Complement Deficiency Clinical Presentation
- Author: Ruchir Agrawal, MD; Chief Editor: Russell W Steele, MD more...
The following may be associated with complement deficiency:
- Patient or family history of recurrent systemic infection caused by encapsulated bacteria, especially meningococci
- Family history of fulminant meningococcal disease occurring in males, suggestive of X-linked properdin deficiency
- Meningococcal disease occurring in persons older than 10 years, especially when caused by non–group B meningococci (especially serogroups Y and W-135)
- Family history of systemic lupus erythematosus (SLE) or occurrence of atypical features of SLE, especially negative lupus serology findings (negative antinuclear antibody [ANA] and negative dsDNA findings)
- Specific syndromes such as partial lipodystrophy, angioedema, and paroxysmal nocturnal hemoglobinuria (PNH): Consider evaluation of the complement system in patients with these syndromes.
- Recurrent pyogenic infection, including severe pneumococcal diseases in infants and young children with normal humoral immune workup findings
See the list below:
- Classical pathway deficiencies - C1, C4, and C2
- Deficiencies of the classical complement pathway have been strongly linked to the development of autoimmune disorders, especially those in which excessive immune complexes are formed. Patients may develop collagen vascular disorders, mainly SLE. Ninety-five percent of patients with C1q deficiency, 75% of those with C4 deficiency, 30% of those who are deficient in C2, and 50-55% of those who are deficient in C1r and C1s (deficiency usually involves both C1r and C1s) develop collagen vascular diseases (mainly SLE). Evidence suggests that this may result from the combination of impaired complement-dependent B-cell tolerance and impaired clearance of immune complex and apoptotic cells.
- C1 deficiency generally leads to severe immune complex disease with features of SLE and glomerulonephritis. Serum levels of anti-C1q antibodies were increased significantly in patients with SLE and proliferative nephritis. Among different serological parameters for assessing the renal activity of SLE, only anti-C1q antibodies titers showed significant differences between quiescent and active lupus nephritis. Patients with C2 deficiency are reported to reveal anti-C1q antibody in the absence of anti-dsDNA.
- Complete C4 deficiency is rare. Two genes, C4A and C4B, encode the C4 complement. Both genes are highly polymorphic, and, to date, at least 35 different alleles have been described. Almost all patients with complete C4 deficiency have discoid or SLE, with or without associated glomerulonephritis.
- C2 deficiency has been the most commonly reported classical pathway defect. Skin and joint manifestations are common, and renal disease is relatively rare. Patients with C2 deficiency are also reported to have recurrent or invasive infections.
- C3 deficiency
- C3 deficiency is rare. Because of its importance as a convergence point of the 3 complement pathways, all patients with C3 deficiency develop recurrent, severe, pyrogenic infections early in life. Some patients may also develop membranoproliferative glomerulonephritis.
- C3 deficiency leads to an inability to formulate membrane attack complex (MAC), thus markedly compromising chemotactic and bactericidal activities of the complement cascade.
- Patients with C3 deficiency generally have less than 1% of the normal amount of C3 antigen and C3 function in their serum.
- Because of ineffective opsonization of pathogens, patients with C3 deficiency present with severe recurrent pyogenic infections, mainly caused by meningococci and pneumococci.
- According to published studies, 78% of patients have repeated infections, and 79% experience autoimmune disorders, such as arthralgia and vasculitic rashes, lupuslike syndrome, and membranoproliferative glomerulonephritis.
- Alternate pathway deficiencies (properdin, factor B, factor D)
- These deficiencies are rare. Properdin deficiency is associated with increased risk of infections with encapsulated bacterial organisms. Patients often present with a history of invasive meningococcal diseases, as well as severe pneumococcal and H influenzae infection. Recurrent infections may be rare in patients with properdin deficiency because the classical pathway can take over the actions of the alternate pathway once antigen-specific adaptive immune responses are established with immunoglobulin (Ig)G and IgM antibody formation.
