Combined immunodeficiencies

Abstract

Objectives
Inborn Errors of Immunity (IEI), also known as primary immunodeficiencies, correspond to a heterogeneous group of congenital diseases that primarily affect immune response components. The main clinical manifestations comprise increased susceptibility to infections, autoimmunity, inflammation, allergies and malignancies. The aim of this article is to review the literature on combined immunodeficiencies (CIDs) focusing on the diagnosis and treatment and the particularities of the clinical management of these patients.

Source of data
Critical integrative review, aimed to present articles related to primary immunodeficiencies combined with a searchin the PubMed and SciELO databases, with evaluation of publications from the last twenty years that were essential for the construction of knowledge on this group of diseases.

Summary of data
We highlight the main characteristics of CIDs, dividing them according to their pathophysiological mechanisms, such as defects in the development of T cells, TCR signaling, co-stimulatory pathways, cytokine signaling, adhesion, migration and organization of the cytoskeleton, apoptosis pathways, DNA replication and repair and metabolic pathways. In CIDs, clinical manifestations vary widely, from sinopulmonary bacterial infections and diarrhea to opportunistic infections, caused by mycobacteria and fungi. Neonatal screening makes it possible to suspect these diseases before clinical manifestations appear.

Conclusions
The CIDs or IEI constitute a complex group of genetic diseases with T-cell involvement. Neonatal screening for these diseases has improved the prognosis of these patients, especially in severe ones, known as SCIDs.

Full text

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REVIEW
ARTICLE
Combined
immunodeficiencies夽
Carolina
Sanchez
Aranda ∗,
Rafaela
Rola
Guimarães
,
Q3Q2
Mariana
de
Gouveia-Pereira
Pimentel
Universidade
Federal
de
São
Paulo,
Departamento
de
Pediatria,
São
Paulo,
SP,
Brazil
Received
30
September
2020;
accepted
6
October
2020
KEYWORDS
Primary
immunodeficiency;
Molecular
biology;
Hematopoietic
stem
cell
transplantation;
Gene
therapy;
Vaccination;
Immunosuppression
Abstract
Objectives:
Inborn
Errors
of
Immunity
(IEI),
also
known
as
primary
immunodeficiencies,
corre-
spond
to
a
heterogeneous
group
of
congenital
diseases
that
primarily
affect
immune
response
components.
The
main
clinical
manifestations
comprise
increased
susceptibility
to
infections,
autoimmunity,
inflammation,
allergies
and
malignancies.
The
aim
of
this
article
is
to
review
the
literature
on
combined
immunodeficiencies
(CIDs)
focusing
on
the
diagnosis
and
treatment
and
the
particularities
of
the
clinical
management
of
these
patients.
Source
of
data: Critical
integrative
review,
aimed
to
present
articles
related
to
primary
immun-
odeficiencies
combined
with
a
searchin
the
PubMed
and
SciELO
databases,
with
evaluation
of
publications
from
the
last
twenty
years
that
were
essential
for
the
construction
of
knowledge
on
this
group
of
diseases.
Summary
of
data: We
highlight
the
main
characteristics
of
CIDs,
dividing
them
according
to
their
pathophysiological
mechanisms,
such
as
defects
in
the
development
of
T
cells,
TCR
sig-
naling,
co-stimulatory
pathways,
cytokine
signaling,
adhesion,
migration
and
organization
of
the
cytoskeleton,
apoptosis
pathways,
DNA
replication
and
repair
and
metabolic
pathways.
In
CIDs,
clinical
manifestations
vary
widely,
from
sinopulmonary
bacterial
infections
and
diarrhea
to
opportunistic
infections,
caused
by
mycobacteria
and
fungi.
Neonatal
screening
makes
it
possible
to
suspect
these
diseases
before
clinical
manifestations
appear.
Conclusions:
The
CIDs
or
IEI
constitute
a
complex
group
of
genetic
diseases
with
T-cell
involve-
ment.
Neonatal
screening
for
these
diseases
has
improved
the
prognosis
of
these
patients,
especially
in
severe
ones,
known
as
SCIDs.
©
2020
Sociedade
Brasileira
de
Pediatria.
Published
by
Elsevier
Editora
Ltda.
This
is
an
open
access
article
under
the
CC
BY-NC-ND
license
(http://creativecommons.org/licenses/by-nc-nd/
4.0/).
夽Please
cite
this
article
as:
Aranda
CS,
Guimarães
RR,
Gouveia-Pereira
Pimentel
MD.
Combined
immunodeficiencies.
J
Pediatr
(Rio
J).
2020.
https://doi.org/10.1016/j.jped.2020.10.014
∗Corresponding
author.
E-mail:
carolaaranda@yahoo.com.br
(C.S.
Aranda).
Q3
https://doi.org/10.1016/j.jped.2020.10.014
0021-7557/©
2020
Sociedade
Brasileira
de
Pediatria.
Published
by
Elsevier
Editora
Ltda.
This
is
an
open
access
article
under
the
CC
BY-NC-ND
license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
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C.S.
Aranda,
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Pimentel
Q2Q3
Introduction
Q4
Inborn
Errors
of
Immunity
(IEI),
also
known
as
primary
immunodeficiencies,
correspond
to
a
heterogeneous
group
of
congenital
diseases
that
primarily
affect
the
immune
response
components.
The
main
clinical
manifestations
are
increased
susceptibility
to
infections,
autoimmunity,
inflam-
mation,
allergies
and
malignancies.1,2
In
the
latest
report
by
IUIS
(International
Union
of
Immunological
Societies),
published
in
January
2020,
more
than
400
different
IEIs
have
been
described,
with
430
genetic
defects
identified
and
classified
into
10
groups1,2:
-
Immunodeficiencies
that
affect
cell
and
humoral
immunity
-
Combined
immunodeficiencies
with
associated
character-
istics
or
syndromes
-
Predominantly
antibody
deficiencies
-
Immune
dysregulation
diseases
-
Phagocyte
quantitative
or
functional
defects
-
Innate
immunity
defects
-
Autoinflammatory
disorders
-
Complement
system
deficiencies
-
Bone
marrow
failure
or
insufficiency
-
IEI
phenocopies
Combined
immunodeficiencies
are
characterized
by
immunological
defects
that
compromise
the
development
or
function
of
T
cells.3Several
genetic
disorders
can
lead
to
this
condition
and
the
Severe
Combined
Immunodeficien-
cies
(SCIDs)
are
differentiated
from
the
rest
of
the
group
because
they
are
caused
by
complete
gene
variants,
with
full
penetrance
and
with
catastrophic
functional
consequences,
leading
to
a
greater
susceptibility
to
potentially
fatal
infec-
tions.
Hypomorphic
genetic
variants
lead
to
a
set
of
immun-
odeficiencies
combined
with
milder
conditions,
the
‘‘leaky
SCID’’.2Another
group
of
patients
has
syndromic
character-
istics
associated
with
combined
immunodeficiencies,
as
a
consequence
of
impaired
gene
function
in
non-immune
cells,
such
as
DiGeorge,
CHARGE,
and
Bloomsyndrome,
among
others.4
Objective
The
objective
of
this
article
is
to
review
the
literature
on
combined
immunodeficiencies
focusing
on
the
diagnosis
and
treatment
and
the
particularities
of
the
clinical
manage-
ment
of
these
patients
in
developing
countries.
Epidemiology
In
the
last
decade,
a
significant
increase
in
knowledge
about
IEI
has
been
observed,
including
clinical
and
molecular
aspects
and
definition
of
phenotypes.
