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Inherited disorders of the complement system

Inherited disorders of the complement system
Literature review current through: May 2024.
This topic last updated: Feb 20, 2024.

INTRODUCTION — Inherited complete deficiencies of complement components are rare disorders that most often predispose to bacterial infections and/or systemic lupus erythematosus (SLE). They are associated with predictable defects in complement-dependent function, as the affected individual loses not only the activity of the deficient protein, but also the functions of the proteins that follow in the cascade. Additionally, increasing recognition of heterozygous deficiency (ie, haploinsufficiency) due to loss-of-function mutations in regulators and gain-of-function mutations in activators has led to new disease associations [1].

Inherited complement deficiencies are classified into two general categories: integral component defects and regulatory component defects [2]. Inherited disorders of the complement system will be reviewed here. Acquired disorders and the general evaluation of the complement system are discussed separately. (See "Acquired disorders of the complement system" and "Overview and clinical assessment of the complement system" and "Complement pathways".)

CLINICAL MANIFESTATIONS

Deficiencies in an integral component of the activating cascades — Inherited disorders of complement components present predominantly with recurrent bacterial infections and/or systemic lupus erythematosus (SLE) [3-5].

Infections – Patients with deficiency of a complement pathway protein are susceptible to recurrent sinopulmonary bacterial infections, bacteremia, and/or meningitis. The pathogens most commonly implicated are encapsulated bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis. (See "Approach to the child with recurrent infections" and "Approach to the adult with recurrent infections".)

Autoimmunity – The most common autoimmune disorder by far among patients with a total complement deficiency is SLE [6-18]. SLE commonly develops in individuals deficient in an early component of the classical pathway (ie, C1q, C1r, C1s, C4, and C2). (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis".)

Deficiencies in regulatory proteins — Patients with deficiencies of certain complement regulatory proteins develop specific disorders resulting from undesirable complement activation. Inherited complete deficiencies of regulators lead to consumption of multiple components in a pathway. In contrast, haploinsufficiency leads to an excessive local inflammatory response at a site of injury or debris accumulation and commonly requires an underlying trigger, such as endothelial cell damage. As examples, heterozygous deficiency of C1 inhibitor causes hereditary angioedema, an autosomal dominant disorder, while haploinsufficiency of factor H predisposes to atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD) [19-23]. Homozygous factor H or factor I deficiency results in alternative pathway activation, cleavage and consumption of C3 and factor B, and increased susceptibility to pyogenic infections. Heterozygous deficiency of factor I is also associated with both aHUS and AMD [19,24]. (See 'Abnormalities in regulatory proteins' below.)

CLASSICAL PATHWAY DEFICIENCIES

Genetics and epidemiology — Most inherited disorders of the integral classical pathway components are transmitted as autosomal codominant (recessive) traits. Two abnormal alleles must be present to yield complete deficiency, and, in most cases, only patients with a complete deficiency are symptomatic. Heterozygous deficiencies in which individuals have 50 percent of a component are almost always asymptomatic (eg, parents of children with C3 or C5 deficiency). The association of partial C4 deficiency with systemic lupus erythematosus (SLE) [25] reflects the presence of a C4A null gene on the associated human leukocyte antigen (HLA) B8, DR3 conserved, extended haplotype [26]. Other extended major histocompatibility complex (MHC) haplotypes with null C4A or null C4B genes are not increased among patients. (See 'C4 deficiency' below.)

Indications for screening — Screening for a classical complement pathway defect as a cause of recurrent infections is indicated in patients with any of the following [27]:

Recurrent, unexplained pyogenic infections in the setting of normal white blood cell counts and immunoglobulin levels in children (ie, no obvious cause)

Recurrent neisserial infections at any age

Multiple family members with neisserial infections

In addition, it is reasonable to check, at least once, a total hemolytic complement (THC or CH50) in any patient with SLE. This is particularly relevant in those with familial lupus or subacute cutaneous lupus in whom C2 deficiency should be considered.

Screening CH50 and interpretation — The total hemolytic complement (THC or CH50) assay is a reliable screen for a homozygous deficiency in an integral component of the classical pathway.

