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IDF PATIENT/FAMILY HANDBOOK | CHAPTER V
Severe Combined Immunodeficiency
Severe Combined Immunodeficiency is an uncommon primary
immunodeficiency in which there is combined absence of T-lymphocyte
and B-lymphocyte function. There are a number of different genetic
defects that can cause Severe Combined Immunodeficiency. These
defects lead to extreme susceptibility to very serious infections. This
condition is generally considered to be the most serious of the primary
immunodeficiencies. Fortunately, effective treatments, such as bone
marrow transplantation, exist that can cure the disorder and the future
holds the promise of gene therapy.
 Definition fo Severe Combined Immunodeficiency:
Severe combined immunodeficiency (SCID,
pronounced "skid") is a rare, potentially fatal
syndrome of diverse genetic cause in which
there is combined absence of T-lymphocyte and
B-lymphocyte function (and in many cases also
natural killer, or NK lymphocyte function). These
defects lead to extreme susceptibility to serious
infections. There are currently twelve known
genetic causes of SCID. Although they vary
with respect to the specific defect that causes
the immunodeficiency, some of their laboratory
findings and their pattern of inheritance, these all
have severe deficiencies in both T-cell and B-cell
function (see chapter titled Inheritance).
Adenosine Deaminase
Deficiency
Another type of SCID is caused by mutations in a
gene that encodes an enzyme called adenosine
deaminase (ADA). ADA is essential for the
metabolic function of a variety of body cells, but
especially T-cells. The absence of this enzyme
leads to an accumulation of toxic metabolic
by-products within lymphocytes that cause the
cells to die. ADA deficiency is the second most
common cause of SCID, accounting for 15% of
cases. Babies with this type of SCID have the
lowest total lymphocyte counts of all, and T, B and
NK-lymphocyte counts are all very low. This form
of SCID is inherited as an autosomal recessive
trait. Both boys and girls can be affected.
Deficiency of the Alpha Chain
of the IL-7 Receptor:
Another form of SCID is due to mutations in a
gene on chromosome 5 that encodes another
growth factor receptor component, the alpha
chain of the IL-7 receptor (IL-7Ra). When T, B and
NK cell counts are done, infants with this type
have B and NK cells, but no T-cells. However, the
B-cells don't work because of the lack of T-cells.
IL-7Ra deficiency is the third most common cause
of SCID accounting for 11% of SCID cases. It is
inherited as an autosomal recessive trait. Both
boys and girls can be affected.
Deficiency of Janus Kinase 3:
Another type of SCID is caused by a mutation
in a gene on chromosome 19 that encodes an
enzyme found in lymphocytes called Janus kinase
3 (Jak3). This enzyme is necessary for function
of the above-mentioned cg. Thus, when T, B and
NK-lymphocyte counts are done, infants with this
type look very similar to those with X-linked SCID,
i.e. they are T-, B+, NK-. Since this form of SCID
is inherited as an autosomal recessive trait both
boys and girls can be affected. Jak3 deficiency
accounts for less than 10% of cases of SCID.
Deficiencies of CD3 Chains:
Three other forms of SCID are due to mutations
in the genes that encode three of the individual
protein chains that make up another component
of the T-cell receptor complex, CD3. These SCID causing
gene mutations result in deficiencies of
CD3δ, ε or ζ chains. These deficiencies are also
inherited as autosomal recessive traits.
Deficiency of CD45:
Another type of SCID is due to mutations in the
gene encoding CD45, a protein found on the
surface of all white cells that is necessary for T-cell
function. This deficiency is also inherited as an
autosomal recessive trait.
Other Causes of SCID:
Four more types of SCID for which the molecular
cause is known are those due to mutations
in genes that encode proteins necessary for
the development of the immune recognition
receptors on T- and B-lymphocytes. These are:
recombinase activating genes 1 and 2 (RAG1 and
RAG2) deficiency (in some instances also known
as Ommen's Syndrome), Artemis deficiency and
Ligase 4 deficiency. Infants with these types of
SCID lack T- and B-lymphocytes but have NK
lymphocytes, i.e. they have a T-B-NK+ phenotype.
