DEFINING IMMUNODEFICIENCY IN HETEROTAXY SYNDROME

Terence Prendiville, MD Pediatric Cardiology fellow Boston Children’s Hospital Heterotaxy Hope Foundation, Minneapolis, MN 06/22/2013

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 for destruction ‘encapsulated’ bacteria that normally get coated in antibodies and labelled

(RADIOLOGICAL) METHODS OF EVALUATING THE SPLEEN:

HISTORICALLY, HOW DO WE ‘MEASURE’ SPLENIC FUNCTION?

Howell Jolly bodies Pocked erythrocyte count

THE EVIDENCE FOR INFECTIOUS RISKS STILL PRESENT EVEN UNDER CURRENT BEST-PRACTICE GUIDELINES:

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

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)

KEEGAN’S SPIRIT FOUNDATION-FUNDED RESEARCH PROJECT INVESTIGATING THE RISK OF INFECTION IN HETEROTAXY SYNDROME

2005-2010 CICU DATA CARDIOVASCULAR PROGRAM (CVP) PATIENTS

CICU CVP Patient Days*

Central Line Days Vent Days Foley Days Number of CLABSI * Number of VAP * Number of UTI * 2005 2006 2007 2008 6,432 3,942 2,956 2,373 7,352 4,681 3,625 2,288 7,620 5,397 3,956 2,240 7,667 5,588 3,946 2,214 25 16 18 24 15 9 7 6 17 18 19 7 2009 8,542 6,366 4,452 2,276 23 4 15 2010 8,436 6,201 4,165 1,817 6 2 CLABSI= central line associated bloodstream infection VAP= ventilator associated pneumonia UTI= catheter associated urinary tract infection *based on midnight census on 8S* 3

CICU Central Line-associated Bloodstream Infection (CABSI) Rate 2010

CABSI Rate CVL utilization ratio 12.0

10.0

8.0

6.0

0.66

0.64

0.71

5.7

0.73

0.74

0.73

4.0

3.4 3.4

4.3

3.7

0.73

0.74

0.66

0.7

0.73

0.71

0.69

0.73

0.78

0.86

0.76

0.7

84 days 2.0

2 2.3

155 days

2.5 2.3

1.7

1.7

1

0.0

2005 Mean 2006 Mean 2007 Mean 2008 2009 2010 Mean Mean mean

0 0 0 0 0 0

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec 1.00

0.80

0.62

0.60

3.3

0.40

0.20

NHSN CICU pooled mean 2006 2008 0.00

NOVEL ‘BIOMARKERS’ OF SEPSIS IN HETEROTAXY

1.

2.

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

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

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)

INITIAL RECRUITMENT

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

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)

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

GENERAL RECOMMENDATIONS: VACCINATION AND ANTIBIOTIC PROPHYLAXIS

Your doctor or immunologist may recommend vaccination with an two additional vaccines: 1.

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.

2.

Meningococcal vaccine (further details on exact dosing from the www.CDC.gov website).

? 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

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