Fw: Complement Deficiencies

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Complement Deficiencies Last Updated: January 7, 2002 Synonyms and related keywords: C1qrs deficiency; C3 deficiency; C2, C4 deficiency; C5-9 deficiency; terminal membrane attack complex deficiencies; mannan-binding lectin deficiency AUTHOR INFORMATION Section 1 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Author: R Krishna Chaganti, MD, Staff Physician, Department of Internal Medicine, Temple University School of Medicine Coauthor(s): Darrilyn Moyer, MD, Associate Program Director, Associate Professor, Department of Internal Medicine, Temple University School of Medicine; Margaret R Donohoe, MD, Consulting Staff, Department of Allergy and Immunology, Albemarle Hospital; A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School Editor(s): Lee Kishiyama, MD, Assistant Clinical Professor of Medicine, University of California at San Francisco School of Medicine, Consulting Staff, Allergy and Asthma Associates of Santa Clara Valley Research Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; R Marney, Jr, MD, Director, Associate Professor, Department of Internal Medicine, Division of Allergy and Immunology, Vanderbilt University School of Medicine; D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, St Louis University; and A Kaliner, MD, Section Chief of Allergy and Immunology, Clinical Professor, Department of Internal Medicine, Washington University School of Medicine INTRODUCTION Section 2 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Background: The complement system is part of the innate immune system. The complement system plays an important part in defense against pyogenic organisms, especially gram-negative bacteria. Deficiencies in the complement cascade can lead to overwhelming infection and sepsis. In addition to playing an important role in host defense against infection, the complement system is a mediator in both the pathogenesis and prevention of immune complex diseases, such as systemic lupus erythematosus (SLE). These findings underscore the duality of the complement system. It has a protective effect when functioning in moderation against appropriate pathogens; at the same time, the inflammation promoted by complement activation can result in cellular damage when not kept in check. We are continuing to learn more about the complement system. New studies point to the complex interplay between the complement cascade and adaptive immune response, and complement also is being studied in association with ischemic injury as a target of therapy. Although the complement system is part of the body’s innate, relatively nonspecific defense against pathogens, its role is hardly primitive or easily understood. This article attempts to outline some of the disease states associated with complement deficiencies and their clinical implications. Pathophysiology: The complement cascade consists of 3 separate pathways that converge in a final common pathway. The pathways include the classical pathway (C1qrs, C2, C4), the alternative pathway (C3, factor B, properdin), and the mannan-binding pathway (mannan-binding lectin [MBL]). These 3 pathways converge at the component C3. The terminal complement pathway consists of all proteins activated after C3; the most notable of these is the C5-9 group of proteins known collectively as the membrane attack complex (MAC). The MAC exerts powerful killing activity by creating perforations in cellular membranes. Deficiencies in complement predispose patients to infection via 2 mechanisms: (1) ineffective opsonization and (2) defects in lytic activity (defects in MAC). Specific complement deficiencies also are associated with an increased risk of developing autoimmune disease, such as SLE. There also is an intricate system that regulates complement activity. The important components of this system are various cell membrane-associated proteins such as complement receptor 1 (CR1), complement receptor 2 (CR2), and decay accelerating factor (DAF). In addition to these cell surface-associated proteins, other plasma proteins regulate specific steps of the classical or alternative pathway; for example, the proteins factor H and factor I inhibit the formation of the enzyme C3 convertase of the alternative pathway. Similarly, the enzyme C1q esterase acts as an inhibitor of the classical pathway serine proteases C1r and C1s. Deficiency of any of these regulatory proteins results in a state of overactivation of the complement system with damaging inflammatory effects. Two clinical manifestations of such deficiencies are paroxysmal nocturnal hemoglobinuria and hereditary angioedema, both of which are discussed in other eMedicine articles. Frequency: Internationally: Complement deficiencies are relatively rare worldwide, and estimates of prevalence are based on screening high-risk populations. Retrospective studies of people with frequent meningococcal infections report varying prevalence based on geographic location. In populations with recurrent meningococcal infection, the prevalence is as high as 30%. Individuals with C1q deficiency have a 93% chance of developing