Traditionally
consid-
ered
as
‘‘rare
diseases’’
due
to
an
estimated
prevalence
of
1:10,000
to
1:50,000,
with
advances
in
science
and
discov-
eries
of
new
diseases,
the
actual
prevalence
is
more
likely
to
be
1:10,000
to
1:5,000.1
Even
with
the
evident
improvement
in
technology
for
the
diagnosis
of
IEI,
there
is
still
a
significant
delay
in
the
Table
1
Registry
of
combined
immunodeficiencies
of
the
Q1
Latin
American
Society
for
Immunodeficiencies
(LASID).
Combined
Immunodeficiencies n
Severe
Combined
Immunodeficiencies
(SCIDs)
JAK3
deficiency
1
cdeficiency
(Common
␥
chain
SCID,
CD132
deficiency)
36
IL7R
deficiency
CD3D
deficiency 2
RAG1
deficiency 9
RAG2
deficiency 2
DCLRE1C
deficiency
(Artemis)
4
DNA
ligase
IV
deficiency
3
Adenosine
Deaminase
(ADA)
deficiency
19
T-B-
SCID
with
unknown
genetic
defect
89
T-B
+
SCID
with
unknown
genetic
defect
76
Omenn
syndrome
18
TOTAL
264
Combined
immunodeficiencies
with
a
milder
picture
than
SCIDs
(Leaky
SCID)
MHC
class
II
group
A
deficiency
66
ICOS
deficiency
1
CD8
deficiency
7
ZAP-70
deficiency/ZAP-70
with
hypomorphic
and
activation
mutations
5
Class
I
MHC
deficiency
---
TAP2 1
Class
II
MHC
deficiency 2
DOCK8
deficiency 2
IKBKB
deficiency 2
NIK1
deficiency 1
Moesin
deficiency 1
TOTAL 88
Combined
immunodeficiencies
with
associated
characteristics
or
syndromic
CIDs
Wiskott-Aldrichsyndrome
172
Ataxia-telangiectasia
370
Nijmegen
breakage
syndrome
2
Bloom
syndrome
10
DiGeorge/velocardiofacial
syndrome
358
CHARGE
syndrome
1
Cartilage-hair
hypoplasia
11
Schimke
immuno-osseous
dysplasia
1
Netherton
syndrome
3
Transcobalamin
deficiency
2
1
Anhidrotic
ectodermal
dysplasia
with
immune
deficiency
(NEMO/
IKBKGdeficiency)
1
Anhidrotic
ectodermal
dysplasia
with
immune
deficiency
(gain-of-function
IKBA
mutation)
3
STAT5b
deficiency
1
TOTAL
934
Source:
LASID.6
identification
of
these
diseases
in
the
developing
world,
specifically
in
Latin
America.5The
Latin
American
Immun-
odeficiency
Society
(LASID)
registry
shows
a
total
of
1,286
cases
of
combined
immunodeficiencies
including
SCIDs,
leaky
SCIDs
and
those
associated
with
syndromes.
This
cor-
responds
to
15%
of
the
total
IEI
in
the
registry
(Table
1).6
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Severe
combined
immunodeficiencies
SCIDs
are
characterized
by
profound
defects
in
T-
and
B-
lymphocyte
function
and
a
significantly
low
T-cell
count.
It
affects
approximately
1:55,000
newborns
and
less
than
a
third
have
a
family
history.
It
is
not
clinically
apparent
at
birth
and
infectious
complications
usually
appear
during
the
first
year
of
life,
being
potentially
fatal
until
the
age
of
two,
if
immune
reconstitution
is
not
performed.7,8
It
is
considered
a
pediatric
emergency
and
an
early
diagnosis
is
essential
for
successful
treatment.
With
the
advent
of
neonatal
screening
for
SCIDs,
there
has
been
an
improvement
in
the
prognosis
of
these
patients,
since
the
performance
of
hematopoietic
stem
cell
transplanta-
tion
(HSCT)
in
children
without
infection
results
in
a
2-year
survival
in
approximately
95%
of
cases.9
However,
in
Latin
America
and
in
many
parts
of
the
world
where
neonatal
screening
for
SCID
is
not
yet
routinely
avail-
able,
the
diagnosis
is
made
most
of
the
time
with
infections
and
severe
complications
and
referral
for
definitive
treat-
ment
at
a
specialized
center
is
delayed.8
In
Brazil,
a
country
of
continental
dimensions,
a
pioneer-
ing
initiative
sponsored
by
the
Jeffrey
Modell
Foundation
investigated
60
cases
of
suspected
SCIDs,
from
2016
to
2018,
from
all
the
regions
of
the
country
and
diagnosed
25
patients
with
a
median
age
of
5.5
months
at
the
diagnosis.10
Classification
of
combined
immunodeficiencies
or
combined
IEI
We
can
classify
the
Combined
IEI
according
to
the
altered
molecular
mechanism:
Defects
in
the
development
of
T
cells
Defects
in
the
development
of
T
cells
can
result
from
changes
in
thymic
development
or
recombination
of
V
(D)
J.
Changes
in
thymic
development
lead
to
thymic
hypoplasia
and
the
T-cell
defect
can
vary
from
mild
to
a
SCID
pheno-
type
in
the
most
severe
cases
(thymus
aplasia).11 Related
genes:
TBX1
haploinsufficiency
caused
by
the
deletion
of
chromosome
22q11.1
causing
DiGeorge
syndrome;
Autoso-
mal
dominant
CHARGE
syndrome
with
a
mutation
in
the
SEMA3E
and
CHD7
genes;
FOXN1
leading
to
autosomal
reces-
sive
SCID.12
The
genetic
recombination
of
V
(D)
J
produces
genes
that
encode
the
T-cell
(TCR)
and
B-cell
(BCR)
antigen
receptor
chains.
This
genetic
recombination
is
important
to
generate
different
specificities
of
receptors
that
pre-
cede
contact
with
different
antigens
and
then
a
varied
repertoire
of
lymphocyte
clones.
Alterations
in
these
genes
generate
severe
B-
and
T-lymphocyte
defects,
leading
to
a
SCID
T-/B-/Natural
Killer
(NK)+
phenotype.
The
main
disease
related
to
this
defect
is
Omenn
Syndrome
(characterized
by
rash,
eosinophilia,
oligoclonal
and
autoreactive
T
cells,
variable
CD3,
which
can
be
>1500).
The
main
genes:
RAG
1
e
2;
Artemis
and
DNA-PKcs;
DNA
ligase
IV,
the
last
ones
with
radio
sensitivity
and
the
latter
also
with
syndromic
characteristics.13
Defects
in
TCR
signaling
Some
genetic
variants
can
lead
to
proximal
signaling
alter-
ationsmediated
by
TCR.
These
diseases
lead
to
a
general
alteration
in
the
T-cell
compartment.
They
have
a
decrease
in
regulatory
T
cells
(TRegs)
and
an
alteration
in
thymic
selection,
with
the
formation
of
self-reactive
T
cells,
leading
to
changes
in
the
activation,
effector
function
and
forma-
tion
of
T-cell
memory.
