Case Report: Benefits and Challengesof Long-term Eculizumab in AtypicalHemolytic Uremic SyndromeNoelle Cullinan, MB, BCh, BAO, LRCSI, MRCPIa, Kathleen Mary Gorman, MB, BCh, NUI, MRCPI, MRCPCHa,Michael Riordan, MB, ChB, MRCPCHa, Mary Waldron, MB, BCh, NUI, MRCPIa, Timothy H.J Goodship, BSc, MD, FRCPb,Atif Awan, MB, BS, FRCPCHa

abstract Atypical hemolytic uremic syndrome (aHUS) is caused by dysregulation of thecomplement system, leading to complement overactivation. A humanizedanti-C5 monoclonal antibody, eculizumab, has been available for the treatmentof aHUS since 2011. The long-term safety and efficacy of this novel drug inthe pediatric population remain under review. We present a child witha hybrid CFH/CFHR3 gene who, having had multiple disease relapses despiteoptimal treatment with plasma exchange, commenced eculizumab therapy inAugust 2010. She remains relapse free in follow-up at 52 months, andtreatment has been well tolerated. The risk of meningococcal disease duringthis treatment is recognized. Despite vaccination against meningococcaldisease and appropriate antibiotic prophylaxis, our patient developedmeningococcal bacteremia 30 months into treatment. She presented withnonspecific symptoms but recovered without sequelae with appropriatetreatment. We recommend that children be vaccinated against invasivemeningococcal infection before beginning eculizumab therapy and takeappropriate antibiotic prophylaxis during treatment, and we suggest thatvaccine responses should be checked and followed annually. Clinicians need tomaintain a high index of suspicion for invasive meningococcal disease. Neithervaccination nor antibiotic prophylaxis provides complete protection inpatients on eculizumab therapy. The appropriate dosage of eculizumab neededto achieve remission in aHUS in the pediatric population is unknown. Havingachieved remission in our patient, we monitor eculizumab and CH50 levelsto evaluate ongoing blockade of the terminal complement cascade. Suchinformation may help guide dosing intervals in the future.

Atypical hemolytic uremic syndrome(aHUS) is a rare disordercharacterized by thromboticmicroangiopathy, thrombocytopenia,and renal failure. It is caused bydysregulation of the alternativecomplement pathway, leading tocomplement overactivation. Theincidence of aHUS in the pediatricpopulation is not well established, butrecent data suggests an incidence of∼0.11 new cases per millionpopulation per year.1,2 aHUS isassociated with significant morbidity

and mortality, with #50% of casesprogressing to end-stage renal diseaseor death.2,3 Approximately 60% ofcases are associated with either aninherited or acquired abnormality ofcomplement.4 Several mutations ingenes responsible for the encoding ofcomplement proteins have beenidentified in patients presenting withaHUS, such as mutations in CFH,factor I, membrane cofactor protein,thrombomodulin, C3, and factor B.Mutations in CFH account for ∼25% ofthe genetic predisposition to aHUS.5

aThe Department for Paediatric Nephrology &Transplantation, The Children’s University Hospital, Dublin 1,Ireland; and bInstitute of Genetic Medicine, NewcastleUniversity, Newcastle upon Tyne, United Kingdom

Drs Cullinan and Gorman drafted, reviewed, andrevised the manuscript; Drs Riordan, Waldron, andAwan and Prof Goodship contributed to the conceptand design of the report; and all authors approvedthe final manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2014-3503

DOI: 10.1542/peds.2014-3503

Accepted for publication Feb 25, 2015

Address correspondence to Noelle Cullinan, MB,BCh, BAO, LRCSI, MRCPI, The Department forPaediatric Nephrology & Transplantation, TheChildren’s University Hospital, Temple Street, Dublin1, Ireland. E-mail: noellemcullinan@gmail.com

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,1098-4275).

Copyright © 2015 by the American Academy ofPediatrics

FINANCIAL DISCLOSURE: Prof Timothy H. J. Goodshipand Dr Atif Awan have received honoraria fromAlexion.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: Prof TimothyH. J. Goodship and Dr Atif Awan have indicated thatthey have a perceived potential conflict of interestwith regard to their receipt of honoraria fromAlexion. The other authors have indicated they haveno potential conflicts of interest to disclose.

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Since 2011, eculizumab,a recombinant humanized anti-C5monoclonal antibody, has beenlicensed to treat aHUS. It blocksactivation of the terminalcomplement cascade and has beenshown to be effective in treatingaHUS. Earlier treatment witheculizumab leads to betterpreservation of renal function, andtherefore early treatment in pediatricpatients is recommended.5 In 2012,a hybrid CFH/CFHR3 gene consistingof CFH exons 1 through 22 and CFHR3exons 2 through 6 arising throughmicrohomology-mediated deletionwas identified in familial atypicalhemolytic syndrome.6 Here wedescribe a 4-year experience ofeculizumab treatment in an affectedchild from this family.