These deficiencies are all inherited as autosomal
recessive traits.
Finally, there are probably other SCID-causing
mutations that have not yet been identified.
Less Severe Combined Immunodeficiencies :
There is another group of genetic disorders of
the immune system that results in combined
immunodeficiencies that usually do not reach
the level of clinical severity to qualify as severe
combined immunodeficiency. A list of several of
these disorders follows, although there may be
additional syndromes that qualify for inclusion as
combined immunodeficiency (CID) that are not
listed. These disorders include Bare Lymphocyte
syndrome (MHC class-II deficiency); purine
nucleoside phosphorylase (PNP) deficiency;
ZAP70 deficiency; CD25 deficiency; Cartilage-Hair
Hypoplasia; and MHC class I deficiency.
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Clinical Presentation of Severe Combined
Immunodeficiency:
An excessive number of infections is the most
common presenting symptom of infants with
SCID. These infections are not usually the same
sorts of infections that normal children have,
e.g., frequent colds. The infections of the infant
with SCID can be much more serious and even
life threatening and may include pneumonia,
meningitis or bloodstream infections. The widespread
use of antibiotics even for minimal infections has
changed the pattern of presentation of SCID, so
the doctor seeing the infant must have a high
index of suspicion in order to detect this condition.
Organisms that cause infections in normal children
may cause infections in infants with SCID, or
they may be caused by organisms or vaccines
which are usually not harmful in children who have
normal immunity. Among the most dangerous is
an organism called Pneumocystis jiroveci which
can cause a rapidly fatal pneumonia (PCP) if not
diagnosed and treated promptly. Another very
dangerous organism is the chickenpox virus
(varicella). Although chickenpox is annoying and
causes much discomfort in healthy children,
it usually is limited to the skin and mucous
membranes and resolves in a matter of days. In
the infant with SCID, it can be fatal because it
doesn't resolve and can then infect the lung, liver
and the brain. Cytomegalovirus (CMV), which
nearly all of us carry in our salivary glands, may
cause fatal pneumonia in infants with SCID.
Other dangerous viruses for SCID infants are
the cold sore virus (Herpes simplex), adenovirus,
parainfluenza 3, Epstein-Barr virus (EBV or the
infectious mononucleosis virus), polioviruses, the
measles virus (rubeola) and rotavirus.
Since vaccines that infants receive for chickenpox,
measles and rotavirus are live virus vaccines, infants
with SCID can contract infections from those
viruses through the immunizations. If it is known
that someone in the family has had SCID in the
past, or currently has SCID, these vaccines should
not be given to new babies born into the family
until SCID has been ruled out in those babies.
Fungal (yeast) infections may be very difficult to
treat. As an example, candida fungal infections of
the mouth (thrush), are common in most babies
but usually disappear spontaneously or with
simple oral medication. In contrast, for the child
with SCID, oral thrush usually persists despite
all medication; it may improve but it doesn't
go completely away or recurs as soon as the
medication is stopped. The diaper area may also
be involved. Occasionally, candida pneumonia,
abscesses, esophageal infection or even
meningitis may develop in SCID infants.
Persistent diarrhea resulting in failure to thrive
is a common problem in children with SCID. It
may lead to severe weight loss and malnutrition.
The diarrhea may be caused by the same
bacteria, viruses or parasites which affect normal
children. However, in the case of SCID, the
organisms are very difficult to get rid of once they
become established.
The skin may be involved in children with SCID.
The skin may become chronically infected with
the same fungus (candida) that infects the mouth
and causes thrush. SCID infants may also have a
rash that is mistakenly diagnosed as eczema, but
is actually caused by a reaction of the mother's
T-cells (that entered the SCID baby's circulation
before birth) against the baby's tissues. This
reaction is called graft-versus-host disease (GVHD).