Types
of
autosomal
recessive
SCID,
with
susceptibility
to
bacteria
and
viruses
plus
the
autoim-
munity
are
associated,
and
variants
that
affect
the
␣
␤
␦
chains
of
the
TCR,
with
variants
in
the
␦
chain
being
more
harmful
than
in
the
chain.14
Other
diseases
related
to
TCR
signaling
defects:
CD8␣
deficiency;
CD45
deficiency
(SCID
with
T-
/B+/NK
+
phenotype);
ZAP-70
(selective
CD8
deficiency
with
normal
CD4
number,
but
with
altered
function)15;
Calcium
influx
diseases:
ORAI-1
and
STIM
1;
deficiency
of
EVER
1
and
2
(verruciform
epidermodysplasia
caused
by
HPV
infection);
bi-allelic
variants
with
loss
of
function
(LOF)
in
PRKCD
(recurrent
infections,
lupus-like,
chronic
lymphadenopathy
and
splenomegaly
due
to
B-cell
hyper-
activation
and
proliferation);
phosphoinositide
signaling
diseases
(proteins
important
for
regulating
T-cell
activation
and
migration):
mutations
with
gain
of
function
(GOF)
in
the
monoallelic
germline
of
PIK3CD/PIK3R1/PTEN
leading
to
immunodeficiency,
immune
dysregulation
and
susceptibility
to
cancer.16
Defects
in
co-stimulatory
pathways
Co-stimulatory
molecules
are
necessary
for
the
complete
activation
of
the
T
lymphocyte,
effector
functions,
memory
formation
and
anergy
prevention,
in
addition
to
stimulation
by
TCR.
These
molecules
are
cell
surface
receptors
that
rec-
ognize
ligands
in
antigen-presenting
cells
(APCs)
or
target
cells
after
infection.
Diseases
related
to
co-stimulatory
pathways
are:
CARMIL2/RLTPRdeficiency
(via
CD28,
induces
NF-kB-
mediated
CADR-11
activation)
leading
to
a
decrease
in
TReg,
with
an
increase
in
the
population
of
naïve
CD4
and
CD8
and
a
decrease
in
memory
populations,
lung
and
skin
infections,
allergy
and
susceptibility
to
EBV;
CTLA-4
insufficiency
(expressed
in
TReg
and
activated
T
cell,
CTLA4
counter
regulates
CD28-dependent
signaling
and
its
deficiency
leads
to
lymphocytic
infiltrates,
autoimmunity
and
immunodeficiency,
with
great
clinical
variability);
ICOS
deficiency
(selective
defect
in
the
formation,
migration
and
function
of
follicular
T
cells,
T
lymphocytes
do
not
produce
IL10
and
IL17
after
stimulation,
leading
to
a
defect
in
the
production
of
antibodies
and
germinal
centers,
with
susceptibility
to
infections,
hepatosplenomegaly
and
malig-
nancies);
CD40
L
mutation
(X-linked
Hyper-IgM
syndrome);
CD27/CD70
mutation
(EBV-associated
lymphoproliferative
diseases).17
Cytokine
signaling
defects
The
cytokine
signaling
pathway
ranges
from
functions
of
the
cytokines
themselves
and
cytokine
receptors
to
JAK
and
STAT
signal
mediators
(signal
transducer
and
transcription
acti-
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C.S.
Aranda,
R.R.
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and
M.
de
Gouveia-Pereira
Pimentel
Q2Q3
Figure
1
Phenotypic
classification
of
SCIDs
according
to
the
presence
or
absence
of
T,
B
and
NK
cells.
vator).
Defects
in
this
pathway
lead
to
immunodeficiency.
Some
diseases
related
to
cytokine
signaling:
mutation
of
the
common
gamma
chain
(X-linked
SCID
with
T-/B-/NK-
pheno-
type);
mutation
in
IL7R␣
(autosomal
recessive
T/B+/NK+);
mutation
in
IL2RA
(CD25)
(IL2Ra
combined
with
IL2Rb
and
common
gamma
chain
form
a
high
affinity
IL2
receptor,
caus-
ing
autosomal
recessive
immunodeficiency
associated
with
autoimmunity
---
this
defect
combines
IPEX-like
with
specific
T-cell
disease);
mutation
in
IL21/IL21R
(recurrent
respira-
tory
infection,
hepatitis,
liver
fibrosis,
diarrhea,
septicemia,
B-lymphocyte
with
decreased
class
switch
and
impaired
T-lymphocyte
response
to
candida);
mutation
in
JAK3
caus-
ing
autosomal
recessive
SCID
(JAK1
makes
a
dyad
with
JAK3
to
trigger
signaling
via
the
common
gamma
chain);
STAT
3
dominant
negative
mutations
(Autosomal
dominant
hyper
IgE
syndrome);
STAT3
GOF
(interstitial
pneumonia,
autoimmune
enteropathy,
arthritis,
lymphadenopathy,
T-
cell
leukemia).18
Defects
in
cytoskeleton
adhesion,
migration
and
organization
The
cells
of
the
immune
system
require
extreme
mobility
and
interaction
with
several
cell
types
so
they
can
migrate
to
the
sites
of
infection,
receive
activation
signals
and
exer-
cise
an
effector
function.
Some
of
the
diseases
related
to
these
functions
are:
DOCK2
(early
onset
of
bacterial
and
viral
infections,
normal
NK
with
poor
function);
DOCK8
(LOF;
sinopulmonary
infections;
bacterial
and
viral
skin
infections;
high
IgE
with
severe
atopy
and
anaphylaxis);
WASP(protein
encoded
by
the
WAS
gene
---depending
on
the
mutation
it
causes:
Wiskott-Aldrich
syndrome,
congenital
neutropenia
and
X-linked
thrombocytopenia);
CXCR4
(WHIM
syndrome:
neutropenia,
warts
caused
by
HPV,
hypogammaglobuline-
mia,
recurrent
infections);
Leukocyte
adhesion
deficiency
(LAD)
I
and
III.
Defects
in
apoptosis
pathways
After
infection
resolution,
the
clonal
expansion
of
B
and
T
lymphocytes
should
be
reversed
to
homeostasis.
The
main
related
IEIs
have
alterations
in
the
apoptosis-inducing
signaling
complexes:
FAZ/FASL/Caspase8/caspase10/FADD
leading
to
APLS
(non-malignant
lymphadenopathy,
double
negative
cells
[CD4-
/
CD8-
/
␣␤
+]
and
autoimmune
cytopenias).19 Another
disease
that
has
a
FAZ-related
patho-
genesis
is
the
X-linked
proliferative
syndrome,
with
a
LOF
mutation
in
XIAP
(recurrent
infections,
Epstein-Barr
virus
viremia,
inflammatory
bowel
disease
and
hemophagocytic
lymphohistiocytosis).
Defects
in
DNA
replication
and
repair
B
and
T
lymphocytes
undergo
periods
of
rapid
DNA
prolif-
eration
and
replication
with
a
high
chance
of
damage,
and
there
pair
of
this
DNA
damage
is
essential
for
the
cell
cycle.
ATM
mutations
(LOF)
lead
to
ataxia-telangiectasia
(ataxia,
telangiectasia,
immunological
defects,
malignancy).20
Defect
in
metabolic
pathways
During
the
ontogeny
and
life
cycle
of
the
T
lymphocyte,
the
metabolic
properties
of
the
T
lymphocyte
are
extremely
important.
Defects
in
this
pathway
cause:
Reticular
dysge-
nesis
(AK2
mutation
leading
to
SCID
with
early
defect
in
the
myeloid
lineage
cells
---absence
of
granulocytes,
severe
lymphopenia,
thymicand
lymph
nodehypoplasia);
ADA
defi-
ciency
(cause
of
SCID,
but
clinical
variety
depends
on
the
amount
of
residual
ADA
activity)21;
PNP
(autosomal
reces-
sive
SCID,
bacterial
and
viral
infections,
absence
or
small
type,
autoimmune
disease).
