This guideline aims to describe the complement system and the functions of the constituent pathways, with particular focus on primary immunodeficiencies (PIDs) and their diagnosis and management. The complement system is a crucial part of the innate immune system, with multiple membrane-bound and soluble components. There are three distinct enzymatic cascade pathways within the complement system, the classical, alternative and lectin pathways, which converge with the cleavage of central C3. Complement deficiencies account for ~5% of PIDs. The clinical consequences of inherited defects in the complement system are protean and include increased susceptibility to infection, autoimmune diseases (e.g., systemic lupus erythematosus), age-related macular degeneration, renal disorders (e.g., atypical hemolytic uremic syndrome) and angioedema. Modern complement analysis allows an in-depth insight into the functional and molecular basis of nearly all complement deficiencies. However, therapeutic options remain relatively limited for the majority of complement deficiencies with the exception of hereditary angioedema and inhibition of an overactivated complement system in regulation defects. Current management strategies for complement disorders associated with infection include education, family testing, vaccinations, antibiotics and emergency planning.

Allergy Associates of the Palm Beaches North Palm Beach FL USA

Clinical Immunology Reference Center on Rare Diseases University Center Health ABC Santo Andre SP Brazil

Department of Clinical Immunology and Allergology St Anne's University Hospital and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pediatrics Children's Hospital Skåne University Hospital Lund Sweden

Division of Allergy and Immunology The Children's Hospital of Philadelphia Philadelphia PA USA

Division of Rheumatology Department of Medicine University of Colorado School of Medicine Aurora CO USA

Immunodeficiency Centre for Wales Cardiff University and University Hospital of Wales Cardiff UK

Institute of Immunology University of Heidelberg Heidelberg Germany

Rare Disease Center Children's Hospital and Adult Primary Immunodeficiency Outpatient Clinic Inflammation Center University of Helsinki and Helsinki University Hospital Helsinki Finland

See more in PubMed

Grumach AS, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014;61(2):110–117. PubMed

Dahl M, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. A population-based study of morbidity and mortality in mannose-binding lectin deficiency. J Exp Med. 2004;199(10):1391–1399. PubMed PMC

Paakkanen R, Vauhkonen H, Eronen KT, Jarvinen A, Seppanen M, Lokki ML. Copy number analysis of complement C4A, C4B and C4A silencing mutation by real-time quantitative polymerase chain reaction. PLoS One. 2012;7(6):e38813. PubMed PMC

Mollnes TE, Jokiranta TS, Truedsson L, Nilsson B, Rodriguez de Cordoba S, Kirschfink M. Complement analysis in the 21st century. Mol Immunol. 2007;44(16):3838–3849. PubMed

ESID registry. ESID database statistics. 2018. https://cci-reporting.uniklinik-freiburg.de/#/. Accessed 10 Nov 2019.

Smith LC, Clow LA, Terwilliger DP. The ancestral complement system in sea urchins. Immunol Rev. 2001;180:16–34. PubMed

Sanghera P, Ghanta M, Ozay F, Ariyamuthu VK, Tanriover B. Kidney diseases associated with alternative complement pathway dysregulation and potential treatment options. Am J Med Sci. 2017;354(6):533–538. PubMed PMC

Engelberts PJ, Voorhorst M, Schuurman J, van Meerten T, Bakker JM, Vink T, et al. Type I CD20 antibodies recruit the B cell receptor for complement-dependent Lysis of malignant B cells. J Immunol. 2016;197(12):4829–4837. PubMed

Hovingh ES, van den Broek B, Jongerius I. Hijacking complement regulatory proteins for bacterial immune evasion. Front Microbiol. 2016;7:2004. PubMed PMC

Barnum SR. Complement: a primer for the coming therapeutic revolution. Pharmacol Ther. 2017;172:63–72. PubMed

Varela JC, Tomlinson S. Complement: an overview for the clinician. Hematol Oncol Clin North Am. 2015;29(3):409–427. PubMed PMC

Ghebrehiwet B. The complement system: an evolution in progress. F1000Research. 2016;5:2840. PubMed PMC

Degn SE, Jensenius JC, Thiel S. Disease-causing mutations in genes of the complement system. Am J Hum Genet. 2011;88(6):689–705. PubMed PMC

Noris M, Remuzzi G. Overview of complement activation and regulation. Semin Nephrol. 2013;33(6):479–492. PubMed PMC

Nesargikar PN, Spiller B, Chavez R. The complement system: history, pathways, cascade and inhibitors. Eur J Microbiol Immunol. 2012;2(2):103–111. PubMed PMC

