Laboratory Studies

One can screen for deficiencies in complement by performing the total serum classic hemolytic complement (CH₅₀) test or the alternative hemolytic complement (AP₅₀) test. The CH₅₀ test specifically tests for deficiencies in the classic pathway by measuring the ability of the patient's serum to lyse antibody-coated sheep erythrocytes. A deficiency in any of the classic proteins results in a CH₅₀ of zero. Similarly, the AP₅₀ tests for alternative pathway activity. Direct measurement of individual serum complement proteins, such as C3 and C4, can also be performed and is helpful in determining the diagnosis.

Dried blood spot samples from newborns, which are already widely used in neonatal screening for selected metabolic diseases, may be employed in the future using reverse phase protein microarrays for determination of complement component C3 levels collected at birth.^[21]In one recent study, normal levels of C3 were detected from healthy newborns, while no C3 was documented in sera and dried blood samples from patients who were C3 deficient in C3.^[21]

Imaging Studies

No specific imaging studies are indicated. Consider performing a head CT scan prior to a lumbar puncture in a patient thought to have meningitis.

Other Tests

Patients with classic complement pathway deficiencies should be screened for sequelae of immune complex diseases. Urinalysis and a complete blood cell count should be performed on these patients.

Procedures

A lumbar puncture should be performed on patients with possible meningitis to assist in the definitive diagnosis of bacterial meningitis.