CASE REPORT

A previously well girl presented at8 months of age with symptoms ofbronchiolitis and associated fever.In addition to respiratory symptoms,she had 4 cm hepatomegaly.Laboratory investigations showedhemoglobin of 80 (96–148) g/L,platelet count of 99 (150–450) 3109/L, and creatinine of 68 (15–50)mmol/L. Lactate dehydrogenase(LDH) was elevated at 5142(230–600) U/L, with normal C3 andC4. Her urine had hematuria andproteinuria.

Renal biopsy demonstrated acutethrombotic microangiopathy (Fig 1).Screening for factor H and Iautoantibodies was negative. Genetictesting showed a heterozygousdeletion extending from CFH intron22 to the 59 region of CFHR3,resulting in the formation of aCFH/CFHR3 hybrid gene.6

Of note, her mother developed severepreeclampsia at 31 weeks’ gestationand needed early delivery because ofa rising creatinine. She hadpreeclampsia in a previouspregnancy. Her renal functiondeteriorated postpartum,necessitating acute hemodialysis and

subsequent long-term peritonealdialysis. Her LDH was 514 (50–150)U/L, with evidence of red cellfragmentation on blood film.Otherwise, there were no overt signsof HUS. Review of her renal biopsyshowed subtle thromboticmicroangiopathy with acute tubularnecrosis. Genetic testing confirmedthe same hybrid gene.6

Our patient was initially treated withaggressive plasma exchange (PE) in thefirst 3 months (40 sessions) and wasmaintained on weekly PE over a periodof 31 months, 212 sessions in total, asrecommended by guidelines publishedby the European Study Group forAtypical HUS in 2009.7 She had adverseevents on PE including electrolytedisturbances, hypocalcemia, venousaccess problems, and episodes ofhypotension. She relapsed on multipleoccasions, necessitating intensificationof PE to stabilize hemolysis andcreatinine in the setting of infectionsand vaccinations. This intensifiedregimen consisted of daily sessions for5 days, alternate-day sessions foranother 5 sessions, and weaning toonce-weekly sessions when biochemicaland clinical markers showed evidence ofimprovement (Fig 2).

In August 2010, she received her firstdose of eculizumab, and PE wasdiscontinued. She received 300 mg ofeculizumab from initiation, with a dose

adjustment to 600 mg for increasedweight in August 2013. She has beentreated with eculizumab for 52 monthswith complete remission and has notrelapsed despite intercurrent illnesses.This information is highlighted in Fig 2,which illustrates hemoglobin, platelets,LDH, and creatinine levels over time,with multiple episodes of relapsedemonstrated while on PE and hersubsequent relapse-free course ona fortnightly eculizumab regimen.

She was vaccinated with both thequadrivalent meningococcal conjugatevaccine (serogroups A, C, W-135, and Y)and the meningococcal C vaccinebefore commencing treatment. After30 months of treatment, she had anepisode of meningococcal bacteremia.She was on amoxicillin prophylaxis formeningococcal disease at the time. Shepresented nonspecifically with fever,headache, and a macular rash. Herinflammatory markers were normal atpresentation, but blood cultures werepositive for Neisseria meningitidis,serogroup W135, at 28 hours, andblood polymerase chain reaction wasalso positive. The N. meningitidis strainshowed intermediate penicillinsensitivity, with a minimal inhibitoryconcentration of 0.13 mg/L (sensitive,0.06 mg/L, resistant .0.25 mg/L).After 24 hours, inflammatory markersrose with neutrophilia of 18(1.8–8.0)3 109/L, C-reactive protein of

FIGURE 1Extensive thrombus in the glomerulus, with red cell and platelet fragments in the capillary loops(hematoxylin and eosin stain, magnification 3400).

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169 (0–10) mg/L, and low platelets of139 (150–450) 3 109/L. She did notdevelop proteinuria during this illness.She was treated with 7 days ofintravenous ceftriaxone and made a fullrecovery.

After this illness, vaccine responseswere found to be suboptimal, withserum bactericidal assay (rSBA) titersof 128, 2, 2, and 2 for serogroups A, C,W-135, and Y, respectively. An rSBAtiter .8 is considered protective (asquoted by the Meningococcal ReferenceUnit, Public Health Englandlaboratories, Manchester). She has beenrevaccinated since this illness, withrepeat vaccine responses in June 2014showing protective levels with rSBAtiters of 2048, 16, 2048, and 1024 forA, C, W-135, and Y, respectively.

Since commencing eculizumabtreatment, she has had viral infectionsand vaccinations without relapses.We have reduced herantihypertensive treatment, and hercreatinine has remained stable with

no proteinuria. Figure 2 reinforcesher stable course since eculizumabtreatment commenced.

