Complement deficiencies, diagnosis and management Classification: Protocol Lead Author: Dr Hana Alachkar Additional author(s): Victoria Blakeley Authors Division: Tertiary Medicine Unique ID: D5 Issue number: 4 Expiry Date: June 2019 Contents Section Page Who should read this document 2 Key points 2 Background/ Scope 2 What is new in this version 2 Policy/Procedure/Guideline 2 1 Use clear section headings 2 Include hyperlinks if you think they will help navigation 3 etc Standards 5 Explanation of terms/ Definitions 5 References and Supporting Documents 6 Roles and Responsibilities 6 1 2 3 Appendix Document control information (Published as separate document) Document Control 7 Policy Implementation Plan 7 Monitoring and Review 8 Endorsement 8 Equality analysis 9 Page 1 of 6
Who should read this document? Immunology medical team Immunology Nurses Other teams in the trust as a reference/guideline Key Messages This protocol describes the evaluation and management of patients with suspected complement deficiency to ensure that diagnostic tests and treatment meets the needs and requirements of such patients and conforms to accepted national guidelines Background & Scope This protocol describes the evaluation and management of patients with suspected complement deficiency to ensure that diagnostic tests and treatment meets the needs and requirements of such patients and conforms to accepted national guidelines What is new in this version? This is an updated version but there are no important changes to the content Policy/ Guideline/ Protocol The complement system is part of the innate immune system. The complement system plays an important part in defence against pyogenic organisms. It promotes the inflammatory response, eliminates pathogens, and enhances the immune response. The complement system is also important for the clearance of immune complexes and apoptotic cells. Deficiencies of the complement components result in susceptibility to infections either specifically to neisserial species in some cases or to bacterial infections generally. There is also a marked susceptibility to autoimmune disease in early complement component defects. Deficiencies in complement predispose patients to infection via 2 mechanisms: (1) ineffective opsonization and (2) defects in lytic activity (defects in MAC). Deficiency of complement components is most commonly secondary to consumption in inflammatory disease processes. Genetically determined primary deficiencies of all the complement cascade factors can occur, but are rare. Page 2 of 6
Complement deficiency and disease association C1, C4 & C2 Deficiency: Autoimmune disease, especially Systemic Lupus Erythematosous (SLE), is the most common presentation in patients with early component deficiency. The incidence rates of SLE in individuals with C1q and C4 are reported to be around 90% and 75%, respectively. Patients with C2 deficiency develop SLE with lesser frequency (around 15%). The proposed mechanisms of high incidence of autoimmune diseases include impaired clearance of immune complex and apoptotic cells and loss of complement-dependent B-cell tolerance. Recurrent bacterial infection is common in patients with C2 deficiency. Mannose-Binding lectin (MBL) pathway including MASP-2 deficiency: Frequent pyogenic infection, including pneumococcal infection in infants and young children. Alternative pathway (properdin, factor B, factor D): Severe fulminant neisserial infections with a high mortality rate. C3, factor H, and factor I: Deficiency of these factors predisposes individuals to severe pyogenic bacterial infections. Factor H and factor I deficiencies cause secondary C3 deficiency with C3 consumption and impose the same infectious risk as primary C3 deficiency. Factor H deficiency is also associated with atypical (diarrhea-negative) hemolytic-uremic syndrome (HUS) and glomerulonephritis. C3 deficiency is associated with membranoproliferative glomerulonephritis. Terminal pathway (C5-C9) Deficiency: The lack of Membrane Attack Complex (MAC) formation results in severe recurrent infection with Neisseria gonorrhoeae or Neisseria meningitidis. C1INH: (hereditary or acquired) leads to uninhibited cleavage of C4 by C1s, results in recurrent episodes of angioedema Decay Accelerating Factor (DAF) and CD59 deficiency: Paroxysmal nocturnal hemoglobinuria (PNH) This protocol does not include C1INH deficiency or DAF and CD59 deficiency management. Differential Diagnosis Hypogammaglobulinemia, SLE with complement consumption, serum sickness. Investigations: Consider complement Deficiency in the following Recurrent meningococcal disease (40% incidence of complement deficiency) Single episode of meningococcal disease caused by an unusual sero-group organism eg W135, X, Y (20-50% incidence of complement deficiency) Family history of meningococcal disease (10% incidence of complement deficiency) Recurrent pneumococcal, streptococcal or haemophilus infections (Consideration should be given to excluding other primary Page 3 of 6