Treatment & Management

Grumach AS, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014 Oct. 61(2):110-117. [QxMD MEDLINE Link].
Bryan AR, Wu EY. Complement deficiencies in systemic lupus erythematosus. Curr Allergy Asthma Rep. 2014 Jul. 14(7):448. [QxMD MEDLINE Link].
Jönsson G, Hansson C, Mellhammar L, Gullstrand B, Bengtsson AA, Sahl C, et al. Increased serum bactericidal activity of autologous serum in C2 deficiency after vaccination against Haemophilus influenzae type b, and further support for an MBL-dependent C2 bypass mechanism. Vaccine. 2021 Feb 22. 39 (8):1297-1302. [QxMD MEDLINE Link].
Botto M, Kirschfink M, Macor P, Pickering MC, Wurzner R, Tedesco F. Complement in human diseases: Lessons from complement deficiencies. Mol Immunol. 2009 Sep. 46(14):2774-83. [QxMD MEDLINE Link].
Skattum L, van Deuren M, van der Poll T, Truedsson L. Complement deficiency states and associated infections. Mol Immunol. 2011 Aug. 48(14):1643-55. [QxMD MEDLINE Link].
Mayilyan KR. Complement genetics, deficiencies, and disease associations. Protein Cell. 2012 Jul. 3(7):487-96. [QxMD MEDLINE Link].
Jlajla H, Dehman F, Jallouli M, Khedher R, Ayadi I, Zerzeri Y, et al. Molecular basis of complement factor I deficiency in Tunisian atypical hemolytic and uremic syndrome Patients. Nephrology (Carlton). 2018 Jan 2. [QxMD MEDLINE Link].
Roumenina LT, Sène D, Radanova M, Blouin J, Halbwachs-Mecarelli L, Dragon-Durey MA, et al. Functional complement C1q abnormality leads to impaired immune complexes and apoptotic cell clearance. J Immunol. 2011 Oct 15. 187(8):4369-73. [QxMD MEDLINE Link].
Grumach AS, Goudouris E, Dortas Junior S, Marcelino FC, Alonso MLO, Martins RO, et al. COVID-19 affecting hereditary angioedema patients with and without C1 inhibitor deficiency. J Allergy Clin Immunol Pract. 2021 Jan. 9 (1):508-510. [QxMD MEDLINE Link].
Arnold DF, Roberts AG, Thomas A, Ferry B, Morgan BP, Chapel H. A novel mutation in a patient with a deficiency of the eighth component of complement associated with recurrent meningococcal meningitis. J Clin Immunol. 2009 Sep. 29(5):691-5. [QxMD MEDLINE Link].
Sonea MJ, Moroz BE, Reece ER. Leiner's disease associated with diminished third component of complement. Pediatr Dermatol. 1987 Aug. 4(2):105-7. [QxMD MEDLINE Link].
Goodyear HM, Harper JI. Leiner's disease associated with metabolic acidosis. Clin Exp Dermatol. 1989 Sep. 14(5):364-6. [QxMD MEDLINE Link].
Arnaout R, Al Shorbaghi S, Al Dhekri H, et al. C5 Complement Deficiency in a Saudi Family, Molecular Characterization of Mutation and Literature Review. J Clin Immunol. 2013 Feb 1. [QxMD MEDLINE Link].
Degn SE, Jensenius JC, Thiel S. Disease-causing mutations in genes of the complement system. Am J Hum Genet. 2011 Jun 10. 88(6):689-705. [QxMD MEDLINE Link]. [Full Text].
van Schaarenburg RA, Magro-Checa C, Bakker JA, Teng YK, Bajema IM, Huizinga TW, et al. C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus. Front Immunol. 2016 Dec 27. 7:647. [QxMD MEDLINE Link].
Peerschke EI, Yin W, Alpert DR, Roubey RA, Salmon JE, Ghebrehiwet B. Serum complement activation on heterologous platelets is associated with arterial thrombosis in patients with systemic lupus erythematosus and antiphospholipid antibodies. Lupus. 2009 May. 18(6):530-8. [QxMD MEDLINE Link]. [Full Text].
Dellepiane RM, Dell'Era L, Pavesi P, Macor P, Giordano M, De Maso L, et al. Invasive meningococcal disease in three siblings with hereditary deficiency of the 8(th) component of complement: evidence for the importance of an early diagnosis. Orphanet J Rare Dis. 2016 May 17. 11 (1):64. [QxMD MEDLINE Link].
Kotilainen H, Lokki ML, Paakkanen R, Seppänen M, Tukiainen P, Meri S, et al. Complement C4 deficiency--a plausible risk factor for non-tuberculous mycobacteria (NTM) infection in apparently immunocompetent patients. PLoS One. 2014. 9(3):e91450. [QxMD MEDLINE Link]. [Full Text].
van den Broek B, van der Flier M, de Groot R, de Jonge MI, Langereis JD. Common Genetic Variants in the Complement System and their Potential Link with Disease Susceptibility and Outcome of Invasive Bacterial Infection. J Innate Immun. 2020. 12 (2):131-141. [QxMD MEDLINE Link].
Brostowski LE, Graf EH. The Brief Case: Meningococcemia Leading to a Diagnosis of Complement Deficiency in a 23-Month-Old. J Clin Microbiol. 2019 Feb. 57 (2):[QxMD MEDLINE Link].
