with long-term renal sequelae\\u003csup\\u003e3 4 5 6\\u003c/sup\\u003e. Streptococcus pneumoniae-associated HUS (SP-HUS) represents approximately 5\\u0026ndash;15% of all HUS cases, of which long-term kidney outcome seems to be similar to STEC-HUS\\u003csup\\u003e\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u003c/sup\\u003e. Higher mortality rate has been reported in 11\\u0026ndash;16% of SP-HUS patients, where neuraminidase-induced endothel damage leads to the activation of the complement system and thrombotic microangiopathy (TMA) \\u003csup\\u003e8 9\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eA recent publication reports that a working group of specialists in thrombotic microangiopathies was convened to reclassify TMA on the basis of the main mechanism/etiology of the underlying disease. Thus, infection-associated TMA is listed as a separate entity, with STEC, pneumococcus, viral infection and sepsis as its background. This approach was believed to best support potential treatment methods and utilization of more tailored therapies\\u003csup\\u003e\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eCurrent management of both STEC-HUS and SP-HUS is based on supportive care, including fluid resuscitation, fluid- and electrolyte balance control, blood pressure control, continuous kidney replacement therapy (CKRT) and hematological support. While there is no validated specific therapy, the role of complement dysregulation has been established in either STEC-HUS or other infection-related cases of HUS, suggesting that eculizumab (ECZ) (trade name Soliris; Alexion Pharmaceuticals) may be a useful therapy\\u003csup\\u003e4 8\\u003c/sup\\u003e. ECZ, a humanized monoclonal C5 antibody inhibits terminal complement complex formation. ECZ has been approved both by the European Medicines Agency (EMA) and by the US Food and Drug Administration (FDA) in September 2011 for the treatment of atypical hemolytic uremic syndrome (aHUS) as standard of care, found to be effective in preventing progression to end-stage renal disease\\u003csup\\u003e\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e\\u003c/sup\\u003e. The role of complement activation (AP) has been established in STEC-HUS, although the exact mechanism is still unclear\\u003csup\\u003e\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e\\u003c/sup\\u003e. Previous case reports and cohort studies as well as a current meta-analysis have demonstrated potential benefits of using ECZ, and described convincing clinical improvement after treatment with ECZ in severe STEC-HUS with progressive neurological involvement\\u003csup\\u003e\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u003c/sup\\u003e. None of these studies was randomized or blinded\\u003csup\\u003e12 14 15 16\\u003c/sup\\u003e. A recent randomized, controlled study revealed no convincing benefit of ECZ used in the acute phase of all STEC-HUS cases, however significantly better long-term kidney outcome was observed in the treated group\\u003csup\\u003e\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e\\u003c/sup\\u003e. Still, decision about the potential use of ECZ requires a multidisciplinary background and judgement is often made on the basis of clinical parameters of disease progression. Conventional complement serology studies (C3, C4, CH50) may not be informative, as often only marginal changes can be detected and kidney biopsy is not performed when diagnosis is otherwise confirmed. An extended complement activation panel may provide further data about the activation profile and help guide clinical decision\\u003csup\\u003e18 19\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eGenetic analysis of the complement regulation cascade is not part of the routine clinical investigation in infection-associated HUS types, even though it may provide additional information about long-term prognosis\\u003csup\\u003e\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eHerein, we are presenting a series of three children diagnosed with infection associated HUS treated with complement C5-inhibitor ECZ.\\u003c/p\\u003e\"},{\"header\":\"Case presentations\",\"content\":\"\\u003cp\\u003eWe retrospectively reviewed three infection-associated HUS cases treated with complement C5-inhibitor ECZ in our institute (Institute of Pediatrics, University of Debrecen, Hungary). HUS was defined as hemolytic anemia, thrombocytopenia and acute kidney injury (AKI) caused by TMA. AKI was defined by KDIGO criteria\\u003csup\\u003e\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e\\u003c/sup\\u003e. The presence of confirmed infection (stool culture, blood culture and/or polymerase chain reaction (PCR) was necessary for the infection-associated HUS diagnosis. ECZ therapy was indicated in patients with signs of alternative complement pathway (AP) activation.\\u003c/p\\u003e \\u003cp\\u003eWe documented demographics (gender, age, body weight (BW), height, body mass index (BMI), microbiological data (primary site of infection, results of bacterial cultures, PCR studies), laboratory panel (haemoglobin, platelet, creatinine, urea, LDH, fragmentocytes, haptoglobin, CRP, direkt Coombs test) including complement factors and activation (ADAMTS13 metalloproteinase activity, CH50, APH50, C3, C4, CFH, CFI, CFB, CFC1q, sC5b-9), results of genetic analysis (mutation of CFH, CFI, CD46, C3, CFB, THBD, CFHR5, DGKE) (Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary). As well as major clinical data including duration and modality of kidney replacement therapy, radiological investigation and administration of ECZ and follow-up parameters (3\\u0026ndash;6 months) included estimated GFR (eGFR) using the Schwartz formula, proteinuria defined by protein-creatinine ratio from spot urine, presence of hematuria and arterial hypertension (defined as blood pressure values above the 95th percentile in at least three individual measurements\\u003csup\\u003e\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePatient 1\\u003c/h2\\u003e \\u003cp\\u003eA 2,5 year old female child, who was well previously, was admitted to our pediatric intensive care unit (PICU) with loss of appetite for 5 days, vomiting, loose stools (with no blood or mucus), abdominal pain, petechiae, orbital and limb oedema, without fever. Laboratory tests on admission were typical for TMA (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Direct Coombs test and virulence marker used to confirm EHEC from a stool sample were negative. Despite the adequate supportive therapy, significant progression was seen as the patient became oliguric over the next 4 days, developed general oedema, her kidney function deteriorated with worsening TMA related hemolysis. Based on the negative stool E.coli test (verotoxin negative) and the suspicion of aHUS due to an uncertain infectious and unknown family history, ECZ was administered on the 7th day. Consequently, within 3 days, the platelet count increased (from 38 G/L to 100 G/L without transfusion), the LDH activity significantly decreased (from 1959 U/L to 1100 U/L), diuresis improved and dialysis became unnecessary (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Given the favorable response to ECZ, it was repeated once 7 days later. In the following 2 weeks, her condition improved dramatically. Eventually, repeated stool bacteriological tests confirmed EHEC. Immunoserological tests (C3, C4, CH50) did not indicate dysregulation of the alternative pathway of the complement system, while the level of the activation complex of the terminal pathway increased markedly, indicating ongoing complement activation (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Subsequent genetic tests confirmed MCPggaac risk haplotype in homozygous form. After 7 days of intensive care treatment and a total of 14 days of hospitalization, the patient was discharged with an eGFR value of 63 ml/min/1,73m\\u003csup\\u003e2\\u003c/sup\\u003e and physiological blood count parameters. During subsequent control examinations, she was free of symptoms and complaints and the eGFR returned to normal (120 ml/min/1,73m\\u003csup\\u003e2\\u003c/sup\\u003e) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eInitial