• Complement deficiencies account for approximately 5–10% of all primary immunodeficiencies ^[2][5].
• Overall prevalence of complement deficiencies is estimated at ~1 in 10,000 (varies widely by specific component and ethnicity).
• Many are autosomal recessive (AR), meaning both alleles must be affected → consanguinity increases risk.
• Properdin deficiency is the only X-linked complement deficiency.
• C2 deficiency is the most common inherited complement deficiency in Caucasians (~1 in 20,000) ^[1][5].
• MBL (Mannose-Binding Lectin) deficiency/low levels are extremely common (5–30% of the general population carry variant alleles), but most are clinically silent; clinical significance is debated.
• C9 deficiency is notably common in Japanese and East Asian populations (including Hong Kong Chinese), with prevalence ~1 in 1,000 in Japan ^[5].
• Partial C4 deficiency (loss of either C4A or C4B, given C4 gene copy number variation) is also relatively common and appears to have a modest effect on host defence ^[1].

• C9 deficiency is the most frequently encountered complement deficiency in East Asian / Hong Kong Chinese paediatric populations.
• SLE prevalence is higher in Orientals (6 per 10,000) compared to Caucasians (1 per 10,000), and complement deficiency (particularly C2, C4, C1q) is associated with ~5% of SLE cases ^[3].
• Hereditary angioedema (C1-inhibitor deficiency) — while technically a complement regulatory protein deficiency — is seen across all ethnicities; awareness has increased in Hong Kong.

• Complement deficiencies may present at any age, but many present in childhood or adolescence with:
  • Recurrent meningococcal disease (terminal pathway defects)
  • Early-onset SLE-like disease (classical pathway defects — C1q, C1r/s, C4, C2)
  • Recurrent pyogenic infections in infancy (C3 deficiency)
  • Neonatal/infantile necrotising enterocolitis (Ficolin 3 deficiency) ^[1]
• Hereditary angioedema (HAE) from C1-inhibitor deficiency often presents with first attacks in late childhood / adolescence, with worsening around puberty.

• C5 is cleaved → C5a (potent anaphylatoxin and chemotactic factor) + C5b.
• C5b sequentially recruits C6, C7, C8, C9 → C9 polymerises to form a pore (MAC) in the target cell membrane → osmotic lysis.
• MAC is particularly important for killing Neisseria spp. because Neisseria have a thin outer membrane vulnerable to MAC-mediated lysis. This is why terminal pathway defects (C5–C9) present with recurrent Neisserial infections (meningitis, meningococcaemia) ^[1][6].

SLE-like syndrome; infections with encapsulated organisms; absent CH50 hemolytic activity ^[1]

Pathophysiology — Why SLE?

• C1q, C4, C2 are all required for classical pathway activation.
• Classical pathway is the primary route for clearing immune complexes (C3b coats immune complexes → CR1 on red blood cells → transport to reticuloendothelial system for clearance).
• Classical pathway also clears apoptotic cells (C1q binds directly to apoptotic blebs).
• Deficiency → failure of immune complex and apoptotic cell clearance → chronic presentation of nuclear self-antigens → loss of tolerance → autoantibody production → SLE.
• There is a "gene dosage" effect: C1q deficiency (earliest in cascade) → > 90% SLE risk; C4 deficiency → ~75%; C2 deficiency → ~15–30%. The further downstream the defect, the less severe the SLE association, because the lectin and alternative pathways can partially compensate for later classical pathway components.

Pathophysiology

• MBL and ficolins recognise carbohydrate patterns (pathogen-associated molecular patterns / PAMPs) on bacteria, particularly encapsulated organisms.
• Deficiency → failure to activate complement via the lectin pathway → impaired opsonisation → susceptibility to pyogenic bacteria.
• Ficolin 3 is particularly important in pulmonary host defence (expressed by type II alveolar epithelial cells and macrophages) → deficiency → lung infections, neonatal NEC ^[1].

