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Synonyms and related keywords: complement, immune complex diseases, membranoproliferative glomerulonephritis, nephritic factor, alternate pathway, classic pathway, membrane attack complex, lectin pathway, mannan-binding pathway, complement deficiency, complement disorders, primary complement disorders, secondary complement disorders, C1 inhibitor deficiency, C1 deficiency, C2 deficiency, C3 deficiency, C1-INH deficiency

Background

In the late 19th century, serum was found to contain a nonspecific heat-labile complementary principle that interacted with antibodies to induce bacteriolysis. Ehrlich and Morgan termed this factor complement.

The complement system as understood today is a multimolecular system composed of more than 20 proteins and consisting of serum proteins, serosal proteins, and cell membrane receptors that bind to complement fragments. They constitute 10% of the globulin fraction of serum. Many of these proteins are designated by the letter C and are assigned numbers in the order of their discovery.

Pathophysiology

The complement system consists of 7 serum and 5 membrane regulatory proteins, 1 serosal regulatory protein, and 8 cell membrane receptors that bind complement fragments. Most are synthesized mainly by the liver. Exceptions are C1, factor D, and properdin. These are probably synthesized by macrophages and even by T lymphocytes.

Activation

The complement system functions as an interactive sequence, with one reaction leading to another in the form of a cascade. It is initiated by a wide variety of substances and has 2 phases. In the first phase, a series of specific interactions leads to formation of intrinsic complement proteinase, termed C3 convertase. Depending on the nature of complement activators, the classic pathway, the alternative pathway, or the newly discovered lectin pathway is activated predominantly to produce C3 convertase. Each of these pathways uses different proteins. The second phase for each involves cleavage of C3b, generating multiple biologically important fragments and large, potentially cytolytic complexes.

Classic pathway

This pathway has 2 units. One, the recognition unit, consists of a trimolecular complex of C1q, 2 molecules of C1r, and 2 molecules of C1s held together by calcium. The other is an activation unit of C2, C3, and C4. The sequence starts with the binding of 2 or more C1q recognition units to the Fc nonantigen binding part of antibody. This induces a conformational change, leading to autoactivation of C1r that then cleaves C1s to its active state. This then acts similarly to C1 esterase and cleaves C2 and C4 to form C2aC4b, which is the C3 esterase that cleaves C3 to form C3b. C1q can also be activated by mycoplasmal organisms, RNA viruses, bacterial endotoxins, and cell membranes of some organelles without the presence of antibody.

Alternate pathway

This was discovered by Pillemer and colleagues in 1954 but was recognized universally some years later. This pathway is activated by viruses, fungi, bacteria, parasites, cobra venom, immunoglobulin A, and polysaccharides and forms an important part of the defense mechanism independent of the immune response. Here, C3b binds to factor B that is cleaved by factor D to Bb. C3bBb complex then acts as the C3 convertase and generates more C3 through an amplification loop. Binding of factor H to C3b increases its inactivation by factor I. Properdin stabilizes it, preventing its inactivation by factors H and I. The alternate pathway does not result in a truly nonspecific activation of complement because it requires specific types of compounds for activation. It simply does not require specific antigen-antibody interactions for initiation.

Lectin pathway

The lectin or mannan-binding pathway is activated similar to the classic pathway except that lectin replaces the antibody and an associated protease replaces C1. Instead, mannose-binding protein binds to sugar residues on the surface of a pathogen. Such lectins are associated with a serine protease, similar to the C1r and C1s subcomponents of the classic pathway, that also activates C4 and C2.

Membrane attack complex

Only 5 proteins are involved in the direct killing of cells. C2a4b3b complex from the classic pathway or C3bBb cleaves C5. C5b activates the terminal complement pathway by associating with C6, C7, and C8 to form macromolecular complexes denoted as C5b-8. C9 binds to this complex, inducing a conformational change that exposes a new antigenic site known as C9 neoantigen. Additional C9 molecules form ringlike pores, leading to transmembrane channels that cause cell lysis.