In
the
case
of
SCIDs,
we
can
classify
the
phenotypes
according
to
the
presence
or
absence
of
B,
T
lymphocytes
and
NK
cells,
as
shown
in
Fig.
1.
4
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202
203
204
205
206
207
208
209
210
211
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214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
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Clinical
manifestations
The
main
clinical
manifestation
of
IEI
is
the
susceptibil-
ity
to
infections.
The
patient
with
recurrent
infections,
unusual
infections
or
infections
that
are
difficult
to
treat
should
be
investigated.22 In
combined
immunodeficiencies,
clinical
manifestations
show
great
variability,
from
sinopul-
monary
bacterial
infections
and
diarrhea
to
opportunistic
infections,
by
mycobacteria
and
fungi
and
vaccinal
reaction
with
loco-regional
to
systemic
symptoms
(by
BCG
---
Bacillus
Calmette-Guérin),
being
more
severe
in
SCIDs,
usually
fatal
in
the
early
years
of
life,
if
left
untreated.23
Compared
to
other
IEIs,
infections
start
before
6
months
of
age
and
are
normally
associated
with
low
weight-
height
gain
in
SCIDs.
Autoimmune
manifestations,
such
as
cytopenias,
can
occur
and
genotypes
that
show
congenital
abnormalities
at
birth
are
rare.
Biochemical
diagnosis
When
the
diagnosis
of
combined
immunodeficiency
is
sus-
pected
after
clinical
evaluation,
initial
laboratory
tests
should
be
requested
(Table
2
and
Fig.
2).
The
patient’s
complete
blood
count
(CBC)
gives
clues
of
immunological
alterations.
The
assessment
of
the
absolute
neutrophil
and
lymphocyte
count
should
be
performed
according
to
the
patient’s
age.24 HIV
diagnosis
should
be
ruled
out
in
all
patients.
The
evaluation
of
specific
immunological
parame-
ters
should
be
performed
through
the
measurement
of
immunoglobulins
(IgA/IgG/IgM/IgE),
vaccinal
response
after
6
months
of
life
(when
maternal
antibodies
transferred
via
the
placenta
decrease)
and
measurement
of
the
larger
leukocyte
subtypes
by
flow
cytometry
(immunophenotyping
of
CD3/CD4/CD8/CD19
and
NK).More
specific
flow
cytometry
evaluations
for
assessing
naïve
and
memory
cells
are
impor-
tant
and
should
also
be
assessed
according
to
the
patient’s
age,24 with
the
lack
of
naïve
lymphocytes
being
a
major
pre-
dictor
of
SCID.
Lymphocyte
function
can
be
measured
by
lymphoproliferation
after
stimulation
with
phytohemagglu-
tinin
(PHA).22
Molecular
diagnosis
The
last
diagnostic
modality
is
the
identification
of
a
genetic
variant
of
which
product
is
involved
in
immunity.
After
the
adoption
and
evolution
of
genomic
technologies,
such
as
next
generation
sequencing
(NGS),
the
number
of
diseases
and
genetic
defects
related
to
IEI
increased
considerably.
Genetic
sequencing
in
SCIDs
is
very
important,
both
for
the
definitive
diagnosis
and
also
for
pre-HSCT
conditioning
and
family
genetic
counseling.25
Pathogenic
DNA
variants,
excluding
copy
number
vari-
ation
(duplications
or
deletions),
can
be
identified
by
sequencing
a
single
gene
or
by
sequencing
the
exome.26
Variants
that
lead
to
the
complete
deletion
of
the
encoded
protein
are
associated
with
increased
immunodeficiency
severity,
and
hypomorphic
mutations
that
preserve
some
function
of
the
protein
result
in
leaky
SCIDs.27
There
are
monogenic
diseases
caused
by
variants
present
in
non-coding
regions
(introns)
that
have
regulatory
ele-
ments,
such
as
promoters
or
non-coding
genes
such
as
the
microRNA
that
regulates
other
IEI-related
proteins,
which
are
not
evaluated
by
the
exome.
Evaluation
of
the
genome
associated
with
transcriptome,
proteome
and
epigenome
is
possible
and
may
be
necessary
--- t h e
use
of
the
exome
com-
bined
with
RNA
sequencing
has
provided
some
answers.25
Neonatal
screening
The
population-based
neonatal
screening
allows
the
early
identification
of
asymptomatic
babies
with
a
variety
of
severe
diseases,
for
which
effective
treatment
exists
and
where
early
diagnosis
and
intervention
prevent
severe
sequelae.28
Until
recently,
it
was
not
possible
to
identify
babies
with
IEI
before
the
onset
of
clinical
symptoms
and
with
complications
of
severe
and
prolonged
infection.
Advances
in
molecular
biology
and
biotechnology
have
allowed
the
identification
of
babies
with
severe
forms
of
IEI
manifested
by
T-
and/or
B-cell
lymphopenia.29
Neonatal
screening
programs
for
IEI,
including
T-cell
receptor
excision
circles
(TRECs)
and
kappa
recombination
excision
circles
(KRECs)
are
screening
approaches
that
assess
the
maturation
of
the
T-cell
(TCR)
and
B-cell
(BCR)
recep-
tor
(Fig.
3).
For
this
sequence
of
events,
these
circles
are
ejected
into
the
bloodstream
by
primary
gene
rearrange-
ment
or
also
the
so-called
VDJ
recombination.30
V(D)J
recombination
occurs
in
the
primary
lymphoid
organs
(bone
marrow
for
B
cells
and
thymus
for
T
cells)
and
semi-randomly
rearranges
the
gene
segments
V
(variable),
J
(joining)
and,
in
some
cases,
D
(diversity).
The
process
results
in
new
amino
acid
sequences
in
the
antigen-binding
regions
of
Immunoglobulins
and
TCRs
that
allow
recogniz-
ing
antigens
from
virtually
all
pathogens,
including
bacteria,
viruses
and
parasites.31
Although
the
identification
of
babies
with
SCIDs
was
the
intended
goal
of
TREC-based
neonatal
screening
programs,
it
became
evident
that,
in
addition
to
this
disorder,
the
assay
would
also
identify
babies
with
T-cell
lymphopenia
due
to
other
primary
and
secondary
causes.
For
example,
low
levels
of
TREC
have
been
detected
in
individuals
with
22q
deletion,
association
with
CHARGE
syndrome
and
Trisomy
21.
More-
over,
babies
with
forms
of
IEI
other
than
SCID
may
have
low
TREC,
for
instance,
in
ataxia-telangiectasia
and
in
combined
immunodeficiencies
(CIDs).
To
date,
in
prospective
pilot
studies,
many
cases
of
CID
without
an
identifiable
molecu-
lar
cause
have
been
detected
using
TREC
and
these
patients
require
clinical
characterization
and
long-term
follow-up.30
Some
limitations
can
happen
when
the
molecular
defect
is
downstream
of
the
T-cell
receptor
rearrangement,
so
it
cannot
be
detected.
This
includes
Zap70
deficiency,
MHC
Class
II
deficiency
and
some
cases
of
ADA.
Defects
in
T-cell
function,
despite
a
quantitatively
normal
number
of
T
cells,
will
also
not
be
detected
by
TREC.28
Prophylaxis
for
combined
immunodeficiencies
a)
Immunoglobulin
replacement
therapy
5
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JPED
944
1---10
ARTICLE IN PRESS
+Model
C.S.
Aranda,
R.R.
