Terminal Complement Component Deficiencies Research Articles

#92: What Is the Optimal Management of Patients Immunosuppressed with the Anti-compliment Monoclonal Antibody, Eculizumab? A Case Report and Review

Abstract Background Patients with deficiencies of terminal components of complement are at hundreds to thousands fold increased risk of severe and fatal Neisseria spp. infections compared with the general population. Eculizumab is a newly approved monoclonal antibody C5 complement inhibitor. It is indicated for the treatment of atypical hemolytic uremic syndrome (atypical HUS), myasthenia gravis, and paroxysmal nocturnal hemoglobinuria. Because of the complement-depleting effect of Eculizumab dosing (Soliris®, Alexion Pharmaceuticals, Munich, Germany), patients are immunosuppressed for specific infectious pathogens (including Neisseria species) against which protection partially relies on normal complement activity. Because Eculizumab treatment is associated with a dramatically increased risk of Neisseria species. infections, recommendations for Neisseria meningitidis vaccination and antibiotic prophylaxis are contained in Eculizumab prescribing information. However, the most appropriate prevention of infections after Eculizumab has yet to be determined. Methods Case report and literature review. Results A previously healthy 7-year-old male was diagnosed with atypical HUS which included renal failure progressing to dialysis, persistent thrombocytopenia, hemolytic anemia, and hemoglobinuria. Stool cultures and a stool multiplex PCR panel did not detect Shiga-like producing E. coli nor E. coli O157/H7. Eculizumab dosing was therefore planned and Infectious Diseases consultation was obtained for appropriate preventions. The FDA Prescribing Information recommends Neisseria meningitidis vaccination before starting Eculizumab or, if immediate Eculizumab is necessary, to use antibiotic prophylaxis until 2 weeks after vaccination. The accepted protective titer after meningococcal vaccination is population based and uses the serum bactericidal assay (SBA). An antibody titer of >1:4 (human compliment) or 1:8 (rabbit complement) is considered protective. However, this “gold standard” assay incorporates the use of exogenous human or rabbit complement. The protective SBA titers in subjects with terminal complement component deficiencies may not be properly assessed using these same SBA titer protective thresholds. Furthermore, serious meningococcal infections have occurred after appropriate vaccination in patients receiving chronic Eculizumab treatments (ie for paroxysmal nocturnal hemoglobinuria). Finally, SBA protective levels after single Neisseria meningitidis vaccination have not been achieved in majorities of patients with renal failure receiving dialysis and or transplant immunosuppression. Conclusions The current Eculizumab prescribing information recommendations for vaccination and antimicrobial prophylaxis may be inadequate to prevent serious Neisseria infections. Repeated Neisseria meningitidis vaccination and extended antibiotic prophylaxis may afford better protection in patients chronically dosed with Eculizumab.

Meningococcal vaccine: Position statement of the Society for Adolescent Medicine

The incidence of meningococcal disease peaks during the neonatal years and again during the adolescent years. Most adolescent cases are vaccine preventable using the current tetravalent meningococcal vaccines. In February 2005 the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention recommended routine immunization with the tetravalent conjugate meningococcal vaccine of all 11–12-year-olds with the interim recommendation including all 14–15-year-olds and special targeted populations to include incoming college freshmen living in dormitories military recruits certain travelers microbiologists working with Neisseria meningitidis and those with terminal complement component deficiencies and asplenia. The Society for Adolescent Medicine strongly supports the ACIP recommendations and encourages vaccination of all youth who are 11 years of age or greater with the tetravalent conjugate meningococcal vaccine. (excerpt)

