An increased susceptibility to infection is a prominent clinical finding in most patients with complement deficiencies. The kinds of infections relate to the biologic functions of those components that are missing. For example, the third component of complement (C3) is an important opsonic ligand. Therefore, patients with a deficiency of C3, or of a component of either of the two pathways that activate C3, are more susceptible to infections caused by encapsulated bacteria for which opsonization is the primary host defense (e.g., Streptococcus pneumoniae, Streptococcus pyogenes, and Haemophilus influenzae). Similarly, C5 through C9 form the membrane attack complex and are responsible for the bactericidal functions of complement. Thus, patients with deficiencies of C5, C6, C7, C8, or C9 are susceptible to gram-negative bacteria, notably Neisseria species, because serum bactericidal activity is an important host defense against these organisms.

A number of studies have examined groups of patients with specific infectious diseases to determine the frequency of complement deficiencies in these infections and to evaluate the utility of screening for complement deficiencies. Between 5% and 15% of unselected patients with systemic meningococcal infections have a genetically determined complement deficiency. The differing estimates may reflect differences in populations examined. In general, the prevalence is higher if the patient has had recurrent meningococcal disease, has a positive family history for meningococcal disease, or is infected with an uncommon meningococcal serotype. Therefore, it seems reasonable to screen children with systemic meningococcal infections for the presence of a complement deficiency. In contrast, although many patients with complement deficiencies present with systemic pneumococcal or H. influenzae infections, the prevalence of complement deficiencies in patients with these specific infections appears to be quite low. Therefore, recommending routine screening for complement deficiencies in patients with bacteremia or meningitis caused by pneumococcus or H. influenzae is more difficult to justify.

Patients with complement deficiencies also have a variety of clinical conditions that can be described best as rheumatic diseases. These include disorders that resemble systemic lupus
erythematosus (SLE) as well as glomerulonephritis, dermatomyositis, anaphylactoid purpura, and vasculitis. The prevalence of these inflammatory disorders is highest in those patients with deficiencies of the classical activating pathway (C1, C4, and C2) and of C3. The pathophysiologic basis for the occurrence of these diseases in complement-deficient patients may relate in part to the physiologic role of the complement system in processing immune complexes or its role in the clearance of apoptotic cells.

Some important differences exist between the rheumatic diseases seen in complement-deficient patients and their counterparts in non–complement-deficient individuals. For example, the SLE-like illness seen in complement-deficient individuals often is characterized by onset in childhood, skin lesions resembling discoid lupus, and relatively limited renal and pleuropericardial involvement. In addition, complement-deficient individuals with the lupus-like syndrome may have absent or low titers of antinuclear antibodies and negative lupus preparations. In contrast, their incidence of anti-Ro antibodies is significantly higher than in non–complement-deficient patients with lupus. Thus, complement-deficient patients with the lupus-like syndrome resemble a subgroup of lupus patients who have subacute, cutaneous lupus.

Patients with a deficiency of one of the control proteins of the classical pathway, C1 esterase inhibitor, usually present with angioedema of the skin or mucous membranes (see following discussion). No large studies have examined the prevalence of C1 esterase inhibitor deficiency in patients with angioedema.

Some patients with genetically determined complement deficiencies are relatively asymptomatic, never having developed a serious infection or a rheumatic disorder. These asymptomatic patients usually are ascertained as a consequence of screening family members of complement-deficient patients who themselves have been ascertained because of clinically significant problems.