SLE. Similarly, C1rs deficiency has a 57% association with SLE, and C4 deficiency has a 75% association with SLE. Mortality/Morbidity: Individuals with complement deficiencies that hinder opsonization present with frequent recurrent infections and a high rate of morbidity and mortality. Patients with a defect in formation of the MAC have a lesser degree of morbidity and mortality than, for example, patients with a defect in C3; it is thought that the deficiency in the lytic component of the complement cascade may have some protective effect against the generation of full-blown sepsis. Despite this theory, the severity of infection in the MAC-deficient patients should not be underestimated, as they can still be potentially life-threatening. Race: While no definitive racial patterns of association have been established for the majority of complement deficiencies, ethnic predispositions for certain of the complement deficiencies have been described. For example, deficiencies in properdin and C2 have been associated with the Caucasian race; C6 deficiencies have been shown to have a possible predisposition in African populations, and deficiencies in C8 have been associated with an Asian racial background. However, in most of these deficiencies, the absolute number of patients studied has been quite small. Sex: Most complement deficiencies affect both sexes equally. The majority of complement deficiencies are inherited in an autosomal recessive pattern (although MBL deficiency has been described as having both an autosomal dominant and recessive pattern). An exception to the autosomal pattern of inheritance is properdin deficiency, which is an X-linked trait. Age: Individuals with complement deficiencies that hinder opsonization often present at an early age (months to a few years old) because of increased susceptibility to overwhelming infection. Patients with deficiencies in formation of the MAC tend to be slightly older (late teenage years) in presentation. Complement deficiencies associated with immune complex diseases, such as SLE, do not show a clear pattern of age at first presentation. CLINICAL Section 3 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography History: Infants may have Leiner disease, which manifests in recurrent diarrhea, wasting, and generalized seborrheic dermatitis. The defect in Leiner disease is usually attributed to a defect of the fifth component of complement (C5). However, a child was described by Sonea and associates who had Leiner disease associated with diminished C3, and another was described by Goodyear and Harper with a low level of the fourth component of complement and reduced neutrophil mobility Thus, the C5 defect may not be the sole cause of Leiner disease, as has been suggested; diminished C3 or C4, or C5 dysfunction or deficiency with hypogammaglobulinemia or other lymphoid deficiency is also required for its expression. This section discusses 3 of the major sequelae of complement deficiencies based on the pathophysiology of each defect: defects that result in inadequate opsonization, defects in cell lysis, and the association of complement deficiencies with immune complex diseases. Defects that result in inadequate opsonization Opsonization is the process of coating a pathogenic organism so that it is more easily ingested by the macrophage system. The complement protein C3b, along with its cleavage product C3bi, is a potent agent of opsonization in the complement cascade. Any defect that causes decreased production of C3b results in inadequate opsonization ability. Such opsonization defects can be caused by deficiencies in components of the classical, alternative, or MBL pathways, or defects may be caused by deficiencies of the C3b component itself. The clinical history of patients with classical pathway deficiencies varies slightly from other complement-deficient patients. In the small number of patients studied, patients with classical pathway deficiencies—deficiency of C1qrs, C2, or C4--are similar in presentation to patients with primary immunoglobulin deficiencies. For example, patients tend to have frequent sinopulmonary infections with organisms such as Streptococcus pneumoniae. In order to generate an antibody response, an antigen must bind to the complement receptor (CR2) on B cells and the complement protein C3d. A deficiency of C1-4 proteins leads to an inadequate humoral response in these patients. Patients also have a decrease in classical pathway production of the opsonin C3b, but it seems that the alternative and MBL pathways compensate for this defect since opsonin is not completely absent. Opsonization defects also can be caused by alternative pathway deficiencies. In the alternative pathway, a deficiency of factor B, factor D, or properdin can result in a decreased amount of C3b. Deficiencies in properdin have been described in some detail. Properdin is a protein encoded on the X chromosome. Properdin stabilizes the C3 convertase (C3bBb) of the alternative pathway. Stabilization of C3 convertase increases the half-life of the complex from 5 minutes to 30 minutes, exponentially increasing the amount of C3b that can be deposited on