Journal of Clinical Immunology

, Volume 35, Issue 2, pp 199–205 | Cite as

Spectrum and Management of Complement Immunodeficiencies (Excluding Hereditary Angioedema) Across Europe

  • A. J. Turley
  • B. Gathmann
  • C. Bangs
  • M. Bradbury
  • S. Seneviratne
  • L. I. Gonzalez-Granado
  • S. Hackett
  • N. Kutukculer
  • H. Alachkar
  • S. Hambleton
  • H. Ritterbusch
  • P. Kralickova
  • L. Marodi
  • M. G. Seidel
  • G. Dueckers
  • J. Roesler
  • A. Huissoon
  • H. Baxendale
  • J. Litzman
  • P. D. ArkwrightEmail author
Original Research



Complement immunodeficiencies (excluding hereditary angioedema and mannose binding lectin deficiency) are rare. Published literature consists largely of case reports and small series. We collated data from 18 cities across Europe to provide an overview of primarily homozygous, rather than partial genotypes and their impact and management.


Patients were recruited through the ESID registry. Clinical and laboratory information was collected onto standardized forms and analyzed using SPSS software.


Seventy-seven patients aged 1 to 68 years were identified. 44 % presented in their first decade of life. 29 % had C2 deficiency, defects in 11 other complement factors were found. 50 (65 %) had serious invasive infections. 61 % of Neisseria meningitidis infections occurred in patients with terminal pathway defects, while 74 % of Streptococcus pneumoniae infections occurred in patients with classical pathway defects (p < 0.001). Physicians in the UK were more likely to prescribe antibiotic prophylaxis than colleagues on the Continent for patients with classical pathway defects. After diagnosis, 16 % of patients suffered serious bacterial infections. Age of the patient and use of prophylactic antibiotics were not associated with subsequent infection risk. Inflammatory/autoimmune diseases were not seen in patients with terminal pathway, but in one third of patients classical and alternative pathway defects.


The clinical phenotypes of specific complement immunodeficiencies vary considerably both in terms of the predominant bacterial pathogen, and the risk and type of auto-inflammatory disease. Appreciation of these phenotypic differences should help both immunologists and other specialists in their diagnosis and management of these rare and complex patients.


Complement immunodeficiency meningococcemia Streptococcus pneumoniae atypical hemolytic uremic syndrome glomerulopathy vaccination antibiotics 



Atypical hemolytic uremic syndrome


European Society for Immunodeficiencies


Gain of function


Hereditary angioedema


Mannose binding lectin


Membrane cofactor protein


Paroxysmal noctural hemoglobinuria


Systemic lupus erythematosus


Declaration of interests

The authors declare no conflict of interests relevant to this study

Author contribution

PDA conceived of and led the study. AT collected and collated all the data. All authors contributed to collation and submission of their centre’s data and to the writing of the final version of the manuscript.