immunodeficiencies, in particular antibody deficiency, before extensive complement investigations are undertaken) Recurrent minor infections in preschool children with normal Igs (MBL pathway) Autoimmune disease: o Severe, familial, early onset or atypical SLE and glomerulonephritis o Antinuclear Antibodies (ANA) negative SLE How to investigate complement defects 1. Check classical and alternative haemolytic pathways (CH50 and AP50) Classical Pathway defect Alternative pathway defect Terminal pathway defect (+factor H and I deficiencies) CH50 Normal AP50 Normal 2. Individual complement components can then be measured 3. Low C3 and C4 levels suggest activation of the classical pathway 4. Low C3 and normal C4 levels suggest activation of the alternate pathway NB: It should be remembered that many of the complement factors are labile so that serum samples need to be separated and frozen at 70 0 C within 3 hours of collection. If transport to the laboratory may be delayed, specimens should be kept and transported on ice. Management Autoimmune disease Management is as for non-complement deficient disease (by Rheumatologists or Nephrologists), although the disease may be more severe and require more aggressive treatment. Infections -Supportive 1. Antibiotic prophylaxis. Penicillin V if susceptibility restricted to neisserial disease. Azithromycin, Augmentin, Cefixime or Septrin if broader susceptibility 2. Vaccinate against as many bacterial pathogens as possible including Hib, meningococcal A, C, W135, and Y conjugate vaccine (2 doses-2 months apart), and conjugate pneumococcal (prevenar) followed by polysaccharide pneumococcal vaccines. Page 4 of 6
3. Conjugate vaccines are preferred over pure polysaccharide vaccines 4. Patients with complement deficiency may receive all routine vaccines safely and are not at increased risk for adverse reactions to live viral vaccines. Responses should be checked and re-vaccination given as necessary. 5. Fresh frozen plasma infusion can be given to replace factors in the context of severe infection but no good evidence that these help. If found to be of benefit in an individual patient and long term or repeated plasma infusions is to be used, use of a detergent treated plasma product should be considered. 6. Policy Implementation Plan It is the responsibility of the Consultant Immunologist in consultation with Specialist registrar and Immunology Specialist nurse to implement this protocol The Clinical immunology team will be responsible for reviewing progress in implementation The protocol will be implemented within Immunology clinic/ team meetings by the all team members Standards United Kingdom Primary Immunodeficiency Network (UKPIN) guidelines www.pinguidelines.org.uk European Society for Immunodeficiency (ESID) diagnostic Criteria for Primary Immune Deficiency (PID). www.esid.org Explanation of terms & Definitions Terms explained in document References and Supporting Documents Adapted from UKPIN guidelines www.pinguidelines.org.uk Figueroa JE, Densen P (1991) Infectious diseases associated with complement deficiencies. Clin Microbiol Rev;4: 359-95 Fijen CAP, Kuijper EJ te BulteMT et al (1999) Assessment of complement deficiency in patients with meningococcal disease in the Netherlands. Clin Inf Dis ;28: 98-105 Sullivan KE, Winkelstein J (1999). Primary Immunodeficiency Diseases. Eds Ochs H, Smith CIE, Puck J. Oxford University Press Page 5 of 6
Roles and responsibilities Consultant Immunologist/ Specialist Registrar: Initial clinic assessment of patient with possible complement deficiency Investigations and diagnosis Discuss management and treatment options with patient/ family/ specialist Nurse Initiate treatment, obtain consent if applicable Follow up patient in clinic Specialist Immunology Nurse: Initiate blood sampling/ investigations Give immunisations if applicable/ follow up samples Discuss treatment options with patient and family Page 6 of 6