Care must be taken in the handling of serum specimens since complement hemolytic activity is unstable and heat labile and can be reduced after a few hours at room temperature. Also, another cause for low- or zero-complement activity in patients is cold activation by immune complexes and/or cryoglobulins [28]. (See "Overview and clinical assessment of the complement system".)

The CH50 measures the capacity of a patient's serum to lyse sheep erythrocytes coated with rabbit antibody directed against antigens on the red blood cell (RBC) membrane. All nine components of the classical pathway (C1 through C9) are required for a normal CH50, which is 150 to 250 units/mL in a commonly used assay system. For example, a CH50 of 200 units/mL means that a serum sample diluted 1:200 lysed 50 percent of the antibody-coated sheep erythrocytes (measured by hemoglobin release) in the test mixture.

An elevated CH50 has no specific clinical significance other than to reflect that complement proteins increase as part of the acute-phase response.

Individuals with heterozygous deficiency will generally have a normal CH50 because the level of a component must be reduced by more than 50 percent before the CH50 is altered. Heterozygous C2 deficiency is one exception. C2 is the limiting component in a CH50 determination, and patients with heterozygous C2 deficiency tend to have mildly low CH50 values. (See 'C2 deficiency' below.)

A complete deficiency of any one integral component gives an undetectable CH50 value (often reported as less than some specified low value), with the exception of C9 deficiency. Homozygous C9 deficiency, which is most often reported in Japanese, Korean, and Chinese individuals, gives a low, but detectable CH50 titer [29,30]. (See 'C5-C9 deficiency' below.)

If a patient is found to have a very low or undetectable CH50, the first step is to repeat the test. If it is low again, then the next step is the measurement of specific complement proteins. C2 deficiency is most commonly observed on the HLA-B18, DR2 extended haplotype. Heterozygotes thus constitute a little over 1 percent of European White individuals, and homozygotes are seen in approximately 1 in 20,000 individuals of this population [9]. If C2 is normal, then a complete deficiency of C1q, C4, C3, or a membrane attack component (C5, C6, C7, C8, or C9) should be tested next. Complete deficiencies of these components (other than C2) have only been described in approximately 30 to 100 individuals each.

Another approach is to perform an alternative pathway (AH50) assay. This test, although not as widely available, can be performed in referral laboratories. A neisserial infection is the most common indication for this diagnostic approach. If AH50 is also very low or undetectable, then the deficiency is most likely of C3, C5, C6, C7, C8, or C9, as these components overlap in CH50 and AH50 assays. If more than one component is low, the problem is almost always an acquired deficiency or lack of a regulator (figure 1).

Genetic screening — Whole genome, whole exome, and targeted deep sequencing are increasingly utilized for the specific diagnosis of complete or partial (haploinsufficiency) complement deficiencies. Examples of the latter are those for atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD). Likewise, testing for copy number variation (CNV) is becoming more common. It is likely that all patients with SLE will be evaluated for CNV of C4 at the time of diagnosis [18]. Relative to aHUS, many centers now perform targeted deep sequencing on 6 to 12 genes for patients with aHUS to facilitate diagnosis, decide on treatment, and evaluate for transplantation in patients with a history of a thrombotic microangiopathy.

Specific disorders

C1 deficiency — Although any one of the three subcomponents (C1q, C1r, or C1s) of the C1 complex may be deficient, the most common inherited deficiency is of C1q.

More than 90 percent of C1q-deficient individuals develop SLE, and they may also have recurrent bacterial infections. Most of these patients have typical clinical and serologic findings of SLE. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis".)

A deficiency of the serine protease C1r or C1s also results in the development of SLE, with prominent renal and cutaneous sequelae. C1r or C1s homozygous deficiency is exceptionally rare (ie, fewer than 10 cases reported). Some of these patients have deficiencies of both C1r and C1s, consistent with the close linkage of the genes for these two homologous proteins.

C4 deficiency — Total deficiency of C4 is rare. Approximately 80 percent of patients present with SLE that is often severe and begins at an early age.