  1. 1.
    Grumach AS, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014;61:110–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Aghamohammadi A, Mohammadinejad P, Abolhassani H, Mirminachi B, Movahedi M, Gharagozlou M, et al. Primary immunodeficiency disorders in Iran: update and new insights from the third report of the national registry. J Clin Immunol. 2014;34:478–90.CrossRefPubMedGoogle Scholar
  3. 3.
    Zelazko M, Carneiro-Sampaio M, de Luigi Cornejo M, de Olarte Garcia D, Porras Madrigal O, Berron Perez R, et al. Primary immunodeficiency diseases in Latin America: first report from eight countries participating in the LAGID. Latin American Group for Primary Immunodeficiency Diseases. J Clin Immunol. 1998;18:161–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Dommett RM, Klein N, Turner MW. Mannose-binding lectin in innate immunity: past, present and future. Tissue Antigens. 2006;68:193–209.CrossRefPubMedGoogle Scholar
  5. 5.
    Khan S, Tarzi MD, Doré PC, Sewell WA, Longhurst HJ. Secondary systemic lupus erythematosus: an analysis of 4 cases of uncontrolled hereditary angioedema. Clin Immunol. 2007;123:14–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11:785–97.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Polley MJ. Inherited c’2 deficiency in man: lack of immunochemically detectable c’2 protein in serums from deficient individuals. Science. 1968;161:1149–51.CrossRefPubMedGoogle Scholar
  8. 8.
    Alper CA, Abramson N, Johnston RB, Jandl JH, Rosen FS. Increased susceptibility to infection associated with abnormalities of complement-mediated functions and of the third component of complement (C3). N Engl J Med. 1970;282:350–4.PubMedGoogle Scholar
  9. 9.
    Torisu M, Sonozaki H, Inai S, Arata M. Deficiency of the fourth component of complement in man. J Immunol. 1970;104:728–37.PubMedGoogle Scholar
  10. 10.
    Miller ME, Nilsson UR. A familial deficiency of the phagocytosis-enhancing activity of serum relates to a dysfunction of the fifth component of complement (C5). N Engl J Med. 1970;282:354–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Moncada B, Day NK, Good RA, Windhorst DB. Lupus-erythematosus-like syndrome with a familial defect of complement. N Engl J Med. 1972;286:689–93.CrossRefPubMedGoogle Scholar
  12. 12.
    Petersen BH, Lee TJ, Snyderman R, Brooks GF. Neisseria meningitidis and Neisseria gonorrhoeae bacteremia associated with C6, C7, or C8 deficiency. Ann Intern Med. 1979;90:917–20.CrossRefPubMedGoogle Scholar
  13. 13.
    Lewis LA, Ram S. Meningococcal disease and the complement system. Virulence. 2014;5:98–126.CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Gaschignard J, Levy C, Chrabieh M, Boisson B, Bost-Bru C, Dauger S, et al. Invasive pneumococcal disease in children can reveal a primary immunodeficiency. Clin Infect Dis. 2014;59:244–51.CrossRefPubMedGoogle Scholar
  15. 15.
    Kavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic syndrome. Semin Nephrol. 2013;33:508–30.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Rodriguez E, Rallapalli PM, Osborne AJ, Perkins SJ. New functional and structural insights from updated mutational databases for complement factor H, Factor I, membrane cofactor protein and C3. Biosci Rep 2014;34(5).Google Scholar
  17. 17.
    Wong EK, Goodship TH, Kavanagh D. Complement therapy in atypical haemolytic uraemic syndrome (aHUS). Mol Immunol. 2013;56:199–212.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis–a new look at an old entity. N Engl J Med. 2012;366:1119–31.CrossRefPubMedGoogle Scholar
  19. 19.
    Servais A, Noël LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon-Durey MA, et al. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 2012;82:454–64.CrossRefPubMedGoogle Scholar
  20. 20.
    Wen L, Atkinson JP, Giclas PC. Clinical and laboratory evaluation of complement deficiency. J Allergy Clin Immunol. 2004;113:585–93.CrossRefPubMedGoogle Scholar
  21. 21.
    Rodriguez-Marco A, Bradbury M, Riley P, Arkwright PD. Autoimmunity and recurrent infections in partial complement C3 immunodeficiency. Rheumatology (Oxford). 2010;49:1017–9.CrossRefGoogle Scholar
  22. 22.
    Arkwright PD, Riley P, Hughes SM, Alachkar H, Wynn RF. Successful cure of C1q deficiency in human subjects treated with hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2014;133:265–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Dragon-Durey MA, Frémeaux-Bacchi V, Loirat C, Blouin J, Niaudet P, Deschenes G, et al. Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol. 2004;15:787–95.CrossRefPubMedGoogle Scholar
  24. 24.
    Bienaime F, Dragon-Durey MA, Regnier CH, Nilsson SC, Kwan WH, Blouin J, et al. Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome. Kidney Int. 2010;77:339–49.CrossRefPubMedGoogle Scholar
  25. 25.
    Roumenina LT, Frimat M, Miller EC, Provot F, Dragon-Durey MA, Bordereau P, et al. A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function. Blood. 2012;119:4182–91.CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Boteva L, Morris DL, Cortés-Hernández J, Martin J, Vyse TJ, Fernando MM. Genetically determined partial complement C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. Am J Hum Genet. 2012;90:445–56.CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Hillmen P, Muus P, Röth A, Elebute MO, Risitano AM, Schrezenmeier H, et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2013;162:62–73.CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–81.CrossRefPubMedGoogle Scholar
