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 ‘encapsulated’ bacteria
that normally get coated in antibodies and labelled
for destruction
(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*
2005
2006
2007
2008
Central
Line
Days
Vent
Days
Foley
Days
Number Number Number
of
of
of
UTI*
CLABSI*
VAP*
6,432 3,942 2,956 2,373 25
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
3
7,352 4,681 3,625 2,288 16
7,620 5,397 3,956 2,240 18
7,667 5,588 3,946 2,214 24
CLABSI= central line associated bloodstream infection
VAP= ventilator associated pneumonia
UTI= catheter associated urinary tract infection
*based on midnight census on 8S*
CICU
Central Line-associated Bloodstream Infection (CABSI) Rate
2010
CVL utilization ratio
12.0
1.00
0.86
0.78
10.0
0.73 0.74 0.73
0.73 0.74
0.73 0.71
0.7
0.66
0.71
8.0
6.0
0.80
0.62
0.7
0.69
0.66
0.64
0.76
0.73
0.60
5.7
4.3
4.0
3.4 3.4
3.7
2
2.0
155
days
2.3
0.40
84
days
2.5 2.3
1.7
3.3
0.20
1.7
1
0
0
0
0
0
0
0.0
0.00
2005 2006 2007 2008 2009 2010
Mean Mean Mean Mean Mean mean
Jan
Feb
Mar
Apr
May Jun
Jul
Aug Sep
Oct
Nov Dec
NHSN
CICU
pooled
mean
20062008
Central line utilization ratio
CABSI per 1000 central line days
CABSI Rate
NOVEL ‘BIOMARKERS’ OF SEPSIS IN HETEROTAXY
1. Howell Jolly Bodies in red cells:
Quantitative analysis by red cell flow cytometry – Litron laboratories
2. 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 at highest risk of infection first –
collate the strongest evidence possible to provide the scientific rationale for a larger
(broader) follow-up study
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