Pathophysiology

• The alternative pathway provides the amplification loop for complement activation and is the first-line innate defence against Neisseria and other Gram-negative bacteria.
• Properdin is the only positive regulator of complement (it stabilises C3bBb convertase). Without it, C3bBb rapidly decays → no AP amplification → no effective lytic activity → Neisseria thrives.
• Why Neisseria specifically? Neisseria spp. are Gram-negative diplococci with a relatively thin peptidoglycan layer and outer membrane → they are uniquely vulnerable to MAC-mediated lysis. Most other Gram-negative bacteria are also susceptible, but they have additional killing mechanisms (phagocytosis). Neisseria's immune evasion strategies (e.g., sialylation of LOS, factor H binding protein) make them particularly dependent on complement-mediated killing ^[6].

Pathophysiology

• C3 is the central convergence point of ALL three pathways. Its deficiency is therefore the most severe "pure" complement deficiency in terms of infection susceptibility.
• C3b is the major opsonin → without it, phagocytes cannot effectively recognise and engulf bacteria → recurrent severe pyogenic infections (pneumonia, meningitis, sepsis) from encapsulated organisms (S. pneumoniae, H. influenzae, N. meningitidis).
• C3 deficiency also impairs the humoral immune response (because C3d/CR2 co-stimulatory signalling on B cells is lost), so antibody responses are suboptimal.
• Also predisposes to SLE-like disease (impaired immune complex clearance) and glomerulonephritis (C3 glomerulopathy).

Disseminated Neisserial infections; absent CH50 and AH50 hemolytic activity ^[1]

Pathophysiology

• C5b–C9 form the MAC. Without any one of C5–C8, MAC cannot form at all → complete inability to lyse Gram-negative bacteria → recurrent/disseminated Neisserial infections (meningitis, meningococcaemia, disseminated gonococcal infection).
• C5 deficiency also eliminates C5a generation → loss of the most potent chemotactic factor → further impaired inflammatory response.
• C9 deficiency is unique: the MAC can still form a partial pore from C5b–C8 (this complex alone can insert into membranes and cause some lysis). C9 polymerisation greatly amplifies pore size, but is not absolutely required → hence mild susceptibility and normal CH50 in many patients ^[1]. This is why C9 deficiency in Japanese/East Asian populations is often clinically silent.

Category VIII: Complement Deficiencies in the IUIS classification of inborn errors of immunity ^[1][2]

This is extremely high yield for understanding which lab test points to which deficiency:

CH50 = Classical Haemolytic 50 = measures the classical pathway (C1–C9 all needed) AH50 = Alternative Haemolytic 50 = measures the alternative pathway (Factor B, D, Properdin, C3–C9 all needed)

The Jeffrey Modell Foundation Warning Signs of Primary Immunodeficiency (paediatric version) include several clues. For complement deficiency specifically, red flags are:

1. ≥ 2 episodes of invasive bacterial infection (meningitis, sepsis, osteomyelitis)
2. Infection with unusual serogroups of Neisseria or recurrent Neisseria
3. Family history of early death from infection, consanguinity, or known complement deficiency
4. Early-onset SLE (< 5 years), especially with severe nephritis and very low C3/C4
5. Recurrent angioedema without urticaria (HAE)
6. aHUS without STEC infection

Primary immunodeficiencies / inborn errors of immunity (10 types) — Table 1 through Table 9 per the IUIS classification ^[2][3]. Complement deficiency is Table 8 ^[2].

The IUIS classifies inborn errors of immunity into 10 tables ^[2]. Any of these can present with recurrent infections. The key is to use the type of infection and type of organism to narrow down which arm of the immune system is likely defective:

Before diagnosing a primary immunodeficiency, always consider acquired causes of immunosuppression:

Nephrotic syndrome is an especially important differential in paediatrics. Children with nephrotic syndrome lose low-molecular-weight complement proteins (Factor B, Factor D, Properdin) in the urine → functional alternative pathway deficiency → increased susceptibility to S. pneumoniae, N. meningitidis. This is acquired complement deficiency, not inherited — but it mimics it clinically.

Differentials: exclude anatomical and functional disorders ^[1]

Why is genetic confirmation important in paediatrics?