presentation, laboratory values and complement diagnostic on admission ​​of patients with infection associated hemolytic uraemic syndrome treated with Eculizumab. Abbreviations: F, female; M, male; LDH, lactate dehydrogenase; PCT, procalcitonin; HUS, hemolytic uremic syndrome; SP-HUS, Streptococcus pneumoniae-associated HUS; STEC-HUS, Shiga toxin-producing Escherichia coli-HUS; AP, complement activation; APH50, alternative payway total complement activity; CFB, complement factor B; CFH, complement factor H; CFI, complement factor I; CH50, total complement activity; SC5b-9, terminal complement complex;\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"4\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePatient\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePatient 1\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePatient 2\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ePatient 3\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eInitial presentation\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAge (months)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e31\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e28\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e125\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGender\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eF\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eF\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eM\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eWeight (kg)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e15\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e11,6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e29\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHeight (cm)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e103\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e90\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e136\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePresenting complaints\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003evomiting, oedema\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003epneumonia, DIC\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003efever, watery diarrhea, abdominal pain\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNeurological symptoms\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEncephalopathy, seizure (tonic), hemiparesis\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eOnset of neurological symptoms from illness\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eDay 4\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHaemoglobin (g/L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e87\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e62\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e98\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eThrombocytes (G/L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e37\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e60\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCreatinine (\\u0026micro;mol/L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e211\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e152\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e730\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eUrea (mmol/L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e27,4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e27,3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e53,7\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLDH (\\u0026lt;\\u0026thinsp;500 U/L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1481\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e6938\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3517\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFragmentocytes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eC-reactive protein (\\u0026lt;\\u0026thinsp;2,2 mg/L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e5,5\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e201\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e23,6\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePCT (\\u0026lt;\\u0026thinsp;0,5 ug/L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eN.A.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e108,19\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e70,63\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDirekt Coombs test\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNegative\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eNegative\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eType of HUS\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSTEC-HUS\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eSP-HUS\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eSTEC-HUS\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eStool culture\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eE.coli stx1/2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003enegative\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eE.coli stx1/2\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBlood culture\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNegative\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePneumococcus\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eNegative\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eComplement diagnostic at admission\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eADAMTS13 metalloproteinase activity (67\\u0026ndash;151%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e90\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e27\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCH50 (48\\u0026ndash;103 CH50/ml)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e59\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e47\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAPH50 (70\\u0026ndash;125%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e113\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e48\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e82\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eC3 (0,9\\u0026thinsp;\\u0026minus;\\u0026thinsp;1,8 g/L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1,13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0,53\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0,9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eC4 (0,15\\u0026thinsp;\\u0026minus;\\u0026thinsp;0,55 g/L\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0,17\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0,1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0,11\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCFH (250-880mg/L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e366\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e175\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e246\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCFI (70\\u0026ndash;130%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e102\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e38\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e90\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCFB (70\\u0026ndash;130%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e97\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e72\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e10\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCFC1q (60\\u0026ndash;180 mg/L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e38\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e88\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e113\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSC5b-9 (110\\u0026ndash;252 ng/mL)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e258\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2459\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e845\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHaptoglobin (0,3\\u0026thinsp;\\u0026minus;\\u0026thinsp;2 g/L)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0,02\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0,2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0,15\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eClinical parameters ​​and outcome data of patients with infection associated hemolytic uremic syndrome treated with Eculizumab. Abbreviations: HUS, Hemolytic uremic syndrome; CVVHDF, continuous venovenous hemo-diafiltration; PLT, platelet; LDH, lactate dehydrogenase; RBC, red blood cell; HFNC, high flow nasal cannule; MV, mechanical ventilation; ICU, intensive care unit;\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"4\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePatient\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePatient 1\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePatient 2\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ePatient 3\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eClinical parameters\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTime from HUS Dg to dialysis (days)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eN.A.