Defining immunodeficiency in heterotaxy syndrome

1. Defining immunodeficiency in heterotaxy syndrome Terence Prendiville, MD Pediatric Cardiology fellow Boston Children’s Hospital Heterotaxy Hope Foundation, Minneapolis, MN 06/22/2013

2. Asplenia and polysplenia: functionally underactive • Normal role of spleen: ‘filter’ for the bloodstream. • - mops up defective or old red blood cells • - removes specific forms of ‘encapsulated’ bacteria that normally get coated in antibodies and labelled for destruction

3. (radiological) Methods of evaluating the spleen:

4. Historically, how do we ‘measure’ splenic function? • Howell Jolly bodies Pocked erythrocyte count

5. The evidence for Infectious risks still present even under current best-practice guidelines:

6. The evidence for Infectious risks still present even under current best-practice guidelines: • Out of 29 patients with heterotaxy syndrome (1999-2009): • 7 developed sepsis (24%) • 6/7 were on preventative (prophylactic) antibiotics (86%) • 5/7 polysplenia, 2/7 asplenia • Sepsis was associated with a 44% mortality

7. What are the bugs evading the immune system in patients with heterotaxy? • (polysaccharide) encapsulated organisms: • Haemophilus influenza type B (meningitis) • Streptococcus pneumonia (sepsis, pneumonia) • Neisseria meningitides (meningitis) • Group B streptococcus (sepsis around birth) • Klebsiella pneumonia (sepsis) • Salmonella typhi (typhoid fever)

8. Keegan’s spirit foundation-funded research project investigating the risk of infection in heterotaxy syndrome

9. 2005-2010 CICU DATACardiovascular Program (CVP) Patients CLABSI= central line associated bloodstream infection VAP= ventilator associated pneumonia UTI= catheter associated urinary tract infection *based on midnight census on 8S*

10. 155 days 84 days

11. Novel ‘biomarkers’ of sepsis in heterotaxy • Howell Jolly Bodies in red cells: Quantitative analysis by red cell flow cytometry – Litron laboratories • IgM memory B cells: Memory B cells - immunological ‘memory’ after activation (30-60% of B cell pool) IgM memory B cells – normally mature in the spleen and are involved in the immune response to encapsulated organisms

12. Analysis of IgM Memory B cells in the peripheral blood of a splenectomized patient, a hyposplenic Inflammatory Bowel Disease (IBD) patient, an eusplenic IBD patient, and a healthy control

13. Goal to correlate the biomarkers in infancy with subsequent risk of (serious) infection • Tool to ‘predict’ or ‘forecast’ which children are at highest risk of infection • Ability to ‘flag’ them as ‘high risk’ of infection – in hospital and at home • Instigate early and aggressive therapy for evolving infections • Reinforce adherence to strict sterile protocol in care of patient (as per an immunocompromised patient)

14. Initial recruitment • Pilot study targeting the patients thought to be at highest risk of infection first – collate the strongest evidence possible to provide the scientific rationale for a larger (broader) follow-up study

15. Study timeline • 6 months (from July 2013) to recruit and complete enrollment of 10 heterotaxy syndrome patients and 10 controls • A further 3 months to finish study (12 weeks from last patient recruited) • 3-6 months to analyze the data, write the report and submit grant applications (AHA) for a larger, multi-site study (assuming pilot study found promising leads)

16. General Recommendations – early warning • Recommend seeking medical attention with: • Fever >100.4F / 38C • Other signs of infection: irritability, lethargy (less alert), poor feeding / vomiting, breathlessness, cool peripheries, rash • Trust your instinct as their parent! The glass test: meningitis rash

17. General recommendations: vaccination and antibiotic prophylaxis • Your doctor or immunologist may recommend vaccination with an two additional vaccines: • Pneumococcal polysaccharide (PPSV23) vaccine after 2 years of age. This vaccine covers a broader spectrum of bacteria that children with heterotaxy syndrome may be exposed to and is not part of the normal vaccination schedule. • Meningococcal vaccine (further details on exact dosing from the www.CDC.gov website).

20. ? Pill-in-pocket approach to antibiotics with early signs of infection Ideally – blood culture and / or lumbar puncture would be done prior to starting broad-spectrum antibiotics Perhaps if travelling or no easy access to immediate medical care, a home supply of a broad spectrum antibiotic may be indicated to administer at the first sign of infection

21. In summary • Susceptibility to infection (encapsulated organisms) is a risk in heterotaxy patients with both asplenia and polysplenia • The risk of infection is STILL relevant today • Promptly seek medical attention with signs of infection (even if many false alarms) • Be compliant with antibiotic therapy and consider broader vaccination coverage • Biomarkers identifying the highest risk heterotaxy syndrome patients are in development