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Diagnosis of Severe Combined Immunodeficiency:
The diagnosis is usually first suspected in children
because of the above clinical features. However,
in some instances there has been a previous child
with SCID in the family and this positive family
history may prompt the diagnosis even before the
child develops any symptoms. One of the easiest
ways to diagnose this condition is to count the
peripheral blood lymphocytes in the child (or those
in the cord blood). This is done by two tests; the
complete blood count and the manual differential
(or a count of the percentage of each different type
of white cell in the blood), from which the doctor
can calculate the absolute lymphocyte count (or
total number of lymphocytes in the blood). There
are usually more than 4000 lymphocytes (per
cubic millimeter) in normal infant blood in the first
year of life, 70% of which are T-cells. Since SCID
infants have no T-cells, they usually have many
fewer lymphocytes than this. The average for all
types of SCID is 1500 lymphocytes (per cubic
millimeter). If a low lymphocyte count is found, this
should be confirmed by repeating the test once
more. If the count is still low, then tests that count
T-cells and measure T-cell function should be done
promptly to confirm or exclude the diagnosis.
The different types of lymphocytes can be
identified with special stains and counted. In this
way, the number of total T-lymphocytes, helper
T-lymphocytes, killer T-lymphocytes, B-lymphocytes
and NK-lymphocytes can be counted. Since
there are other conditions that can result in lower
than normal numbers of the different types of
lymphocytes, the most important tests are those
of T-cell function. The most definitive test to
examine the function of the T-lymphocytes is to
place blood lymphocytes in culture tubes, treat
them with various stimulants and then incubate
them for several days. Normal T-lymphocytes react
to these stimulants by undergoing cell division.
In contrast, lymphocytes from patients with SCID
usually do not react to these stimuli.
Immunoglobulin levels are usually very low in
SCID. Most commonly (but not always), all
immunoglobulin classes are depressed (i.e. IgG,
IgA, IgM and IgE). Since IgG from the mother
passes into the baby's blood through the placenta,
it will be present in the newborn's and young
infant's blood at nearly normal levels. Therefore,
the immunoglobulin deficiency may not be
recognized for several months until the transferred
maternal IgG has been metabolized away.
The diagnosis of SCID can also be made in
utero (before the baby is born) if there has been
a previously affected infant in the family and
if the molecular defect has been identified. If
mutational analysis had been completed on the
previously affected infant, a diagnosis can be
determined for the conceptus (an embryo or fetus
with surrounding tissues). This can be done by
molecular testing of cells from a chorionic villous
sampling (CVS) or from an amniocentesis, where
a small amount of fluid (which contains fetal
cells) is removed from the uterine cavity. Even
if the molecular abnormality has not been fully
characterized in the family, there are tests that can
rule out certain defects. For example, adenosine
deaminase deficiency can be ruled in or out by
enzyme analyses on the above-mentioned CVS
or amnion cells. If there is documentation that the
form of SCID is inherited as an X-linked recessive
trait and the conceptus is a female, she would not
be affected.
In a majority of cases, unless termination of the
pregnancy is a consideration if the fetus is affected,
the diagnosis is best made at birth on cord blood
lymphocytes. This is because there is some risk
to the fetus by the above procedures if blood is
collected for lymphocyte studies while he or she is
in utero.
Early diagnosis, before the infant has had a
chance to develop any infections, is extremely
valuable since bone marrow transplants given in
the first 3 months of life have a 96% success rate.
In fact, screening all newborns to detect SCID
soon after birth is technically possible because of
recent scientific advances. In fact, pilot programs
to test the feasibility of newborn screening in
all infants are planned. If simple screening tests
were done on the cord blood of all babies born in
the United States, all infants with SCID could be
diagnosed at birth and transplantation could be
accomplished shortly after that with expectation of
a greater than 96% success rate.