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eType of dialysis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eN.A.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eCVVHDF\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eCVVHDF\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDuration of dialysis (days)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e13\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTime to PLT normalization (days)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTime to LDH normalization (days)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e14\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e14\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTime from HUS Dg to Eculizumab treatment (days)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eEculizumab doses\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eProven bacterial infection within 6 weeks of Eculizumab administration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eProven viral infection within 6 weeks of Eculizumab administration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePlasma exchange\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNeed for transfusion\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNo. of RBC transfusion (unit)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNo. of PLT transfusion (unit)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e20\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e16\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVentilation support\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eHFNC\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eMV\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCatecholamines use\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAntibiotic use\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePleural effusion\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eEffusion drainage\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eThrorascopy\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNeurologic symptoms\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGastrointenstinal complications\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eOutcome\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDeath\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLength of ICU stay (days)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e17\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e14\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLength of stay total in hospital (days)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e14\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e24\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e25\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eRenal function recovery (days)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e13\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eeGFR at exmission (ml/min/1,73 m2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e63\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e67\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e81\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHypertension\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eProteinuria\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNeurologic symptoms at exmission\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eYes\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003ePatient 2\\u003c/h3\\u003e\\n\\u003cp\\u003eA 28 month old female child presented at our institute with a 4-day history of pneumonia-associated fever, vomiting, shortness of breath and oliguria in association with gross hematuria. Her previous history was uneventful, she received the mandatory vaccinations, including pneumococcal polysaccharide vaccine containing 13 serotypes. The admission lab tests were characteristic of TMA with elevated inflammatory markers and evidence of disseminated intravascular coagulation (DIC). Direct Coombs test was positive (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). The radiological examinations confirmed right-sided pneumonia with pleural effusion. Overall, the results of the clinical, laboratory and radiological examinations corresponded with the diagnosis of invasive pneumococcus infection and an associated SP-HUS which was supported by hemoculture positivity for Streptococcus pneumoniae. Her management included combined antibiotic treament and supportive therapy (transfusion, intravenous immunoglobulin, respiratory support), which was supplemented from day 2 with continuous kidney replacement therapy (CKRT) due to oliguric AKI, significant fluid overload and metabolic acidosis. Due to worsening respiratory distress with increasing fibrinopurulent chest fluid, critical thrombocytopenia, and coagulopathy, primary video-assisted thoracic surgery (VATS) and chest drainage were performed. Due to onging significant hematological activity, uncontrolled complement activation (reduced C3, C4 and CH50 levels and alternative pathway activity, extremely elevated terminal pathway activation markers) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e), administration of ECZ was initiated on Day 7 with excellent clinical response (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). ECZ was discontinued after two doses of ECZ as kidney function improved, the child recovered without residual symptoms. As expected, no genetic abnormalities were detected. After 17 days of intensive care treatment and a total of 24 days of hospitalization, she was discharged home with an eGFR value of 67 ml/min/1,73m\\u003csup\\u003e2\\u003c/sup\\u003e and physiological blood count parameters. During the subsequent control examinations, she was free of symptoms, urinanalysis revealed only microscopic hematuria (no acanthocytes, no proteinuria) while eGFR returned to normal (130 ml/min/1,73m\\u003csup\\u003e2\\u003c/sup\\u003e). A high normal eGFR value might have reflected a modest hyperfiltration which was not observed later (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e\\n\\u003ch3\\u003ePatient 3\\u003c/h3\\u003e\\n\\u003cp\\u003eThe previously healthy 10-year-old boy was admitted with complaints of watery, non-bloody diarrhea, abdominal pain, and fever lasting for 4 days. The laboratory tests performed at the time of admission confirmed TMA with leukocytosis, markedly elevated inflammatory values (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). In addition to the clinical picture, the EHEC positivity confirmed by the PCR test from stool sample suggested the diagnosis of STEC-HUS. The critically ill patient required antibiotic treatment (meropenem) for severe abdominal symptoms, presumed sepsis caused by bacterial enterocolitis. Despite the administration of intravenous fluids and diuretics, on the 2nd day after admission CKRT was started due to prolonged anuria, volume overload and polyserositis (mainly pleural effusions). Despite CKRT, progressive bilateral pleural effusion developed requiring bilateral pleural drainage, and non-invasive ventilation therapy. Due to severe hematological activity, regular transfusions