Janzi M, Sjoberg R, Wan J, et al. Screening for C3 deficiency in newborns using microarrays. PLoS One. 2009. 4(4):e5321. [QxMD MEDLINE Link]. [Full Text].
Audemard-Verger A, Descloux E, Ponard D, Deroux A, Fantin B, et al. Infections Revealing Complement Deficiency in Adults: A French Nationwide Study Enrolling 41 Patients. Medicine (Baltimore). 2016 May. 95 (19):e3548. [QxMD MEDLINE Link].
Dellepiane RM, Baselli LA, Cazzaniga M, Lougaris V, Macor P, Giordano M, et al. Hereditary Deficiency of the Second Component of Complement: Early Diagnosis and 21-Year Follow-Up of a Family. Medicina (Kaunas). 2020 Mar 10. 56 (3):[QxMD MEDLINE Link].
Beynon HL, Davies KA, Haskard DO, Walport MJ. Erythrocyte complement receptor type 1 and interactions between immune complexes, neutrophils, and endothelium. J Immunol. 1994 Oct 1. 153(7):3160-7. [QxMD MEDLINE Link].
Brandtzaeg P, Mollnes TE, Kierulf P. Complement activation and endotoxin levels in systemic meningococcal disease. J Infect Dis. 1989 Jul. 160(1):58-65. [QxMD MEDLINE Link].
Carroll MC. The role of complement in B cell activation and tolerance. Adv Immunol. 2000. 74:61-88. [QxMD MEDLINE Link].
Davies KA, Erlendsson K, Beynon HL, et al. Splenic uptake of immune complexes in man is complement-dependent. J Immunol. 1993 Oct 1. 151(7):3866-73. [QxMD MEDLINE Link].
Davies KA, Peters AM, Beynon HL, Walport MJ. Immune complex processing in patients with systemic lupus erythematosus. In vivo imaging and clearance studies. J Clin Invest. 1992 Nov. 90(5):2075-83. [QxMD MEDLINE Link].
Dempsey PW, Allison ME, Akkaraju S, et al. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science. 1996 Jan 19. 271(5247):348-50. [QxMD MEDLINE Link].
Densen P, Weiler JM, Griffiss JM, Hoffmann LG. Familial properdin deficiency and fatal meningococcemia. Correction of the bactericidal defect by vaccination. N Engl J Med. 1987 Apr 9. 316(15):922-6. [QxMD MEDLINE Link].
Doody GM, Dempsey PW, Fearon DT. Activation of B lymphocytes: integrating signals from CD19, CD22 and Fc gamma RIIb1. Curr Opin Immunol. 1996 Jun. 8(3):378-82. [QxMD MEDLINE Link].
Fauci A, Braunwald E, Isselbacher KJ. Meningococcal Infections. Fauci A, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL, Harrison TR. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998. 910-5.
Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin Microbiol Rev. 1991 Jul. 4(3):359-95. [QxMD MEDLINE Link]. [Full Text].
Frank MM. Complement deficiencies. Pediatr Clin North Am. 2000 Dec. 47(6):1339-54. [QxMD MEDLINE Link].
Girardin E, Grau GE, Dayer JM, et al. Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med. 1988 Aug 18. 319(7):397-400. [QxMD MEDLINE Link].
Goodnow CC. Pathways for self-tolerance and the treatment of autoimmune diseases. Lancet. 2001 Jun 30. 357(9274):2115-21. [QxMD MEDLINE Link].
Kang HJ, Kim HS, Lee YK, Cho HC. High incidence of complement C9 deficiency in Koreans. Ann Clin Lab Sci. 2005. 35(2):144-8. [QxMD MEDLINE Link].
Kuby J. The Complement System. Immunology. 3rd ed. New York, NY: WH Freeman; 1997. 335-55.
Lehner PJ, Davies KA, Walport MJ, et al. Meningococcal septicaemia in a C6-deficient patient and effects of plasma transfusion on lipopolysaccharide release. Lancet. 1992 Dec 5. 340(8832):1379-81. [QxMD MEDLINE Link].
Leitao MF, Vilela MM, Rutz R, et al. Complement factor I deficiency in a family with recurrent infections. Immunopharmacology. 1997 Dec. 38(1-2):207-13. [QxMD MEDLINE Link].
Lutz HU. How pre-existing, germline-derived antibodies and complement may help induce a primary immune response to nonself. Scand J Immunol. 1999 Mar. 49(3):224-8. [QxMD MEDLINE Link].
Manzi S, Ahearn JM, Salmon J. New insights into complement: a mediator of injury and marker of disease activity in systemic lupus erythematosus. Lupus. 2004. 13(5):298-303. [QxMD MEDLINE Link].
Medof ME, Iida K, Mold C, Nussenzweig V. Unique role of the complement receptor CR1 in the degradation of C3b associated with immune complexes. J Exp Med. 1982 Dec 1. 156(6):1739-54. [QxMD MEDLINE Link].
Pickering MC, Botto M, Taylor PR, et al. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol. 2000. 76:227-324. [QxMD MEDLINE Link].