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Inheritance of Severe Combined
Immunodeficiency:
All types of SCID are probably due to genetic
defects. These defects can be inherited from the
parents or can be due to new mutations that arise
in the affected infant. As already noted, the defect
can be inherited either as an X-linked (sex-linked)
defect where the gene is inherited from the mother
or as one of multiple types of autosomal recessive
defects (see previous section on the causes SCID)
where both parents carry a defective gene. The
reader should turn to the chapter titled Inheritance
to more fully understand how autosomal recessive
and sex-linked recessive diseases are inherited,
the risks for having other children with the disease
and how these patterns of inheritance affect other
family members. Parents should seek genetic
counseling so that they are aware of the risks of
future pregnancies.
It should be emphasized that there is no right
or wrong decision about having more children.
The decision must be made in light of the special
factors involved in the family structure, the basic
philosophy of the parents, their religious beliefs
and background, their perception of the impact of
the illness upon their lives, and the lives of all the
members of the family. There are countless factors
that may be different for each family.
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General Treatment of Severe Combined
Immunodeficiency:
Infants with this life-threatening condition
need all the support and love that parents can
provide. They may have to tolerate repeated
hospitalizations which, in turn, may be associated
with painful procedures. Parents need to call upon
all of their inner resources to learn to handle the
anxiety and stress of this devastating problem.
They must have well-defined and useful coping
mechanisms and support groups. The demands
on the time and energies of the parents caring
for a patient with SCID can be overwhelming. If
there are siblings, parents must remember that
they need to share their love and care with them.
Parents also need to spend energy in maintaining
their own relationship with each other. If the stress
of the child's illness and treatment destroys the
family structure, a successful therapeutic outcome
for the patient is a hollow victory indeed.
The infant with SCID needs to be isolated from
children outside the family, especially from young
children. If there are siblings who attend daycare,
religious school, kindergarten or grade school, the
possibility of bringing chickenpox into the home
represents the greatest danger. Fortunately, this
threat is being diminished by the widespread use
of the chickenpox vaccine (Varivax). Nevertheless,
the parents need to alert the school authorities as
to this danger, so that they can be notified if and
when chickenpox is in the school. If the siblings
have been vaccinated or have had chickenpox,
there is no danger. If the siblings have a close
exposure and they have not been vaccinated
nor had chickenpox themselves, they should live
in another house during the incubation period
(11 to 21 days). Examples of close contacts for
the sibling would be sitting at the same reading
table, eating together or playing with a child who
breaks out in the "pox" anytime within 72 hours of
that exposure. If the sibling breaks out with "pox"
at home and exposes the patient, the patient
should receive varicella immunoglobulin (VZIG) or
immunoglobulin replacement therapy immediately.
If, despite this, the SCID infant breaks out with
"pox", he or she should be given intravenous
acyclovir in the hospital for 5-7 days. Children who
have been vaccinated with live polio vaccine may
excrete live virus which could be dangerous to
the SCID infant. Therefore, children who come in
contact with the patient (such as siblings) should
receive the killed polio vaccine.
Usually the infant with SCID should not be taken
to public places (daycare nurseries, church
nurseries, doctors' offices, etc.) where they are
likely to be exposed to other young children who
could be harboring infectious agents. Contact with
relatives should also be limited, especially those
with young children. Neither elaborate isolation
procedures nor the wearing of masks or gowns
by the parents is necessary at home. However,
frequent hand-washing is essential.
Although no special diets are helpful, nutrition is
nevertheless very important. In some instances,
the child with SCID cannot absorb food normally,
which in turn can lead to poor nutrition. As a
result, in some instances the child may need
continuous intravenous feedings to maintain
normal nutrition. Sick children generally have poor
appetites, so maintaining good nutrition may not
be possible in the usual fashion (see chapter titled
General Care).
Death from infection with Pneumocystis jiroveci, a
widespread organism which rarely causes infection
in normal individuals, but causes pneumonia in
SCID patients, used to be a common occurrence
in this syndrome. Pneumonia from this organism
can be prevented by prophylactic treatment with
trimethoprim-sulfamethoxazole. All infants with
SCID should receive this preventive treatment until
their T-cell defect has been corrected.
Live virus vaccines and non-irradiated blood
or platelet transfusions are dangerous.