Merle NS, Noe R, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina LT. Complement system part II: role in immunity. Front Immunol. 2015;6:257. PubMed PMC

Liszewski MK, Elvington M, Kulkarni HS, Atkinson JP. Complement’s hidden arsenal: new insights and novel functions inside the cell. Mol Immunol. 2017;84:2–9. PubMed PMC

Botto M, Kirschfink M, Macor P, Pickering MC, Wurzner R, Tedesco F. Complement in human diseases: lessons from complement deficiencies. Mol Immunol. 2009;46(14):2774–2783. PubMed

Baines AC, Brodsky RA. Complementopathies. Blood Rev. 2017;31(4):213–223. PubMed PMC

Barnum SR, Schein T, editors. The complement factsbook. 2. Cambridge: Academic; 2017.

Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT. Complement system part I - molecular mechanisms of activation and regulation. Front Immunol. 2015;6:262. PubMed PMC

Tegla CA, Cudrici C, Patel S, Trippe R, 3rd, Rus V, Niculescu F, et al. Membrane attack by complement: the assembly and biology of terminal complement complexes. Immunol Res. 2011;51(1):45–60. PubMed PMC

Baiu DC, Prechl J, Tchorbanov A, Molina HD, Erdei A, Sulica A, et al. Modulation of the humoral immune response by antibody-mediated antigen targeting to complement receptors and fc receptors. J Immunol. 1999;162(6):3125–3130. PubMed

Erdei A, Sandor N, Macsik-Valent B, Lukacsi S, Kremlitzka M, Bajtay Z. The versatile functions of complement C3-derived ligands. Immunol Rev. 2016;274(1):127–140. PubMed

West EE, Kolev M, Kemper C. Complement and the regulation of T cell responses. Annu Rev Immunol. 2018;36:309–338. PubMed PMC

Macedo AC, Isaac L. Systemic lupus erythematosus and deficiencies of early components of the complement classical pathway. Front Immunol. 2016;7:55. PubMed PMC

Shih AR, Murali MR. Laboratory tests for disorders of complement and complement regulatory proteins. Am J Hematol. 2015;90(12):1180–1186. PubMed

Prohaszka Z, Nilsson B, Frazer-Abel A, Kirschfink M. Complement analysis 2016: clinical indications, laboratory diagnostics and quality control. Immunobiology. 2016;221(11):1247–1258. PubMed

Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014;5:162. PubMed PMC

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 ÖN, Kirschfink M. Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders. Clin Exp Immunol. 2017;187(2):304–315. PubMed PMC

Mollnes TE, Garred P, Bergseth G. Effect of time, temperature and anticoagulants on in vitro complement activation: consequences for collection and preservation of samples to be examined for complement activation. Clin Exp Immunol. 1988;73(3):484–488. PubMed PMC

Nilsson B, Ekdahl KN. Complement diagnostics: concepts, indications, and practical guidelines. Clin Dev Immunol. 2012;2012:962702. PubMed PMC

Palarasah Y, Nielsen C, Sprogoe U, Christensen ML, Lillevang S, Madsen HO, et al. Novel assays to assess the functional capacity of the classical, the alternative and the lectin pathways of the complement system. Clin Exp Immunol. 2011;164(3):388–395. PubMed PMC

Blazina S, Debeljak M, Kosnik M, Simcic S, Stopinsek S, Markelj G, et al. Functional complement analysis can predict genetic testing results and long-term outcome in patients with complement deficiencies. Front Immunol. 2018;9:500. PubMed PMC

Frazer-Abel A, Sepiashvili L, Mbughuni MM, Willrich MA. Overview of laboratory testing and clinical presentations of complement deficiencies and dysregulation. Adv Clin Chem. 2016;77:1–75. PubMed

Seelen MA, Roos A, Wieslander J, Mollnes TE, Sjoholm AG, Wurzner R, et al. Functional analysis of the classical, alternative, and MBL pathways of the complement system: standardization and validation of a simple ELISA. J Immunol Methods. 2005;296(1–2):187–198. PubMed

Mayilyan KR. Complement genetics, deficiencies, and disease associations. Protein Cell. 2012;3(7):487–496. PubMed PMC

Gomes A, Korf B. Chapter 5 - Genetic testing techniques. In: Robin NH, Farmer MB, editors. Pediatric Cancer Genetics. Amsterdam: Elsevier; 2018. pp. 47–64.