1. Definitive diagnosis → informs prognosis, treatment, and genetic counselling.
2. Prenatal diagnosis for future pregnancies if parents wish.
3. Newborn screening context: TREC-based newborn screening catches SCID but does NOT screen for complement deficiency. Genetic diagnosis enables cascade testing of siblings.
4. Phenocopy exclusion: Table 10 "Phenocopies of PID" — conditions that present as inherited immunodeficiencies but are not due to germline mutations and instead arise from acquired mechanisms ^[5] (e.g., autoantibodies against Factor H). Genetic testing distinguishes true inherited from phenocopy.

• Most complement deficiencies are AR → both parents are carriers → 25% recurrence risk per pregnancy.
• Properdin deficiency is X-linked → mother is carrier → 50% of sons affected, 50% of daughters are carriers.
• HAE and regulatory protein defects (Factor H, MCP, THBD, C3 GOF, Factor B GOF) are often AD → 50% risk for each child of an affected parent.
• Screen all first-degree relatives with functional assays (CH50, AH50) and the specific component assay. Offer genetic testing.
• Vaccinate affected family members (meningococcal, pneumococcal, Hib) regardless of whether they are symptomatic.

Vaccination is the single most important intervention. The rationale: since the child cannot mount effective complement-mediated killing, maximising antibody-mediated opsonisation and phagocytosis through vaccination provides a partial compensatory defence.

Encapsulated bacteria — Pneumococcus, Neisseria meningitidis, Haemophilus influenzae are the key target organisms ^[3][11]

Paediatric-specific vaccination points:

• In Hong Kong, the Childhood Immunisation Programme (CIP) includes PCV13 and Hib but does not routinely include meningococcal vaccines → these must be specifically ordered and funded for complement-deficient children.
• Live vaccines (MMR, varicella, rotavirus, BCG) are generally safe in isolated complement deficiency (complement defects do not impair T-cell immunity). This is different from SCID or CGD where live vaccines may be contraindicated.
• Vaccine efficacy may be reduced in complement-deficient children (because complement normally enhances B-cell responses via C3d–CR2 co-stimulation). This is why booster doses and checking post-vaccination antibody titres are important.

Antibiotic prophylaxis is listed as the treatment for complement deficiency (C3 deficiency) in the lecture summary ^[3]

Duration: Lifelong in most inherited complement deficiencies (the genetic defect is permanent). Some experts recommend lifelong prophylaxis only for children and those with previous invasive infection, transitioning to vaccination-only strategy in adulthood — but this is debated.

Why prophylaxis works: Even though complement-mediated lysis is impaired, maintaining a low-level antibiotic cover reduces the bacterial load before it can overwhelm the host. Antibody-mediated opsonophagocytosis (enhanced by vaccination) provides a partial alternative killing pathway.

Every family must have a written emergency action plan:

1. Any fever ≥ 38°C → go to Emergency Department immediately (do not wait for next-day GP appointment)
2. Blood cultures must be drawn before antibiotics
3. Empirical broad-spectrum antibiotics started within 1 hour of presentation (e.g., IV ceftriaxone 50–100 mg/kg, max 4 g)
4. Do not wait for culture results — treat empirically for presumed meningococcal/pneumococcal sepsis
5. MedicAlert bracelet/necklace worn at all times

This mirrors the approach for post-splenectomy patients and febrile neutropenia — all share the principle of immediate empirical broad spectrum antibiotics for any febrile episode ^[11][12]

If a complement-deficient child has close contact with a case of invasive meningococcal disease:

Post-exposure prophylaxis for meningococcal disease: single dose oral ciprofloxacin, or single dose IM ceftriaxone → if contraindications for ciprofloxacin (young children, pregnant women) ^[11]

C1-INH deficiency results in the inability to inhibit kallikrein → resulting in excess bradykinin activation and bradykinergic angioedema ^[3] — therefore acute treatment targets the bradykinin pathway, NOT histamine.