- Only 3 adults with factor D deficiency have been described in the literature. A 6-day-old newborn boy with pneumococcal sepsis and meningitis was diagnosed with complete deficiency of factor D and diminished functional factor B. The addition of purified factor D restored the capacity of the patient's serum to generate the alternate pathway fluid-phase C3 convertase (C3bBbP) in response to zymosan. This also restored activity of factor B in the patient's serum. In contrast, the addition of factor B did not alter factor D activity in the serum, indicating requirement of factor D for function of factor B.
- Late complement component deficiencies - C5, C6, C7, C8, and C9
- MAC cannot be formed; hence, bactericidal activity is depressed.
- Patients are susceptible to recurrent pyogenic infections.
- Patients typically present with meningococcal meningitis or extragenital gonococcal infection.
- Two thirds of patients experience at least one episode of meningococcal disease, and as many as one half of patients experience recurrent neisserial infections.
- Patients with C9 deficiency have the ability to kill Neisseria, but at a slower rate.
- Deficiency of C1INH (HAE): This leads to recurrent episodes of angioedema. See Angioedema (Hereditary).
- Mannose-binding lectin (MBL) pathway deficiency
- Newborns with MBL deficiency are at increased risk for infection. Individuals with MBL deficiency have a higher propensity for severe infection in early life.
- In young children and newborns with repeated infections, MBL defects should be considered.
- Worsening clinical features are also reported in patients with rheumatoid arthritis and MBL deficiency.
- In a study of patients with cystic fibrosis (CF) with or without MBL variant alleles, Garred et al found the following:
- Lung function in carriers of MBL variant alleles was significantly reduced compared with patients with normal homozygotes.
- The negative impact of variant alleles on lung function was especially confined to patients with CF and chronic Pseudomonas aeruginosa infection.
- Burkholderia cepacia (previously named Pseudomonas cepacia) infection was significantly more frequent in patients with CF and MBL variant alleles.
- Using a modified life table analysis, the authors estimated that the predicted age of survival was reduced by 8 years in patients with CF who carried variant alleles compared with normal homozygotes with CF.
- C3 nephritic factor (C3NeF) and mesangiocapillary glomerulonephritis (MCGN)
- C3Nef is an autoantibody that binds to and stabilizes the C3 convertase (C3bBb).
- The association of C3NeF and MCGN, especially MCGN type II, has been well defined. Different isotypes of C3NeF are recognized, the main one being an IgG autoantibody against factor H. Factor H is an important regulator of the C3 conversion step in the alternate pathway. C3NeF inhibits functions of factor H, which leads to overwhelming complement activation at the stage of C3 conversion. Continuous C3 activation in vivo results in the well-known consequences of very low serum levels of C3 in MCGN.
- C3NeF may act directly within glomeruli to cause local complement activation and ensuing renal damage.
- C3Nef is also associated with partial lipodystrophy.
- Factor H deficiency
- Factor H deficiency is associated with hemolytic-uremic syndrome (HUS), especially in familial cases that involve homozygous factor H deficiency.
- Factor H deficiency also occurs with membranoproliferative glomerulonephritis.
- Parents have one half the normal levels of factor H.
- HUS associated with factor H deficiency is characterized by verotoxin-negative (diarrhea-negative) HUS. Atypical and recurrent HUS is also seen in CD46 deficiency.
See the list below:
- Classical pathway deficiencies (C1, C4, C2) are inherited in an autosomal recessive pattern.
- C3 deficiency is inherited in an autosomal recessive pattern.
- No known homozygous deficiency of factor B has been reported, although one heterozygous case has been described. Properdin deficiency is the only X-linked complement deficiency. All reported cases of properdin deficiency involve males.
- Late complement component deficiencies (ie, C5, C6, C7, C8, C9) are inherited in an autosomal recessive fashion.