were given. On the 4th day of treatment, fluctuating and later worsening consciousness was noticed. Despite plasma exchange (PLEX) treatment severe extrarenal symptoms (polyserositis, central nervous system involvement) including neurological symptoms progressed (tonic-clonic convulsion, aphasia, right-sided hemiparesis). Cranial MRI revealed a symmetric, hyperintense, banded abnormality on FLAIR and DWI images in the area of ​​the thalamus on both sides, which corresponded to Percheron arteriopathy (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e). Serological studies obtained earlier confirmed the global abnormal activation of the complement system with low level of complement factors (C3, C4, CH50) and a markedly elevated terminal pathway activation (sC5b-9) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). As a consequence of an unsatisfactory clinical response to supportive therapy and plasmapheresis the use of ECZ was indicated. ECZ was administered on the 9th day, after which sudden and dramatic improvement was seen in TMA related hematological activity with no further need for transfusions (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Dialysis was stopped after a total of 13 days of treatment (Fig.\\u0026nbsp;4). A gradual improvement in neurological symptoms was observed. After 14 days of intensive care treatment and a total of 25 days of hospitalization, the patient was discharged home with an eGFR value of 81 ml/min/1,73m\\u003csup\\u003e2\\u003c/sup\\u003e and physiological hematological parameters. Urinanalysis revealed modest proteinuria (3 g/L) on admission. During complex rehabilitation, his neurological symptoms fully regressed. Low dose ACE-I treament managed to control systolic hypertension and proteinuria while eGFR returned to normal (120 ml/min/1,73m\\u003csup\\u003e2\\u003c/sup\\u003e) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). Subsequent genetic tests confirmed that the patient carries the MCPggaac risk haplotype in homozygous form.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e\"},{\"header\":\"Discussion and conclusions\",\"content\":\"\\u003cp\\u003eIn the presented case series we report about the clinical course and outcome of three children with severe HUS. In all three cases the typical triad of TMA related hemolytic anemia, thrombocytopenia and AKI were observed with the activation of the complement system. The clinical presentation showed substantial differencies and variations among the cases (2 STEC-HUS and 1 SP-HUS) highlighting the difficulties of diagnosing and managing pediatric TMA cases. Initial management was provided on the basis of best supportive care in each case\\u003csup\\u003e20 22\\u003c/sup\\u003e (KDIGO). Eventually, all three patients received C5-complement inhibitor (ECZ), either due to the suspicion of aHUS case or due to the progressive course of the disease with prolonged CKRT requirement, persistent hematological activity, central nervous system (CNS)/multiorgan involvement and evidence of complement activation. In the first patient (Patient 1), in addition to the negativity of the first stool for verotoxin, based on the progression observed in the clinic (worsening kidney function, prolonged anuria and severe hematological activity), ECZ therapy was started with the suspicion of aHUS. Rapid improvement was observed within 72 hours including hematological parameters and diuresis returning to normal. Interestingly, repeated test (verotoxin PCR from stool) in a reference laboratory finally revealed STEC-HUS. The serum complement parameters showed only borderline activation with normal C3, C4, CH50 levels and mild elevation of sC5b-9. Atypical HUS requires an immediate intervention and decision to start ECZ is recommended at an early stage\\u003csup\\u003e23 24\\u003c/sup\\u003e. The other patient with STEC-HUS (Patient 3) had severe extrarenal manifestations including CNS involvement and polyserositis. The Percheron artery is a rare anatomical variant, in which both side vessels originate from the same main trunk, and its injury (vasculitis, thromboembolism) causes a symmetrical deviation. Symptoms such as fluctuating cognitive impairment, aphasia, and memory impairment were detectable in our patient with hemiparetic symptoms on the right side corresponding to the deviation seen in the MR image\\u003csup\\u003e25 26\\u003c/sup\\u003e (Fig.\\u0026nbsp;4). In agreement with our current institutional protocol we performed a series of plasma exchange (PLEX) with fresh frozen plasma (FFP) (4 sessions) without detectable clinical improvement. Global activation of the complement system with markedly decreased C3, C4, CH50 levels and highly elevated sC5b-9 value was observed. Worsening CNS symptoms triggered the use of ECZ treatment. ECZ treatment resulted in remarkable improvement in the kidney function parameters (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e) as well as in CNS complications and hematological activity (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). Cognitive dysfunctions, hemiparetic symptoms and aphasia were quickly resolved. A rapid improvement in both clinical and laboratory parameters correlate well with outcome of similar cases reported by others with ECZ treatment of STEC-HUS associated with severe CNS complications\\u003csup\\u003e27 12 16 28 29\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eOur SP-HUS patient\\u0026rsquo;s (Patient 2) clinical and laboratory findings corresponded with sepsis, bilateral pleuropneumonia, MOF, DIC and parallel TMA with unusually high level of LDH, deep thrombocytopenia (PLT: 7 G/L) and severe AKI. Severe global activation of the complement system and an extended endothelial damage was detected with charactheristic alterations in TMA related values (ADAMST13, C3, C4, CH50, MAC) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). In the management of SP-HUS both the drainage of the pleural effusion and intravenous immunoglobulin (blocking autoantibodies and neutralizing neuramidase) are important therapeutic steps which may explain the partial early improvement observed with LDH decrease and modest elevation of PLT count (from 7 G/L to about 30 G/L) (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). However, prolonged need of CKRT, oligoanuria and severe AKI corresponded with a progressive clinical course of TMA/HUS. ECZ administration resulted in an impressive clinical improvement. Literature data about the use of C5-inhibitor in pediatric SP-HUS patients ECZ is scarce. Only few case reports and case series reports recount successful use of ECZ particularly in desperate clinical situations (severe CNS involvement or progressive and therapeutic refracter cases) where dysregulation of the complement pathway was presumed to play a central role in the disease pathomechanism\\u003csup\\u003e30 19 21 31\\u003c/sup\\u003e. A Czech study published in 2023 reported the use of ECZ in 4 cases out of 7 SP-HUS patients, with no evident advantage of ECZ in their cohort\\u003csup\\u003e\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e\\u003c/sup\\u003e. Beyond TMA related microangiopathic cell damage, in all three cases the core element of the pathomechanism was the predominant activation of the complement alternative pathway with consumptive decrease in complement factor C3 and C4 (Patient 2 and 3) and increased MAC levels (Patient 1, 2, 3) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). The first patient had normal C3 and C4 levels measured during admission. It was common in all three cases that regardless of standard \\u0026bdquo;best supportive care\\u0026rdquo; we observed either progression or at least unchanged clinical state regarding many important aspects of TMA-HUS such as oligoanuria, deteriorated kidney function, severe hematological activity, CNS involvement (Patient 2), polyserositis (Patient 2 and 3) and CKRT dependency (Patient 2 and 3). Both detailed complement activation profile and genetical analysis were obtained in all three cases in line with the institutional recommendation. Previous experimental and clinical observations proved that dysregulation of the complement