Turley AJ, Gathmann B, Bangs C, Bradbury M, Seneviratne S, Gonzalez-Granado LI, Hackett S, Kutukculer N, Alachkar H, Hambleton S, Ritterbusch H, Kralickova P, Marodi L, Seidel MG, Dueckers G, Roesler J, Huissoon A, Baxendale H, Litzman J, Arkwright PD. Spectrum and management of complement immunodeficiencies (excluding hereditary angioedema) across Europe. J Clin Immunol. 2015;35(2):199–205. PubMed

Hamblin A, Wordsworth S, Fermont JM, Page S, Kaur K, Camps C, et al. Clinical applicability and cost of a 46-gene panel for genomic analysis of solid tumours: retrospective validation and prospective audit in the UK National Health Service. PLoS Med. 2017;14(2):e1002230. PubMed PMC

Guy’s and St Thomas’ NHS. Whole-exome sequencing in clinical genetics 2017. http://www.phgfoundation.org/documents/PHGF-whole-exome-sequencing-in-clinical-genetics.pdf.

Ram S, Lewis LA, Rice PA. Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin Microbiol Rev. 2010;23(4):740–780. PubMed PMC

Lewis LA, Ram S. Meningococcal disease and the complement system. Virulence. 2014;5(1):98–126. PubMed PMC

Kavanagh D, Yu Y, Schramm EC, Triebwasser M, Wagner EK, Raychaudhuri S, Daly MJ, Atkinson JP, Seddon JM. Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels. Hum Mol Genet. 2015;24(13):3861–3870. PubMed PMC

Triebwasser MP, Roberson ED, Yu Y, Schramm EC, Wagner EK, Raychaudhuri S, et al. Rare variants in the functional domains of complement factor H are associated with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2015;56(11):6873–6878. PubMed PMC

Schramm EC, Clark SJ, Triebwasser MP, Raychaudhuri S, Seddon J, Atkinson JP. Genetic variants in the complement system predisposing to age-related macular degeneration: a review. Mol Immunol. 2014;61(2):118–125. PubMed PMC

Geerlings MJ, de Jong EK, den Hollander AI. The complement system in age-related macular degeneration: a review of rare genetic variants and implications for personalized treatment. Mol Immunol. 2017;84:65–76. PubMed PMC

Fijen CA, van den Bogaard R, Schipper M, Mannens M, Schlesinger M, Nordin FG, Dankert J, Daha MR, Sjöholm AG, Truedsson L, Kuijper EJ. Properdin deficiency: molecular basis and disease association. Mol Immunol. 1999;36(13–14):863–867. PubMed

Maurer M, Magerl M, Ansotegui I, Aygoren-Pursun E, Betschel S, Bork K, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-the 2017 revision and update. Allergy. 2018;73(8):1575–1596. PubMed

Rosain J, Ngo S, Bordereau P, Poulain N, Roncelin S, Vieira Martins P, Dragon-Durey MA, Frémeaux-Bacchi V. Complement deficiencies and human diseases. Ann Biol Clin. 2014;72(3):271–280. PubMed

Skattum L, van Deuren M, van der Poll T, Truedsson L. Complement deficiency states and associated infections. Mol Immunol. 2011;48(14):1643–1655. PubMed

Pettigrew HD, Teuber SS, Gershwin ME. Clinical significance of complement deficiencies. Ann N Y Acad Sci. 2009;1173:108–123. PubMed

Zhang K, Lu Y, Harley KT, Tran MH. Atypical hemolytic uremic syndrome: a brief review. Hematol Rep. 2017;9(2):7053. PubMed PMC

Hamilton AJ, Lyons CB, Goodship TH, Bingham C. Prevalence in the general population of a CFH sequence variant associated with atypical haemolytic uraemic syndrome in an extensive family from Southwest England. Nephron Extra. 2013;3(1):86–90. PubMed PMC

Shiang R, Murray JC, Morton CC, Buetow KH, Wasmuth JJ, Olney AH, et al. Mapping of the human complement factor I gene to 4q25. Genomics. 1989;4(1):82–86. PubMed

Aygören-Pürsün E, Magerl M, Maetzel A, Maurer M. Epidemiology of Bradykinin-mediated angioedema: a systematic investigation of epidemiological studies. Orphanet J Rare Dis. 2018;13(1):73. PubMed PMC

Liesmaa I, Paakkanen R, Jarvinen A, Valtonen V, Lokki ML. Clinical features of patients with homozygous complement C4A or C4B deficiency. PLoS One. 2018;13(6):e0199305. PubMed PMC

National Hemophilia Foundation. Factor XII (Hageman Factor) deficiency. 2018. https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Other-Factor-Deficiencies/Factor-XII. Accessed 12 Nov 2018.