  29. 29.
    Radhakrishnan S, Lunn A, Kirschfink M, Thorner P, Hebert D, Langlois V, et al. Eculizumab and refractory membranoproliferative glomerulonephritis. N Engl J Med. 2012;366:1165–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Platonov AE, Vershinina IV, Kuijper EJ, Borrow R, Käyhty H. Long term effects of vaccination of patients deficient in a late complement component with a tetravalent meningococcal polysaccharide vaccine. Vaccine. 2003;21:4437–47.CrossRefPubMedGoogle Scholar
  31. 31.
    Gomez-Lus ML, Giménez MJ, Vázquez JA, Aguilar L, Anta L, Berrón S, et al. Opsonophagocytosis versus complement bactericidal killing as effectors following Neisseria meningitidis group C vaccination. Infection. 2003;31:51–4.CrossRefPubMedGoogle Scholar
  32. 32.
    Brown JS, Hussell T, Gilliland SM, Holden DW, Paton JC, Ehrenstein MR, et al. The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice. Proc Natl Acad Sci U S A. 2002;99:16–969.Google Scholar
  33. 33.
    Yuste J, Sen A, Truedsson L, Jönsson G, Tay LS, Hyams C, et al. Impaired opsonization with C3b and phagocytosis of Streptococcus pneumoniae in sera from subjects with defects in the classical complement pathway. Infect Immun. 2008;76:3761–70.CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Alba-Domínguez M, López-Lera A, Garrido S, Nozal P, González-Granado I, Melero J, et al. Complement factor I deficiency: a not so rare immune defect: characterization of new mutations and the first large gene deletion. Orphanet J Rare Dis. 2012;7:42.CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Risitano AM. Paroxysmal nocturnal hemoglobinuria and the complement system: recent insights and novel anticomplement strategies. Adv Exp Med Biol. 2013;735:155–72.CrossRefPubMedGoogle Scholar
  36. 36.
    Ambati J, Atkinson JP, Gelfand BD. Immunology of age-related macular degeneration. Nat Rev Immunol. 2013;13:438–51.CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Centers for Disease Control and Prevention. Prevention and control of meningococcal disease. Recommendations of the advisory committee on immunization practices. Morbidy and Mortality weekly report. 2013; 62:2.Google Scholar
  38. 38.
    Ladhani SN, Cordery R, Mandal S, Christensen H, Campbell H, Borrow R, et al. Preventing secondary cases of invasive meningococcal capsular group B (MenB) disease using a recently-licensed, multi-component, protein-based vaccine (Bexsero(®)). J Infect. 2014;69:470–80.CrossRefPubMedGoogle Scholar
  39. 39.
    Kuruvilla M, de la Morena MT. Antibiotic prophylaxis in primary immune deficiency disorders. J Allergy Clin Immunol Pract. 2013;1:573–82.CrossRefPubMedGoogle Scholar
  40. 40.
    Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frémeaux-Bacchi V, French Study Group for aHUS/C3G. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol. 2012;8:643–57.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • A. J. Turley
    • 1
  • B. Gathmann
    • 2
  • C. Bangs
    • 3
  • M. Bradbury
    • 4
  • S. Seneviratne
    • 5
  • L. I. Gonzalez-Granado
    • 6
  • S. Hackett
    • 7
  • N. Kutukculer
    • 8
  • H. Alachkar
    • 9
  • S. Hambleton
    • 10
  • H. Ritterbusch
    • 2
  • P. Kralickova
    • 11
  • L. Marodi
    • 12
  • M. G. Seidel
    • 13
  • G. Dueckers
    • 14
  • J. Roesler
    • 15
  • A. Huissoon
    • 16
  • H. Baxendale
    • 17
  • J. Litzman
    • 18
  • P. D. Arkwright
    • 19
    • 20
    Email author
  1. 1.Paediatric ImmunologyUniversity of ManchesterManchesterUK
  2. 2.For the ESID Registry working party, Center for Chronic Immunodeficiency (CCI)University Medical Centre Freiburg and University of FreiburgFreiburgGermany
  3. 3.Immunology, Royal Manchester InfirmaryManchesterUK
  4. 4.Paediatric NephrologyRoyal Manchester Children’s HospitalManchesterUK
  5. 5.Immunology, Royal Free HospitalLondonUK
  6. 6.Pediatric Immunodeficiencies UnitHospital Universitario 12 OctubreMadridSpain
  7. 7.Paediatric ImmunologyBirmingham HeartlandsBirminghamUK
  8. 8.Paediatric ImmunologyEge UniversityIzmirTurkey
  9. 9.Immunology, Salford Royal Foundation TrustManchesterUK
  10. 10.Paediatric ImmunologyUniversity of NewcastleNewcastleUK
  11. 11.Allergology & Clinical ImmunologyFaculty Hospital Hradec KraloveHradec KraloveCzech Republic
  12. 12.Medical & Health Science CenterUniversity of DebrecenDebrecenHungary
  13. 13.Pediatric Hematology-OncologyMedical University-GrazGrazAustria
  14. 14.HELIOS ClinicChildrens Hospital KrefeldKrefeldGermany
  15. 15.Kinder und JugendmedizinUniversitatsklinkkum Carl Gustav CarusDresdenGermany
  16. 16.Immunology, Birmingham Heartlands HospitalBirminghamUK
  17. 17.Immunology, Addenbrookes HospitalCambridgeUK
  18. 18.Clinical Immunology & Allergology, St. Anne’s University Hospital and Faculty of MedicineMasaryk UniversityBrnoCzech Republic
  19. 19.Paediatric ImmunologyRoyal Manchester Children’s HospitalManchesterUK
  20. 20.Department of Paediatric Allergy and ImmunologyRoyal Manchester Children’s HospitalManchesterUK

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