In contrast, partial deficiency of C4 is common and is part of the HLA-B8, DR3 extended haplotype that also predisposes to the development of SLE [17,25,31]. A borderline or low C4 (with normal C3) is observed in 1 to 3 percent of the White population, and most of these individuals are asymptomatic. Among White persons with SLE, 5 to 10 percent will be C4A deficient. It is unclear whether the C4A deficiency alone or some other gene on the 1.4 to 5 Mb haplotype is also responsible. Complete C4A deficiency (missing both C4A genes, reflecting homozygosity for HLA-B8, DR3) increases one's risk of SLE. Approximately 1 to 2 percent of the White population lacks both copies of C4A and may have C4 serum concentrations as low as half the usual normal range.

C4 is encoded as two highly polymorphic genes, C4A and C4B, which are located in the MHC on chromosome 6. Fifty to 65 percent of the population carries two C4A and two C4B genes. In the rest of the population, at least one or more C4A and/or C4B gene(s) are deleted or duplicated. An individual may carry one to eight functional C4 genes. These differences in gene number are referred to as "copy number variation."

The more null (nonexpressed) C4 alleles an individual possesses, the greater the predisposition to SLE. Genetic testing is required to determine the number and type of C4 genes. In the future, there will be genetic tests to allow for rapid assessment of gene copy number, although at present this is usually performed for research purposes. Levels of C4 may be 0, 25, 50, or 75 percent of normal depending upon whether the individual inherits four, three, two, or one nonexpressed allele(s), respectively. In these individuals, C4 is borderline low throughout life, and, if SLE develops, C4 drops even lower. Such patients will continue to show low or low-normal total C4, even with successful treatment of the disease. This can cause confusion when a patient with SLE is treated and there is resolution of clinical symptoms and C3 levels normalize but C4 levels remain low. There are two explanations for this picture:

The disease is in remission and patient is C4A deficient (lacks expressed C4A genes, for example) such that the patient will always have a low C4.

or

There is ongoing but reduced classical pathway activation. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults".)

Low C4 in the patient with SLE — The interpretation of a low C4 in a patient with systemic lupus erythematosus (SLE) can be complicated, as noted above. Reduced levels may be due to consumption as well as to deficiency of one or more alleles. Both causes may be present in a given patient. The underlying mechanisms can sometimes be distinguished by the following observations:

Consumption is associated with a reduction in multiple complement components. As an example, low C4, C2, and C3 indicate consumption. In addition, consumption fluctuates over time.

Inherited complement deficiency is characterized by the fixed absence of a single complement component.

If there is still uncertainty, a blood sample can be sent to a commercial laboratory specializing in complement tests. To determine the number of C4 alleles at the deoxyribonucleic acid (DNA) level, the sample would need to be sent to a research laboratory. HLA typing can determine if the patient carries the HLA-B8, DR3 haplotype. Definitive reviews have been published on determining copy number of C4 genes in a large number of normal controls and SLE patients [25,32-34]. Tests to measure C4 and C3 antigen levels in the plasma or serum are widely available, reliable, and can be obtained within a few hours. Assessment of C4 and C3 can be useful in diagnosing and monitoring the clinical status of patients with SLE. In addition, assessment of complement activation products, such as C3a, C5a, and sC5b-9, may also prove useful, although proper handling of blood samples poses a major technical challenge, and it is often difficult to standardize sample collection adequately. The more stable end products of complement activation, cell-bound C4d and C3d, are covalently bound to RBCs, platelets, and/or peripheral blood B and T lymphocytes. Several reports suggest that monitoring C4d bound to RBCs and lymphocytes is superior in diagnosing and monitoring a response to therapy in patients with SLE compared with following C4 and C3 antigen levels [35,36]. However, additional investigations (including longer-term studies) are needed before such tests can be routinely used, and they will likely not replace C3 and C4 antigen levels. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Assessment of disease activity'.)

Other associated disorders — Deficiency of C4A or C4B as parts of various extended MHC haplotypes has also been associated with the development of other disorders. These include scleroderma, immunoglobulin A (IgA) nephropathy, immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP]), childhood diabetes mellitus, chronic forms of noninfectious hepatitis, membranous nephropathy, and subacute sclerosing panencephalitis.