Regulation

The complement system serves a very important role in host defense, but if it is directed against itself, it can lead to serious illness. Therefore, it is closely regulated at almost every step.

Classic pathway

The classic pathway requires the identification of a target by the presence of an antibody. C1 inhibitor (C1-INH) inhibits C1r and C1s by binding covalently to them, causing disassembly of C1 macromolecular complex. The inhibitor is synthesized in the liver and blood monocytes; its gene is located on chromosome 11. C2a4b is very labile and undergoes spontaneous decay with release of C2a and loss of enzymatic activity. C4 binding protein binds C4, accelerates its rate of dissociation from C2a, and makes C4b more susceptible to proteolysis by factor I. Membrane-bound decay-accelerating factor (DAF) promotes release of C2a from C4b2a by physically interfering with C4b and C2a association.

Alternate pathway

Carbohydrate composition and its sialic acid content on the cell surface play an important role in the activation of the alternate pathway. Sialic acid blocks activation by favoring the binding of factor H to C3b, which is then inactivated by factor I. Microorganisms lacking sialic acid are killed, whereas human cells covered with glycophorin A, a sialoglycoprotein, are protected.

C3bBb is relatively labile and undergoes spontaneous decay through dissociation of Bb. Properdin is synthesized by monocytes and T lymphocytes. Properdin binds to C3bBb and stabilizes it, preventing its decay. Factor H competes with factor B for binding to C3b and displaces Bb from C3bBb. It accelerates the inactivation of C3b by factor I. Factor I inactivates C3b to iC3b, a molecule that cannot function enzymatically. Complement receptor 1 (CR1) has factor H–like activity, permitting factor I to cleave C3b. Membrane cofactor protein also has factor H–like activity, mainly for alternative C3 convertase.

Membrane attack complex

Homologous restriction factor, C8 binding protein, is a cell membrane protein with significant sequence homology to both C8 and C9 and is widely distributed on peripheral blood cells. It prevents the interaction of C8 and C9. Membrane-bound CD59, also known as homologous restriction factor 20, prevents the binding of C5b-8 to C9 and inhibits the unfolding of C9 that is required for polymerization and formation of macroscopic pores in the cell membrane. S protein (vitronectin) binds to C5b-7 and abolishes its activity. SP-40,40 (clusterin) has effects similar to vitronectin.

Biologic effects

The biologic effects of complement include promotion of chemotaxis and anaphylaxis, opsonization and phagocytosis of microorganisms, and removal of immune complexes from the circulation. Most complement components are acute phase reactants, and their concentration increases in states of infection, trauma, and injury.

C4a, C3a, and C5a are anaphylatoxins and bind to mast cells, triggering the release of histamine and other mediators, leading to vasodilation, erythema, and swelling. C5a is a major stimulus for influx of neutrophils, basophils, monocytes, and eosinophils.

C3b fixes to the antigen-antibody complex and permits its adherence to cells (eg, neutrophils, basophils, eosinophils, monocytes) that have receptors for C3b. This particular action of opsonization helps in phagocytosis. C3b-coated particles also bind to B lymphocytes and activate them to enhance the primary antibody response. Immune complexes formed in the circulation are coated with C3b and bind to erythrocytes, which then transport them to the liver and spleen for removal. This process maintains the solubility of the immune complexes. In the early phases of viral infection, when the amount of antibody is limited, the fixation of C3b to the viral antigen-antibody complex increases neutralization.

The terminal components of the complement system result in lysis of virus-infected cells, tumor cells, and most microorganisms. They also have a role in neutralization of endotoxins in vitro and protection from their lethal effects in experimental animal models.

Causes

Causes may be primary or secondary in nature.

Primary complement disorders

Congenital complement deficiencies can involve most of the complement components.

Classic pathway disorders

• C1q
  • Although any one of the 3 subcomponents of the C1 complex may be deficient, C1q deficiency is the most common. C1q deficiency may be hereditary or acquired. Hereditary deficiencies are usually complete and are transmitted as an autosomal recessive trait. Low-to-absent levels of C1q are found; a dysfunctional protein has been found in some patients.