a microbial surface. The role of C3b as an opsonin is essential in defense against neisserial infection, and the risk of overwhelming neisserial infection increases in the absence of properdin. The third pathway whose deficiencies can result in opsonization defects is the MBL pathway. MBL is one of the collectin proteins. These proteins share specific structural characteristics, namely the presence of a collagenlike region and a Ca2+-dependent lectin domain. Of all of the lectin proteins, only MBL has been shown to have the ability to activate the complement system. The MBL protein can activate the C4 and C2 components of complement by forming a complex with serine proteases known as MASP1 and MASP2. MASP1 and MASP2 activation results in the protein products C3 and C3b. The MBL protein is versatile because it can bind to a variety of substrates, prompting some to describe the MBL as a kind of universal antibody. Clinically, MBL deficiencies increase risk of infection with the yeast Saccharomyces cerevisiae and encapsulated bacteria such as Neisseria meningitidis and S pneumoniae. Finally, absolute deficiencies of C3 itself also result in defective opsonization. The C3 component occupies an important place at the junction of both the classical and alternative pathways. As such, C3 deficiency results in severe opsonization dysfunction. C3 deficiency also causes deficient leukocyte chemotaxis because of decreased C3a concentrations and decreased bactericidal killing secondary to decreased formation of MAC. Clinically, patients present at an early age with overwhelming infections from encapsulated bacteria. In addition to opsonization problems, C3 deficiency also impairs adequate clearance of circulating immune complexes, and 79% of C3-deficient patients develop some form of collagen-vascular disease. Deficiencies of the inhibitory proteins of the classical and alternative pathways also can result in a functional C3 deficiency through uncontrolled consumption of C3. Factor H and factor I are proteins that inhibit C3 formation in the alternative and classical pathways, respectively. Deficiencies in either of these C3 inhibitors can result in an overactivation of C3 and subsequent C3 depletion. Clinically, patients are similar to other absolute C3-deficient patients described above. Defects in cell lysis Complement deficiencies of the terminal cascade proteins also predispose patients to infection, but the clinical history of these patients is different. The terminal complement proteins are the proteins in the cascade that form the MAC—complement proteins C5-9. These proteins are responsible for bactericidal killing of organisms such as N meningitidis. The frequency of meningococcal infection in terminal complement-deficient patients is as high as 66%. In addition to this high rate of first-time infection, frequency of recurrence with the same organism also is as high as 50%. The serogroups of N meningitidis responsible for infections in this group tend to be the more rare serogroups Y and W135, rather than the more common serogroups B, A, and C. Clinically, terminal-deficient patients tend to present with infection at a later age than patients with other complement deficiencies. These terminal-deficient individuals also have less morbidity and mortality associated with infection. Unlike classical pathway-deficient patients, humoral immunity is intact, but lysis of pathogenic organisms is impaired. While recurrent infection with Neisseria species has been the predominant clinical finding in patients with complement deficiencies, the complement system is important in defending against other pathogens as well. Both the opsonization and lytic function of complement protect against a variety of other nonbacterial pathogens, such fungi, viruses, and mycobacteria. The role of complement in defense against viral infection is sufficiently important that pathogenic viruses have had to develop strategies to evade complement activation. For example, human immunodeficiency virus 1 (HIV-1) recently has been described as escaping complement-mediated lysis through the incorporation of regulatory proteins, such as DAF, into the viral envelope. Similarly, other viruses also have evolved complement-specific means of escape. Complement deficiencies and associated immune complex diseases Patients with complement deficiencies of the classical pathway are predisposed to develop immune complex diseases. History in these patients is similar to that of other patients who meet the criteria for immune complex diseases, such as SLE; however, the pathophysiology behind the association of complement deficiency and the pathogenesis of diseases such as SLE is only beginning to be understood. Complement itself is the source of several stimulators of an inflammatory response through generation of anaphylatoxin byproducts and the final MAC. It would seem that complement deficiencies should decrease the amount of inflammation responsible for the pathology found in autoimmune diseases; however, early classical pathway complement deficiencies have been associated with an increased frequency of autoimmune diseases, such as SLE. Patients