Tamara C' Pozos, MD PhD

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• Tamara C. Pozos, MD PhD
• Childrens Hospitals and Clinics of Minnesota
• CIS 8/12/08

2
Case Presentation

• 2.5 year old boy with 4 episodes of pneumococcal
  bacteremia/sepsis
• First episode he was hypotensive and
  unresponsive subsequent episodes less severe
• PMHx
• Born at 30 weeks gestation
• No pneumonia, sinusitis, diarrhea, skin
  infections
• Vaccines including Prevnar up to date
• FHx
• No family history of severe infections, 1.5 year
  old brother is healthy
• Paternal aunt died at 20 years of age due to
  heart disease
• PE
• Weight 14kg (gt50), height 90cm (lt25)
• Normal exam
• During last hospitalization WBC 21.3, 57
  neutrophils, 22 bands
• Chest Xray clear, no mention of thymus

3
Immune workup
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Cases 2 and 3

• 7 year old boy
• Pneumococcal meningitis in 2004
• Prevnar _at_ 2,4,6 mo missed 12 - 15mo dose
• Complement
• CH50 lt 4, measured twice in 2004
• Normal C1, C3, C4, C5-9
• AH50 50 (normal 28 - 144)
• C2 undetectable
• 3.5 year old girl, sister of case 2
• Asymptomatic, no history of infections
• Complement
• CH50 18 - 32 (normal 26 -50)
• C1, C3, C4, C5-9 normal
• C2 undetectable

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Complement pathway

• Serum component which complemented antibodies
• gt 30 known proteins
• Constitutes 15 of the globulin fraction
• Components numbered in order of discovery

Key functions Defense against
infection Opsonization of pyogenic bacteria Lysis
of gram-negative organisms Chemotaxis and
activation of leukocytes Bridge between innate
and adaptive immunity C3 receptors on B cells,
antigen presenting cells, dendritic
cells Disposal of immune complexes
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MANNOSE BINDING LECTIN PATHWAY lectin binds
pathogen surfaces ( C2C4, MBL, MASP-1, MASP-2 )
CLASSICAL PATHWAY activated by antigen-antibody (
C1, C2, C4 )
ALTERNATIVE PATHWAY activated directly by
pathogen surface ( C3, Factors B, D, and I )
C3 Convertase
C3
C3b
C3a, C4a, C5a Phagocyte recruitment
Membrane Attack Complex
C5-C6-C7-C8-C9 Lysis of Neisseria spp. and other
pathogens
Binds complement receptors on phagocytes Opsonizat
ion of pathogens Removal of immune complexes
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Complement Deficiencies

• Recurrent infection
• C1-C4 classical pathway infections with
  encapsulated/pyogenic organisms
• C3 defects associated with a wide range of
  infections
• C5-C9 (membrane attack complex) 5 - 10,000 fold
  increased risk of Neisseria
• Early complement defects are also associated with
  autoimmune diseases
• Angioedema

• C2 deficiency
• Most common complete complement deficiency
• Autosomal recessive
• Estimated prevalence 1/10,000
• 50 develop recurrent infections
• 30 - 40 develop lupus
• Some impaired production of functional antibodies
• Infection is usually systemic (sepsis and
  meningitis)
• Infections usually with encapsulated organisms
  (S. pneumoniae, H. flu)

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Diagnosis and Treatment

• CH50 is the best screening test
• Severe classical pathway deficiencies are usually
  lt5 of normal
• C9 deficiency can be 30 to 50 of normal
• AH50
• Used to assess for deficiencies of Factor B, H,
  and I, and properidin (alternative)
• Will also detect deficiencies in C5-C9
• Specific component assays are also available for
  each component

• Treatment is individualized with no
  well-established guidelines
• Prophylactic antibiotics may be helpful in some
  early complement deficiencies
• Vaccines - conjugated H. flu, pneumococcus,
  menningococcus, plus polysaccharide pneumococcus
• Reports of plasma replacement for acute disease

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Complement Questions

• 1. Should all patients with invasive
  pneumococcal, H. influenzae or meningococcal
  infections have complement evaluations?
• 2. With increasing pneumococcal resistance, what
  prophylactic treatment makes sense?
• 3. Does complement deficiency compromise
  adaptive immunity?
• 4. Which vaccines are important?
• 5. What autoimmune screening should be done in
  those with early complement deficiencies?

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When to screen for complement deficiency?

• Invasive Meningococcal disease
• 1 - 47 in primary, 40 in recurrent disease
• 10 if family history of meningococcal infection
• 20 - 50 if unusual serotype
• ? Invasive pneumococcal/H. flu
• 1 case in series of 398 (0.25)
• Densen, et al, Interscience Conference on AAC,
  1990
• Screening for complement deficiencies in
  unselected meningitis
• No homozygous deficiencies in 209 possible
  meningitis cases
• 100 confirmed, 22 of these with decreased
  complement
• Rasmussen, et al, Clin. Exp. Immunology, 1987
• No data in modern vaccine era

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Complement Questions, continued

• 1. Should all patients with invasive
  pneumococcal, H. flu, menningococcus have
  complement evaluations?
• 2. With increasing pneumococcal resistance what
  prophylactic treatment makes sense - when to
  abandon PCN?
• 2007 CHRMC susceptible
• 56 PCN, 57 TMP/SMZ, 75 cefuroxime, 92
  ceftriaxone, 100 vancomycin
• 3. Does complement deficiency compromise adaptive
  immunity?
• Case 1 had poor pneumococcal titers despite
  Prevnar x 4 and Pneumococcus x 5
• An association has been described (Ochs, et al,
  1983, Ochs, et al, Clinical Imm/Immunpathology,
  2002)
• ? poor antigen presentation to dendritic cells
• 4. Which vaccines are important?
• 5. What autoimmune screening should be done in
  those with early complement deficiencies?