  • Most patients (>90%) with C1q deficiency have systemic lupus erythematosus (SLE) and demonstrate a variety of autoantibodies, such as immunoglobulin G (IgG) autoantibodies to C1q, antinuclear antibody and double-stranded DNA (dsDNA) antibody; low total hemolytic complement activity (CH₅₀) values; and low C1q levels, with normal levels of other complement proteins. SLE is more severe in persons with homozygous deficiencies, suggesting that C1q is vital in clearing immune complexes, probably through its participation in the generation of C3. Deposition of this C3 on autoimmune complexes facilitates their removal from the circulation through binding to CR1 on erythrocytes, with subsequent transport to the liver and spleen.

  • Low levels of C1q also are found in persons with SLE-like syndrome without typical serology, hypocomplementemic urticarial vasculitis syndrome, multiple myeloma, hypogammaglobulinemia, and membranoproliferative glomerulonephritis.

  • Plasmapheresis has been used for restoration of C1q levels. The use of fresh frozen plasma is associated with the development of antibodies to C1q, thereby limiting its use.

• C1r/C1s: The loci of these 2 components are closely linked, and the deficiencies usually occur together. The transmission is autosomal recessive in nature. A high prevalence of SLE is found, with prominent renal and cutaneous sequelae.

• C4
  • C4 is encoded as 2 tandem, highly polymorphic genes, C4A and C4B, located in the major histocompatibility complex on chromosome 6. Two copies of each gene determine the phenotype. Null alleles are called C4a*Q0 and C4b*Q0. Deletion of the C4A gene is the most common mechanism. A single null allele reduces the C4 level by 35-40%. Four null alleles encode a complete deficiency of C4. It is transmitted as an autosomal recessive trait.

  • Partial C4 deficiency predisposes to SLE. Deficiency of C4A or C4B has been associated with the development of scleroderma, immunoglobulin A nephropathy, Henoch-Schönlein purpura, diabetes mellitus, chronic hepatitis and membranous nephropathy. Complete C4 deficiency is rare. Characteristics of SLE with complete C4 deficiency include early onset, mild renal disease, skin manifestations, anti-SSA antibody, and an absence of anti-dsDNA antibody. Complete C4 deficiency also may manifest with infection or may not be associated with any symptoms.

  • Defective expression or function also may lead to SLE, as occurs with medications such as hydralazine, penicillamine, and procainamide, which react with the thioester bond of C4a and block its function.

• C2
  • This is the most common inherited complement deficiency. The transmission is autosomal recessive in nature. Homozygous deficiency of C2 occurs in 1 in 10,000 whites, with up to 30% presenting with an SLE-like illness.

  • It may also manifest as recurrent pyogenic infections due to encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis. It is also sometimes associated with IgG subclass deficiency.

  • The gene frequency of heterozygous C2 deficiency is 1%. Immune complex disease is common. It may manifest as life-threatening septicemia, especially due to infection with pneumococci.

• C3
  • C3 is the most important central molecule in the complement system because both the classic and alternative pathways activate it, and its activation products mediate opsonization and anaphylactic activity and activate the terminal pathway.

  • C3 deficiency is transmitted as an autosomal recessive trait. Patients with C3 deficiency develop severe episodes of recurrent pneumonia, meningitis, peritonitis, or sepsis. The most common pathogens are S pneumoniae, N meningitidis, H influenzae, and Staphylococcus aureus. Lupuslike illness and mesangiocapillary glomerulonephritis may occur in 15-20% of patients.

Membrane attack pathway

Deficiency is transmitted as an autosomal recessive trait. Patients with deficiency of C5-9 components usually have a history of meningococcal meningitis and even extragenital or disseminated gonococcal infection. The reasons for the predisposition to Neisseria infection are not clear, but deficient serum bacteriolysis may be the predisposing cause. Some patients develop collagen-vascular disease.