One report identified a strikingly high frequency of capillary leak syndrome (CLS) in children undergoing cardiac surgery with cardiopulmonary bypass who were C4A null (ie, no C4A protein in their blood) [37]. If these patients were given C4A-rich blood, only 3 of 58 developed CLS. If they were given blood lacking C4A, 56 (97 percent) developed CLS. The authors are unaware of a confirmatory report. (See "Idiopathic systemic capillary leak syndrome".)

C2 deficiency — Homozygous, complete deficiency of C2 occurs mainly in White individuals at a frequency of approximately 1 in 20,000 [9,27]. Twenty to 60 percent of females with C2 deficiency present with an SLE-like illness [9,38,39]. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults".)

Another presentation, especially in early childhood, is recurrent pyogenic infections with encapsulated bacteria, such as S. pneumoniae, H. influenza type b, and N. meningitidis [38,40].

C2 deficiency is also sometimes associated with immunoglobulin G (IgG) subclass deficiency. Other disease associations include discoid lupus erythematosus, polymyositis, glomerulonephritis, Hodgkin lymphoma, vasculitis, and IgAV. (See "Approach to the child with recurrent infections" and "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Primary humoral immunodeficiencies: An overview".)

Tests for antinuclear antibodies may be positive in a low titer and often demonstrate a speckled pattern. Tests for antibodies to double-stranded DNA are usually negative. However, more than 50 percent of patients have antibodies to the Ro (SS-A) antigen. (See "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems".)

Partial C2 deficiency appears to have no clinical significance in most individuals, and its frequency does not appear to be increased among patients with SLE [9,10,41]. It is sometimes detected because it can yield a low CH50, as previously discussed. (See 'Screening CH50 and interpretation' above.)

Patients may also have a combination of multiple autoimmune phenomena, especially various cutaneous manifestations, and pyogenic infections. In one such case, a patient appeared to respond to treatment with rituximab, although IgG declined, requiring immune globulin replacement therapy [39].

C3 deficiency — Complete deficiency of C3, the major opsonin of the complement system, results in severe, recurrent infections with encapsulated bacteria that begin shortly after birth [6,27]. Patients with C3 deficiency are particularly prone to infections with the pneumococcus and, less frequently, H. influenza or N. meningitidis.

Children who survive these infections subsequently may develop problems secondary to excess immune complex formation, especially glomerulonephritis. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)

Partial C3 deficiency, which results in one-half the normal serum level of C3, appears to have no clinical significance.

Total deficiency of factors H or I gives rise to a secondary C3 deficiency. A deficiency of one of these regulatory proteins and a C3 or C4 nephritic factor (autoantibody to a C3 convertase, C3bBb or C4b2a) should be considered in the evaluation of a child with presumed C3 deficiency [42,43]. (See 'Factor H, factor I, and membrane cofactor protein' below.)

C5-C9 deficiency — A deficiency of a component of the membrane attack complex (MAC, C5-C9) is associated with infection by Neisseria species (especially the meningococcus), which are characteristically of an unusual serotype (for reasons that are unclear). Neisserial infections in these patients with a deficient protein of the MAC tend to be recurrent and clinically mild to moderate, with a low (approximately 2 percent) mortality rate [6,44-54]. Patients are otherwise healthy in most cases. (See "Clinical manifestations of meningococcal infection" and "Microbiology and pathobiology of Neisseria meningitidis" and "Epidemiology of Neisseria meningitidis infection" and "Gonococcal infection in the newborn".)

In the United States, C5, C6, or C8 deficiency is the most common [44-46,50-53]. C6 deficiency is usually reported in African Americans with South African ancestry [45,46].

C7 deficiency has been reported worldwide [47-49,55-58].

C9 deficiency is almost always observed in people of Japanese or Korean ancestry, in whom it is inherited as an autosomal recessive trait [29,30]. It is one of the most frequent genetic disorders in the Japanese population. It is associated with lower rates of mortality compared with complement-normal patients, so this variant may confer an evolutionary advantage in the heterozygous state [29]. C9 deficiency is a less severe defect because cells can still be lysed by C5b-8, albeit with less efficiency than if C9 is present.