Guimarães
and
M.
de
Gouveia-Pereira
Pimentel
Q2Q3
Table
2
Scheme
for
the
evaluation
and
management
of
patients
with
combined
IEI.
Clinical
history
including
infections,
family
history
and
consanguinity
Detailed
physical
examination:
visceromegaly,
rash
or
erythroderma,
congenital
abnormalities
such
as
microcephaly
Serum
tests:
CBC,
immunoglobulin
levels,
t,
B
and
NK
lymphocyte
immunophenotyping,
TREC/KREC
Evaluation
of
memory
cells
in
immunophenotyping;
Lymphoproliferation
with
PHA
Assessment
of
autoimmune
cytopenias,
liver
function
PCR
for
CMV,
Herpes
virus,
EBV
and
HIV;
maternal
serology
can
be
performed
If
the
mother
is
breastfeeding:
PCR
for
CMV
for
the
mother
---
if
negative,
encourage
breastfeeding.
IF
positive,
suspend
Vaccinal
evaluation
to
date
and
contraindicate
live
vaccines
Contact
persons:
do
not
vaccinate
with
oral
polio;
avoid
contact
if
sick
Start
prophylaxis:
Sulfa,
fluconazole
and
acyclovir.
If
person
received
BCG,
start
isoniazid
Start
human
immunoglobulin
replacement
therapy,
maintain
IgG>800
mg/dL
Nutritional
support
Administer
Palivizumab
during
RSV
season
HLA
collection
for
BMT
assessment
If
there
are
characteristics
of
DiGeorge
or
heart
disease,
perform
CGH-array
for
chromosome
22q11
Evaluate
NGS/genetic
panel/exome
according
to
SCID
phenotype
If
there
is
non-SCID
lymphopenia,
assess
differential
diagnoses:
alpha-fetoprotein
measurement
(>7
months
of
life)
NGS,
next
generation
sequencing;
PHA,
phytohemagglutinin;
SCID,
severe
combined
immunodeficiency.
Initial assessment: Altered neonatal screening or infections
Analysis of lymphocytes (CD3/CD4/CD8/CD19/NK) and evaluation of memory cells
If CD3 >1500 and CD naïve >200, it is not necessary to continue evaluation after altered TREC
Measurement of IgG, IgA, IgM, IgE/evaluation of vaccinal response (patients >6 months)/Lymphocyte proliferation
with PHA/PCR for HIV, CMV/Array for 22q11 syndrome
Initial treatment
Immunoglobulin replacement/Do not vaccinate patient/Antibiotic prophylaxis with PJP prophylaxis
If individual received BCG at birth, start isoniazid and evaluate systemic infection by M. bovis
Suspend breastfeeding until assessment of maternal CMV infection
(low CD3 and naïve CD4 <200) Non-SCID lymphopenia (low CD3 with some naïve CD4
and lymphoproliferation with normal PHA)
Initiate process for BMT
(HLA collection and
search for donors and
transplant center)
Typical SCID (CD<300)
Leaky SCID (CD>300)
Genetic sequencing
(gene/panel/exome)
Genetic sequencing
(gene/panel/
exome)
If the etiology is defined,
treat according to diagnosis
WITH congenital anomalies Evaluation in 3 months
Evaluation after 7 months of life
Measurement of alpha-fetoprotein
(Ataxia-telangiectasia)
Repeat lymphoproliferation with PHA
Targeted functional or genetic studies
Analysis of lymphocyte subclasses
Without syndromic characteristics:
Analysis of lymphocyte subclasses
Figure
2
Evaluation
and
management
of
patients
with
lymphopenia.
If
non-SCID
lymphopenia,
patient
follow-up
is
necessary
to
assess
the
degree
and
persistence
of
the
immune
damage
and
whether
it
is
possible
to
determine
the
cause.
Immunoglobulin
replacement
therapy
is
the
most
impor-
tant
treatment
for
IEIs
with
antibody
production
defects.
The
predominantly
antibody
defects,
combined
defects
of
T
and
B
cells
and
syndromes
associated
with
immunode-
ficiencies
stand
out,
according
to
the
latest
classification
published
in
early
2020.2
The
usual
replacement
dose
is
400
to
600
mg/kg/month
for
intravenous
(IV)
presentation
or
100---150
mg/kg/week
for
the
subcutaneous
(SC)
presentation.
Higher
doses,
called
immunomodulatory
( 1 --- 2
g/kg
of
weight),
are
used
in
autoimmune
manifestations.32
The
most
frequent
adverse
effects
are
headache,
malaise,
nausea,
tremors,
fever,
chest
pain
and
coagulation
6
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944
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J
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(Rio
J).
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(xxxx)
xxx---xxx
Figure
3
Simplified
TREC
collection
and
detection
scheme.
Adapted
from
Somech
and
Etzioni.28
changes,
particularly
with
the
intravenous
administration,
and
are
directly
related
to
the
dose
and
the
velocity
of
administration.
With
the
subcutaneous
presentation,
systemic
adverse
effects
are
much
less
frequent.
More
com-
monly,
the
SC
use
is
associated
with
local
irritation,
which
decreases
with
continuing
treatment.33
b)
Prophylactic
antimicrobials
Susceptibility
to
infections
is
an
important
characteristic
ofcombined
immunodeficiencies
and
determines
the
clinical
evolution
of
patients
and,
for
this
reason,
antimicrobial
pro-
phylaxis
are
frequently
used
to
prevent
infections
and
their
complications.34,35 The
choice
of
prophylactics
should
take
into
consideration
the
type
of
infectious
agent
to
which
the
patient
is
susceptible
based
on
laboratory
alterations,
their
clinical
history,
the
infectious
agents
isolated
from
previous
infections
or
that
colonize
this
patient,
as
well
as
informa-
tion
obtained
from
the
literature.
Patients
with
combined
immunodeficiencies,
especially
severe
ones
(SCIDS)
are
susceptible
to
all
types
of
infections
and
infectious
agents.
Given
the
severity
and
high
mortality
in
the
first
years
of
life,
a
portion
of
these
patients
should
receive
definitive
treatments
with
hematopoietic
stem
cell
transplantation
and
thymus
transplantation
in
patients
with
complete
DiGeorge
syndrome.
However,
while
awaiting
definitive
treatment,
these
patients
should
receive
antimicrobial
prophylaxis
with
reg-
ular
immunoglobulin
replacement,
palivizumab
during
the
respiratory
syncytial
virus
season
and
prophylactic
antibi-
otics
for
P.
jirovecii,
herpes
family
viruses
and
Candida.35
The
antimicrobials
used
and
their
doses
are
shown
in
Table
3.
Patients
who
received
BCG
vaccine
and
do
not
have
adverse
reactions
should
also
receive
prophylaxis
with
isoniazid
and
anti-tuberculosis
treatment
in
case
of
BCG
complications
(Tables
2
and
3).36
Vaccines
for
patients
with
combined
immunodeficiencies
Vaccination
is
an
efficient
tool
in
preventing
infections
and
represents
a
major
advance
in
public
health.
However,
patients
with
IEI,
depending
on
the
type
and
severity
of
the
immunological
compromising,
may
experience
an
absent
or
reduced
response
to
vaccination.8Additionally,
some
patients
with
IEI
may
be
susceptible
to
the
occurrence
of
infectious
complications
when
submitted
to
vaccines
con-
taining
live
attenuated
agents,
as
already
mentioned
in
BCG
vaccination
(Table
4).37 Therefore,
decisions
about
indicat-
ing
or
contraindicating
vaccines
to
a
patient
with
IEI
must
take
into
account
the
immunological
condition
determined
by
the
underlying
disease,
which
may
be
aggravated
by
complications
or
the
use
of
medications.