Nakar CHB, Mehta R, Shapiro AD. Plasminogen Deficiency. In: Rare Coagulation Disorders Resource Room. 2018. http://www.rarecoagulationdisorders.org/diseases/plasminogen-deficiency/disease-overview. Accessed 07 Nov 2018.

Bork K, Wulff K, Witzke G, Hardt J. Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations. Allergy. 2015;70(8):1004–1012. PubMed

Holmes LV, Strain L, Staniforth SJ, Moore I, Marchbank K, Kavanagh D, Goodship JA, Cordell HJ, Goodship TH. Determining the population frequency of the CFHR3/CFHR1 deletion at 1q32. PLoS One. 2013;8(4):e60352. PubMed PMC

Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers. 2017;3:17028. PubMed PMC

Janeway CA, Travers P, Walport MJ, Shlomchik MJ. The complement system and innate immunity. In: Immunobiology: the immune system in health and disease. 5th ed: Garland Science, New York City; 2001. https://www.ncbi.nlm.nih.gov/books/NBK27100/. Accessed July 2019.

Sarma JV, Ward PA. The complement system. Cell Tissue Res. 2011;343(1):227–235. PubMed PMC

Stegert M, Bock M, Trendelenburg M. Clinical presentation of human C1q deficiency: how much of a lupus? Mol Immunol. 2015;67(1):3–11. PubMed

Jonsson G, Truedsson L, Sturfelt G, Oxelius VA, Braconier JH, Sjoholm AG. Hereditary C2 deficiency in Sweden: frequent occurrence of invasive infection, atherosclerosis, and rheumatic disease. Medicine (Baltimore) 2005;84(1):23–34. PubMed

Weckerle CE, Niewold TB. The unexplained female predominance of systemic lupus erythematosus: clues from genetic and cytokine studies. Clin Rev Allergy Immunol. 2011;40(1):42–49. PubMed PMC

Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin Microbiol Rev. 1991;4(3):359–395. PubMed PMC

Bryan AR, Wu EY. Complement deficiencies in systemic lupus erythematosus. Curr Allergy Asthma Rep. 2014;14(7):448. PubMed

Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60. PubMed PMC

Qiao F, Atkinson C, Kindy MS, Shunmugavel A, Morgan BP, Song H, et al. The alternative and terminal pathways of complement mediate post-traumatic spinal cord inflammation and injury. Am J Pathol. 2010;177(6):3061–3070. PubMed PMC

Hourcade DE. The role of properdin in the assembly of the alternative pathway C3 convertases of complement. J Biol Chem. 2006;281(4):2128–2132. PubMed

Lee JX, Yusin JS, Randhawa I. Properdin deficiency-associated bronchiectasis. Ann Allergy Asthma Immunol. 2014;112(6):557–559. PubMed

Overturf GD. Indications for the immunological evaluation of patients with meningitis. Clin Infect Dis. 2003;36(2):189–194. PubMed

Helminen M, Seitsonen S, Jarva H, Meri S, Jarvela IE. A novel mutation W388X underlying properdin deficiency in a Finnish family. Scand J Immunol. 2012;75(4):445–448. PubMed PMC

Hiemstra PS, Langeler E, Compier B, Keepers Y, Leijh PC, van den Barselaar MT, Overbosch D, Daha MR. Complete and partial deficiencies of complement factor D in a Dutch family. J Clin Invest. 1989;84(6):1957–1961. PubMed PMC

Sng CCT, O’Byrne S, Prigozhin DM, Bauer MR, Harvey JC, Ruhle M, et al. A type III complement factor D deficiency: structural insights for inhibition of the alternative pathway. J Allergy Clin Immunol. 2018;142(1):311–4.e6. PubMed PMC

Slade C, Bosco J, Unglik G, Bleasel K, Nagel M, Winship I. Deficiency in complement factor B. N Engl J Med. 2013;369(17):1667–1669. PubMed

Nester CM, Barbour T, de Cordoba SR, Dragon-Durey MA, Fremeaux-Bacchi V, Goodship TH, Kavanagh D, Noris M, Pickering M, Sanchez-Corral P, Skerka C, Zipfel P, Smith RJ. Atypical aHUS: state of the art. Mol Immunol. 2015;67(1):31–42. PubMed

Mathern DR, Heeger PS. Molecules great and small: the complement system. Clin J Am Soc Nephrol. 2015;10(9):1636–1650. PubMed PMC

Bresin E, Rurali E, Caprioli J, Sanchez-Corral P, Fremeaux-Bacchi V, Rodriguez de Cordoba S, et al. Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J Am Soc Nephrol. 2013;24(3):475–486. PubMed PMC