Clarke EV, Weist BM, Walsh CM, Tenner AJ. Complement protein C1q bound to apoptotic cells suppresses human macrophage and dendritic cell-mediated Th17 and Th1 T cell subset proliferation. J Leukoc Biol. 2014 Nov 7. [Medline].
Ghannam A, Fauquert JL, Thomas C, Kemper C, Drouet C. Human complement C3 deficiency: Th1 induction requires T cell-derived complement C3a and CD46 activation. Mol Immunol. 2014 Mar. 58(1):98-107. [Medline].
Garred P, Pressler T, Madsen HO, et al. Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. J Clin Invest. 1999 Aug. 104(4):431-7. [Medline].
Tedesco F. Inherited complement deficiencies and bacterial infections. Vaccine. 2008 Dec 30. 26 Suppl 8:I3-8. [Medline].
Daures M, John M, Balter CV, Simon O, Barguil Y, Missotte I, et al. Relationships Between Clinico-Epidemiological Patterns of Invasive Meningococcal Infections and Complement Deficiencies in French South Pacific Islands (New Caledonia). J Clin Immunol. 2014 Oct 29. [Medline].
AAP 2000 Red Book. Report of the Committee on Infectious Diseases. 25th ed. 2000. 56-7.
Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005 May. 94(5 Suppl 1):S1-63. [Medline].
Carroll MC. CD21/CD35 in B cell activation. Semin Immunol. 1998 Aug. 10(4):279-86. [Medline].
Cicardi M, Castelli R, Zingale LC, Agostoni A. Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients. J Allergy Clin Immunol. 1997 Feb. 99(2):194-6. [Medline].
Cohen J. Meningococcal disease as a model to evaluate novel anti-sepsis strategies. Crit Care Med. 2000 Sep. 28(9 Suppl):S64-7. [Medline].
Endo M, Ohi H, Ohsawa I, et al. Complement activation through the lectin pathway in patients with Henoch-Schonlein purpura nephritis. Am J Kidney Dis. 2000 Mar. 35(3):401-7. [Medline].
Frank MM. Complement deficiencies. Pediatr Clin North Am. 2000 Dec. 47(6):1339-54. [Medline].
Jackson LA, Schuchat A, Reeves MW, Wenger JD. Serogroup C meningococcal outbreaks in the United States. An emerging threat. JAMA. 1995 Feb 1. 273(5):383-9. [Medline].
Jansen AG, Sanders EA, Hoes AW, van Loon AM, Hak E. Effects of influenza plus pneumococcal conjugate vaccination versus influenza vaccination alone in preventing respiratory tract infections in children: a randomized, double-blind, placebo-controlled trial. J Pediatr. 2008 Dec. 153(6):764-70. [Medline].
Kainulainen L, Peltola V, Seppänen M, Viander M, He Q, Lokki ML, et al. C4A deficiency in children and adolescents with recurrent respiratory infections. Hum Immunol. 2012 Feb 26. [Medline].
Kang HJ, Kim HS, Lee YK, et al. High incidence of complement C9 deficiency in Koreans. Ann Clin Lab Sci. 2005. 35(2):144-8. [Medline].
Kumar A, Gupta R, Varghese T, et al. Anti-C1q antibody as a marker of disease activity in systemic lupus erythematosus. Indian J Med Res. 1999 Dec. 110:190-3. [Medline].
Levi M, Choi G, Picavet C, Hack CE. Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency. J Allergy Clin Immunol. 2006 Apr. 117(4):904-8. [Medline].
Manderson AP, Botto M, Walport MJ. The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol. 2004. 22:431-56. [Medline].
Momeni N, Bergquist J, Brudin L, Behnia F, Sivberg B, Joghataei MT. A novel blood-based biomarker for detection of autism spectrum disorders. Transl Psychiatry. 2012. 2:e91. [Medline].
Moroni G, Trendelenburg M, Del Papa N, et al. Anti-C1q antibodies may help in diagnosing a renal flare in lupus nephritis. Am J Kidney Dis. 2001 Mar. 37(3):490-8. [Medline].