As
a
general
rec-
ommendation
for
decisions
related
to
the
vaccination
of
immunocompromised
patients,
we
should
always
carefully
evaluate
risks
and
benefits,
consider
that
inactivated
vac-
cines
are
generally
safe,
and
that
those
that
contain
live
attenuated
agents
are,
in
general,
contraindicated.38
Hematopoietic
stem-cell
transplantation
HSCT
is
currently
the
curative
treatment
of
choice
for
patients
with
severe
and
lethal
forms
of
IEI.
The
aim
of
HSCT
is
to
replace
the
patient’s
deficient
immune
system
by
an
effective
immune
system
from
a
healthy
donor.
The
success
of
HSCT
is
directly
associated
with
the
availability
of
a
donor
(degree
of
compatibility
between
donor
and
recipient
in
the
HLA---
human
leukocyte
antigen---
system),
the
characteristics
and
particularities
of
each
disease
to
be
treated,
and
the
patient’s
clinical
condi-
tion
at
the
time
of
transplantation.
The
donor
for
the
transplant
is
sought
for
compatibil-
ity
in
the
HLA
system
and
can
be
found
within
the
family
(related)
or
in
the
voluntary
donor
bank
(unrelated).
The
cell
sources
used
include
bone
marrow,
peripheral
blood
or
umbilical
cord
stem
cells.
The
conditioning
regimen
is
used
for
the
patient’s
immunosuppression,
preventing
transplant
rejection,
with
chemotherapy
and/or
radiation
therapy
usually
being
used.39 There
are
different
types
of
condi-
tioning
regimens,
chosen
according
to
the
patients’
clinical
and
immunological
characteristics.
Some
new
studies
also
consider
genetic
variants
to
decide
about
the
condition-
ing.
Briefly,
it
can
be
divided
into
RIC
(Reduced
Intensity
conditioning),
which
is
a
lighter
conditioning,
and
MAC
(Myeloablative
conditioning),
this
one
being
more
severe.40
The
donor
stem
cells
are
infused
through
a
central
venous
catheter.
The
recovery
of
the
leukocytes
from
the
donor
cells
(>500
cells/mm3)
is
called
graft
‘‘taking’’
and
occurs
approximately
2 --- 4
weeks
after
the
infusion.
The
main
complications
associated
with
transplantation
include:
toxicity
directly
associated
with
the
chemotherapy
7
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391
392
393
394
395
396
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398
399
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474

JPED
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C.S.
Aranda,
R.R.
Guimarães
and
M.
de
Gouveia-Pereira
Pimentel
Q2Q3
Table
3
Prophylactic
antimicrobials
suggested
for
patients
with
severe
combined
immunodeficiency
awaiting
definitive
therapy.
Prophylaxis
Medication
Start
Comments
Pneumocystosis
TMF-SMX
(5
mg/kg/day)
1
month
Liver
function
Herpes
andvaricella
zoster Acyclovir
20
mg/kg/dose
3×/day
At
diagnosis
Kidney
function
RSV
Palivizumab
1
month
Seasonality
General
infections
Human
immunoglobulin
1
month
Serum
IgG
level
Fungalinfections
Fluconazole
6
mg/kg/day
1
month
Liver
function
Source:
Adapted
from
Aguilar
et
al.33
Table
4
Recommendations
for
the
vaccination
of
patients
with
combined
immunodeficiencies.a
IEI
Contraindicated
vaccines
Efficacy
T
lymphocytes
(cell
and
humoral)
Complete
defects
(SCID,
full
DiGeorge
syndrome)
All
containing
live
attenuated
agents
All
vaccines
will
be
ineffective
Pneumococcal
and
Hib
vaccine
are
recommended
Post-HSCT
SCID
Vaccines
containing
live
agents
depending
on
the
immune
reconstitution
status
Vaccine
efficacy
depends
on
the
immunosuppression
degree
Partial
defects
(some
patients
com
DiGeorge,
Wiskott-Aldrich,
Ataxia-telangiectasia
syndrome)
BCG,
Salmonella
typhi,
attenuated
flu
vaccine,
MMR,
chickenpox,
herpes
zoster,
OPV,
yellow
fever,
smallpox,
rotavirus
Vaccine
efficacy
depends
on
the
immunosuppression
degree.
Pneumococcal,
meningococcal
and
Hib
vaccines
are
recommended
Source:
Adapted
from
Immune
Deficiency
Foundation.37
BCG,
Bacillus
Calmette-Guérin;
Hib,
Haemophilus
influenzae;
SCID,
severe
combined
immunodeficiency;
HSCT,
hematopoietic
stem
cell
transplantation;
MMR,
measles-mumps-rubella;
CGD,
chronic
granulomatous
disease.
aFor
patients
under
6
years
old,
the
immunocompetence
values
proposed
by
the
CDC
for
HIV
can
be
used:
<1
year,
T
CD4+
lymphocytes
>1,500/mm3;
1 --- 5
years,
T
CD4+
lymphocytes
>1,000/mm3;
>6
years,
T
CD4+
lymphocytes
>500/m.
used
(veno-occlusive
liver
disease,
mucositis,
hemorrhagic
cystitis);
infections
(bacterial,
viral
or
fungal);
and
graft-
versus-host
disease
(caused
by
the
reactivity
of
donor
cytotoxic
T
cells
against
the
recipient’s
cells
---
mainly
affect-
ing
the
skin,
gastrointestinal
tract
and
liver).
Long-term
complications
include
chronic
graft-versus-host
disease,
endocrinological
problems
and
infertility.39
Gene
therapy
Gene
therapy
can
be
understood
as
the
capacity
for
genetic
improvement
through
the
correction
of
altered
genes
or
site-specific
modifications,
which
target
therapeutic
treat-
ment.
Didactically,
three
techniques
are
available
for
the
cure
of
IEI,
which
are:
gene
addition/insertion,
gene
editing,
and
gene
silencing
(most
used
in
IEI
with
gain
of
function).
The
first
is
most
often
used
and
consists
of
recombinant
DNA
technology,
in
which
the
gene
of
interest
or
healthy
gene
is
inserted
into
a
vector,
which
can
be
plasmodial,
nano-
structured
or
viral,
with
the
latter
being
the
most
often
used,
due
to
its
efficiency
in
invading
cells
and
introducing
their
genetic
material
into
them.41
Although
several
protocols
have
been
successful,
the
gene
therapy
process
remains
complex
and
many
techniques
need
improvement.
There
is
also
the
important
question
of
the
cell
type
targeted
by
the
gene
therapy,
which
is
cur-
rently
divided
into
two
major
groups:
germline
gene
therapy
(sperm
and
egg)
and
somatic
cell
gene
therapy
(therapeutic
genes
are
transferred
into
somatic
cells
of
a
patient).41
In
the
1980s,
a
region
with
an
unusual
pattern
was
iden-
tified
in
the
genome
of
the
Escherichia
coli
bacterium,
in
which
a
highly
variable
sequence
was
intercalated
with
a
repeated
sequence
with
no
known
function.