As mentioned previously, a complete deficiency of any one component of the MAC gives an undetectable CH50 value. The exception is C9 deficiency, which gives a low but detectable CH50 titer. The CH50 should be the initial screening test. The usual clinical indication is recurrent neisserial infections. If the CH50 is zero or very low, then the specific deficiency is diagnosed by measuring levels of C5, C6, C7, C8, and C9. C6 should be measured first in African American patients, while C5 and C8 should be checked initially in White individuals and C9 in patients of Japanese, Korean, or Chinese descent.

ALTERNATIVE PATHWAY DEFICIENCIES — An inherited defect in a component of the alternative pathway is rare. Affected patients present with serious neisserial and pneumococcal infections [27]. An alternative pathway (AH50) assay is a screen for such a deficiency. If very low or undetectable, individual components (factor B, factor D, or properdin) can be assessed. Recall that if the CH50 is also low, the defect must be in C3 or a terminal pathway component. (See "Overview and clinical assessment of the complement system".)

Properdin deficiency is the only one of the early components of the alternative pathway for which more than a few cases have been reported [27,59-62]. Properdin-deficient individuals have no activity of the alternative pathway in most assay systems (figure 2) [63]. This disorder affects one-half of males within an affected family because the gene is on the X chromosome [6,59,64]. N. meningitidis is the most frequently implicated infection and is often of an unusual serotype. Thus, a male child with a family history of neisserial meningitis should be evaluated for properdin deficiency. Recurrent otitis media and pneumonia have also been reported [64]. The mortality rate for properdin deficiency is in the range of 34 to 63 percent [59,63].

A small number of patients (<5) with factor D deficiency have been reported [27,63,65]. To date, the disorder has been observed in children of consanguineous parents, and all have developed meningococcal sepsis.

The first recognized case of factor B deficiency was reported in 2013 in a 32-year-old woman with nonconsanguineous parents who had experienced several serious pneumococcal and meningococcal infections since the age of two years [27,66]. One parent carried a frameshift mutation and the other a nonsense mutation. Heterozygous family members did not have a history of recurrent infections.

Factor H and factor I are sometimes included in the discussions of the alternative pathway, although they are more accurately classified as regulatory proteins. (See 'Factor H, factor I, and membrane cofactor protein' below.)

LECTIN PATHWAY DEFICIENCIES — Inherited defects in components of the lectin pathway include deficiencies of mannan-binding lectin-associated protease 2 (MASP2), ficolin 3 [67,68], and the 3MC syndrome [69-71].

MASP2 deficiency — A deficiency of MASP2 has been described [72]. Severe pneumococcal pneumonia and immune disorders, including ulcerative colitis and erythema multiforme bullosum, were reported in one patient with this abnormality. Another study found a deficiency of MASP2 was associated with an increased risk of fever and neutropenia in pediatric patients treated with chemotherapy for cancer [73].

Ficolin 3 deficiency — A patient homozygous for a frameshift mutation of the ficolin 3 gene (FCN3) resulting in the absence of serum ficolin 3 has been reported [27,74]. This patient had recurrent severe pulmonary infections since early childhood that resulted in bronchiectasis, pulmonary fibrosis, and progressive obstructive lung disease. He also had recurrent warts on his fingers and brain abscesses beginning in early adulthood. He had normal activity of the three complement pathways as routinely measured clinically (using mannan-binding lectin [MBL] to trigger the lectin pathway), but lacked complement deposition on acetylated structures. His heterozygous parents and a sibling were healthy, which suggests an autosomal recessive pattern of inheritance. Ficolin 3 deficiency was also reported in a 50-year-old male suffering from membranous nephropathy and an 11-month-old male infant following surgery to repair a congenital heart defect [75].

3MC syndrome — Homozygous mutations in either of two genes (collectin subfamily member 11 [COLEC11] and MBL-associated serine protease 1 [MASP1]), encoding for distinct but related secreted proteins involved in lectin pathway activation, can be responsible for this developmental disorder. It features facial dysmorphic traits (hypertelorism, eyebrow abnormalities, cleft lip and palate, and other developmental, growth, and cognitive impairments). The MASP protein is required for lectin pathway activation, and CL-K1 (lectin-like protein of the COLEC11 gene) has a carbohydrate-recognition domain. Thus, early in life, these proteins are important for development, and then, at birth, they are involved in host defense [70,71].

