Severe infantile Bordetella pertussis pneumonia in monozygotic twins with a congenital C3 deficiency Roel A.J. Kurvers,
1 MSc ,
Dineke Westra,
1 MSc ,
Arno F. van Heijst, MD
3 PhD ,
Twiggy L.M. Walk
4 MD ,
Adilia Warris, MD PhD
2,5,
Nicole C.A.J. van de Kar, MD PhD
1
Departments of 1 Paediatric Nephrology, 2 Paediatric Infectious Diseases & Immunology, 3 Neonatology and 4 Paediatric Intensive Care, 5 Nijmegen Institute for Infection, Immunity and Inflammation, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Introduction
Materials and methods
Bordetella pertussis (Bp) infection or whooping cough is a vaccine preventable respiratory disease that still remains a serious infection in neonates and young infants. Most deaths occur before receiving the first dose of pertussis vaccine. These deaths might be partially explained by low maternal antibody titers against Bp in neonates and a maturing immune system. Low Bp antibody titers are found in preterm neonates1. We describe 2 young infants, monozygotic twins, with a severe Bp pneumonia associated with a congenital C3 deficiency. One of the twins was successfully treated with extracorporeal membrane oxygenation (ECMO).
The twins were born prematurely at a gestational age of 31 weeks and 6 days. They developed an increasing cough at the age of 7 weeks. Laboratory findings showed an extreme leucocytosis (> 50 x 109/L) and elevated CRP (> 150 mg/L) in combination with a positive PCR for Bp. Twin A needed 2 weeks of mechanical ventilation. Twin B also needed mechanical ventilation and eventually 16 days of ECMO-treatment. Diagnostic work-up of unexplained hematuria and proteinuria of twin B, revealed persistent low serum C3 levels (< 600 mg/L). Genes encoding the most important
Genetic analysis
Structural implications of the mutation
By PCR and sequencing analysis, a heterozygous mutation (c.2696delT, p.Val899AlafsX5) located at exon 21 of the C3 gene was found in both siblings and their mother. This change causes a frameshift leading to a preliminary stop. The mutant protein is almost 46% shorter than wild type C3, resulting in the loss of important binding sites for complement factor B (CFB) and the loss of the thioëster bond that is important for the function of the protein (Figure 1). The mutation probably leads to absent secretion of mutant C3, indicated by the low serum C3 levels. However, it is also plausible that the mutated C3 protein is secreted, but cannot be active, due to the missing binding domain for CFB and the missing thioëster. Figure 1. The 3D structure of C3b (green) in complex with CFB (blue) and the domain structure of C3 are depicted for both the wild type (A) and the mutant protein (B). In red, the C3 domains involved in CFB binding are indicated.
alternative complement pathway proteins were investigated.
Clinical implication of the C3 mutation As a result of their C3-mutation both twins most likely have a congenital C3 deficiency. In addition to the fact that Bp is able to evade the immune system by binding different complement inhibitors2-6 (figure 2), this deficiency might have led to the development of a ‘malignant pertussis’ in two twin infants before receiving their first immunizations. .
Figure 1.
5. Berggard K, et al, Eur J Immunol 2001;31:2771-80. 6. Marr N et al, J Infect Dis 2007;195:585-8.
Figure 2. A simplified scheme of the complement system is visualized. Activation of C3 leads to the formation of MAC and elimination of bacteria. The different complement inhibitors are shown.
Figure 2.
Conclusion We identified a possible pathogenic, previously unknown mutation in the C3 gene. The severe disease course of the presented cases could be explained by deficient C3 levels in combination with a pathogen that is able to evade the complement system when establishing an infection. Accordingly, one should be cautious for complement disorders when faced with such a severe infection due to B. pertussis or other pathogens that interfere by using a similar mechanism. References:
1. Heininger U et al, Pediatr Infect Dis J 2009;28 2. Amdahl H. et al, Mol Immunol 2011;48:697-705. 3. Barnes MG et al, FEMS Microbiol Lett 200328;220:271-5. 4. Berggard K, et al, Infect Immun 1997; 65:3638-43. 5. Berggard K, et al, Eur J Immunol 2001;31:2771-80. 6. Marr N et al, J Infect Dis 2007;195:585-8.