The immune system is the body’s defense mechanism against infections and is made of two pathways - the innate and adaptive pathway. The innate pathway is present from birth and is pre-programmed. The innate immune system consists of the cellular component, which includes monocytes, macrophage, and natural killer cells, and the humoral component, which includes the complement system. The adaptive pathway develops during life with exposure to infection and increases affinity with experience. It consists of the cellular component, which is T cells, and the humoral component, which consists of antibodies made by B cells. The adaptive pathway facilitates improved destruction of the organism as well as form memory cells for future infections.
The complement system is a crucial part of the innate humoral immune system. The purpose of the complement system is to orchestrate opsonization, facilitate cytotoxic destruction and formulate membrane attack complexes (MAC), and liberation of peptides that promote the inflammatory response. The complement system consists of 3 pathways, the classical, alternative, and lectin, that are initiated by distinct mechanisms. The classical pathway is initiated by C1, C2, C4, and antigen-antibody immune complex. The lectin pathway is initiated by lectins, mannose-binding protein, sugar residues on the microbial surface, C4, and C2. The alternative pathway is initiated by C3, factor B, factor D, and properdin. These 3 pathways all share a common terminal pathway consisting of C5 to C9. The final outcome of the late pathway is to form a MAC that penetrates the cell membrane and facilitates cell death by lysis. Opsonization is the process of utilizing cleaved components of complement, C3b, and C4b, whereas inflammation is the process utilizing C3a and C5a, as anaphylatoxins.
Complement deficiencies are usually hereditary. The most common type is autosomal recessive form, including C1, C2, C3, C4, C5, C6, C7, C8, C9, and Mannan-binding lectin deficiencies. The X-linked recessive pattern has been described for properdin deficiency. Other complement deficiencies are acquired through complement overconsumption, protein synthesis dysfunction, protein loss disorders, autoimmunity, and high catabolic states. Deficiencies of early components of the classical complement pathway, including C1, C4, and C2, are associated with encapsulated bacterial infections like streptococcus pneumoniae and Haemophilus Influenza Type b. A deficiency of C3 is associated with severe recurrent pyogenic infections early in life. Deficiencies of the late common pathway (C5, C6, C7, C8, and C9) are associated with increased Neisseria infections, including Neisseria meningitidis and Neisseria gonorrhoeae. A deficiency of properdin in the early alternative pathway is also associated with recurrent Neisseria infection. A deficiency of mannan-binding lectin has been linked to an increased frequency of pyogenic infections and sepsis, particularly in children and neonates, when the adaptive immune system has not been matured. In addition to increased incidence of infection, an individual with early classical complement deficiency (C1, C4, or C2) frequently has a higher incidence of autoimmunity, especially systemic lupus erythematosus. Early classical complements like C1 bind to cells undergoing apoptosis and facilitate the elimination of such cells. The body produces autoantibodies against these uncleared cells that result in autoimmune disorders.
The mannan-binding lectin (MBL) pathway of the lectin-based pathway is the most prevalent form of complement deficiency at 5% of the White population and may be clinically silent. Apart from the MBL pathway, complement deficiencies are prevalent in 0.03% of the population. Deficiency of C2 protein is the second most common form after MBL deficiency and is also clinically silent. C3 is a crucial player in the complement system as this protein is the last step of the early pathway, a precursor to C3a the anaphylatoxin as well as a facilitator of chemotaxis for neutrophils and macrophages. Among all patients with primary immunodeficiency diseases, approximately 5% have complement deficiency. The most common type of primary immunodeficiency is antibody deficiency consisting of approximately 65% of the cases.
History is the most important initial diagnostic tool for ruling out complement immunodeficiency. Recurrent Neisseria infection indicates possible late complement deficiencies (C5-C9) and early alternative pathway deficiency (properdin) deficiency. Severe recurrent pyogenic infection early in life should be an indication to rule out C3 immunodeficiency. One should also suspect complement deficiency in a patient with recurrent sinopulmonary infection with normal humoral (antibody) immunity and with/without autoimmunity. Pyogenic infections and sepsis in children and neonates should make one suspect mannan-binding lectin deficiency.
The examination may be normal if the patient is not actively infected or has autoimmunity. If the patients have active pneumococcal pneumonia, physical exam shows crackles or bronchial breath sounds on lung auscultation at peripheral lung fields. Egophony can be noted when significant consolidation is present. Examination of patients with meningitis includes a stiff neck. Patients may have positive Kernig or Brudzinski signs that show meningeal irritation. Other signs of Neisseria meningitidis infection include petechial rash and, in severe cases, can present with septic shock or DIC. Patients with early classical complement deficiencies may present swollen and/or inflamed joints, suggesting autoimmunity.
Patients with recurrent infections of respiratory tract without risk factors (negative HIV, no asplenia, no other immunodeficiencies) as well as recurrent infections of encapsulated organisms such as Streptococcus pneumoniae, Neisseria meningitidis, and Hemophilus influenzae should be screened for complement deficiency. Patients with family members who have recurrent pneumococcal and meningococcal disease should also be screened.
