Gonococcemia in an Immune-Suppressed Patient Receiving Eculizumab

PRACTICE | CASES SEPSIS CPD

Risks of novel therapeutics: gonococcemia in an immune-suppressed patient receiving eculizumab

Aditi Khandelwal MD, Julie K. Wright MD MSc, Katerina Pavenski MD, Linda R. Taggart MD MPH n Cite as: CMAJ 2017 December 18;189:E1558-60. doi: 10.1503/cmaj.170508

23-year-old woman presented to a hemodialysis appoint- ment with a one-day history of fever and rigours. Blood KEY POINTS cultures grew Gram-negative diplococci, raising concern • Patients who are prescribed immunosuppressive medications forA Neisseria species bacteremia. should undergo appropriate screening, preventive therapy and The patient’s previous medical diagnoses included systemic counselling to reduce the risk of infection. lupus erythematosus with lupus nephritis (proliferative glomeru- • Eculizumab is a recombinant monoclonal antibody to the lonephritis), arthritis, pericarditis, myositis and adenopathy. Sys- terminal complement protein C5 and increases susceptibility to temic lupus erythematosus was complicated by flares with hypo- infection, most notably owing to Neisseria meningitidis; patients complementemia and increased anti–double-stranded DNA, should be vaccinated against N. meningitidis at least two weeks before beginning therapy, whenever possible. idiopathic intracranial hypertension and systemic hypertension. Two months before presentation, the patient had developed • Terminal complement deficiency is also associated with an increased risk of disseminated infection owing to Neisseria systemic thrombotic microangiopathy and severe kidney injury gonorrhoeae; health care providers should inform patients who that required hemodialysis. She received a diagnosis of atypical are receiving eculizumab of this risk and counsel patients on hemolytic uremic syndrome, based on high-titre anti–complement strategies to prevent the sexual transmission of N. gonorrhoeae. factor H antibody. Moreover, a kidney biopsy showed thrombotic microangiopathy without features of active lupus nephritis; serum anti–double-stranded DNA levels were normal; and there were no The patient’s medications included eculizumab 1200 mg every clinical features of a lupus flare. two weeks (last dose 8 d before presentation); prednisone 15 mg Notably, the patient had recently returned from Cuba and daily; mycophenolate mofetil 1000 mg twice daily; hydroxychloro- had positive dengue immunoglobulin M serology, suggesting quine 100 mg daily; bisoprolol; olmesartan; vitamins B, C and D; dengue virus infection as a possible trigger for her atypical and calcium carbonate. hemolytic uremic syndrome. The systemic microangiopathy was On physical examination, the patient’s core body temperature refractory to high-dose corticosteroids, blood pressure control was 38.7°C, heart rate was 120 beats/min and blood pressure was and plasma exchange, so therapy with eculizumab was started. 116/64 mm Hg. Her neck was supple, with no meningeal signs or The patient was vaccinated with quadrivalent conjugate menin- focal neurologic deficits. An examination of her head and neck did gococcal vaccine and the multicomponent meningococcal B not show oral lesions or lymphadenopathy. Respiratory, cardio- vaccine. Eculizumab therapy could not be delayed, so she was vascular, abdominal and genital examinations were normal. There also prescribed prophylactic penicillin, taken orally, for two were no skin lesions, nodules or joint effusions. The patient had a weeks after vaccination; in addition, she received Streptococcus tunnelled central venous device in her right internal jugular vein pneumoniae and Haemophilus influenzae vaccinations as per the and the insertion site had no erythema or discharge. local protocol. Laboratory investigations showed an elevated leukocyte count At presentation, the patient had fever and generalized malaise, of 16.6 × 109/L and hemoglobin of 68 g/L with no evidence of hemo- but no localizing symptoms. There was no history of headache, lysis. Box 1 shows the results of the investigations. The patient was photophobia, neck stiffness, cough or dyspnea. She did not have empirically treated with piperacillin-tazobactam and vancomycin. joint pain or swelling, new skin rashes, or genitourinary symptoms. Blood cultures were positive for Gram-negative diplococci, which She had one male sexual partner in the preceding six months and were subsequently identified as N. gonorrhoeae. After identification did not use barrier protection for sexual activity. Coincident with of N. gonorrhoeae, we changed the antimicrobial regimen to ceftri- the onset of her symptoms, her partner received a diagnosis of axone 2 g intravenously daily for 14 days. A single dose of azithro- Neisseria gonorrhoeae urethritis. mycin 1 g was given orally. Tests for HIV, syphilis and hepatitis C