alternative pathway could be a major pathogenetic event in both STEC-HUS and SP-HUS\\u003csup\\u003e18 19 32\\u003c/sup\\u003e. Even though ECZ received both FDA and EMA approval for the treatment of aHUS\\u003csup\\u003e33 34\\u003c/sup\\u003e, its use in STEC-HUS or SP-HUS remained elusive\\u003csup\\u003e17 27 35\\u003c/sup\\u003e. A recently published randomized controlled trial (RCT) about C5 inhibitor (ECZ) treatment in STEC-HUS found no convincing evidence in the short-term outcome as measured in time of CKRT need and eGFR in the acute phase, however convincing evidence was shown for the long-term benefit (significantly better eGFR in the treated group) of ECZ treatment in STEC-HUS\\u003csup\\u003e\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e\\u003c/sup\\u003e. Surprisingly good outcome was reported in case series of STEC-HUS associated with CNS complications, where ECZ indication was solely based on the clinical situation (TMA activity and severity of CNS invovement)\\u003csup\\u003e29 27 12\\u003c/sup\\u003e. One of the important issues is timing of ECZ administration. On the basis of previous experience with aHUS, early administration of ECZ has been associated with better long-term kidney outcome\\u003csup\\u003e11 23 24\\u003c/sup\\u003e. In our cases evaluation of complement activation markers was helpful, even though the disease course and clinical presentation were the major determinants in decision making, of which a multidisciplinary approach (ICU specialist and pediatric nephrologist) was preferred. Both parental consent and the Hungarian National Drug Administration license was obtained before the administration of ECZ. In agreement with available guidelines patients received antibiotic treatment or prophylaxis for the safe administration of ECZ and vaccination against all Neisseria strains in the earliest possible time\\u003csup\\u003e36 37\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eWe believe that all three patients responded impressively well to ECZ. Global activation of the complement system (Patient 2 and 3) may correspond with more extensive activation process that is not limited to the alternative pathway. In case 2 with SP-HUS, sepsis, DIC and neuraminidase-induced extensive endothelial damage while in case 3 STEC-related cell destruction augmented by inevitable antibiotic treatment may explain enhanced and global activation of the complement system. Consequently, inhibition of C5 may have been a valid strategy to blunt ongoing complement-mediated pathological events\\u003csup\\u003e12 32 38\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003ePrevious publications did not present convincing data about the advantage of ECZ use in STEC-HUS, however some benefits of long-term outcome were reported\\u003csup\\u003e17 27 35\\u003c/sup\\u003e. In our cases both quick recovery and excellent outcome after ECZ treament convinced us that in similar clinical situtations (CNS involvement and/or severe multiorgan dysfunction) we would consider using ECZ again. We emphasize that complement activation data in hand may help clinical decision.\\u003c/p\\u003e \\u003cp\\u003eUpon dismission modestly decreased kidney function was detected in all the patients (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). However, in the early follow-up (6\\u0026ndash;12 weeks) tests only modest proteinuria requiring low dose ACE-I treatment and borderline systolic hypertension were seen in one of our patients (Patient 2). In association with proteinuric state, relatively higher eGFR values (\\u0026gt;\\u0026thinsp;95% for age and BSA) were temporarily seen at a later check-up (3\\u0026ndash;6 month) in patients 2 and 3 that may be accounted for hyperfiltration.\\u003c/p\\u003e\\n\\u003ch3\\u003eAdverse events with the administration of ECZ\\u003c/h3\\u003e\\n\\u003cp\\u003eAdministration of ECZ is known to increase the risk of infections\\u003csup\\u003e\\u003cspan citationid=\\\"CR37\\\" class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e\\u003c/sup\\u003e. Therefore, antibiotic prophylaxis and vaccination against Neisseria species are recommended before the administration of the drug (see Solaris (eculizumab) package insert). Less is known about the incidence of other potential infective agents\\u003csup\\u003e\\u003cspan citationid=\\\"CR39\\\" class=\\\"CitationRef\\\"\\u003e39\\u003c/span\\u003e\\u003c/sup\\u003e. In two patients symptomatic cytomegalovirus (CMV) infection was detected with relatively higher copy number (Patient 2 and 3) after the 2nd dose of ECZ. In both cases specific antiviral therapy was indicated. The incidence of CMV infection is unknown in ECZ treated pediatric patients. Our cases highlight the importance of checking on CMV status upon ECZ treatment since C5-inhibiton in a sense is an immunocompromised state and an ongoing CMV-disease may compromise clinical improvement\\u003csup\\u003e40 41\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eTo our best knowledge, genetical analysis is not part of the routine diagnostics in infective HUS\\u003csup\\u003e\\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e\\u003c/sup\\u003e. Even though infection is the major trigger of disease manifestations, current literature data suggest that risk haplotypes of complement regulatory genes are ocassionally detected in cases of HUS. Indeed, in two patients (Patient 1 and 3) we detected MCPggaac risk haplotype in homozygous form, which may increase the chance of a more severe HUS/TMA manifestation\\u003csup\\u003e\\u003cspan citationid=\\\"CR42\\\" class=\\\"CitationRef\\\"\\u003e42\\u003c/span\\u003e\\u003c/sup\\u003e. We did not consider long-term ECZ treament in these cases, and we do not expect and have not experienced recurrence as yet.\\u003c/p\\u003e \\u003cp\\u003eTiming of ECZ treatment inititation seems to be an important issue, even though there is no consensus on the optimal time or indication for the administration of ECZ in infection-associated HUS. We strongly believe that detailed complement activation data, when it is available in a short turnaround time, is helpful in deciding about the use of ECZ and may in the future be an important part of the diagnostic panel. Timing of ECZ administration depended on many variable factors including parental consent or institutional and other official approvals. In our cases we managed to get all the necessary documents in 7 days for the off-label use of the drug. We report excellent outcome of our patients suggesting that the time-window for ECZ treatment is not yet defined\\u003csup\\u003e40 43\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eSummary\\u003c/h2\\u003e \\u003cp\\u003eThe use of complement C5 inhibition is still controversal in the treatment of infection-associated HUS types. Currently, the standard of care in infection-associated HUS types is mainly supportive. In selected HUS cases with CNS involvement and other severe extrarenal manifestations C5-inhibitor treatment (ECZ) may be used. Parental consent and/or institutional and other official approvals are all necessary for off-label use of ECZ. Early use of ECZ may improve both short-term and definitely long-term outcome especially in cases where complement system (AP) is overactivated. Detailed complement activation profile, particularly sC5b-9 is helpful to indicate ECZ administration. Proper antibiotic profilaxis/treament and vaccination against Neisseria species are recommended for safer use of ECZ. Monitoring of bacterial, viral infection including CMV is neccessary for patient\\u0026rsquo;s assessment. Well-designed multicenter RCTs should be done to gain further evidence to support the benefit of complement inhibition in the treament of severe pediatric HUS with multiorgan involvement.