DISCUSSION

Atypical HUS is a rare conditionassociated with significant morbidityand mortality.2,3 While renalcomplications are most common,extrarenal disease occurs in ∼20% ofcases, primarily neurologic andcardiovascular involvement.5

Eculizumab is an anti-C5 monoclonalantibody that prevents formation ofthe membrane attack complex andgeneration of C5b.8 Its use in aHUSwas first reported in 2009.9 Althougheculizumab has been licensed for usefor .10 years in patients withparoxysmal nocturnalhemoglobinuria, experience in thepediatric population is limited.10

There are no randomized controlledtrials examining the treatment ofaHUS. There are small case reportsand case series11–14 and a prospective

trial15 of patients who weresuccessfully treated with eculizumab.Evidence suggests that earliertreatment leads to greaterimprovement in renal function andreversal of target organ damage.15 Asin our case, many patients were ableto discontinue plasma exchange afterstarting treatment. A systematicreview article identified only 3 smalluncontrolled studies indicating thateculizumab is effective in patients withaHUS, with a reduction in frequency ofthrombotic microangiopathy events.16

Data on the safety profile ofeculizumab in aHUS are limited. Thesafety record in the short term isreassuring, with no cumulativetoxicity noted. Case reports have beenpublished with follow-up rangingfrom 1 to 3 years from initiation oftreatment.11,14 Respiratory tractinfections, hypertension, andgastrointestinal disturbances are themost common adverse eventsreported,16 and meningococcalsepticemia has been described.16,17

Administration of eculizumab inimmunosuppressed patients may becomplicated by meningococcaldisease despite previousvaccination,17 as described in ourpatient. The bactericidal efficiency ofthe immune response is unknown inpatients with complementdeficiencies or under complementblockade, and the effectiveness ofantibiotic prophylaxis may becomeproblematic with the emergence ofresistant strains going forward.

The recommended eculizumab levelfor complete blockage of C5 is notestablished in aHUS, because the

TABLE 1 CH50 Levels and ConcomitantEculizumab Levels

CH50(70%–130%)

EculizumabLevela

September 2, 2013 ,10 504September 16, 2013 ,10 734November 25, 2013 ,10 .800February 14, 2014 ,10 700February 27, 2014 ,10 740a Eculizumab level .100 mg/mL for complete blockage asrecommended by drug manufacturer, Alexion.

FIGURE 2Hemoglobin, platelets, LDH, and creatinine levels while the patient was on PE alone (red arrow) andon fortnightly eculizumab regimen (green arrow). Episodes of relapse are indicated by blackarrows, and an episode of meningococcal sepsis is indicated by a blue arrow.

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correlation between CH50 andeculizumab has not been documentedin this disease. Previous studies havebeen carried out in the setting ofparoxysmal nocturnalhemoglobinuria.10 The drugmanufacturer (AlexionPharmaceuticals, Cheshire, CT)recommends a level .100 µg/mL forcomplete blockage. During treatment,we monitored eculizumab levels andconcomitant CH50 levels to ascertainwhether complete blockage of theterminal complement cascade wasachieved. Our patient had multipleeculizumab levels of .500 µg/mLdespite being on the appropriate dosefor age (Table 1). There are no studieswith regard to reduction in dose orfrequency if high levels persist. Thishighlights the need for more trials todetermine appropriate pediatricdosages and assessment of treatmentresponses. Measurement ofeculizumab levels, CH50, hemoglobin,platelets, LDH, and proteinuria mayhelp validate dosing regimens in thispopulation.

CONCLUSIONS

We report 4-year safety and efficacyof eculizumab in a 7-year-old girlwith atypical HUS caused by aCFH/CFHR3 hybrid gene mutation. Inour experience, eculizumab iseffective, safe, and well tolerated. Ourpatient has received eculizumab for52 months on a fortnightly schedule,with no relapses and no side effects,even in the setting of infections andvaccinations, allowing cessation ofplasma exchange therapy. We expectshe will continue lifelong treatment.Notably, on presentation withmeningococcal bacteremia, ourpatient had nonspecific symptoms.This observation highlights the needfor a high clinical suspicion forinvasive meningococcal disease, evenwith mild symptoms. All childrenshould be vaccinated againstmeningococcal infection and treated

with prophylactic antibiotics while oneculizumab therapy. In addition,children should have theirvaccination titres checked annually,with advice to revaccinate children ifimmunity wanes. This is particularlytrue for children who have heavyproteinuria. Eculizumab levels, CH50,hemoglobin, platelets, LDH, andproteinuria should be studied tovalidate dosing regimens ofeculizumab in this patient population.

ACKNOWLEDGMENTS

The authors acknowledge thecontribution of Dr Chia Wei Teoh to thiscase report. Dr Teoh contributed to thisreport with data in relation to Figure 2.

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