Emergency airway management: Laryngeal oedema can be fatal. If stridor or respiratory compromise:

• Administer C1-INH concentrate or icatibant immediately
• Prepare for intubation (note: airway may be very oedematous → call most experienced airway practitioner)
• If intubation fails → surgical airway (cricothyroidotomy in adolescents; needle cricothyroidotomy/tracheostomy in younger children)
• ALL HAE patients should carry on-demand treatment (self-administered or carer-administered icatibant or C1-INH concentrate) at all times

Indicated when the child has frequent attacks (≥ 1/month or significantly impairing quality of life).

Before any procedure that may trigger an attack (especially dental work, intubation, surgery involving the head/neck/airway):

Eculizumab is a monoclonal antibody therapeutic that inhibits the complement pathway by binding to C5 and preventing formation of membrane attack complex. Infections by Neisseria meningitidis is expected to be the MOST COMMON in patients on eculizumab ^[6]

Supportive measures during acute aHUS:

• RBC transfusion for severe anaemia (avoid platelet transfusion unless active bleeding — may fuel microvascular thrombosis)
• Dialysis if oliguric/anuric renal failure
• BP control (amlodipine, labetalol as first-line in paediatric hypertensive emergency)
• Monitor for extra-renal TMA (CNS, cardiac, GI)

Duration of eculizumab: Often continued indefinitely in children with genetic complement mutations (high relapse risk off therapy). In those with MCP mutations, relapse rate off therapy is lower → trial discontinuation with close monitoring may be considered.

• No specific complement-targeted therapy approved, but eculizumab has been tried with variable success.
• Standard immunosuppressive therapy (MMF, steroids) for active GN.
• Avacopan (C5a receptor antagonist) and iptacopan (Factor B inhibitor) are under investigation in clinical trials (2025).

C5–C9 deficiency → Neisserial infections; C3 deficiency → Pneumococcal infections ^[13]

Complement — classical-alternate: Infectious complications — systemic bacterial infections; Common microorganisms — pyogenic bacteria: Streptococci, Neisseria ^[14]

Which deficiencies? Terminal pathway (C5–C9), alternative pathway (Properdin, Factor D), and to a lesser extent C3 and classical pathway deficiencies.

Pathophysiology from first principles:

• Neisseria meningitidis is a Gram-negative diplococcus with a thin outer membrane → uniquely dependent on MAC-mediated lysis for host defence.
• Without MAC (C5–C9), or without the alternative pathway amplification loop (Properdin, Factor D) that feeds into MAC formation, the bacterium proliferates in the bloodstream unchecked.
• Neisseria has evolved immune evasion strategies (sialylated lipooligosaccharide, Factor H binding protein) that specifically counteract complement → in a complement-deficient host, these evasion strategies are even more effective, tipping the balance decisively toward the pathogen.

Clinical manifestations in children:

• Meningitis: headache, fever, neck stiffness, photophobia, altered consciousness, bulging fontanelle in infants. Kernig and Brudzinski signs may be present in older children but are unreliable in infants.
• Meningococcaemia: fever, non-blanching petechial/purpuric rash (especially on trunk and lower extremities), rapidly progressive septic shock.
• Purpura fulminans: widespread purpura with skin necrosis due to DIC (disseminated intravascular coagulation) complicating meningococcal sepsis → can lead to limb ischaemia and gangrene requiring amputation.
• Waterhouse-Friderichsen syndrome: bilateral adrenal haemorrhage secondary to DIC in overwhelming meningococcal sepsis → adrenal crisis → cardiovascular collapse. This is a paediatric emergency with very high mortality.

Key paediatric point: Meningococcal disease in children < 5 years has the highest incidence in the general population. In complement-deficient children, the risk extends across all ages and includes unusual serogroups (W, X, Y) that are less common in the general paediatric population.

C3 deficiency → recurrent pyogenic infections; defective opsonisation and humoral response ^[4]

Encapsulated bacteria — Pneumococcus, Neisseria meningitidis, Haemophilus influenzae ^[3]

Which deficiencies? Primarily C3 deficiency (loss of the central opsonin), classical pathway deficiencies (C1q, C4, C2), and Ficolin 3 deficiency.