ABNORMALITIES IN REGULATORY PROTEINS — Clinically important deficiencies/defects of complement regulatory proteins include those of C1 inhibitor, factor H, factor I, membrane cofactor protein (MCP), complement receptor 3 (CR3), decay-accelerating factor (DAF), and CD59. (See "Regulators and receptors of the complement system".)

C1 inhibitor deficiency — Deficiency of C1 inhibitor gives rise to hereditary angioedema, which is discussed in detail elsewhere. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis" and "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis" and "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis" and "Hereditary angioedema: Acute treatment of angioedema attacks".)

Factor H, factor I, and membrane cofactor protein — Plasma factors H and I regulate C3 and a complete deficiency of either factor allows the alternative pathway to fire to exhaustion and thereby consume C3 [4,5,76].

As a result, afflicted individuals exhibit symptoms and findings similar to that of C3-deficient patients (ie, recurrent infections). (See 'C3 deficiency' above.)

In homozygous factor H or factor I deficiency, factor B is also low, while it is normal in isolated C3 deficiency. Protein levels of factor H or factor I should be assessed in a patient with very low C3 levels, especially if factor B is also reduced.

Alternative pathway dysregulation due to haploinsufficiency has also been associated with the pathogenesis of hematopoietic cell transplant (HCT) associated thrombotic microangiopathy (TMA) in children [77]. In this case study, a high prevalence of genetic variations in the factor H gene cluster as well as the presence of factor H autoantibodies correlated with post-HCT TMA.

Additionally, heterozygous deficiency of factors H or I predispose to atypical (nondiarrheal) hemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD). Heterozygous deficiency of MCP (CD46) also predisposes to aHUS:

aHUS – Heterozygous mutations in the genes for factor H, factor I, as well as those for MCP (CD46), have been associated with aHUS (table 1) [24,78-82]. Approximately 50 percent of patients with aHUS have a defect in one of these three complement regulatory proteins. In addition, these patients may have autoantibodies to factor H or a gain-of-function mutation in C3 or factor B. This is discussed in detail separately. (See "Complement-mediated hemolytic uremic syndrome in children".)

More than 60 disease-associated mutations in the gene for MCP have now been identified [80]. These heterozygous dysfunctional rare variants in MCP account for 10 to 20 percent of aHUS patients. Complete deficiency of MCP has only been reported in a few (<10) cases. These patients presented with aHUS, and several had hypogammaglobulinemia in association with a T helper cell defect [83]. In the mouse, knockout of a widely expressed protein related to MCP (known as Crry) led to chronic alternative pathway activation on cells and was embryonic lethal but could be rescued by maternal C3, factor B, factor D, or properdin deficiency [84].

AMD – An association exists between a polymorphism in factor H and AMD. The 402H variant (the uncommon allele) is carried by approximately 30 percent of the White population. This variant increases the risk of developing AMD by 1.5- to 3-fold if heterozygous and up to 10-fold if homozygous. It accounts for approximately 50 percent of the attributable genetic risk for AMD. This association is most consistent with a decrease in functional activity of the variant in controlling alternative pathway activation in the retina. Rare variants in factor H, factor I, C3, and factor B have been shown to predispose strongly to AMD. Up to 5 percent of advanced AMD patients carry a rare variant in factor I. Such mutations tend to associate with early age of onset (<70 years) and more severe disease [19,85-87]. Relative to the regulators, it is a loss of function, while, in the integral components of the alternative pathway, it is a gain of function. Of note, many of the gain-of-function variants in C3 are in the site where regulators attach to inactivate C3b. Thus, variants that increase the activity of the alternative pathway predispose to AMD.

C3 glomerulopathies and membranoproliferative glomerulonephritis (types 1 to 3) – Abnormal deposition of C3 fragments has been increasingly described as a consequence of genetic or acquired defects causing over activation of the alternative pathway activation [88,89].

Elevated serum levels of factor H – In two reports, high levels of factor H resulted in reduced complement activity and increased susceptibility to meningococcal disease [90,91]. The responsible defect was an alteration in the promoter region of the gene encoding factor H.