with deficiencies of the classical pathway components C1qrs, C2, or C4 have been shown to have an increased likelihood of developing SLE. Homozygous deficiency of C1q has the highest association with SLE, with a recently quoted prevalence of 93%. Subsequent components of the classical pathway have a respective prevalence of 57% for C1rs deficiency, 75% association with homozygous C4 deficiencies, and 10% prevalence in patients with C2 deficiencies. Why does complement deficiency increase the risk of developing SLE? Complement helps in the prevention of immune complex disease by decreasing the number of circulating immune complexes; the greater the concentration of these precipitating immune complexes, the higher the likelihood that they will deposit in nearby tissues and cause an inflammatory response. Complement aids in neutralization and clearance of antigen-antibody complexes in several ways. The classical pathway acts to inhibit immune complex precipitation by physically interfering with immune complex aggregation. Secondly, complement enhances the clearance of circulating immune complexes by binding to complement receptors (CR1) on cells such as erythrocytes, B lymphocytes, T lymphocytes, and macrophages. When complement (specifically C3b) binds to CR1 on erythrocytes, the immune complex can be transported through the circulation to be presented to the macrophage systems in the spleen and liver. Lastly, the classical pathway also can recognize and clear apoptotic cells, which decreases the possibility that these cells can act as autoantigens. Physical: There are no specific physical findings that are pathognomonic for complement deficiencies. Rather, clinical manifestations are representative of the infections and immune complex diseases to which patients are prone. Since N meningitidis is the overwhelmingly prevalent bacterial pathogen in these patients, knowledge of the physical characteristics of disseminated meningococcal disease is important. The characteristic maculopapular rash that occurs in up to 75% of individuals with meningococcemia occurs soon after disease onset. The rash consists of pink lesions on the trunk and extremities; lesions are approximately 2-10 mm in diameter. As described elsewhere, the rash can quickly progress to hemorrhagic lesions. Petechiae also are a prominent finding and can occur on the skin of the trunk and extremities or on mucous membranes, such as the palate and conjunctivae. Noninfectious diseases, such as SLE, that are associated with complement deficiencies also can have a characteristic physical presentation. Complement deficiencies associated with the deposition of immune complexes in various tissues can result in many of the sequelae of SLE, such as glomerulonephritis, arthralgia, uveitis, and vasculitic rash. Causes: Most complement deficiencies are caused by a genetic defect in one of the genes that codes for the various complement proteins. No clear environmental or drug-related causes have been identified. DIFFERENTIALS Section 4 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Hypocomplementemia Hypogammaglobulinemia Immunoglobulin A Deficiency Immunoglobulin D Deficiency Immunoglobulin G Deficiency Immunoglobulin M Deficiency Immunosuppression Meningococcal Infections Meningococcemia Sepsis, Bacterial Septic Shock Systemic Lupus Erythematosus Urticaria Other Problems to be Considered: Hypocomplementemic urticarial vasculitis syndrome (HUVS) childhood seborrheic dermatitis childhood erythroderma Related Articles Hypocomplementemia Hypogammaglobulinemia ImmunoglobulinA Deficiency ImmunoglobulinD Deficiency ImmunoglobulinG Deficiency ImmunoglobulinM Deficiency Immunosuppression Meningococcal Infections Meningococcemia Sepsis,Bacterial Septic Shock Systemic Lupus Erythematosus Urticaria WORKUP Section 5 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Lab Studies: Deficiencies in complement can be screened for by using the CH50 test or AP50 test. The CH50 specifically tests for deficiencies in the classical pathway by measuring the ability of the patient’s serum to lyse antibody-coated sheep erythrocytes. A deficiency in any of the classical 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, also can be done and is helpful in determining the diagnosis. Imaging Studies: No specific imaging studies are indicated. Consider a head CT prior to lumbar puncture in a patient with suspected meningitis. Other Tests: As mentioned in the outpatient management section, patients with classical complement pathway deficiencies should be screened for sequelae of immune-complex diseases. Urinalysis and complete blood count should be performed on these patients. Procedures: In a patient with suspected meningitis, a lumbar puncture should be performed to assist in the definitive diagnosis of bacterial meningitis. TREATMENT Section 6 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Medical Care: Definitive treatment of complement deficiencies would require replacement of the missing component of the cascade, either through direct infusion of the protein or through gene therapy. Since neither of these options is currently available, treatment