Dr. Chaim Roifman from Ontario opened the 2013 Immunodeficiency Symposium at #CSACI meeting, expanding the boundaries of combined immunodeficiency (CID).Severe combined immunodeficiency (SCID)
Ontario now screens all newborns for SCID. Rate of primary immunodeficiency diagnosis is changing with rate now approaching 1/25,000. New tools are identifying new diseases/defects.
SCID immunotype includes:
- T cell lymphopenia
- lack of mitogen response
- undetectable TRECs
- dysplastic thymus
CD3+ cells are below 500 in SCID vs. consistently above 500 in other forms of combined immunodeficiency (CID).
Primary immunodeficiency disorders (PIDD) (click to enlarge the image).
ZAP-70 deficiency
Dr Roifman reviewed CD8 deficiency (Zap 70) that was first identified in a Mennonite family. The case was startling case, a 13-month-old previously well baby presenting with ZAP-70 deficiency, dying within 10 days. There is a variable clinical course.
Late onset CID
Late onset combined (genetic) immunodeficiency presents with:
- recurrent infections
- chronic lung disease
- autoimmunity
Patients with late onset CID typically die in childhood (not infancy) from overwhelming viral infection (similar to SCID, but at older age).
STAT-1 mutations
Patients with late onset CID usually have colitis, villous atrophy, progressive decline in T and NK cells, and STAT-1 mutation.
There are several different STAT-1 mutations, with variable inheritance, and variable clinical expression of combined immunodeficiency (CID). Life threatening CID can develop over time; BMT should be considered; other types of STAT1 deficiency should also be considered.
STAT1 deficient pts can survive to adulthood and present with multiple viral infections and other complications depending on genotype.
Newborn screening for SCID
Dr. James Verbsky reviewed the experience with newborn screening for SCID in Wisconsin during 2008-2012. Wisconsin was the first U.S. state to address this. At the cost of 50 cents per test, newborn SCID screening for all of Wisconsin only costs $30,000 per year.
SCID occurs at a rate of 1:70,000 to 1:100,000 live births; 100% fatal without prompt diagnosis and treatment, early stem cell transplant is essential. Newborn screening is very important in SCID to identify children before multiple infections complicate bone marrow transplantation (BMT).
TRECs
The state of Wisconsin is using TREC assay for screening tool for SCID by assessing T cell function. TRECs are a surrogate marker of naive T cells; this is real time PCR newborn screening on dried blood spots. The mean value is 225 TRECs/ul, median 186 TRECs/ul in 71,000 infants; this has helped to establish a cutoff at 25 TRECs/ul for screening.
TRECs and CD3+ cells correlate well; if TRECs are low, then B-actin level is measured; if normal, then the diagnosis SCID. If B-actin level is also low, repeat screening card.
Children born prematurely will have abnormal TREC's but they do not have SCID. This is false positive equivalent in these “preemies”. Approximately 0.03% of term births have abnormal TREC screening; the incidence is much higher in preterm infants for variety of reasons related to the assay.
Among 110 infants with abnormal TRECs screen:
- 51% proved to be normal on flow cytometry
- 21% had secondary causes (metabolic, sepsis, etc)
- 12% had mild lymphopenia
- 6% 22q11 deletion
- 7% SCID
- 2% had other forms of CID
The fundamental question is “what is SCID?” The diagnosis probably requires a SCID-defining illness regardless of TRECs and flow cytometry numbers. It can be difficult to determine need for transplant.
T and B Cells - Naive and Memory Cell Markers (click to enlarge the image).
Severe combined immunodeficiency (SCID) - 4 groups according to T/B/NK cells (click to enlarge the image).
Dr. Eyal Grunebaum discussed improving management of patients with severe primary immunodeficiencies (PID).
There has been a tremendous improvements in long-term survival following HSCT for PID (more than 92% with related identical donors). HSCT often results in excellent immune reconstitution, and most recipients are able to discontinue IVIG replacement.
However, there are much poorer results from HSCT for those with ADA or PNP deficiency forms of SCID.
ADA and PNP deficiency
ADA deficiency presents within the first year of life, the immunophenotype is T-B-NK- while PNP deficiency presents in a bit older patients, and immunophenotype isT-B+NK+.