Alternative pathway

This is inherited through an autosomal recessive mode of transmission. Deficiency in factor D or factor B manifests as recurrent infection.

Control proteins

• Factor I: It has an autosomal recessive transmission and leads to the prolonged presence of C3b, causing a constant activation of the alternative pathway that ultimately leads to a depletion of C3. It was initially reported as C3 deficiency due to hypercatabolism of C3. It manifests as severe pyogenic infections.

• Factor H: It helps factor I in the breakdown of C3 convertase of the alternative pathway, so its effects are essentially the same. The C3 level, factor B level, CH₅₀ value, and alternate pathway activity are low or undetectable. Patients have sustained systemic infections, especially from meningococci. Membranoproliferative glomerulonephritis and hemolytic uremic syndrome are associated with it. An association between familial hemolytic uremic syndrome and mutations in the genes for factor H and factor I have also been reported.

• Properdin: It is transmitted as an X-linked trait. All patients are male, and a family history of male deaths due to meningococcal meningitis is common. CH₅₀ results are without abnormality. Patients may have discoid lupus or dermal vasculitis.

• C4 binding protein: It is rarely found. It has no typical manifestations.

• C1 inhibitor
  • C1-INH disorders are transmitted as an autosomal dominant trait. However, 50% of patients may have spontaneous mutations, and a family history may be absent. In 85% of patients, a marked reduction of the inhibitor is found (5-30% of normal values are present). In 15% of patients, a dysfunctional protein is present. The absence of the inhibitor causes uncontrolled C1 activity with breakdown of C4 and C2 and release of a vasoactive peptide from C2.

  • The deficiency of C1 esterase leads to hereditary angioedema, which is manifested by episodic attacks of nonpitting, nonpruritic, localized edema that progresses rapidly without urticaria or erythema. Swelling of the intestinal wall can cause intense abdominal cramping associated with vomiting and diarrhea. Laryngeal edema may prove fatal. Attacks last 2-3 days and gradually subside. Attacks occur after menses, emotional stress, trauma, or vigorous exercise. They may begin in the first 2 years of life but usually are not severe until late childhood or adolescence. Collagen-vascular disease and glomerulonephritis have been reported. The diagnosis is suggested by a positive family history, edema with lack of accompanying pruritus or urticaria, and decreased C4 levels during an episode. Further laboratory testing is performed by measuring the amount of C1-INH, but some kindred have a dysfunctional protein and require a functional assay.

  • Acquired disease may occur from autoantibody to C1-INH, usually associated with B-cell cancer.

  • See Hereditary angioedema for more information.

• Complement receptor 1, 2, or 3
  • Deficiency of CR1 on erythrocytes leads to impaired clearance of immune complexes, thereby contributing to collagen-vascular disease. The disorder possibly is inherited.

  • An inherited deficiency of complement receptor 3 causes recurrent and severe bacterial (eg, S aureus and/or Pseudomonas) infections. This condition is known as leukocyte adhesion deficiency syndrome (CD11/CD18 deficiency). It is suspected if delayed separation of the umbilical cord occurs and omphalitis develops. Most patients die in childhood of refractory infections involving soft tissue and mucosal surfaces.

• DAF, CD59, C8 binding protein
  • The vascular endothelium of the skin of patients with diffuse or limited scleroderma has been shown to be deficient in DAF. This may lead to vascular injury, finally leading to fibrosis.

  • Paroxysmal nocturnal hemoglobinuria (PNH) is a disease characterized by hemolytic anemia, venous thrombosis, and deficient hematopoiesis. It is an acquired clonal disease due to a somatic mutation of a gene on the X chromosome (PIGA) in a hematopoietic stem cell that encodes the glycosyl-phosphatidylinositol molecule, which anchors approximately 20 proteins (including DAF, CD59, and C8 binding protein) to cell membranes. The absence of this anchor results in an absence of these proteins, making the erythrocytes more susceptible to complement-mediated lysis.