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cp\\u003eaHUS\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;atypical Hemolytic Uremic Syndrome\\u003c/p\\u003e\\n\\u003cp\\u003eAKI\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Acute Renal Injury\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAP \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;complement activation\\u003c/p\\u003e\\n\\u003cp\\u003eAPH50 \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;alternative payway total complement activity\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eBMI\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;body mass index\\u003c/p\\u003e\\n\\u003cp\\u003eBW\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;body weight\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eCFB \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;complement factor B\\u003c/p\\u003e\\n\\u003cp\\u003eCFH \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;complement factor H\\u003c/p\\u003e\\n\\u003cp\\u003eCFHR5 \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;complement factor H-related protein-5\\u003c/p\\u003e\\n\\u003cp\\u003eCFI \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;complement factor I\\u003c/p\\u003e\\n\\u003cp\\u003eCH50 \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;total complement activity\\u003c/p\\u003e\\n\\u003cp\\u003eCKRT\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Continuous Kidney Replacement Therapy\\u003c/p\\u003e\\n\\u003cp\\u003eCMV\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Cytomegalovirus\\u003c/p\\u003e\\n\\u003cp\\u003eCNS\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Central Nervous System\\u003c/p\\u003e\\n\\u003cp\\u003eDGKE \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;diacylglycerol kinase epsilon\\u003c/p\\u003e\\n\\u003cp\\u003eDIC\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Disseminated Intravascular Coagulation\\u003c/p\\u003e\\n\\u003cp\\u003eECZ\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Eculizumab\\u003c/p\\u003e\\n\\u003cp\\u003eEMA\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;European Medicines Agency\\u003c/p\\u003e\\n\\u003cp\\u003eFDA\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;US Food and Drug Administration\\u003c/p\\u003e\\n\\u003cp\\u003eFFP\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Fresh Frozen Plasma\\u003c/p\\u003e\\n\\u003cp\\u003eHUS\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Hemolytic Uremic Syndrome\\u003c/p\\u003e\\n\\u003cp\\u003ePICU\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Pediatric Intensive Care Unit\\u003c/p\\u003e\\n\\u003cp\\u003ePLEX\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Plasma Exchange Therapy\\u003c/p\\u003e\\n\\u003cp\\u003eRCT\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Randomized Controlled Trial\\u003c/p\\u003e\\n\\u003cp\\u003esC5b-9 \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;solubilis terminal complement complex\\u003c/p\\u003e\\n\\u003cp\\u003eSP-HUS\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Streptococcus pneumoniae-associated HUS\\u003c/p\\u003e\\n\\u003cp\\u003eSTEC-HUS\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;Shiga toxin-producing Escherichia coli-HUS\\u003c/p\\u003e\\n\\u003cp\\u003eTHBD \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;thrombomodulin\\u003c/p\\u003e\\n\\u003cp\\u003eTMA\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026nbsp;Thrombotic Microangopathy\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eVATS\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;video-assisted thoracic surgery\\u003c/p\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003eEthics approval and consent to participate: The study was approved by the Scientific and Research Ethics Committee of the University of Debrecen under the registration number of 6879-2024 (DE KK RKEB/IKEB). Patients were enrolled in accordance with the Declaration of Helsinki.\\u003c/p\\u003e\\n\\u003cp\\u003eDuring anonymous data management, a general patient information sheet and an informed consent form were used. No additional intervention was performed, only the necessary and usual therapeutic and diagnostic methods were used.\\u003c/p\\u003e\\n\\u003cp\\u003eInformed Consent Statement: Written informed consent was obtained from the parent(s) or legal guardian of each child before the study.\\u003c/p\\u003e\\n\\u003cp\\u003eConsent for publication: not applicable \\u0026nbsp; \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAvailability of data and materials: Dataset analyzed during the study represent patient\\u0026rsquo;s data available in their medical documentation and the electronic patients\\u0026rsquo; database (MedSolution, UDMed) of the University of Debrecen for authorized personnel. Petra Varga, the first author can be contacted for additional data request (varga.petra@med.unideb.hu)\\u003c/p\\u003e\\n\\u003cp\\u003eCompeting interests: The authors declare no conflict of interest.\\u003c/p\\u003e\\n\\u003cp\\u003eFunding: This research received no external funding.\\u003c/p\\u003e\\n\\u003cp\\u003eAuthors\\u0026apos; contributions: All of the listed authors contributed significantly to the publication. TSZ indicated laboratory tests. PV, EB performed data collection. In addition, PV analyzed and interpreted data from pediatric patients with HUS. ZP performed complement diagnostic data, TSZ played a significant role in writing the manuscript. All authors read and approved the final manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eAcknowledgements: N/A\\u003c/p\\u003e\\n\\u003cp\\u003eAuthors\\u0026apos; information (optional)\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eNoris, M.; Remuzzi, G. Hemolytic Uremic Syndrome. Journal of the American Society of Nephrology. 2005;16 (4), 1035\\u0026ndash;1050.\\u003c/li\\u003e\\n\\u003cli\\u003eSheerin, N. S.; Glover, E. Haemolytic Uremic Syndrome: Diagnosis and Management. 2019;F1000Res 8, F1000 Faculty Rev-1690. https://doi.org/10.12688/f1000research.19957.1.\\u003c/li\\u003e\\n\\u003cli\\u003eGould, L. H.; Demma, L.; Jones, T. F.; Hurd, S.; Vugia, D. J.; Smith, K.; Shiferaw, B.; Segler, S.; Palmer, A.; Zansky, S.; Griffin, P. M. Hemolytic Uremic Syndrome and Death in Persons with Escherichia Coli O157:H7 Infection, Foodborne Diseases Active Surveillance Network Sites, 2000-2006. Clin Infect Dis. 2009;49(10), 1480\\u0026ndash;1485. https://doi.org/10.1086/644621.\\u003c/li\\u003e\\n\\u003cli\\u003eTrachtman, H.; Austin, C.; Lewinski, M.; Stahl, R. A. K. Renal and Neurological Involvement in Typical Shiga Toxin-Associated HUS. Nat Rev Nephrol. 2012;8(11),658\\u0026ndash;669. https://doi.org/10.1038/nrneph.2012.196.\\u003c/li\\u003e\\n\\u003cli\\u003eLoos, S.; Aulbert, W.; Hoppe, B.; Ahlenstiel-Grunow, T.; Kranz, B.; Wahl, C.; Staude, H.; Humberg, A.; Benz, K.; Krause, M.; Pohl, M.; Liebau, M. C.; Schild, R.; Lemke, J.; Beringer, O.; M\\u0026uuml;ller, D.; H\\u0026auml;rtel, C.; Wigger, M.; Vester, U.; Konrad, M.; Haffner, D.; Pape, L.; Oh, J.; Kemper, M. J. Intermediate Follow-up of Pediatric Patients With Hemolytic Uremic Syndrome During the 2011 Outbreak Caused by E. Coli O104:H4. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2017;64(12),1637\\u0026ndash;1643. https://doi.org/10.1093/cid/cix218.\\u003c/li\\u003e\\n\\u003cli\\u003eRosales, A.; Hofer, J.; Zimmerhackl, L.-B.; Jungraithmayr, T. C.; Riedl, M.; Giner, T.; Strasak, A. Orth-H\\u0026ouml;ller, D.; W\\u0026uuml;rzner, R.; Karch, H.; German-Austrian HUS Study Group. Need for Long-Term Follow-up in Enterohemorrhagic Escherichia Coli-Associated Hemolytic Uremic Syndrome Due to Late-Emerging Sequelae. Clin Infect Dis. 2012;54(10),1413\\u0026ndash;1421. https://doi.org/10.1093/cid/cis196.\\u003c/li\\u003e\\n\\u003cli\\u003eScobell, R. R.; Kaplan, B. S.; Copelovitch, L. New Insights into the Pathogenesis of Streptococcus Pneumoniae-Associated Hemolytic Uremic Syndrome. Pediatr Nephrol. 2020;35(9),1585\\u0026ndash;1591. https://doi.org/10.1007/s00467-019-04342-3.\\u003c/li\\u003e\\n\\u003cli\\u003eCopelovitch, L.; Kaplan, B. S. Streptococcus Pneumoniae-Associated Hemolytic Uremic Syndrome. Pediatr Nephrol. 2008;23 (11),1951\\u0026ndash;1956. https://doi.org/10.1007/s00467-007-0518-y.\\u003c/li\\u003e\\n\\u003cli\\u003ePrestidge, C.; Wong, W. Ten Years of Pneumococcal-Associated Haemolytic Uraemic Syndrome in New Zealand Children. J Paediatr Child Health. 2009;45(12),731\\u0026ndash;735. https://doi.org/10.1111/j.1440-1754.2009.01603.x.