ADA deficiency is associated with alveolar proteinosis, and skeletal abnormalities (rosary costochondral swelling). Alveolar pulmonary proteinosis is a complication specific to ADA deficiency and they often have neurological abnormalities. Neurological abnormalities are more common in PNP than in ADA deficiency, for example, spastic diplegia, hypertonia, ataxia.
ADA and PNP deficient cells appear more prone to apoptosis. This appears to be a systemic metabolic condition affecting immune function.
Gene therapy
ADA deficiency is the first human disease to be treated with gene therapy. The therapy is working much better following the adherence to the Milan protocol.
Gene therapy for ADA deficiency is promising, with improved outcomes (from 15 patients), using the Milan protocol since 2000, with no malignancy.
There is also enzyme replacement therapy for ADA deficiency, with bovine ADA linked to PEG. It provides partial temporary benefits in 80% of patients.
PEG-ADA is one of the present treatments for ADA deficiency but it costs $4,000 per week and still does not get well into cell cytoplasm.
Invasive Group A streptococcal infection (iGAS) infections
Dr. Isabel Fernandez spoke on innate immune defects in children with invasive Group A streptococcal infection (iGAS) infections.
Risk factors for iGAS in pediatrics include:
- young age
- humoral ID
- varicella infection
- bacterial virulence factors
The increased incidence of iGAS in healthy children and the variability of the host response suggests that genetic factors are important.
TLR defects can predispose to invasive Group A Strep in children. For example, MyD88 or IRAK4 defect and French Canadian founder effect are associated with increased susceptibility to iGAS in Quebec children.
Dr. Stuart Turvey spoke on subtle common forms of PID. There is a he spectrum of "subtle" primary immunodeficiency. Newborn screening will increase our awareness of PID.
Exome sequencing allows for analysis of the parts of the genome that are actually functioning. Exome sequencing is applied to both parents and affected child (you need pedigree for exome sequencing). Look for a heterozygous variant in patients vs. homozygous in patient, especially if not present in an unaffected siblings.
There are new emerging patterns of SCID with mutations in CARMA-1, and MALT-1. The unifying feature is abnormal NF-kB activation.
Dr. Vy Kim discussed long-term immune reconstitution after matched unrelated hematopoietic stem cell transplantation (HSCT) for PID.
HSCT is the treatment of choice for SCID and some other forms of PID. Related identical donor are optimal, but unfortunately they are often unavailable. Related identical HSCT is associated with better than 90% survival, matched unrelated HSCT now has 80% survival or better. Mismatched related donors have poorer survival, however this is also improving over time. Matched unrelated donors (MUDs) are a necessary group if there is no familial match. Graft vs host disease is a common complication of using matched unrelated donors (MUDs) for BMT in PID. In Dr. Kim’s patient series, 100% of BMT-treated PID patients received from MUDs had no further need for IVIG therapy.
Overall the HSCT survival is 70%, a significant improvement from 1960s when it was closer to 50%. Improvements in HLA typing, better supportive care and earlier identification have led to a significant improvement in 10-year-survival post-HCT.
Twitter summary made possible by @IgECPD @allergydoc4kidz @DrAnneEllis
Three allergists did a great job posting updates from the 2013 meeting of the Canadian Society of Allergy and Clinical Immunology (#CSACI): @IgECPD @allergydoc4kidz @DrAnneEllis. Compared to year 2011, this represents 300% growth in Twitter use by the Canadian allergists (from one to three participants, stable since 2012.
For comparison, here are the tweets from the previous #CSACI meetings: http://allergynotes.blogspot.com/search/label/CSACI
Sign up for 2014 #AAAAI Twitter list and meeting of tweeting allergists in real life (tweetup)
The AAAAI has the advantage of a larger membership base compared to #CSACI and not surprisingly ten times more allergists (30) posted Twitter updates from the 2012 #AAAAI meeting. The AAAAI is now on Twitter at @AAAAI_org
This is a list of the allergists who are planning to use Twitter to post updates from the 2014 #AAAAI meeting. The list is open for edit, please feel free to add your own info.
The list shows the availability of the allergists by date and if they are planning to attend a tweetup (meeting of people who use Twitter or are following the tweets). See you at 2014 #AAAAI meeting in sunny San Diego!
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