Why? Streptococcus pneumoniae has a thick polysaccharide capsule that resists phagocytosis unless opsonised by C3b or antibodies. Without C3b opsonisation, neutrophils and macrophages cannot "see" the bacterium. The classical pathway also contributes to pneumococcal clearance via immune-complex-mediated opsonisation.

Manifestations: Bacteraemia, pneumonia (lobar or bronchopneumonia), meningitis, empyema, peritonitis, septic arthritis.

Same mechanism as pneumococcal disease — encapsulated organism dependent on complement-mediated opsonisation.

Relevant in adolescents with terminal complement deficiency who become sexually active. Neisseria gonorrhoeae (same genus as N. meningitidis) is also MAC-dependent for killing. Presents as the arthritis-dermatitis syndrome: migratory polyarthralgia, tenosynovitis, sparse vesiculopustular skin lesions, ± septic monoarthritis.

Ficolin 3 deficiency: infections mainly in the lungs; abscesses, necrotising enterocolitis in infancy ^[4]

Age group: Neonates and young infants.

Pathophysiology: Ficolin 3 is expressed by type II alveolar epithelial cells and macrophages, and is important in gut mucosal immunity. Its deficiency impairs lectin pathway activation on gut bacteria → bacterial translocation → mucosal necrosis → NEC. This is distinct from the typical NEC of prematurity (which is multifactorial), but the clinical presentation overlaps.

In children with recurrent lower respiratory tract infections (especially C3, Ficolin 3, classical pathway deficiencies), repeated lung parenchymal damage leads to bronchiectasis — irreversible dilation of the bronchi with chronic productive cough, recurrent exacerbations, and progressive loss of lung function. This is a long-term complication that significantly impacts quality of life.

Compare with antibody deficiency (XLA, CVID) where bronchiectasis is also a common complication for the same reason — recurrent sinopulmonary infections ^[3].

SLE-like syndrome; infections with encapsulated organisms; absent CH50 hemolytic activity — for classical pathway deficiencies ^[4]

Which deficiencies? Classical pathway (C1q > C4 > C2 >> C3). The hierarchy of SLE risk:

• C1q deficiency: > 90% develop SLE-like disease
• C4 deficiency: ~75%
• C2 deficiency: ~15–30%

Pathophysiology (recapped for the complications framing): The classical complement pathway normally clears immune complexes (via C3b → CR1 on RBCs → transport to reticuloendothelial system) and apoptotic cells (C1q directly binds apoptotic blebs). When this "garbage disposal" system fails:

1. Immune complexes accumulate → deposit in tissues (glomeruli, skin, joints, serosal surfaces) → type III hypersensitivity → inflammation and tissue damage
2. Apoptotic cell debris persists → nuclear self-antigens (dsDNA, histones, ribonucleoproteins) are chronically presented to the immune system → loss of self-tolerance → autoantibody production (ANA, anti-dsDNA, anti-Sm, etc.)

Specific organ complications of SLE in complement-deficient children:

C2 deficiency → vasculitis, polymyositis, atherosclerosis; C7 deficiency → + vasculitis ^[4]

Pathophysiology: Immune complex deposition in vessel walls → activation of what residual complement exists (or direct activation of endothelial cells) → neutrophil recruitment → vessel wall inflammation and necrosis.

Manifests as cutaneous vasculitis (palpable purpura, livedo reticularis, skin ulceration), or systemic vasculitis affecting multiple organs. C2 deficiency is particularly associated with leukocytoclastic vasculitis and has also been linked to atherosclerosis (chronic vascular inflammation).