  • Isolated DAF deficiency does not cause PNH. Isolated CD59 deficiency has been reported to cause mild PNH.

Serosal protease

Evidence suggests that serosal fluids contain a complement regulatory protease that destroys C5a and interleukin 8, which are chemotactic for neutrophils. Deficiency of this regulatory protein in peritoneal and synovial fluids results in familial Mediterranean fever, characterized by recurrent episodes of fever and painful inflammation of joints, pleura, and the peritoneal cavity.

Inherited lectin pathway deficiencies

Point mutations of the MBL mannose-binding lectin (MBL) gene occur in the coding exons and promoter region. MBL contains 3 identical polypeptide chains. Substitutions in these exons lead to the formation of chains that do not interact normally. Persons with mutations of both MBL alleles (3-5% of the population) have undetectable or extremely low levels of MBL. People with 1 normal and 1 abnormal allele have a sixth to an eighth of the normal functional level of MBL.

MBL deficiency is associated with an increased frequency of pyogenic infections in children, In the presence of MBL deficiency, chronic inflammatory conditions may be more severe. A 2- to 3-fold increase in MBL deficiencies is noted in persons with SLE. More frequent and more severe infections occur in patients treated with steroids and cytotoxic agents.

A deficiency of MBL-associated proteases has been described that results in severe pneumococcal pneumonia and immune disorders, including ulcerative colitis and erythema multiforme bullosum.

Secondary complement disorders

A number of diseases that are not inherited affect the complement system.

Immunologic

These are mediated by immune complexes, and complement proteins are consumed in the process.

• Systemic lupus erythematosus
  • Complement is consumed via the classic pathway during active immune complex deposition; therefore, patients with active lupus characteristically have decreased C3 levels, C4 levels, and CH₅₀ results. However, hypocomplementemia can also be found in patients with SLE without active disease.

  • A subset of patients has congenital complement deficiencies. Normal C3 levels with very low or absent CH₅₀ values are suggestive of a congenital deficiency. C2 and C4 deficiencies are common.

  • Elevated levels of complement-activating products may be useful in predicting SLE flares.

• Hypocomplementemic glomerulonephritis
  • Serum from patients with membranoproliferative glomerulonephritis contains nephritic factor (NeF), which causes activation of the alternative pathway. NeF is an IgG autoantibody that binds and stabilizes C3bBb and prevents its dissociation by factor H. This leads to prolonged C3 conversion, leading to its depletion. This disorder has been described in association with partial lipodystrophy. Exposure to NeF destroys adipocytes, which can synthesize C3, factor D, and factor B.

  • An IgG NeF that binds and protects C4,2 has been described in association with acute postinfectious nephritis. Complement levels usually return to normal in 8 weeks.

  • Mesangioproliferative glomerulonephritis, idiopathic proliferative glomerulonephritis, and focal sclerosing glomerulonephritis have been described in association with complement depletion. Lupus nephritis is one of the important causes. Other causes, such as fibrillary glomerulonephritis and immunotactoid glomerulonephritis, have been reported.

• Infective endocarditis: Circulating immune complexes have been found in 90% of patients with endocarditis. Rheumatoid factor is present in 10-70% of cases. Hypocomplementemia is a frequent but nonspecific marker of glomerulonephritis in persons with bacterial endocarditis. Approximately 90% of patients with diffuse glomerulonephritis and approximately 60% of patients with focal glomerulonephritis have reduced complement levels. Typically, the classic pathway has been implicated, but reports of primary alternative pathway activation are found in the literature. Complement levels return to normal with bacteriological cure and resolution of glomerulonephritis.

• Miscellaneous causes: Formation of immune complexes with complement consumption has been found in association with acute hepatitis B and C. These are responsible for extrahepatic manifestations of arthralgias and nephritis. Immune complexes also are present in association with infectious mononucleosis, malaria, dengue fever, lepromatous leprosy, and bacteremic shock. Reye syndrome, primary biliary cirrhosis, celiac disease, multiple myeloma, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and urticarial vasculitis have also been implicated. Burns, hemodialysis with cellophane membranes, cardiopulmonary bypass, and perhaps the injection of iodinated radiocontrast material can also cause direct activation of the alternative pathway and serious effects thereof.