In
2005,
it
was
postulated
that
the
variable
sequences
were
of
extrachro-
mosomal
origin,
acting
as
an
immunological
memory
against
phages
and
plasmids,
initiating
the
then
unknown
Clustered
Regularly
Interspaced
Short
Palindromic
Repeats
(CRISPR)
and
Cas
(Associated
Proteins)
system,
which
has
been
shin-
ing
since
2012
as
one
of
the
main
biotechnological
tools
for
genome
editing.41
Coming
from
the
immune-adaptive
system
of
prokary-
otes,
this
mechanism
recognizes
the
invading
genetic
material,
cleaves
it
into
small
fragments
and
integrates
it
into
its
own
DNA.
When
a
second
infection
by
the
same
agent
occurs,
the
following
ensues:
transcription
of
the
CRISPR
locus,
mRNA
processing
and
creation
of
small
fragments
of
RNA
(crRNAs),
which
form
complexes
with
Cas
proteins,
and
these
recognize
foreign
nucleic
acids
and
finally
destroy
it.
Based
on
this
natural
mechanism,
the
CRISPR
technique
was
developed,
which
makes
it
possible
to
edit
target-specific
8
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476
477
478
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523

JPED
944
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J
Pediatr
(Rio
J).
xxx
(xxxx)
xxx---xxx
DNA
sequences
in
the
genome
of
any
organism
through
the
exclusive
action
of
only
3
molecules:
the
nuclease
(Cas9),
responsible
for
the
cleavage
of
double-stranded
DNA;
a
guide
RNA,
which
guides
the
complex
to
the
target;
and
the
target
DNA.41,42
Gene
therapy
is
now
being
tested
as
a
therapeutic
option
for
an
increasing
number
of
diseases,
based
primarily
on
the
successful
treatment
of
patients
with
IEI
in
the
past
two
decades,
including
severe
combined
immunodeficiency
(SCIDs)
and
Wiskott-Aldrich
syndrome.
The
field
has
devel-
oped
from
the
use
of
gamma-retroviral
vectors
to
more
sophisticated
lentiviral
platforms
that
offer
an
improved
biosafety
profile,
in
addition
to
greater
efficiency
in
the
transfer
of
genes
from
hematopoietic
stem
cells.42
Conclusions
Combined
immunodeficiencies
or
combined
IEI
constitute
a
complex
group
of
genetic
diseases
with
T-cell
involve-
ment.
Neonatal
screening
for
these
diseases
has
improved
the
prognosis
of
these
patients,
especially
in
SCIDs.
Devel-
oping
countries
still
do
not
routinely
have
these
tests
for
the
entire
population,
resulting
in
delayed
diagnosis.
The
care
related
to
the
replacement
of
human
immunoglobulin
and
the
use
of
prophylactic
antimicro-
bials
contribute
to
the
reduction
of
infections
and
their
complications.
Major
advances
related
to
hematopoietic
stem
cell
transplantation
and
gene
therapy
will
allow
the
definitive
treatment
of
many
patients
with
IEI,
especially
for
combined
immunodeficiencies.
Conflicts
of
interest
The
authors
declare
no
conflicts
of
interest.
Q5
References
1.
Tangye
SG,
Al-Herz
W,
Bousfiha
A,
Chatila
T,
Cunningham-
Rundles
C,
Etzioni
A,
et
al.
Human
inborn
errors
of
immunity:
2019
update
on
the
classification
from
the
international
union
of
immunological
societies
expert
committee.
J
Clin
Immunol.
2020;40:24---64.
2.
Bousfiha
A,
Jeddane
L,
Picard
C,
Al-Herz
W,
Ailal
F,
Chatila
T,
et
al.
Human
inborn
errors
of
immunity:
2019
update
of
the
iuis
phenotypical
classification.
J
Clin
Immunol.
2020;40:66---81.
3.
Azizi
G,
Pouyani
MR,
Abolhassani
H,
Sharifi
L,
Dizaji
MZ,
Mohammadi
J,
et
al.
Cellular
and
molecular
mechanisms
of
immune
dysregulation
and
autoimmunity.
Cell
Immunol.
2016;310:14---26.
4.
Al-Herz
W,
Al-Mousa
H.
Combined
immunodeficiency:
the
Middle
East
experience.
J
Allergy
Clin
Immunol.
2013;131:658---60.
5.
Villavicencio
MF,
Pedroza
LA.
Diagnosis
of
primary
immunodefi-
ciency
diseases
in
the
developing
world:
the
need
for
education
and
networking
with
the
developed
world.
Curr
Opin
Pediatr.
2019;31:835---42.
6.
Latin
American
Society
for
Immunodeficiencies
(LASID).
[Site].
[cited
20
Oct.
2020].
Available
from:
https://lasid.org/.
7.
Madkaikar
M,
Aluri
J,
Gupta
S.
Guidelines
for
screening,
early
diagnosis
and
management
of
severe
combined
immunodefi-
ciency
(SCID)
in
India.
Indian
J
Pediatr.
2016;83:455---62.
8.
Bustamante
Ogando
JC,
Partida
Gaytán
A,
Aldave
Becerra
JC,
Álvarez
Cardona
A,
Bezrodnik
L,
Borzutzky
A,
et
al.
Latin
Amer-
ican
consensus
on
the
supportive
management
of
patients
with
severe
combined
immunodeficiency.
J
Allergy
Clin
Immunol.
2019;144:897---905.
9.
Taki
M,
Miah
T,
Secord
E.
Newborn
screening
for
severe
combined
immunodeficiency.
Pediatr
Clin
North
Am.
2019;66:913---23.
10.
Mazzucchelli
J,
Aranda
CS,
Gouveia-Pereira
M,
Barreiros
LA,
Costa
Carvalho
BT,
Condino-Neto
A,
et
al.
The
panorama
in
diag-
noses
of
severe
combined
immunodeficiency
begins
to
change
in
Brazil.
J
Allergy
Clin
Immunol.
2020;145:1029.
11.
Giardino
G,
Borzacchiello
C,
De
Luca
M,
Romano
R,
Prencipe
R,
Cirillo
E,
et
al.
T-Cell
immunodeficiencies
with
congenital
alterations
of
thymic
development:
genes
implicated
and
dif-
ferential
immunological
and
clinical
features.
Front
Immunol.
2020;11:1837.
12.
Rota
IA,
Dhalla
F.
FOXN1
deficient
nude
severe
combined
immunodeficiency.
Orphanet
J
Rare
Dis.
2017;12:6.
13.
Fayez
EA,
Qazvini
FF,
Mahmoudi
SM,
Khoei
S,
Vesaltalab
M,
Teimourian
S.
Diagnosis
of
radiosensitive
severe
com-
bined
immunodeficiency
disease
(RS-SCID)
by
Comet
Assay,
management
of
bone
marrow
transplantation.
Immunobiology.
2020;225:151961.
14.
Dadi
HK,
Simon
AJ,
Roifman
CM.
Effect
of
CD3delta
defi-
ciency
on
maturation
of
alpha/beta
and
gamma/delta
T-cell
lineages
in
severe
combined
immunodeficiency.
N
Engl
J
Med.
2003;349:1821---8.
15.
Sharifinejad
N,
Jamee
M,
Zaki-Dizaji
M,
Lo
B,
Shaghaghi
M,
Mohammadi
H,
et
al.
Clinical,
immunological,
and
genetic
fea-
tures
in
49
patients
with
ZAP-70
deficiency:
a
systematic
review.
Front
Immunol.
2020;11:831.
16.
Nunes-Santos
CJ,
Uzel
G,
Rosenzweig
SD.
PI3K
pathway
defects
leading
to
immunodeficiency
and
immune
dysregulation.
J
Allergy
Clin
Immunol.
2019;143:1676---87.
17.