C3 GOF → glomerulonephritis; increased activation of complement; MCP deficiency → glomerulonephritis ^[4]

C3 glomerulopathy (including dense deposit disease / DDD and C3 glomerulonephritis / C3GN):

• Caused by dysregulated alternative pathway activation (C3/Factor B GOF, Factor H/I deficiency, C3 nephritic factor)
• C3b deposits in the glomerular basement membrane without immunoglobulin → distinguished from immune-complex GN on IF staining (C3-dominant, Ig-negative)
• Can lead to progressive CKD and ESRD in childhood
• Recurrence is common after renal transplantation (the complement defect is systemic, not renal)

C2 deficiency → vasculitis, polymyositis, atherosclerosis ^[4]

Inflammatory myopathy with proximal muscle weakness, elevated CK, and characteristic EMG/MRI findings. Uncommon but described specifically in C2-deficient patients.

The most feared complication of HAE. Bradykinin-mediated oedema of the laryngeal and pharyngeal mucosa can cause complete upper airway obstruction and asphyxiation.

• Mortality: Historically, up to 25–30% of HAE patients died from laryngeal oedema before targeted therapies became available. With modern on-demand treatment, this has dropped dramatically, but it remains a risk.
• Paediatric specificity: Children have narrower airways than adults → even modest laryngeal swelling can cause critical obstruction sooner. The Poiseuille equation tells us that resistance to airflow is proportional to 1/r⁴ — a small reduction in radius causes a huge increase in resistance. This is why stridor progresses to obstruction much faster in younger children.
• Prevention: Every HAE family must have an emergency action plan and carry on-demand treatment (C1-INH concentrate or icatibant) at all times.

Bowel wall oedema from bradykinin-mediated capillary leak causes:

• Severe colicky abdominal pain
• Nausea, vomiting, diarrhoea
• Ascites (fluid leaking into peritoneal cavity)
• Can closely mimic surgical acute abdomen (appendicitis, intussusception, bowel obstruction)

Complication of the complication: Unnecessary surgery. HAE patients (especially undiagnosed ones) may undergo unnecessary laparotomy or laparoscopy for suspected surgical abdomen. This is a well-documented iatrogenic complication. Recognition of the pattern (recurrent abdominal crises, family history, association with peripheral oedema, resolution within 48–72 hours) is key to avoiding this.

• Unpredictable attacks impair school attendance, social activities, and self-confidence
• Anxiety about potential fatal laryngeal oedema
• Body image concerns (facial swelling episodes)
• Need for ongoing psychosocial support, especially in adolescence

Factor H deficiency → spontaneous activation of the alternative complement pathway with consumption of C3; Factor I deficiency → spontaneous activation of alternative pathway with consumption of C3 ^[4]

Pathophysiology recap: Uncontrolled complement activation on glomerular endothelium → endothelial damage → platelet activation → thrombotic microangiopathy → glomerular ischaemia → progressive renal failure.

Without treatment (eculizumab/ravulizumab), up to 50–70% of children with complement-mediated aHUS progress to ESRD within the first episode or first year. Even with treatment, some children sustain irreversible renal damage and require renal replacement therapy (dialysis or renal transplantation).

Critical complication of renal transplantation in aHUS: The complement defect is systemic (circulating proteins produced by the liver) → the disease recurs in the transplanted kidney unless complement inhibition (eculizumab) is continued post-transplant. Recurrence rates without eculizumab:

• Factor H deficiency: ~80–90% recurrence in graft
• C3 GOF / Factor B GOF: high recurrence
• MCP deficiency: lower recurrence (~15–20%) because MCP is membrane-bound and the donor kidney brings its own MCP → this is the one regulatory defect where renal transplant alone may suffice

aHUS can affect organs beyond the kidneys:

• CNS: seizures, encephalopathy, stroke
• Cardiac: cardiomyopathy, myocardial ischaemia
• GI: pancreatitis, hepatic ischaemia, intestinal ischaemia
• Pulmonary: diffuse alveolar haemorrhage (rare)

These extra-renal manifestations are particularly devastating in children and can cause permanent disability.

Factor H deficiency, Factor I deficiency, MCP deficiency → preeclampsia ^[4]

In adolescents who become pregnant (relevant in the Hong Kong context for teenage pregnancies, though uncommon), complement regulatory protein deficiencies predispose to preeclampsia due to placental endothelial complement activation. This requires close obstetric-immunology collaboration.