Bourne RR, Jonas JB, Flaxman SR, Keeffe J, Leasher J, Naidoo K, Parodi MB, Pesudovs K, Price H, White RA, Wong TY, Resnikoff S, Taylor HR, Vision Loss Expert Group of the Global Burden of Disease Study Prevalence and causes of vision loss in high-income countries and in Eastern and Central Europe: 1990-2010. Br J Ophthalmol. 2014;98(5):629–638. PubMed

Geerlings MJ, Volokhina EB, de Jong EK, van de Kar N, Pauper M, Hoyng CB, van den Heuvel L, den Hollander A. Genotype-phenotype correlations of low-frequency variants in the complement system in renal disease and age-related macular degeneration. Clin Genet. 2018;94(3–4):330–338. PubMed PMC

Dobo J, Pal G, Cervenak L, Gal P. The emerging roles of mannose-binding lectin-associated serine proteases (MASPs) in the lectin pathway of complement and beyond. Immunol Rev. 2016;274(1):98–111. PubMed

Mortensen SA, Sander B, Jensen RK, Pedersen JS, Golas MM, Jensenius JC, Hansen AG, Thiel S, Andersen GR. Structure and activation of C1, the complex initiating the classical pathway of the complement cascade. Proc Natl Acad Sci U S A. 2017;114(5):986–991. PubMed PMC

Kjaer TR, Le le TM PJS, Sander B, Golas MM, Jensenius JC, et al. Structural insights into the initiating complex of the lectin pathway of complement activation. Structure. 2015;23(2):342–351. PubMed

Kasperkiewicz K, Eppa L, Swierzko AS, Bartlomiejczyk MA, Zuber ZM, Siniewicz-Luzenczyk K, et al. Lectin pathway factors in patients suffering from juvenile idiopathic arthritis. Immunol Cell Biol. 2017;95(8):666–675. PubMed

Eisen DP, Minchinton RM. Impact of mannose-binding lectin on susceptibility to infectious diseases. Clin Infect Dis. 2003;37(11):1496–1505. PubMed

Michalski M, Szala A, St Swierzko A, Lukasiewicz J, Maciejewska A, Kilpatrick DC, Matsushita M, Domzalska-Popadiuk I, Borkowska-Klos M, Sokolowska A, Szczapa J, Lugowski C, Cedzynski M. H-ficolin (ficolin-3) concentrations and FCN3 gene polymorphism in neonates. Immunobiology. 2012;217(7):730–737. PubMed

Bjarnadottir H, Arnardottir M, Ludviksson BR. Frequency and distribution of FCN2 and FCN3 functional variants among MBL2 genotypes. Immunogenetics. 2016;68(5):315–325. PubMed PMC

Swierzko AS, Szala-Pozdziej A, Kilpatrick DC, Sobocinski M, Chojnacka K, Sokolowska A, et al. Components of the lectin pathway of complement activation in paediatric patients of intensive care units. Immunobiology. 2016;221(5):657–669. PubMed

Garcia-Laorden MI, Sole-Violan J, Rodriguez de Castro F, Aspa J, Briones ML, Garcia-Saavedra A, et al. Mannose-binding lectin and mannose-binding lectin-associated serine protease 2 in susceptibility, severity, and outcome of pneumonia in adults. J Allergy Clin Immunol. 2008;122(2):368–374. PubMed

Schlapbach LJ, Latzin P, Regamey N, Kuehni CE, Zwahlen M, Casaulta C, Aebi C, Frey U. Mannose-binding lectin cord blood levels and respiratory symptoms during infancy: a prospective birth cohort study. Pediatr Allergy Immunol. 2009;20(3):219–226. PubMed PMC

Lundbo LF, Sorensen HT, Clausen LN, Hollegaard MV, Hougaard DM, Konradsen HB, et al. Mannose-binding lectin gene, MBL2, polymorphisms do not increase susceptibility to invasive meningococcal disease in a population of Danish children. Open Forum Infect Dis. 2015;2(4):ofv127. PubMed PMC

de Rooij BJ, van Hoek B, ten Hove WR, Roos A, Bouwman LH, Schaapherder AF, et al. Lectin complement pathway gene profile of donor and recipient determine the risk of bacterial infections after orthotopic liver transplantation. Hepatology. 2010;52(3):1100–1110. PubMed

Vekemans M, Robinson J, Georgala A, Heymans C, Muanza F, Paesmans M, Klastersky J, Barette M, Meuleman N, Huet F, Calandra T, Costantini S, Ferrant A, Mathissen F, Axelsen M, Marchetti O, Aoun M. Low mannose-binding lectin concentration is associated with severe infection in patients with hematological cancer who are undergoing chemotherapy. Clin Infect Dis. 2007;44(12):1593–1601. PubMed