HELLP – Like aHUS, the pregnancy-related HELLP (ie, hemolysis with a microangiopathic blood smear, elevated liver enzymes, and a low platelet count) syndrome features endothelial cell damage, although the liver rather than the kidney appears to be the main organ undergoing injury. In one series, heterozygous mutations in complement regulators factor I, factor H, and MCP were observed in approximately 50 percent of severe HELLP patients, but, in another series, it was much lower [92-95]. The etiology of HELLP remains enigmatic, and further studies in a complement/HELLP connection are required. (See "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".)

Complement receptor 3 — An inherited deficiency of complement receptor 3 (CR3 or CD11b/CD18), an integrin that binds inactive iC3b as well as other noncomplement ligands, causes recurrent and severe bacterial (Staphylococcus aureus and/or Pseudomonas) infections. This condition, known as leukocyte-adhesion deficiency syndrome I (CD11/CD18 deficiency), may present shortly after birth with delayed separation of the umbilical cord and development of omphalitis. (See "Leukocyte-adhesion deficiency".)

Decay-accelerating factor — A deficiency of decay-accelerating factor (DAF, CD55) caused by a biallelic loss-of-function mutation has been linked to early-onset protein-losing enteropathy and thrombosis (the CHAPLE syndrome) [96]. (See "Acquired disorders of the complement system", section on 'Somatic mutation of a complement gene'.)

CARE OF THE COMPLEMENT-DEFICIENT PATIENT

Vigilance for early signs of serious infection — Patients with complement deficiencies who have experienced one or more serious infections should wear a medical identification badge identifying their specific condition.

Patients should be instructed to seek medical assistance for high fevers, stiff neck, severe headache, severe myalgias, or petechial and/or purpuric rash. Once they have had meningococcal disease, most patients are very cognizant of the symptoms.

Vaccination — Patients with complement deficiency may receive all routine bacterial and viral vaccines safely and are not at increased risk for adverse reactions to live-viral vaccines. It is important to ensure that patients are vaccinated against those diseases for which they are at increased risk, especially the meningococcus and the pneumococcus.

When immunizing patients with complement deficiency, "conjugate" vaccines are preferred over pure polysaccharide vaccines.

Vaccination against meningococcus is particularly critical for patients deficient in properdin and for those deficient in C5, C6, C7, C8, or C9 [97]. (See "Meningococcal vaccination in children and adults", section on 'Immunization of persons at increased risk'.)

The pneumococcal and Haemophilus influenzae b (Hib) conjugated vaccines are also indicated [98,99]. (See "Pneumococcal vaccination in adults" and "Prevention of Haemophilus influenzae type b infection", section on 'Routine childhood immunization in the United States'.)

Antibiotic prophylaxis — Antibiotic prophylaxis may be beneficial for some complement-deficient patients. There are few data about this practice, although controlled studies do suggest that, for terminal complement component deficiencies, injection therapy (benzathine penicillin, 2.4 million units monthly for adults) or more commonly, oral prophylaxis, is efficacious [100,101]. In most other cases, antibiotic prophylaxis is individualized based upon the frequency, type, and severity of infectious illnesses.

Specifically, several reports found that, while optimizing vaccination status is mandatory to reduce episodes of meningitis, it does not provide complete protection [102-104]. Prophylactic antibiotics were also helpful in some patients in lowering the frequency of infectious events. Due to a lack of longer-term studies with appropriate controls, most patients require an individualized stratification plan relative to medication usage. For example, those in areas of high bacterial exposure (endemic or work related) as well certain other factors (such as availability of drugs, history of drug usage, access to nearby clinicians and hospitals) would need to be taken into account. Benefits of prophylactics versus potential development of resistance to antibiotics must also be considered.

Replacement therapy — With rare exceptions, complement component-deficient patients are not treated with regular plasma infusions, because this is impractical and, over a lifetime, would be associated with risk of bloodborne diseases [27]. In addition, there is a risk of the development of antibody against the missing component. In the setting of an infection, replacement therapy, such as with fresh frozen plasma (to replace the missing component), is usually not necessary as the patients respond to standard antibiotic therapy. However, in the setting of a slow or inadequate response, infusion therapy is an alternative, although there is very limited experience, and it is not a substitute for more standard treatments.