Abolhassani
H,
Edwards
ES,
Ikinciogullari
A,
Jing
H,
Borte
S,
Buggert
M,
et
al.
Combined
immunodeficiency
and
Epstein-Barr
virus-induced
B
cell
malignancy
in
humans
with
inherited
CD70
deficiency.
J
Exp
Med.
2017;214:91---106.
18.
Olbrich
P,
Freeman
AF.
STAT1
and
STAT3
mutations:
important
lessons
for
clinical
immunologists.
Expert
Rev
Clin
Immunol.
2018;14:1029---41.
19.
Bartels
AK,
Banks
TA,
Bay
JL.
Pearls
and
pitfalls:
autoim-
mune
lymphoproliferative
syndrome
and
autoimmune
lym-
phoproliferative
syndrome-like
disease.
Allergy
Asthma
Proc.
2017;38:317---21.
20.
Amirifar
P,
Ranjouri
MR,
Yazdani
R,
Abolhassani
H,
Aghamoham-
madi
A.
Ataxia-telangiectasia:
a
review
of
clinical
features
and
molecular
pathology.
Pediatr
Allergy
Immunol.
2019;30:277---
88.
21.
Bradford
KL,
Moretti
FA,
Carbonaro-Sarracino
DA,
Gaspar
HB,
Kohn
DB.
Adenosine
Deaminase
(ADA)-Deficient
Severe
Com-
bined
Immune
Deficiency
(SCID):
molecular
pathogenesis
and
clinical
manifestations.
J
Clin
Immunol.
2017;37:626---37.
22.
Hawley
TS,
Hawley
RG.
Flow
Cytometry
Protocols.
(Methods
in
Molecular
Biology
Series).
4th
ed.
New
York,
NY:
Humana
Press;
2018.
23.
Cirillo
E,
Giardino
G,
Gallo
V,
D’Assante
R,
Grasso
F,
Romano
R,
et
al.
Severe
combined
immunodeficiency---an
update.
Ann
N
Y
Acad
Sci.
2015;1356:90---106.
24.
Moraes-Pinto
MI,
Ono
E,
Santos-Valente
EC,
Almeida
LC,
Andrade
PR,
Dinelli
MI,
et
al.
Lymphocyte
subsets
in
human
immunodeficiency
virus-unexposed
Brazilian
individuals
from
birth
to
adulthood.
Mem
Inst
Oswaldo
Cruz.
2014;109:989---
98.
25.
Farmer
JR,
Mahajan
VS.
Molecular
diagnosis
of
inherited
immune
disorders.
Clin
Lab
Med.
2019;39:685---97.
26.
Comrie
WA,
Lenardo
MJ.
Molecular
classification
of
pri-
mary
immunodeficiencies
of
T
lymphocytes.
Adv
Immunol.
2018;138:99---193.
9
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
583
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
615
616
617
618
619
620
621
622
623
624
625
626
627
628
629
630
631
632
633
634
635
636
637
638
639
640
641
642
643
644
645
646
647

JPED
944
1---10
ARTICLE IN PRESS
+Model
C.S.
Aranda,
R.R.
Guimarães
and
M.
de
Gouveia-Pereira
Pimentel
Q2Q3
27.
Fischer
A,
Notarangelo
LD,
Neven
B,
Cavazzana
M,
Puck
JM.
Severe
combined
immunodeficiencies
and
related
disorders.
Nat
Rev
Dis
Primers.
2015;1:15061.
28.
Rajabi
F.
Updates
in
newborn
screening.
Pediatr
Ann.
2018;47:e187---90.
29.
Somech
R,
Etzioni
A.
A
call
to
include
severe
combined
immunodeficiency
in
newborn
screening
program.
Rambam
Mai-
monides
Med
J.
2014;5:e0001.
30.
King
J,
Ludvigsson
JF,
Hammarström
L.
Newborn
screening
for
primary
immunodeficiency
diseases:the
past,
the
present
and
the
future.
Int
J
Neonatal
Screen.
2017;3:19.
31.
van
Zelm
MC,
van
der
Burg
M,
Langerak
AW,
van
Dongen
JJ.
PID
comes
full
circle:
applications
of
V(D)J
recombination
excision
circles
in
research,
diagnostics
and
newborn
screening
of
pri-
mary
immunodeficiency
disorders.
Front
Immunol.
2011;2:12.
32.
Condino-Neto
A,
Costa-Carvalho
BT,
Grumach
AS,
King
A,
Bezrodnik
L,
Oleastro
M,
et
al.
Guidelines
for
the
use
of
human
immunoglobulin
therapy
in
patients
with
primary
immunod-
eficiencies
in
Latin
America.
Allergol
Immunopathol
(Madr).
2014;42:245---60.
33.
Goudouris
ES,
Silva
AM
do
R,
Ouricuri
AL,
Grumach
AS,
Condino-
Neto
A,
Costa-Carvalho
BT,
et
al.
II
Brazilian
Consensus
on
the
use
of
human
immunoglobulin
in
patients
with
primary
immun-
odeficiencies.
Einstein
(São
Paulo).
2017;15:1---16.
34.
Aguilar
C,
Malphettes
M,
Donadieu
J,
Chandesris
O,
Coignard-
Biehler
H,
Catherinot
E,
et
al.
Prevention
of
infections
during
primary
immunodeficiency.
Clin
Infect
Dis.
2014;59:1462---70.
35.
Papadopoulou-Alataki
E,
Hassan
A,
Davies
EG.
Prevention
of
infection
in
children
and
adolescents
with
primary
immunodefi-
ciency
disorders.
Asian
Pac
J
Allergy
Immunol.
2012;30:249---58.
36.
Barkai
G,
Somech
R,
Stauber
T,
Barziali
A,
Greenberger
S.
Bacille
Calmette-Guerin
(BCG)
complications
in
children
with
severe
combined
immunodeficiency
(SCID).
Infect
Dis
(Lond).
2019;51:585---92.
37.
Immune
Deficiency
Foundation.
IDF
Physician
Advisory
Committee
(PAC).
[cited
20
Oct.
2020].
Available
from:
https://primaryimmune.org/idf-physician-advisory-committee.
38.
Shetty
AK,
Winter
MA.
Immunization
of
children
receiving
immunosuppressive
therapy
for
cancer
or
hematopoietic
stem
cell
transplantation.
Ochsner
J.
2012;12:228---43.
39.
Notarangelo
LD,
Forino
C,
Mazzolari
E.
Stem
cell
transplantation
in
primary
immunodeficiencies.
Curr
Opin
Allergy
Clin
Immunol.
2006;6:443---8.
40.
Castagnoli
R,
Delmonte
OM,
Calzoni
E,
Notarangelo
LD.
Hematopoietic
stem
cell
transplantation
in
primary
immunode-
ficiency
diseases:
current
status
and
future
perspectives.
Front
Pediatr.
2019;7:295.
41.
Gonc¸alves
GAR,
Paiva
RMA.
Gene
therapy:
advances,
challenges
and
perspectives.
Einstein
(Sao
Paulo).
2017;15:369---75.
42.
Booth
C,
Romano
R,
Roncarolo
MG,
Thrasher
AJ.
Gene
therapy
for
primary
immunodeficiency.
Hum
Mol
Genet.
2019;28:R15---23.
10
648
649
650
651
652
653
654
655
656
657
658
659
660
661
662
663
664
665
666
667
668
669
670
671
672
673
674
675
676
677
678
679
680
681
682
683
684
685
686
687
688
689
690
691
692
693
694
695
696
697
698