Screening for the complement system includes tests for the classical complement pathway (CH50), the alternate pathway (AH50), and the mannose-binding lectin (MBL) pathway (MBL by Elisa). Low CH50 and normal AH50 suggest early classical complement component (C1, C2, and C4) deficiency. Low AH50 with normal CH50 suggests deficiency of early alternative complement pathway factors (factor B, factor D, and properdin). Low AH50 and low CH50 suggest common terminal complement (C3, C5, C6, C7, C8, or C9) deficiency. If CH50 and AH50 are both normal and the clinician still suspects complement deficiency, MBL functional assay is indicated to screen for MBL deficiency.
Complement deficiency is not typically treated with complement protein supplementation due to the infeasibility of overly frequent infusions, risk for bloodborne infections, and risk of developing antibodies to exogenous complement proteins. This condition is managed on a case-by-case basis with antibiotics for each episode of infection as well as regular visits with their immunologist. Due to this population’s vulnerability to encapsulated organisms, patients need to be aware of the symptoms of meningococcal infection and contact their doctor immediately. Patients with complement deficiency should undergo all routine bacterial and viral vaccinations, especially meningococcal and pneumococcal vaccinations, and do not have a contraindication to live vaccines.
The differential diagnosis for these recurrent infections broadly includes B cell immunodeficiency, combined immunodeficiency, acquired immunodeficiencies, as well as asplenia with predisposition for encapsulated organisms. The differential includes complement deficiency, asplenia, common variable deficiency, hypogammaglobulinemia, HIV, chronic granulomatous disease, Chediak-Higashi syndrome, leukocyte adhesion deficiency, cyclic neutropenia, and SLE.
Prognosis of this condition depends on the recurrence infection rate as well as the severity of the episode of infection at the time. Many of these patients are at high risk for meningitis that can be life-threatening if untreated. Infections need to be treated on an episodic basis, and patients may be given prophylactic antibiotics for sudden recurrences. Vaccination is an important preventive measure, especially vaccination, to prevent meningococcal and pneumococcal infections.
Complications include severe pneumococcal and meningococcal infections that can be fatal if not evaluated and treated adequately. Patients may also develop autoimmune disorders, especially systemic lupus erythematosus.
Patients with recurrent pneumococcal and/or meningococcal infections without predisposing risk factors should be referred to the allergist/immunologist.
Patients with recurrent infections are simply treated without evaluation of infection recurrence. Patients continue to have recurrent infections, further damaging the affected organ. Better education to healthcare providers of expected signs and symptoms of pneumococcal and meningococcal infections may improve patient outcomes with more expedited evaluation.
Complement deficiency can lead to life-threatening infections as well as long term autoimmune conditions and organ injuries. The interdisciplinary team of the primary care physician and emergency medicine team must be aware of the clinical features of patients with complement deficiency or immunodeficiency in general. Relying on acute treatment when the patient is acutely ill may not be adequate to improve the patient's quality of life and clinical outcome. A high index of suspicion is important, and early referral to allergist/immunologists may be important when the diagnosis of immunodeficiency is not clear.
|||Müller-Eberhard HJ, Complement. Annual review of biochemistry. 1975; [PubMed PMID: 1094920]|
|||Gigli I, Immunochemistry and immunobiology of the complement system. The Journal of investigative dermatology. 1976 Sep; [PubMed PMID: 787430]|
|||Schröder-Braunstein J,Kirschfink M, Complement deficiencies and dysregulation: Pathophysiological consequences, modern analysis, and clinical management. Molecular immunology. 2019 Oct; [PubMed PMID: 31421540]|
|||Grumach AS,Kirschfink M, Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Molecular immunology. 2014 Oct; [PubMed PMID: 25037634]|
|||Schur PH, Inherited complement component abnormalities. Annual review of medicine. 1986; [PubMed PMID: 3010807]|
|||Lewis LA,Ram S, Meningococcal disease and the complement system. Virulence. 2014 Jan 1; [PubMed PMID: 24104403]|
|||Audemard-Verger A,Descloux E,Ponard D,Deroux A,Fantin B,Fieschi C,John M,Bouldouyre A,Karkowsi L,Moulis G,Auvinet H,Valla F,Lechiche C,Davido B,Martinot M,Biron C,Lucht F,Asseray N,Froissart A,Buzelé R,Perlat A,Boutboul D,Fremeaux-Bacchi V,Isnard S,Bienvenu B, Infections Revealing Complement Deficiency in Adults: A French Nationwide Study Enrolling 41 Patients. Medicine. 2016 May; [PubMed PMID: 27175654]|
|||Ekdahl KN,Persson B,Mohlin C,Sandholm K,Skattum L,Nilsson B, Interpretation of Serological Complement Biomarkers in Disease. Frontiers in immunology. 2018; [PubMed PMID: 30405598]|
|||Ram S,Lewis LA,Rice PA, Infections of people with complement deficiencies and patients who have undergone splenectomy. Clinical microbiology reviews. 2010 Oct; [PubMed PMID: 20930072]|
|||Sobh A,Bonilla FA, Vaccination in Primary Immunodeficiency Disorders. The journal of allergy and clinical immunology. In practice. 2016 Nov - Dec; [PubMed PMID: 27836056]|
|||Műzes G,Sipos F, [Primary immunodeficiency and autoimmune diseases]. Orvosi hetilap. 2018 Jun; [PubMed PMID: 29860882]|