Kleinstein SE, Shea PR, Allen AS, Koelle DM, Wald A, Goldstein DB. Genome-wide association study (GWAS) of human host factors influencing viral severity of herpes simplex virus type 2 (HSV-2) Genes Immun. 2019;20(2):112–120. PubMed PMC

Seppanen M, Lokki ML, Lappalainen M, Hiltunen-Back E, Rovio AT, Kares S, et al. Mannose-binding lectin 2 gene polymorphism in recurrent herpes simplex virus 2 infection. Hum Immunol. 2009;70(4):218–221. PubMed

Walport MJ. Complement. First of two parts. N Engl J Med. 2001;344(14):1058–1066. PubMed

Takahashi R, Tsutsumi A, Ohtani K, Muraki Y, Goto D, Matsumoto I, et al. Association of mannose binding lectin (MBL) gene polymorphism and serum MBL concentration with characteristics and progression of systemic lupus erythematosus. Ann Rheum Dis. 2005;64(2):311–314. PubMed PMC

Dobo J, Schroeder V, Jenny L, Cervenak L, Zavodszky P, Gal P. Multiple roles of complement MASP-1 at the interface of innate immune response and coagulation. Mol Immunol. 2014;61(2):69–78. PubMed

Garred P, Genster N, Pilely K, Bayarri-Olmos R, Rosbjerg A, Ma YJ, Skjoedt MO. A journey through the lectin pathway of complement-MBL and beyond. Immunol Rev. 2016;274(1):74–97. PubMed

Rooryck C, Diaz-Font A, Osborn DP, Chabchoub E, Hernandez-Hernandez V, Shamseldin H, Kenny J, Waters A, Jenkins D, Kaissi AA, Leal GF, Dallapiccola B, Carnevale F, Bitner-Glindzicz M, Lees M, Hennekam R, Stanier P, Burns AJ, Peeters H, Alkuraya FS, Beales PL. Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome. Nat Genet. 2011;43(3):197–203. PubMed PMC

Stengaard-Pedersen K, Thiel S, Gadjeva M, Moller-Kristensen M, Sorensen R, Jensen LT, et al. Inherited deficiency of mannan-binding lectin-associated serine protease 2. N Engl J Med. 2003;349(6):554–560. PubMed

Genetic testing registry. MASP2 deficiency. 2018. https://www.ncbi.nlm.nih.gov/gtr/conditions/C3151085/.

Schlapbach LJ, Aebi C, Otth M, Leibundgut K, Hirt A, Ammann RA. Deficiency of mannose-binding lectin-associated serine protease-2 associated with increased risk of fever and neutropenia in pediatric cancer patients. Pediatr Infect Dis J. 2007;26(11):989–994. PubMed

Fu J, Wang J, Luo Y, Zhang L, Zhang Y, Dong X, et al. Association between MASP-2 gene polymorphism and risk of infection diseases: a meta-analysis. Microb Pathog. 2016;100:221–228. PubMed

Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009;9(10):729–740. PubMed

Michels M, van de Kar N, Okroj M, Blom AM, van Kraaij SAW, Volokhina EB, et al. Overactivity of alternative pathway convertases in patients with complement-mediated renal diseases. Front Immunol. 2018;9:612. PubMed PMC

Liszewski MK, Atkinson JP. Complement regulators in human disease: lessons from modern genetics. J Intern Med. 2015;277(3):294–305. PubMed

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(23):2169–2181. PubMed

Seddon JM, Yu Y, Miller EC, Reynolds R, Tan PL, Gowrisankar S, Goldstein JI, Triebwasser M, Anderson HE, Zerbib J, Kavanagh D, Souied E, Katsanis N, Daly MJ, Atkinson JP, Raychaudhuri S. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat Genet. 2013;45(11):1366–1370. PubMed PMC

Kavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic syndrome. Semin Nephrol. 2013;33(6):508–530. PubMed PMC

Karpman D, Tati R. Complement activation in thrombotic microangiopathy. Hamostaseologie. 2013;33(2):96–104. PubMed

Kerr H, Richards A. Complement-mediated injury and protection of endothelium: lessons from atypical haemolytic uraemic syndrome. Immunobiology. 2012;217(2):195–203. PubMed PMC

Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol. 2012;8(11):622–633. PubMed

Caccia S, Suffritti C, Cicardi M. Pathophysiology of hereditary angioedema. Pediatr Allergy Immunol Pulmonol. 2014;27(4):159–163. PubMed PMC