Notarangelo L, Casanova JL, Conley ME, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005. J Allergy Clin Immunol. 2006 Apr. 117(4):883-96. [Medline].
Ratnoff WD. Inherited deficiencies of complement in rheumatic diseases. Rheum Dis Clin North Am. 1996 Feb. 22(1):75-94. [Medline].
Ross SC, Densen P. Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. Medicine (Baltimore). 1984 Sep. 63(5):243-73. [Medline].
Rougier N, Kazatchkine MD, Rougier JP, et al. Human complement factor H deficiency associated with hemolytic uremic syndrome. J Am Soc Nephrol. 1998 Dec. 9(12):2318-26. [Medline].
Salzman MB, Rubin LG. Meningococcemia. Infect Dis Clin North Am. 1996 Dec. 10(4):709-25. [Medline].
Sjoholm AG, Jonsson G, Braconier JH, et al. Complement deficiency and disease: an update. Mol Immunol. 2006 Jan. 43(1-2):78-85. [Medline].
Sturfelt G, Truedsson L. Complement and its breakdown products in SLE. Rheumatology (Oxford). 2005 Oct. 44(10):1227-32. [Medline].
Sullivan KE. Genetics of systemic lupus erythematosus. Clinical implications. Rheum Dis Clin North Am. 2000 May. 26(2):229-56, v-vi. [Medline].
Ten RM, Carmona EM, Babovic-Vuksanovic D, Katzmann JA. Mannose-binding lectin deficiency associated with neutrophil chemotactic unresponsiveness to C5a. J Allergy Clin Immunol. 1999 Aug. 104(2 Pt 1):419-24. [Medline].
U. S. Department of Health and Human Services. Control and Prevention of Meningococcal Disease and Control and Prevention of Serogroup C Meningococcal Disease: Evaluation and Mangement of Suspected Outbreaks. Morbidity and Mortality Weekly Report. February 14, 1997. 46:[Full Text].
van Geffen M, Cugno M, Lap P, Loof A, Cicardi M, van Heerde W. Alterations of coagulation and fibrinolysis in patients with angioedema due to C1-inhibitor deficiency. Clin Exp Immunol. 2012 Mar. 167(3):472-8. [Medline].
Walport MJ. Complement. First of two parts. N Engl J Med. 2001 Apr 5. 344(14):1058-66. [Medline].
Walport MJ. Complement. Second of two parts. N Engl J Med. 2001 Apr 12. 344(15):1140-4. [Medline].
Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med. 1996 Jun 20. 334(25):1630-4. [Medline].
Weiss SJ, Ahmed AE, Bonagura VR. Complement factor D deficiency in an infant first seen with pneumococcal neonatal sepsis. J Allergy Clin Immunol. 1998 Dec. 102(6 Pt 1):1043-4. [Medline].
Wen L, Atkinson JP, Giclas PC. Clinical and laboratory evaluation of complement deficiency. J Allergy Clin Immunol. 2004 Apr. 113(4):585-93; quiz 594. [Medline].
West CD, McAdams AJ. The alternative pathway C3 convertase and glomerular deposits. Pediatr Nephrol. 1999 Jun. 13(5):448-53. [Medline].
Whaley K, Ruddy S. Modulation of C3b hemolytic activity by a plasma protein distinct from C3b inactivator. Science. 1976 Sep 10. 193(4257):1011-3. [Medline].
Wiertsema SP, Herpers BL, Veenhoven RH, et al. Functional polymorphisms in the mannan-binding lectin 2 gene: effect on MBL levels and otitis media. J Allergy Clin Immunol. 2006 Jun. 117(6):1344-50. [Medline].
Williams DG. C3 nephritic factor and mesangiocapillary glomerulonephritis. Pediatr Nephrol. 1997 Feb. 11(1):96-8. [Medline].