Atypical hemolytic uremic syndrome (aHUS) – Infusion of plasma, which contains factors H and I, normalizes the C3 level in patients with a complete deficiency or with a partial deficiency presenting as aHUS and may temporarily alleviate clinical symptoms. However, there are no long-term studies of supplying these regulatory proteins by plasma transfusions. Purified preparations of factor H or factor I are not available for infusion. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Plasma therapy'.)

Other applications of plasma infusions – A patient with C1q deficiency was treated with fresh frozen plasma infusions over a 10-year period [105]. A small number of cases of C2 deficiency and refractory lupus have been successfully treated with plasma replacement therapy [106]. However, most patients with C2 deficiency and systemic lupus erythematosus (SLE) have mild-to-moderate disease and respond to standard therapies.

Specific therapies – Specific treatments are available for very few inherited disorders of complement. One available treatment is eculizumab, a humanized monoclonal antibody that binds to the C5 component of complement and inhibits terminal complement activation. Eculizumab has been approved for treatment of aHUS. It has also been approved for treatment of the acquired complement deficiency disorder paroxysmal nocturnal hemoglobinuria (PNH) and two autoimmune disorders: refractory generalized myasthenia gravis in adults and neuromyelitis optica spectrum disorder. However, patients are at an increased risk of invasive meningococcal disease as compared with the general population, and a boxed warning was added to the product label in 2023 [107]. Case reports describe fatal infection in eculizumab recipients caused by nongroupable meningococcal strains, which rarely cause disease, despite meningococcal vaccination [108,109]. (See "Chronic immunotherapy for myasthenia gravis", section on 'Eculizumab' and "Neuromyelitis optica spectrum disorder (NMOSD): Treatment and prognosis" and "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria", section on 'Eculizumab'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

Homozygous complement deficiencies – Homozygous deficiencies in complement components are rare. The main clinical manifestations are recurrent infections with encapsulated bacteria, systemic lupus erythematosus (SLE), or both. (See 'Deficiencies in an integral component of the activating cascades' above.)

Classical pathway components:

Deficiencies in the early components of the classical complement pathway (ie, C1q, C1r, C1s, C4, and C2) predispose patients to autoimmune disorders, particularly SLE. Recurrent infections may also be seen. (See 'C1 deficiency' above and 'C4 deficiency' above and 'C2 deficiency' above.)

Deficiencies in late components (C3-C9) of the classical complement pathway predispose patients to recurrent infections, especially pneumococcal and Haemophilus influenzae (with C3 deficiency) and neisserial infections (with C5, C6, C7, C8, or C9 deficiency). (See 'C3 deficiency' above and 'C5-C9 deficiency' above.)

Screening with CH50 – The total hemolytic complement (THC or CH50) assay is an effective screening test for a complete deficiency of a component of the classical pathway. Complete deficiency generally yields a very low or undetectable CH50 value (with the exception of complete C9 deficiency). Individuals with a heterozygous component deficiency are usually healthy and have normal CH50 values. (See 'Screening CH50 and interpretation' above.)

Screening with AH50 – The alternative pathway (AH50) assay is a screen for deficiencies in properdin, factor B, and factor D. Properdin is the most common component of the alternative pathway to be deficient. Properdin deficiency is X linked and presents in males as a familial predisposition to neisserial infections, especially meningitis. Inherited defects in factors D and B have only been described in a few case reports. (See 'Alternative pathway deficiencies' above.)

Deficiencies in regulatory proteins – Deficiencies and defects in complement regulatory proteins can lead to specific disorders resulting from unregulated activity of the alternative pathway. Clinically important deficiencies/defects of complement regulatory proteins include those of C1 inhibitor, factor H, factor I, membrane cofactor protein (MCP), complement receptor 3 (CR3), decay-accelerating factor (DAF), and CD59. (See 'Abnormalities in regulatory proteins' above.)

Principles of management – The management of complement-deficient patients primarily involves education of the patient in vigilance for early signs of infection and vaccination against the organisms to which the patient is susceptible. (See 'Care of the complement-deficient patient' above.)

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  107. Letter regarding addition of boxed warning is available at https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/125166Orig1s446ltr.pdf (Accessed on February 20, 2024).
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Topic 3962 Version 33.0

References

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