\\u003c/li\\u003e\\n\\u003cli\\u003eNester, C. M.; Feldman, D. L.; Burwick, R.; Cataland, S.; Chaturvedi, S.; Cook, H. T.; Cuker, A.; Dixon, B. P.; Fakhouri, F.; Hingorani, S. R.; Java, A.; Van De Kar, N. C. A. J.; Kavanagh, D.; Leung, N.; Licht, C.; Noris, M.; O\\u0026rsquo;Shaughnessy, M. M.; Parikh, S. V.; Peyandi, F.; Remuzzi, G.; Smith, R. J. H.; Sperati, C. J.; Waldman, M.; Walker, P.; Vivarelli, M. An Expert Discussion on the Atypical Hemolytic Uremic Syndrome Nomenclature\\u0026mdash;Identifying a Road Map to Precision: A Report of a National Kidney Foundation Working Group. Kidney International. 2024;106(3),326\\u0026ndash;336. https://doi.org/10.1016/j.kint.2024.05.021.\\u003c/li\\u003e\\n\\u003cli\\u003eLegendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, Bingham C, Cohen DJ, Delmas Y, Douglas K, Eitner F, Feldkamp T, Fouque D, Furman RR, Gaber O, Herthelius M, Hourmant M, Karpman D, Lebranchu Y, Mariat C, Menne J, Moulin B, N\\u0026uuml;rnberger J, Ogawa M, Remuzzi G, Richard T, Sberro-Soussan R, Severino B, Sheerin NS, Trivelli A, Zimmerhackl LB, Goodship T, Loirat C. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368(23):2169-81. doi: 10.1056/NEJMoa1208981. PMID: 23738544.Licht C. \\u003c/li\\u003e\\n\\u003cli\\u003eWalsh, P. R.; Johnson, S. Eculizumab in the Treatment of Shiga Toxin Haemolytic Uraemic Syndrome. Pediatr Nephrol. 2019;34(9),1485\\u0026ndash;1492. https://doi.org/10.1007/s00467-018-4025-0.\\u003c/li\\u003e\\n\\u003cli\\u003eMahat, U.; Matar, R. B.; Rotz, S. J. Use of Complement Monoclonal Antibody Eculizumab in Shiga Toxin Producing Escherichia Coli Associated Hemolytic Uremic Syndrome: A Review of Current Evidence. Pediatr Blood Cancer. 2019;66(11), e27913. https://doi.org/10.1002/pbc.27913.\\u003c/li\\u003e\\n\\u003cli\\u003eWeber, B.; Chan, D.; Hammer, S. Eculizumab Use in a Temporarily Dialysis-Dependent Patient With Shiga Toxin\\u0026ndash;Producing Escherichia Coli Hemolytic Uremic Syndrome With Neurological Complications. J Pediatr Pharmacol Ther. 2022;27(1), 90\\u0026ndash;95. https://doi.org/10.5863/1551-6776-27.1.90.\\u003c/li\\u003e\\n\\u003cli\\u003eMonet-Didailler, C.; Chevallier, A.; Godron-Dubrasquet, A.; Allard, L.; Delmas, Y.; Contin-Bordes, C.; Brissaud, O.; Llanas, B.; Harambat, J. Outcome of Children with Shiga Toxin-Associated Haemolytic Uraemic Syndrome Treated with Eculizumab: A Matched Cohort Study. Nephrol Dial Transplant. 2020;35 (12),2147\\u0026ndash;2153. https://doi.org/10.1093/ndt/gfz158.\\u003c/li\\u003e\\n\\u003cli\\u003eLapeyraque, A.-L.; Malina, M.; Fremeaux-Bacchi, V.; Boppel, T.; Kirschfink, M.; Oualha, M.; Proulx, F.; Clermont, M.-J.; Le Deist, F.; Niaudet, P.; Schaefer, F. Eculizumab in Severe Shiga-Toxin-Associated HUS. N Engl J Med. 2011;364(26),2561\\u0026ndash;2563. https://doi.org/10.1056/NEJMc1100859.\\u003c/li\\u003e\\n\\u003cli\\u003eGarnier, A.; Brochard, K.; Kwon, T.; Sellier-Leclerc, A.-L.; Lahoche, A.; Launay, E. A.; Nobili, F.; Caillez, M.; Taque, S.; Harambat, J.; Michel-Bourdat, G.; Guigonis, V.; Fila, M.; Cloarec, S.; Djamal-Dine, D.; de Parscaux, L.; Allard, L.; Salomon, R.; Ulinski, T.; Fr\\u0026eacute;meaux-Bacchi, V.; Morin, C.; Olivier-Abbal, P.; Colineaux, H.; Auriol, F.; Arnaud, C.; Kieffer, I.; Brusq, C. Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial. J Am Soc Nephrol. 2023;34(9),1561\\u0026ndash;1573. https://doi.org/10.1681/ASN.0000000000000182.\\u003c/li\\u003e\\n\\u003cli\\u003eSinkovits, G.; Proh\\u0026aacute;szka, Z. Update on the Role of the Complement System in the Pathogenesis of Thrombotic Microangiopathies. Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2014;35(1),115\\u0026ndash;122.\\u003c/li\\u003e\\n\\u003cli\\u003eSzil\\u0026aacute;gyi, A.; Kiss, N.; Bereczki, C.; T\\u0026aacute;losi, G.; R\\u0026aacute;cz, K.; T\\u0026uacute;ri, S.; Gy\\u0026ouml;rke, Z.; Simon, E.; Horv\\u0026aacute;th, E.; Kelen, K.; Reusz, G. S.; Szab\\u0026oacute;, A. J.; Tulassay, T.; Proh\\u0026aacute;szka, Z. The Role of Complement in Streptococcus Pneumoniae-Associated Haemolytic Uraemic Syndrome. Nephrol Dial Transplant. 2013;28(9),2237\\u0026ndash;2245. https://doi.org/10.1093/ndt/gft198.\\u003c/li\\u003e\\n\\u003cli\\u003eKhwaja, A. KDIGO Clinical Practice Guidelines for Acute Kidney Injury. Nephron Clinical Practice. 2012;120(4),c179\\u0026ndash;c184. https://doi.org/10.1159/000339789.\\u003c/li\\u003e\\n\\u003cli\\u003eHolle, J.; Habbig, S.; Gratopp, A.; Mauritsch, A.; M\\u0026uuml;ller, D.; Thumfart, J. Complement Activation in Children with Streptococcus Pneumoniae Associated Hemolytic Uremic Syndrome. Pediatr Nephrol. 2021;36(5),1311\\u0026ndash;1315. https://doi.org/10.1007/s00467-021-04952-w.\\u003c/li\\u003e\\n\\u003cli\\u003eIgarashi, T.; Ito, S.; Sako, M.; Saitoh, A.; Hataya, H.; Mizuguchi, M.; Morishima, T.; Ohnishi, K.; Kawamura, N.; Kitayama, H.; Ashida, A.; Kaname, S.; Taneichi, H.; Tang, J.; Ohnishi, M. Study group for establishing guidelines for the diagnosis and therapy of hemolytic uremic syndrome. Guidelines for the Management and Investigation of Hemolytic Uremic Syndrome. Clin Exp Nephrol. 2014;18(4),525\\u0026ndash;557. https://doi.org/10.1007/s10157-014-0995-9.\\u003c/li\\u003e\\n\\u003cli\\u003eNester, C. M.; Thomas, C. P. Atypical Hemolytic Uremic Syndrome: What Is It, How Is It Diagnosed, and How Is It Treated? Hematology. 2012;(1),617\\u0026ndash;625. https://doi.org/10.1182/asheducation.V2012.1.617.3798924.\\u003c/li\\u003e\\n\\u003cli\\u003eNoris, M.; Remuzzi, G. Atypical Hemolytic\\u0026ndash;Uremic Syndrome. New England Journal of Medicine. 2009;361 (17),1676\\u0026ndash;1687. https://doi.org/10.1056/NEJMra0902814.\\u003c/li\\u003e\\n\\u003cli\\u003eMusa, J.; Rahman, M.; Guy, A.; Kola, E.; Guy, A.; Hyseni, F.; Cobo, A.; Saliaj, K.; Bushati, F.; Ahmetgjekaj, I. Artery of Percheron Infarction: A Case Report and Literature Review. Radiol Case Rep. 2021;16(6),1271\\u0026ndash;1275. https://doi.org/10.1016/j.radcr.2021.02.059.\\u003c/li\\u003e\\n\\u003cli\\u003eBain, S. E.; Hsieh, D. T.; Vezina, L. G.; Chang, T. Bilateral Paramedian Thalamic and Mesencephalic Infarcts in a Newborn Due to Occlusion of the Artery of Percheron. J Child Neurol. 2009;24(2),219\\u0026ndash;223. https://doi.org/10.1177/0883073808322672.\\u003c/li\\u003e\\n\\u003cli\\u003ePercheron, L.; Gramada, R.; Tellier, S.; Salomon, R.; Harambat, J.; Llanas, B.; Fila, M.; Allain-Launay, E.; Lapeyraque, A.-L.; Leroy, V.; Adra, A.-L.; B\\u0026eacute;rard, E.; Bourdat-Michel, G.; Chehade, H.; Eckart, P.; Merieau, E.; Pi\\u0026egrave;trement, C.; Sellier-Leclerc, A.-L.; Fr\\u0026eacute;meaux-Bacchi, V.; Dimeglio, C.; Garnier, A. Eculizumab Treatment in Severe Pediatric STEC-HUS: A Multicenter Retrospective Study. Pediatr Nephrol. 2018;33(8),1385\\u0026ndash;1394. https://doi.org/10.1007/s00467-018-3903-9.\\u003c/li\\u003e\\n\\u003cli\\u003ePape, L.; Hartmann, H.; Bange, F. C.; Suerbaum, S.; Bueltmann, E.; Ahlenstiel-Grunow, T. Eculizumab in Typical Hemolytic Uremic Syndrome (HUS) With Neurological Involvement. Medicine (Baltimore). 2016;94(24),e1000. https://doi.org/10.1097/MD.0000000000001000.\\u003c/li\\u003e\\n\\u003cli\\u003eWildes, D. M.; Harvey, S.; Costigan, C. S.; Sweeney, C.; Twomey, \\u0026Eacute;.; Awan, A.; Gorman, K. M. Eculizumab in STEC-HUS: A Paradigm Shift in the Management of Pediatric Patients with Neurological Involvement. Pediatr Nephrol. 2024;39(1),315\\u0026ndash;324. https://doi.org/10.1007/s00467-023-06102-w.\\u003c/li\\u003e\\n\\u003cli\\u003eGilbert, R. D.; Nagra, A.; Haq, M. R. Does Dysregulated Complement Activation Contribute to Haemolytic Uraemic Syndrome Secondary to Streptococcus Pneumoniae? Med Hypotheses. 2013;81(3),400\\u0026ndash;403. https://doi.org/10.1016/j.mehy.2013.05.030.\\u003c/li\\u003e\\n\\u003cli\\u003eKonop\\u0026aacute;sek, P.; Zieg, J. Eculizumab Use in Patients with Pneumococcal-Associated Hemolytic Uremic Syndrome and Kidney Outcomes. Pediatr Nephrol. 2023;38(12),4209\\u0026ndash;4215. https://doi.org/10.1007/s00467-023-06037-2.\\u003c/li\\u003e\\n\\u003cli\\u003eAgarwal, H. S.; Latifi, S. Q. Streptococcus Pneumoniae-Associated Hemolytic Uremic Syndrome in the Era of Pneumococcal Vaccine. Pathogens. 2021;10(6),727. https://doi.org/10.3390/pathogens10060727.