of these patients is focused on managing the sequelae of the particular complement deficiencies. For many patients, treatment will need to be focused on eradicating a particular infection, especially with encapsulated organisms such as N meningitidis. In most cases of meningococcal disease, treatment with meningeal doses of a third-generation cephalosporin covers most strains of N meningitidis. For other patients, the complement deficiency may manifest as episodic flares of autoimmune diseases; treatment of these patients should focus on immunosuppressive therapy of these diseases. It is important to note, however, that some overlap often exists between an increased susceptibility to infection and the greater tendency to develop autoimmune disease; both of these clinical situations may need to be addressed simultaneously in any one patient. Consultations: In a patient with a suspected complement deficiency, consider an allergy and immunology consult to determine appropriate diagnostic tests. Also, consider rheumatology or infectious disease consult to manage acute complications of the complement deficiency. Diet: There are no specific diet restrictions. Activity: Activity can continue as tolerated. MEDICATION Section 7 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Cephalosporins often are used for treatment of N meningitidis infection in complement-deficient patients. Third-generation or fourth-generation cephalosporins are used for coverage of infection with any of the encapsulated bacteria. Drug Category: Antibiotics -- Therapy must cover all likely pathogens in the context of this clinical setting. Antibiotic selection should be guided by blood culture sensitivity whenever feasible. Drug Name Ceftriaxone (Rocephin) -- Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins. Adult Dose Meningitis: 2 g IV qd Pediatric Dose Not established Contraindications Documented hypersensitivity Interactions Probenecid may increase ceftriaxone levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Adjust dose in renal impairment; caution in breastfeeding women and allergy to penicillin Drug Name Cefepime (Maxipime) -- Fourth-generation cephalosporin with good gram-negative coverage. Similar to third-generation cephalosporins, but has better gram-positive coverage. Adult Dose 1-2 g IV q12h for 5-10 d; may administer higher or more frequent dosages depending on severity of infection Pediatric Dose Not established Contraindications Documented hypersensitivity Interactions Probenecid may increase effects; aminoglycosides increase nephrotoxic potential of cefepime Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Adjust dose in severe renal insufficiency (high doses may cause CNS toxicity); prolonged use of cefepime may predispose patients to superinfection FOLLOW-UP Section 8 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Further Inpatient Care: Serious infectious states warrant hospitalization for treatment. Inpatient stay is not necessarily needed to screen for complement deficiencies if the patient is asymptomatic. Further Outpatient Care: Patients with a known complement deficiency should be screened for glomerular or immune complex disease. Obtain a urinalysis to check for proteinuria and rheumatologic serologies to screen for SLE. In/Out Patient Meds: Cephalosporins (third or fourth generation) are needed for treatment of meningeal infection. Deterrence/Prevention: Administration of the multivalent meningococcal vaccine in patients with known complement deficiency is recommended, especially those patients deficient in the MAC proteins. Similarly, administration of the pneumococcal vaccine and the Haemophilus Influenzae vaccine also may provide protection against these encapsulated organisms. Complications: Complications of complement deficiencies can be serious; severe CNS damage and death from meningitis are among the worst possible adverse outcomes. Prognosis: In general, the prognosis for patients with C3 deficiencies is poorer than that of other complement-deficient individuals. Patients may have severe, recurrent episodes of meningococcal infection from as early as a few months of age. Many can succumb to sepsis early in life. Patients with deficiencies in the MAC, while still highly susceptible to infection, can have a slightly less severe course than C3-deficient patients. They too can present with neisserial infections, but the infection is not always as overwhelming in its course. Patient Education: Patients with an identified complement deficiency should be counseled regarding possible complications and risks associated with this deficiency. Family members should be screened for complement deficiencies and counseled regarding possible risks. MISCELLANEOUS Section 9 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Medical/Legal Pitfalls: Missed diagnosis BIBLIOGRAPHY Section 11 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Beynon HL, Davies KA, Haskard DO: Erythrocyte complement receptor type 1 and interactions between immune complexes, neutrophils, and endothelium. J Immunol 1994 Oct 1; 153(7): 3160-7[Medline]. 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