Nonimmunologic

Patients with severe malnutrition and anorexia nervosa have low complement levels. Improvement in serum concentration of complement has occurred after correction of the nutritional deficiency. Severe cirrhosis of the liver and hepatic failure result in decreased C3 production. Preterm infants, and even newborn children, have mild-to-moderate deficiency of all complement components. Deficiencies in the alternate pathway and suboptimal opsonization have been described in persons with sickle cell disease, postsplenectomy patients, and persons with nephrotic syndrome.

Lab Studies

• Candidates for evaluation
• • Complement function should be evaluated in any patient with collagen-vascular disease, PNH, chronic nephritis, recurrent pyogenic infections and severe recurrent angioedema not responsive to antihistamines, N meningitides or disseminated gonococcal infections, or a second attack of septicemia at any age.

  • A family history of recurrent systemic infections caused by encapsulated bacteria, especially meningococci, should suggest complement deficiency.

• Hemolytic assays
• • Hemolytic assays were devised as early as the beginning of the 20th century, and they measure the ability of the complements to participate in hemolysis.

  • CH₅₀ tests the capacity of proteins of the classic pathway and membrane attack complex to lyse antibody-coated erythrocytes. The dilution of the serum that lyses 50% of the cells marks the end point.
    • The CH₅₀ value is zero in congenital deficiencies of C1 to C8, and its value is half-normal in C9 deficiency. Also, deficiencies in factors H or I result in a low value due to C3 consumption. The test does not measure deficiencies of the alternative pathway.

    • It is very useful as a screening test for most diseases of the complement system. Because of the unstable nature of several of the complement proteins, the CH₅₀ assay requires appropriate collection, processing, and storage of specimens. Serum samples should be assayed the day of collection or stored frozen. A common cause of a decreased CH₅₀ values is improper specimen handling.

  • The alternative hemolytic complement activity (AH₅₀), although less commonly used, measures alternative pathway function.

• Selective complement assay
• • Serum concentrations of C3, C4, and factor B are measured by radial immunodiffusion, and testing is easily available. A decrease in C4 levels represents classic pathway activation, a decrease in factor B levels signifies alternative pathway activation, and a decrease in C3 levels reflects activation of either pathway.

  • In hereditary angioedema, depression of C4 and C2 levels during an attack reduces the CH₅₀ value. The C4 level is characteristically low with a normal C3 level. Concentration of C1-INH can be determined with an antibody. A functional test for C1-INH should be performed in patients in whom a high index of suspicion exists but the protein level is normal.

  • Low titers of both C3 and C4 suggest activation of the classic pathway by immune complexes. On the other hand, low C3 and normal C4 levels suggest alternative pathway activation. This difference may be useful in differentiating nephritis due to immune complex deposition from that due to NeF. Also, factor B levels are reduced in persons with NeF-induced nephritis. However, normal complement levels do not exclude complement activation that is biologically important but not massive enough to lower the serum concentrations.

  • Abnormal elevations of Ba, Bb, C3a, C4a, and iC3b levels have been found to correlate with lupus flares in patients. However, larger prospective studies are required before this type of testing is recommended for routine use. Synovial fluid from patients with rheumatoid arthritis or gout has markedly increased levels of C3a, whereas C5a levels are within the reference range. C3a is a more sensitive marker of in vivo complement activation than C5a, which is rapidly cleared from the circulation. Cerebrospinal levels of C5b-9 are increased in persons with autoimmune neurologic diseases, such as multiple sclerosis and lupus cerebritis.

Medical Care

No specific therapy is recommended at present for most of the complement disorders. However, hereditary angioedema does respond to specific therapy.

• With regard to hereditary angioedema, epinephrine administered early may produce some improvement.
• • Clonal C1-INH administered by infusion aborts acute attacks, and it also is safe and effective for surgical or dental prophylaxis. It has not yet been approved by the US Food and Drug Administration for use in the United States.