\\u003c/li\\u003e\\n\\u003cli\\u003eSoliris (eculizumab) Approved by FDA for All Patients with Atypical Hemolytic Uremic Syndrome (aHUS). Drugs.com. https://www.drugs.com/newdrugs/soliris-eculizumab-approved-fda-all-patients-atypical-hemolytic-uremic-syndrome-ahus-2872.html (accessed 2024-08-17).\\u003c/li\\u003e\\n\\u003cli\\u003eEuropean Medicines Agency - Human medicines - EU/3/09/653. https://web.archive.org/web/20170923013346/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Forphans%2F2009%2F11%2Fhuman_orphan_000657.jsp\\u0026amp;mid=WC0b01ac058001d12b (accessed 2024-08-17).\\u003c/li\\u003e\\n\\u003cli\\u003eCostigan, C.; Raftery, T.; Carroll, A. G.; Wildes, D.; Reynolds, C.; Cunney, R.; Dolan, N.; Drew, R. J.; Lynch, B. J.; O\\u0026rsquo;Rourke, D. J.; Stack, M.; Sweeney, C.; Shahwan, A.; Twomey, E.; Waldron, M.; Riordan, M.; Awan, A.; Gorman, K. M. Neurological Involvement in Children with Hemolytic Uremic Syndrome. Eur J Pediatr. 2022;181(2),501\\u0026ndash;512. https://doi.org/10.1007/s00431-021-04200-1.\\u003c/li\\u003e\\n\\u003cli\\u003eRovin, B. H.; Adler, S. G.; Barratt, J.; Bridoux, F.; Burdge, K. A.; Chan, T. M.; Cook, H. T.; Fervenza, F. C.; Gibson, K. L.; Glassock, R. J.; Jayne, D. R. W.; Jha, V.; Liew, A.; Liu, Z.-H.; Mej\\u0026iacute;a-Vilet, J. M.; Nester, C. M.; Radhakrishnan, J.; Rave, E. M.; Reich, H. N.; Ronco, P.; Sanders, J.-S. F.; Sethi, S.; Suzuki, Y.; Tang, S. C. W.; Tesar, V.; Vivarelli, M.; Wetzels, J. F. M.; Floege, J. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney International. 2021;100(4),S1\\u0026ndash;S276. https://doi.org/10.1016/j.kint.2021.05.021.\\u003c/li\\u003e\\n\\u003cli\\u003eRam S, Lewis LA, Rice PA. Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin Microbiol Rev. 2010;Oct;23(4):740-80. doi: 10.1128/CMR.00048-09. PMID: 20930072; PMCID: PMC2952982.\\u003c/li\\u003e\\n\\u003cli\\u003eKeenswijk, W.; Raes, A.; Vande Walle, J. Is Eculizumab Efficacious in Shigatoxin-Associated Hemolytic Uremic Syndrome? A Narrative Review of Current Evidence. Eur J Pediatr. 2018;177(3),311\\u0026ndash;318. https://doi.org/10.1007/s00431-017-3077-7.\\u003c/li\\u003e\\n\\u003cli\\u003eBenamu, E.; Montoya, J. G. Infections Associated with the Use of Eculizumab: Recommendations for Prevention and Prophylaxis. Curr Opin Infect Dis. 2016;29(4),319\\u0026ndash;329. https://doi.org/10.1097/QCO.0000000000000279.\\u003c/li\\u003e\\n\\u003cli\\u003eSonata Jodele, Christopher E. Dandoy, Adam Lane, Benjamin L. Laskin, Ashley Teusink-Cross, Kasiani C. Myers, Gregory Wallace, Adam Nelson, Jack Bleesing, Ranjit S. Chima, Russel Hirsch, Thomas D. Ryan, Stefanie Benoit, Kana Mizuno, Mikako Warren, Stella M. Davies; Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood. 2020;135(13):1049\\u0026ndash;1057. doi: https://doi.org/10.1182/blood.2019004218\\u003c/li\\u003e\\n\\u003cli\\u003eOsawa, R., Singh, N. Cytomegalovirus infection in critically ill patients: a systematic review. Crit Care. 2009;13,R68 https://doi.org/10.1186/cc7875\\u003c/li\\u003e\\n\\u003cli\\u003eTurudic, D.; Pokrajac, D.; Tasic, V.; Kasumovic, D.; Prohaszka, Z.; Milosevic, D. The Rationale of Complement Blockade of the MCPggaac Haplotype Following Atypical Hemolytic Uremic Syndrome of Three Southeastern European Countries with a Literature Review. International Journal of Molecular Sciences. 2023;24(17),13041. https://doi.org/10.3390/ijms241713041.\\u003c/li\\u003e\\n\\u003cli\\u003eWehling, C.; Amon, O.; Bommer, M.; Hoppe, B.; Kentouche, K.; Schalk, G.; Weimer, R.; Wiesener, M.; Hohenstein, B.; T\\u0026ouml;nshoff, B.; B\\u0026uuml;scher, R.; Fehrenbach, H.; G\\u0026ouml;k, \\u0026Ouml;.-N.; Kirschfink, M. Monitoring of Complement Activation Biomarkers and Eculizumab in Complement-Mediated Renal Disorders. Clinical and Experimental Immunology. 2017;187(2),304\\u0026ndash;315. https://doi.org/10.1111/cei.12890.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-pediatrics\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bped\",\"sideBox\":\"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bped/default.aspx\",\"title\":\"BMC Pediatrics\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Hemolytic uremic syndrome, Infection-associated HUS, STEC-HUS, SP-HUS, Eculizumab, CNS involvement\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-5389564/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-5389564/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground\\u003c/strong\\u003e: Hemolytic uremic syndrome (HUS), characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury (AKI), remains a leading cause of pediatric AKI. The complement system has a crucial role in the pathogenesis of atypical hemolytic uremic syndrome (aHUS) and eculizumab (ECZ) was approved as standard of care for its treatment. The two widely characterized forms of infection-associated HUS are Shiga toxin-producing E. coli (STEC)-HUS and Streptococcus pneumoniae-associated (SP)- HUS. Extrarenal manifestations such as central nervous system (CNS) involvement occur approximately in 20% of the cases and are accompanied by higher mortality. Abnormalities of the alternative complement pathway may also contribute to the development of both STEC-HUS and SP-HUS, offering a potential treatment option for complement C5 inhibition. Beyond best supportive care as standard therapeutic approach, ECZ has been succesfully used in both STEC-HUS and SP-HUS patients.\\u003c/p\\u003e\\n\\u003cp\\u003eWe provide further support that early use of ECZ for infection-associated HUS with severe clinical manifestation and abnormal complement-activation profile may be an effective therapeutic approach.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCase presentation: \\u003c/strong\\u003eWe report on three children (median age: 2 years, range: 2-10 years) diagnosed with infection associated HUS treated with complement C5-inhibitor ECZ. All three patients were treated with ECZ and had excellent outcome. We retrospectively analyzed the clinical course, laboratory data and outcome of children with infection associated HUS treated with ECZ.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusion: \\u003c/strong\\u003eIn accordance with previous observations ECZ is an efficacious therapeutic choice in severe HUS patients with multiorgan involvement. A detailed complement activation profile, especially sC5b-9, is useful to indicate ECZ administration.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Use of complement C5-inhibitor eculizumab in patients with infection-associated hemolytic uremic syndrome – a case-series report\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-12-16 10:38:29\",\"doi\":\"10.21203/rs.3.rs-5389564/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2024-11-12T07:25:44+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2024-11-11T04:50:48+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2024-11-11T04:50:02+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"BMC Pediatrics\",\"date\":\"2024-11-04T15:56:37+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-pediatrics\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bped\",\"sideBox\":\"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bped/default.aspx\",\"title\":\"BMC Pediatrics\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"1be9d17b-cc43-4f3f-a5e3-b24e49c73cc7\",\"owner\":[],\"postedDate\":\"December 16th, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-03-17T16:07:12+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-5389564\",\"link\":\"https://doi.org/10.1186/s12887-025-05546-3\",\"journal\":{\"identity\":\"bmc-pediatrics\",\"isVorOnly\":false,\"title\":\"BMC Pediatrics\"},\"publishedOn\":\"2025-03-11 15:57:54\",\"publishedOnDateReadable\":\"March 11th, 2025\"},\"versionCreatedAt\":\"2024-12-16 10:38:29\",\"video\":\"\",\"vorDoi\":\"10.1186/s12887-025-05546-3\",\"vorDoiUrl\":\"https://doi.org/10.1186/s12887-025-05546-3\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-5389564\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-5389564\",\"identity\":\"rs-5389564\",\"version\":[\"v1\"]},\"buildId\":\"qtupq5eGEP_6zYnWcrvyt\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}