8 4 For For and and 1 3 If, as Eculi- E1559 5 5,6 pneumonia pneumonia N. gonorrhoeae. 1 Health Canada has The risk of serious of risk The 5 4 Adults on protracted 9 7 Typical presentations 10 children who are prescribed 6 may also be indicated in certain in certain may also be indicated Screening for HIV, tuberculosis 3 2 A Canadian guideline recommends recommends A Canadian guideline 1 and atypical hemolytic uremic syndrome. 6 ISSUE 50 ISSUE | Patients who are already receiving eculizumab should should Patients who are already receiving eculizumab 1 Individuals with congenital terminal complement deficiency Individuals with congenital terminal complement deficiency VOLUME 189 VOLUME approved eculizumab for the treatment of paroxysmal nocturnalapproved eculizumab for the treatment of hemoglobinuria adults, the Canadian National Advisory Committee on Immuniza- adults, the Canadian National Advisory Committee meningococcal vac- tion recommends the quadrivalent conjugate meningococcal Bcine and consideration of the multicomponent vaccine. have an increased susceptibility to infection with infection to susceptibility increased an have not receive the multicomponent meningococcal B vaccine until B vaccine until not receive the multicomponent meningococcal and the eculizumab the underlying disease is well controlled concentration in the blood is high, as postmarketing surveillance has identified an increased risk of hemolysis. include urethritis and epididymitis (men) or cervicitis (women). or cervicitis (women). epididymitis (men) include urethritis and Pharyngitis, conjunctivitis and infection of the rectal mucosa can was the case in our patient, eculizumab therapy cannot be therapy cannot be was the case in our patient, eculizumab be provided immedi- delayed, meningococcal vaccination should antibiotics. ately, followed by two weeks of prophylactic eculizumab receive vaccination against S. pneumoniae and H. prescribers alsoinfluenzae according to national guidelines. Some provide these additional vaccinations to adults. Considerations when starting eculizumab Considerations when humanized monoclonal antibody Eculizumab is a recombinant that binds the complement protein C5 and (immunoglobulin G) of C5a and C5b, preventing the formation inhibits its cleavage into the terminal membrane attack complex C5b-9. Disseminated gonococcal infection Gram-negative transmitted sexually a is Neisseria gonorrhoeae organism that causes a range of diseases. - B in all patients who will receive immuno screening for hepatitis suppressive medications. should be considered with some immunosuppressive regimens. should be considered Pneumocystis jiroveci against Pneumocystis patients. Prophylaxis therapy with eculizumab should receive the quadrivalent conju- therapy with eculizumab should receive years. five every vaccine meningococcal gate zumab increases the risk of infection, most importantly owing to owing most importantly risk of infection, the zumab increases - Neisseria meningitidis. Patients should receive meningococcal vac eculizumab. cination at least two weeks before beginning anticipate their risks of infection. Important considerations considerations Important infection. risks of their anticipate pre-existing conferred by specific immune defects include the - or previous immunosuppres and any current medical conditions where should be completed Routine vaccination sive therapies. in some be contraindicated as live vaccines may possible, on spe- may be indicated based vaccinations patients. Additional cific immune defects. At least two cases of N. gonorrhoeae bacteremia in patients receiv- both in patients eculizumab have been previously reported, ing with paroxysmal nocturnal hemoglobinuria. Strongyloides stercoralis Strongyloides meningococcal infection is not completely eliminated with vacci- meningococcal infection is not completely to prescribe ongoingnation, so health care providers may choose antimicrobial prophylaxis despite vaccination. Patients and health care providers must remain vigilant for signs of infection. The eculizumabtoin addition product monograph recommends that, vaccination against N. meningitidis, | 1.41 Negative Negative Negative Negative Negative 14 (7–40) 6 (10–45) 13 (0–23) DECEMBER 18, 2017 no nitrites | 426 (42–102) 68 (115–155) 163 (140–400) 1.02 (0.36–1.95) 0.41 (0.79–1.52) 0.11 (0.16–0.38) 14.6 (2.00–6.30) 87.1 (82.0–97.0) 0.840 (1.00–3.20) 16.6 (4.00–11.00) Gross proteinuria, proteinuria, Gross (reference range)* (reference Result on admission on Result tubo-ovarian abscess. tubo-ovarian Neisseria gonorrhoeae in the right adnexa and in the right adnexa moderate fluid in the left moderate CMAJ adnexa, but no evidence of but no evidence adnexa, trace blood, no leukocytes, blood, no leukocytes, trace Mild amount of simple fluid /L) 9 /L) 9 /L) 9 /L) 9 We reported our patient’s case of N. gonorrhoeae to the public Note: NAAT = nucleic acid amplification test. = nucleic acid amplification NAAT Note: applicable. *Where Creatinine (μmol/L) Creatinine (U/L) aminotransferase Aspartate (U/L) Alanine aminotransferase μmol/L) ( Bilirubin total (g/L)Haptoglobin Complement, C3 (g/L) Complement, C4 (g/L) chorionic gonadotropin Beta–human Urinalysis (g/L) quantification Urine protein Blood cultures Chlamydia Cervical for swab and Neisseria NAAT trachomatis gonorrhoeae culture Neisseria gonorrhoeae and Urine for NAAT trachomatis Chlamydia Neisseria for swab Throat gonorrhoeae culture Neisseria for swab Rectal gonorrhoeae culture and transvaginal Transabdominal pelvic ultrasound Box 1: Results of investigations of 1: Results Box Test Absolute lymphocyte count ( × 10 count lymphocyte Absolute Leukocyte count ( × 10 count Leukocyte Absolute neutrophil count ( × 10 count neutrophil Absolute Hemoglobin (g/L)Hemoglobin (fL) volume corpuscular Mean ( × 10 Platelets