  • In the absence of clonal C1-INH, infusion of fresh frozen plasma has been used successfully in acute attacks of angioedema. Fresh frozen plasma has been used prior to dental and surgical procedures; however, this also provides substrate for C1-INH protein and may worsen angioedema, and, hence, it is not recommended for life-threatening laryngeal edema.

  • Danazol, a synthetic androgen, increases the serum concentration of C1-INH and prevents attacks in adults. It is not recommended in children.

  • Stanozolol may be given to the pediatric population.

  • Precipitating factors, such as trauma, estrogens, and angiotensin-converting enzyme inhibitors, should be avoided.

  • The antifibrinolytic agents, epsilon-aminocaproic acid and tranexamic acid, may be effective in both hereditary and acquired C1-INH deficiency. However, these drugs may be associated with intravascular thrombosis.

• Fresh frozen plasma also has been used to restore C3 levels in persons with C3 deficiency. Therapeutic plasma exchange using fresh frozen plasma has been used to replace the deficient complement proteins, but, overall, it has not proved to be a safe and efficient mode of therapy. Its use in patients with SLE has not met with definite success.
• Supportive management can prove helpful in these patients.
• Every attempt should be made to identify the specific defect.

• With the development of fever in these patients, cultures should be obtained and the threshold for beginning antibiotic therapy should be low. The use of prophylactic antibiotics is controversial. Prophylactic antibiotics reduce the frequency of infection in patients with C6 deficiency, who are susceptible to meningococcal infection. However, concern for the development of antibiotic resistance and the duration of prophylaxis remain unresolved issues.

• Make certain adequate information is provided to the patient or guardian for possible use by school, camp, or other health care personnel or physicians.

• Immunization of the patient and household contacts for pneumococci, H influenzae, and N meningitidis is recommended.

• Replacement therapy with recombinant complement proteins may soon be possible; gene therapy may become a viable option in the near future.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Androgens, synthetic

In hereditary angioedema, stanozolol and danazol increase level of deficient C1-INH and prevent attacks. Danazol not recommended in children.

Drug Name	Danazol (Danocrine)
Description	Increases C4 levels and reduces attacks associated with angioedema.
Adult Dose	200 mg PO bid/tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; seizure disorders; hepatic, renal, or cardiovascular insufficiency; pregnancy; lactation; undiagnosed genital bleeding; porphyria; a history of thromboembolism
Interactions	Inhibits hepatic metabolism of carbamazepine, warfarin, cyclosporin, and (possibly) tacrolimus; reduces maintenance requirement for alfacalcidol
Pregnancy	X - Contraindicated in pregnancy
Precautions	Caution in renal, hepatic, or cardiac insufficiency; caution in seizure disorders and epilepsy; use care in patients with diabetes mellitus, polycythemia, and a history of thrombosis

Drug Name	Stanozolol (Winstrol)
Description	Synthetic androgen with immunosuppressive properties. Increases C1 esterase inhibitor and C4 levels.
Adult Dose	2 mg PO tid initially; reduce to maintenance dose of 2 mg/d or 2 mg qod after 1-3 mo
Pediatric Dose	<6 years: 1 mg/d PO 6-12 years: 2 mg/d PO >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; nephrosis, breast or prostate cancer
Interactions	Increases hypoprothrombinemic effects of oral anticoagulants and hypoglycemic effects of insulin and sulfonylureas
Pregnancy	X - Contraindicated in pregnancy
Precautions	May cause peliosis hepatitis, liver cell tumors, and blood lipid changes, with increased risk of arteriosclerosis; caution in cardiac, renal, or hepatic disease or epilepsy; may increase PT; phallic or clitoral enlargement, hirsutism, gynecomastia, acne, edema, nausea, vomiting, and diarrhea may occur

Medical/Legal Pitfalls

• Failure to consider the diagnosis is a possible medicolegal pitfall.