Csuka D, Veszeli N, Varga L, Prohaszka Z, Farkas H. The role of the complement system in hereditary angioedema. Mol Immunol. 2017;89:59–68. PubMed

Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M. C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med. 2009;15(2):69–78. PubMed

Zuraw BL. Hereditary angioedema with normal C1 inhibitor: four types and counting. J Allergy Clin Immunol. 2018;141(3):884–885. PubMed

Germenis AE, Margaglione M, Pesquero JB, Farkas H, Cichon S, Csuka D, Lera AL, Rijavec M, Jolles S, Szilagyi A, Trascasa ML, Veronez CL, Drouet C, Zamanakou M. Hereditary Angioedema International Working Group. International Consensus on the Use of Genetics in the Management of Hereditary Angioedema. J Allergy Clin Immunol Pract. 2019. 10.1016/j.jaip.2019.10.004. PubMed

Marcelino-Rodriguez I, Callero A, Mendoza-Alvarez A, Perez-Rodriguez E, Barrios-Recio J, Garcia-Robaina JC, Flores C. Bradykinin-mediated angioedema: An update of the genetic causes and the impact of genomics. Front Genet. 2019;10:900. 10.3389/fgene.2019.00900. PubMed PMC

Fijen CA, Kuijper EJ, Te Bulte M, van de Heuvel MM, Holdrinet AC, Sim RB, et al. Heterozygous and homozygous factor H deficiency states in a Dutch family. Clin Exp Immunol. 1996;105(3):511–516. PubMed PMC

Vyse TJ, Morley BJ, Bartok I, Theodoridis EL, Davies KA, Webster AD, Walport MJ. The molecular basis of hereditary complement factor I deficiency. J Clin Invest. 1996;97(4):925–933. PubMed PMC

Heurich M, Preston RJ, O’Donnell VB, Morgan BP, Collins PW. Thrombomodulin enhances complement regulation through strong affinity interactions with factor H and C3b-factor H complex. Thromb Res. 2016;145:84–92. PubMed

Salmon JE, Heuser C, Triebwasser M, Liszewski MK, Kavanagh D, Roumenina L, Branch DW, Goodship T, Fremeaux-Bacchi V, Atkinson JP. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 2011;8(3):e1001013. PubMed PMC

Vaught AJ, Braunstein EM, Jasem J, Yuan X, Makhlin I, Eloundou S, et al. Germline mutations in the alternative pathway of complement predispose to HELLP syndrome. JCI Insight. 2018;3(6):e99128. PubMed PMC

Grumach AS, Leitao MF, Arruk VG, Kirschfink M, Condino-Neto A. Recurrent infections in partial complement factor I deficiency: evaluation of three generations of a Brazilian family. Clin Exp Immunol. 2006;143(2):297–304. PubMed PMC

Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804–2811. PubMed PMC

Ozen A, Comrie WA, Ardy RC, Dominguez Conde C, Dalgic B, Beser OF et al. CD55 deficiency, early-onset protein-losing enteropathy, and thrombosis. N Engl J Med. 2017;377(1):52–61. PubMed PMC

Ardicli D, Taskiran EZ, Kosukcu C, Temucin C, Oguz KK, Haliloglu G, Alikasifoglu M, Topaloglu H. Neonatal-onset recurrent Guillain-Barre syndrome-like disease: clues for inherited CD59 deficiency. Neuropediatrics. 2017;48(6):477–481. PubMed

Costa-Carvalho BT, Grumach AS, Franco JL, Espinosa-Rosales FJ, Leiva LE, King A, Porras O, Bezrodnik L, Oleastro M, Sorensen RU, Condino-Neto A. Attending to warning signs of primary immunodeficiency diseases across the range of clinical practice. J Clin Immunol. 2014;34(1):10–22. PubMed PMC

Regal JF, Gilbert JS, Burwick RM. The complement system and adverse pregnancy outcomes. Mol Immunol. 2015;67(1):56–70. PubMed PMC

Patel RR, Liang SY, Koolwal P, Kuhlmann FM. Travel advice for the immunocompromised traveler: prophylaxis, vaccination, and other preventive measures. Ther Clin Risk Manag. 2015;11:217–228. PubMed PMC

Genetic Disorders UK. Going on holiday - travel tips and getting travel insurance. 2017. http://www.piduk.org/whatarepids/management/traveltipsandtravelinsurance. Accessed 05 Dec 2018.