Discussion When immunosuppressive therapy is prescribed, it is necessary to assess patients’ overall state of immunosuppression and were negative. The patient had evidence of hepatitis B immunity owing to previous infection. The dialysis catheter was removed and replaced when repeat blood cultures were negative. health department. Her partner had already been prescribed treatment for gonococcal urethritis. She and her partner were counselled to have follow-up screening for sexually transmitted infections. PRACTICE had arthritis,only60%feverand38%dermatitis. found that99%ofpatientswithdisseminatedgonococcalinfection skin lesions on the extremities.Asingle-centreretrospectivereview gia, tenosynovitis,anddermatitisthatincludespapularorpustular manifest as the “arthritis-dermatitis syndrome,” with polyarthral cmaj.ca/lookup/suppl/doi:10.1503/cmaj.170508/-/DC1). Itcan ciencies. partum state,recentmenstruationandterminalcomplementdefi- of suspicion.Riskfactorsincludepregnancy,theimmediatepost- Identifying disseminated gonococcal infection requires a high index cases, have arecenthistoryofsymptomaticgenitalinfection.In80% women aged15–19yearsamongthemostaffected. cases ofgonorrheasince1997,withmenaged20–24yearsand surveillance datahaveshownagradualincreaseinreported E1560 well, withnorecurrence ofN.gonorrhoeaeinfection. for systemiclupuserythematosus. Aftersixmonths,shewasdoing undetectable), butshecontinued toreceivemaintenancetherapies opathy (aftertheanti–complement factorHantibodybecame ally stoppedafterresolutionof the systemicthromboticmicroangi- after sexualexposuretoN.gonorrhoeae . Eculizumabwaseventu- eculizumab increasedourpatient’svulnerabilitytogonococcemia and disseminated gonococcal infection, we suspect that the use of Given theassociationbetweenterminalcomplementdeficiency ment witheculizumab,mycophenolatemofetilandcorticosteroids. temic lupuserythematosus;end-stagerenaldisease;andtreat - Our patientwassubstantiallyimmunocompromisedowingtosys - Case revisited culture ispositiveinabout40%ofcases. nancy, peritonitis,perihepatitisandfemaleinfertility. inflammatorydisease,tubo-ovarianabscess,ectopicpreg- pelvic also occur.Amongwomen,additionalcomplicationsinclude with alosporin-resistant gonorrhea,andeffectivelytreatscoinfection azithromycin improvesefficacy,maydelaytheemergenceofceph- facilitate casefinding,partnernotificationandtreatment. safer sexpractices.Publichealthauthoritiesshouldbenotifiedto other sexuallytransmittedinfectionsandreceivecounsellingon barrier precautionsduringsexualactivity. discuss preventivepractices,suchasabstinenceortheuse of orrhea inpatientsatriskforsexuallytransmittedinfection,and risk ofseriousgonococcalinfection,considerscreeningforgon- counsel patientswhowillreceiveeculizumabonthepotential with terminal complement deficiency, we suggest that providers tion, plusazithromycin1gtakenorallyinasingledose. cularly, withtreatmentdurationdeterminedbythesite(s)ofinfec- guidelines recommendceftriaxone2gintravenouslyorintramus- bination therapyusingtwodifferentantibioticclasses.Canadian up to4%ofgonorrhealinfections include endocarditis, meningitis, osteomyelitis and septic shock. common manifestations of disseminated gonococcal infection Given theincreasedriskofdisseminatedgonococcalinfection Treatment ofdisseminatedgonococcalinfectioninvolvescom- Disseminated gonococcalinfectionisuncommon,complicating Chlamydia trachomatis. N. gonorrhoeaecanberecoveredfrommucosalsites. 11 Blood cultures are frequently sterile and synovial fluid Bloodculturesarefrequentlysterileandsynovialfluid 12 Patientsshouldbescreenedfor 10 (Appendix1,availableatwww. CMAJ 11 Most patients do not Mostpatientsdonot | DECEMBER 18,2017 12 11 Canadian 12 12 11 Use of Useof 11 Less Less 10 -