Prodinger WM. Complement receptor type two (CR2,CR21): a target for influencing the humoral immune response and antigen-trapping. Immunol Res. 1999. 20(3):187-94. [QxMD MEDLINE Link].
Ross GD, Yount WJ, Walport MJ, et al. Disease-associated loss of erythrocyte complement receptors (CR1, C3b receptors) in patients with systemic lupus erythematosus and other diseases involving autoantibodies and/or complement activation. J Immunol. 1985 Sep. 135(3):2005-14. [QxMD MEDLINE Link].
Rother K, Till GO, Hansch GM, eds. The Complement System. New York, NY: Springer-Verlag; 1997.
Schlesinger M, Nave Z, Levy Y, et al. Prevalence of hereditary properdin, C7 and C8 deficiencies in patients with meningococcal infections. Clin Exp Immunol. 1990 Sep. 81(3):423-7. [QxMD MEDLINE Link].
Soderstrom C, Braconier JH, Danielsson D, Sjoholm AG. Bactericidal activity for Neisseria meningitidis in properdin-deficient sera. J Infect Dis. 1987 Jul. 156(1):107-12. [QxMD MEDLINE Link].
Sullivan KE, Winkelstein JA. Genetically Determined Deficiencies of the Complement System. Ochs HD, Edvard Smith CI, Puck J. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. New York, NY: Oxford University Press; 1999. 397-416.
Sumiya M, Super M, Tabona P, et al. Molecular basis of opsonic defect in immunodeficient children. Lancet. 1991 Jun 29. 337(8757):1569-70. [QxMD MEDLINE Link].
Summerfield JA, Sumiya M, Levin M, Turner MW. Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series. BMJ. 1997 Apr 26. 314(7089):1229-32. [QxMD MEDLINE Link].
Super M, Thiel S, Lu J, et al. Association of low levels of mannan-binding protein with a common defect of opsonisation. Lancet. 1989 Nov 25. 2(8674):1236-9. [QxMD MEDLINE Link].
Tolnay M, Tsokos GC. Complement receptor 2 in the regulation of the immune response. Clin Immunol Immunopathol. 1998 Aug. 88(2):123-32. [QxMD MEDLINE Link].
Turner MW. Mannose-binding lectin: the pluripotent molecule of the innate immune system. Immunol Today. 1996 Nov. 17(11):532-40. [QxMD MEDLINE Link].
Volanakis JE, Frank MM, eds. The Human Complement System in Health and Disease. New York, NY: Marcel Dekker; 1998.
Walport MJ. Complement. First of two parts. N Engl J Med. 2001 Apr 5. 344(14):1058-66. [QxMD MEDLINE Link].
Walport MJ. Complement. Second of two parts. N Engl J Med. 2001 Apr 12. 344(15):1140-4. [QxMD MEDLINE Link].
Walport MJ, Davies KA, Botto M. C1q and systemic lupus erythematosus. Immunobiology. 1998 Aug. 199(2):265-85. [QxMD MEDLINE Link].
Walport MJ, Lachmann PJ. Erythrocyte complement receptor type 1, immune complexes, and the rheumatic diseases. Arthritis Rheum. 1988 Feb. 31(2):153-8. [QxMD MEDLINE Link].
Wisnieski JJ, Baer AN, Christensen J, et al. Hypocomplementemic urticarial vasculitis syndrome. Clinical and serologic findings in 18 patients. Medicine (Baltimore). 1995 Jan. 74(1):24-41. [QxMD MEDLINE Link].
Zipfel PF, Heinen S, Jozsi M, Skerka C. Complement and diseases: defective alternative pathway control results in kidney and eye diseases. Mol Immunol. 2006 Jan. 43(1-2):97-106.

Media Gallery

Complement pathways and deficiencies.

of 1

Author

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, New York Academy of Medicine, Royal College of Physicians of Edinburgh, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Coauthor(s)

R Krishna Chaganti, MD Assistant Clinical Professor, Division of Rheumatology, UCSF

R Krishna Chaganti, MD is a member of the following medical societies: American College of Rheumatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy

Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians

Disclosure: Nothing to disclose.

Acknowledgements

Margaret R Donohoe, MD Consulting Staff, Department of Allergy and Immunology, Albemarle Hospital

Disclosure: Nothing to disclose.

Samuel R Marney, Jr, MD Director, Associate Professor, Department of Internal Medicine, Division of Allergy and Immunology, Vanderbilt University School of Medicine

Samuel R Marney, Jr, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians, and Tennessee Medical Association

Disclosure: Nothing to disclose.

Darrilyn Moyer, MD Associate Program Director, Associate Professor, Department of Internal Medicine, Temple University School of Medicine

Disclosure: Nothing to disclose.