Ejstrud P, Kristensen B, Hansen JB, Madsen KM, Schonheyder HC, Sorensen HT. Risk and patterns of bacteraemia after splenectomy: a population-based study. Scand J Infect Dis. 2000;32(5):521–525. PubMed

Bonilla FA. Update: vaccines in primary immunodeficiency. J Allergy Clin Immunol. 2018;141(2):474–481. PubMed

Shearer WT, Fleisher TA, Buckley RH, Ballas Z, Ballow M, Blaese RM, et al. Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts. J Allergy Clin Immunol. 2014;133(4):961–966. PubMed PMC

Sobh A, Bonilla FA. Vaccination in primary immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4(6):1066–1075. PubMed

Eibl MM, Wolf HM. Vaccination in patients with primary immune deficiency, secondary immune deficiency and autoimmunity with immune regulatory abnormalities. Immunotherapy. 2015;7(12):1273–1292. PubMed

Practice Nurse. Travel health update. 2014. https://www.janechiodini.co.uk/wp-content/uploads/2017/08/PN-update-March-2014.pdf. Accessed 5 Dec 2018.

CDC Updated recommendations for use of meningococcal conjugate vaccines --- advisory committee on immunization practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep. 2011;60(3):72–76. PubMed

Ekdahl K, Truedsson L, Sjoholm AG, Braconier JH. Complement analysis in adult patients with a history of bacteremic pneumococcal infections or recurrent pneumonia. Scand J Infect Dis. 1995;27(2):111–117. PubMed

Reddy YN, Siedlecki AM, Francis JM. Breaking down the complement system: a review and update on novel therapies. Curr Opin Nephrol Hypertens. 2017;26(2):123–128. PubMed

McKeage K. Ravulizumab: first global approval. Drugs. 2019;79(3):347–352. PubMed

Johnson NM, Phillips MA. New treatments for hereditary angioedema. Skin Therapy Lett. 2018;23(1):6–8. PubMed

Pawaskar D, Tortorici MA, Zuraw B, Craig T, Cicardi M, Longhurst H, Li HH, Lumry WR, Martinez-Saguer I, Jacobs J, Bernstein JA, Riedl MA, Katelaris CH, Keith PK, Feussner A, Sidhu J. Population pharmacokinetics of subcutaneous C1-inhibitor for prevention of attacks in patients with hereditary angioedema. Clin Exp Allergy. 2018;48(10):1325–1332. PubMed

Shire. Takhzyro now approved. 2018. https://www.takhzyro.com/#takhzyro. Accessed 20 Sept 2018.

NICE. Lanadelumab for preventing recurrent attacks of hereditary angiodema [TA606], 16 Oct 2019. Available from: https://www.nice.org.uk/guidance/indevelopment/gid-ta10333/documents. 2019.

Qiu T, Chiuchiolo MJ, Whaley AS, Russo AR, Sondhi D, Kaminsky SM, et al. Gene therapy for C1 esterase inhibitor deficiency in a murine model of hereditary angioedema. Allergy. 2018. PubMed PMC

Olsson RF, Hagelberg S, Schiller B, Ringden O, Truedsson L, Ahlin A. Allogeneic hematopoietic stem cell transplantation in the treatment of human C1q deficiency: the Karolinska experience. Transplantation. 2016;100(6):1356–1362. PubMed

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(1):265–267. PubMed

Klausegger A, Wiednig M, Urban C, Lackner H, Reiter H, Bauer JW, Aberer W. Successful allogeneic cord blood transplantation in a patient with Evans syndrome leads to correction of hereditary angioedema type I as secondary effect. Bone Marrow Transplant. 2012;47(9):1259–1261. PubMed

Kiss TL, Messner HA, Galal A, Lipton J. Correction of recurrent angioedema related to C1 esterase inhibitor deficiency as a secondary event following nonmyeloablative allogeneic stem cell transplantation in a patient with myelofibrosis. Bone Marrow Transplant. 2005;35(2):213–214. PubMed

Zegers IH, Aaldering KN, Nieuwhof CM, Schouten HC. Non-myeloablative allogeneic stem cell transplantation: a new treatment option for acquired angioedema? Neth J Med. 2015;73(8):383–385. PubMed

Coppo R, Bonaudo R, Peruzzi RL, Amore A, Brunati A, Romagnoli R, Salizzoni M, Galbusera M, Gotti E, Daina E, Noris M, Remuzzi G. Liver transplantation for aHUS: still needed in the eculizumab era? Pediatr Nephrol. 2016;31(5):759–768. PubMed

van Schaarenburg RA, Schejbel L, Truedsson L, Topaloglu R, Al-Mayouf SM, Riordan A, et al. Marked variability in clinical presentation and outcome of patients with C1q immunodeficiency. J Autoimmun. 2015;62:39–44. PubMed