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References

VOLUME 189 3 8 9 6 4 5 7 2 1 ...... Correspondence to:LindaTaggart,[email protected] lance dataofgonorrhea. Laboratories fortheirassistancein compiling epidemiologicsurveil- Vanessa AllenandMr.MichaelWhelan atthePublicHealthOntario Acknowledgements: Theauthorswouldliketoacknowledge Dr. of thework. version tobepublishedandagreedaccountableforallaspects cally forimportantintellectualcontent,gavefinalapprovalofthe ception anddesignofthearticle,draftedreviseditcriti- Contributors: Alloftheauthorscontributedsubstantiallytocon- University ofToronto,Ont. Diseases (Taggart),DepartmentofMedicine,St.Michael’sHospital, ski), DepartmentofLaboratoryMedicine;DivisionInfectious icine, University of Toronto; Division of Transfusion Medicine (Paven- son Clinician-ScientistTrainingProgram(Wright),DepartmentofMed- Internal Medicine;DivisionofInfectiousDiseasesandtheEliotPhillip- Affiliations: PGY-4,AdultHematology(Khandelwal),Departmentof The authorshaveobtainedpatientconsent. This articlehasbeenpeerreviewed. terests weredeclared. for speakingfromAlexionPharmaceuticals.Noothercompetingin- Competing interests:KaterinaPavenskireportsreceivinghonoraria women. Limper 42: consensus guidelines. agement ofchronichepatitisB:CanadianAssociationfortheStudyLiver prevention, assessment and management guidelines. cine andTravel(CATMAT). Boggild Bleich 2011. terns ofdisseminatedgonococcalinfectioninFrance:cross-sectionaldata2009– Legendre 2011; infections inadultpulmonaryandcriticalcarepatients. Group. 2013; modified2014Sept.26]. Gonococcal infections.Ottawa:PublicHealthAgencyofCanada;[RevisedJuly ted infections: Section 5 — Management and treatment of specific infections — Romanowski Belkacem 2016; of eculizumabforparoxysmalnocturnalhemoglobinuriainJapan. Ram cessed 2017 hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/soliris-bexsero-eng.php ( and vaccinatedwithBexsero.Ottawa:HealthCanada; potential riskofhemolysisandlowhemoglobininpatientstreatedwithSoliris mary safetyreview—SOLIRIS(eculizumab)andBEXSEROAssessingthe Health Products and Food Branch, Marketed Health Products Directorate. Sum- ( in atypicalhemolytic-uremicsyndrome. Coffin Jan. 17). Available: Canadian ImmunizationGuide.Ottawa:PublicHealthAgencyofCanada; cgsti-ldcits/section-5-6-eng.php ( resistance ofNeisseriagonorrhoeae. International; Soliris (eculizumab)productmonograph.NewHaven(CT):AlexionPharmaceutical Ninomiya accessed 2017Jan.15). 12- S 104: 183: Sex TransmInfect 9 , CS, AT, . Cullinane AH, An officialAmericanThoracicSocietystatement:treatmentoffungal AK, Obstet Gynecol 548- 96- H CM, Fung Sheffield A www.phac-aspc.gc.ca/publicat/cig-gci/index-eng.php ( , Knox

Libman , Obara ). Mar. 4). 128. Caumes 58. B | Licht ISSUE 50 , 2016. SK, Robinson KS, M N , Ma M JS, C Blom , Sarosi , , Chiba E Available: Can JGastroenterol Muus Greenaway , MM; Wendel

2013; 2012; Ouanich AM, J CATMAT statement on disseminated strongyloidiasis: CATMAT statementon disseminated strongyloidiasis: Canadian AssociationfortheStudyofLiver. S GA, , P , Wong 89: 119: , et al. et al. et al. GD et al.; Available: 613- http://soliris.net/resources/pdf/soliris_pi.pdf J accessed 2017Jan.17). 597- C , Jr, Int Immunopharmacol Interim analysis of post-marketing surveillance Interim analysisofpost-marketingsurveillance et al.; T , C4bp binding to porin mediates stable serum C4bp bindingtoporinmediatesstableserum 5 et al.; Terminal complement inhibitor eculizumab Terminal complementinhibitoreculizumab . . American Thoracic Society Fungal Working American ThoracicSocietyFungalWorking et al. 602. Canadian guidelinesonsexuallytransmit- N EnglJMed Working GroupFRA-DGI. 2012; Committee toAdviseonTropicalMedi- www.phac-aspc.gc.ca/std-mts/sti-its/ Disseminated gonococcal infection in Disseminated gonococcalinfectionin 26: 917-

2013; Can CommunDisRep 38. Am JRespirCritCareMed 2001; 2016. 368: 1 2169- : 423- Available: accessed 2016 accessed 2016 Changing pat- Int JHematol 32. 81. www. 2013. 2016 Man- ac‑ ;