CH50 and Its Use in the Allergist–Clinical Immunologist's Practice

The CH50 reflects the ability of serum complement to lyse sheep red blood cells (RBCs); its value is the reciprocal of the dilution of serum to lyse 50% of antibody coated sheep RBCs. Reduction of the CH50 occurs when individual complement component(s) are deficient or consumed. The CH50 may be useful for a variety of medical specialties and is most helpful diagnostically when laboratory results are interpreted in the context of the history and physical exam. The primary utility of the CH50 in the practice of an allergist-immunologist is to screen for complement-deficiency associated immunodeficiency (primarily classic or terminal complement component deficiencies) and some vasculitides (usually immune-complex induced and/or small vessel vasculitis). Absent or significantly reduced individual complement components may result in recurrent sinopulmonary bacterial infections, Neisserial meningitis, or sepsis. A reduced CH50 in this situation warrants quantification and functional assays of individual complement components The sensitivity and specificity of a reduced CH50 limit the value of using this test for vasculitis screening unless painful, persistent urticarial lesions or purpura is observed. Thus, the CH50 has definite limitations but serves as a costeffective, screening test with the appropriate clinical presentation.

C7 complement deficiency in an Israeli Arab village.

Deficiencies of terminal complement components, particularly the latter ones, are often detected because of increased susceptibility to Neisserial infections. Herein we document the first report of C7 deficiency among a highly inbred Arab population living in the lower Galilee region of Israel. Both biochemical and molecular analysis were performed on samples from infected survivors and parents of children who succumbed to Neisserial infections in a 4-year period. Only the index case who suffered recurrent infections and a sibling who had not suffered an infection during the outbreak were found to be C7-deficient. The mutation was found to be the one previously described to be prevalent among Israeli Jews of Moroccan ancestry (mutation G1135C). The implications of this finding are discussed in the context of family pedigree, the protective effect of complement deficiency, and the clinical outcome.

C7 deficiency in an Irish family: a deletion defect which is predominant in the Irish.

Human deficiencies of terminal complement components are known to be associated with increased susceptibility to Neisseria meningitidis infection. Polymorphic DNA marker studies in complement deficient investigations allow identification of haplotypes associated with the deficiency and enable the possible identification of heterozygote carriers of the defect. We report studies of an Irish family in which the index case had suffered recurrent meningococcal disease and was found to be deficient in the seventh component of complement (C7). The availability of all family members enabled us to determine the segregating haplotypes. The defects in the family segregated with two very closely related C6 and C7 DNA haplotypes, one of which is known to be associated with the large Irish C7 DNA deletion defect. The index case and two C7 deficient siblings were found to be homozygous for this defect, a deletion that spans approx. 6.8 kbp and encompasses exons 7 and 8. The deletion defect of exons 7 and 8 of C7 has been found in homozygous form in another C7 deficient Irish individual, and is present in heterozygous form in C7 deficient members of a third Irish family. Therefore, this deletion defect occurs in five of the six deficient chromosomes of these three unrelated Irish families, raising the interesting question of how prevalent this defect may be within the Irish community.

Properdin deficiency and meningococcal disease—identifying those most at risk

Properdin deficiency and meningococcal disease—identifying those most at risk

Prevalence of Homozygous C4B Deficiency in Patients with Deficiencies of Terminal Complement Components and Meningococcemia

Prevalence of Homozygous C4B Deficiency in Patients with Deficiencies of Terminal Complement Components and Meningococcemia

COMPLEMENT DEFICIENCIES IN PATIENTS OVER TEN YEARS OLD WITH MENINGOCOCCAL DISEASE DUE TO UNCOMMON SEROGROUPS

46 patients in whom meningococcal disease due to serogroups X, Y, Z, W135, or 29E had developed after the age of 10 years were investigated retrospectively for complement deficiency. Complement deficiency was found in half of the patients: properdin deficiency in 9 patients, C3 deficiency syndromes in 5, and homozygous deficiency of a terminal component (C5, C6, C7, or C8) in 9. Meningococcal infections recurred in 5 of the 9 patients with terminal complement component deficiencies but not in the other complement-deficient patients. The findings show that meningococcal disease due to uncommon serogroups is often associated with complement deficiency.

Recurrent Bacterial Meningitis due to Genetic Deficiencies of Terminal Complement Components (C5 and C6)

Recurrent Bacterial Meningitis due to Genetic Deficiencies of Terminal Complement Components (C5 and C6)