If
you or your doctor suspect that your child has a
serious immunodeficiency, you should not allow
rotavirus, chickenpox, mumps, measles, live virus
polio or BCG vaccinations to be given to your child
until their immune status has been evaluated. As
mentioned above, the patient's siblings should not
receive live poliovirus vaccine or the new rotavirus
vaccine. If viruses in the other live virus vaccines
are given to the patient's siblings, they are not
likely to be shed or transmitted from the sibling
to the patient. The exception to this could be the
chickenpox vaccine if the sibling develops a rash
with blisters.
If your SCID infant needs to have a blood or
platelet transfusion, your infant should always get
irradiated (CMV-negative, leukocyte-depleted)
blood or platelets. This precaution is necessary
in order to prevent fatal GVHD from T-cells in
blood products and to prevent your infant from
contracting an infection with CMV.
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Specific Therapy for Severe Combined
Immunodeficiency:
Immunoglobulin (IVIG) replacement therapy should
be given to SCID infants who are more than 3
months of age and/or who have already had
infections. Although immunoglobulin therapy will
not restore the function of the deficient T-cells, it
does replace the missing antibodies resulting from
the B-cell defect and is, therefore, of some benefit.
For patients with SCID due to ADA deficiency,
replacement therapy with a modified form of
the enzyme (from a cow, called PEG-ADA) has
been used with some success. The immune
reconstitution effected by PEG-ADA is not a
permanent cure and requires 2 subcutaneous
injections weekly for the rest of the child's life.
PEG-ADA treatment is not recommended if the
patient has an HLA-matched sibling available as a
donor for a marrow transplant.
The most successful therapy for SCID is immune
reconstitution by bone marrow transplantation.
Bone marrow transplantation for SCID is best
performed at medical centers that have had
experience with SCID and its optimal treatment
and where there are pediatric immunologists
overseeing the transplant. In a bone marrow
transplant, bone marrow cells from a normal donor
are given to the immunodeficient patient to replace
the defective lymphocytes of the patient's immune
system with the normal cells of the donor's
immune system. The goal of transplantation in
SCID is to correct the immune dysfunction. This
contrasts with transplantation in cancer patients,
where the goal is to eradicate the cancer cells and
drugs suppressing the immune system are used
heavily in that type of transplant.
The ideal donor for a SCID infant is a perfectly
HLA-type matched normal brother or sister.
Lacking that, techniques have been developed
over the past three decades that permit good
success with half-matched related donors
(such as a mother or a father). Pre-transplant
chemotherapy is usually not necessary. Several
hundred marrow transplants have been performed
in SCID infants over the past 30 years, with an
overall survival rate of 60-70%. However, the
outcomes are better if the donor is a matched
sibling (>85% success rate) and if the transplant
can be performed soon after birth or less than 3.5
months of life (>96% survival even if only halfmatched).
HLA-matched bone marrow or cord
blood transplantation from unrelated donors has
also been used successfully to treat SCID.
There does not appear to be any advantage to
in utero marrow stem cell transplantation over
transplantaion performed immediately after birth.
Moreover, the mother would probably not be able
to be used as the donor since anesthesia would
cause some risk to the fetus, the procedures carry
risk to both mother and fetus, and there would be
no way to detect GVHD.
Finally, another type of treatment that has been
explored over the past two decades is gene
therapy. There have been successful cases of
gene therapy in both X-linked and ADA-deficient
SCID. However, research in this area is still being
conducted to make this treatment safer. One
cannot perform gene therapy unless the abnormal
gene is known, hence the importance of making a
molecular diagnosis.
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Expectations for Severe Combined
Immunodeficiency Patients:
Severe combined immunodeficiency syndrome
is generally considered to be the most serious
of the primary immunodeficiencies. Without a
successful bone marrow transplant or gene
therapy, the patient is at constant risk for a severe
or fatal infection. With a successful bone marrow
transplant, the patient's own defective immune
system is replaced with a normal immune system,
and normal T-lymphocyte function is restored.
The first bone marrow transplantation for SCID
was performed in 1968. That patient is alive and
well today.
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