Immunodeficiency Diseases Innate Immune System Adaptive Immune System Innate Immune system Physical epithelial barriers Phagocytic leukocytes MonocytesMacrophages Neutophils Dendritic cells ID: 931941
Download Presentation The PPT/PDF document "Recurrent infections in children" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Recurrent infections in children
Immunodeficiency Diseases
Slide2Innate Immune System
Adaptive Immune System
Slide3Innate Immune system:
Physical epithelial barriers
Phagocytic leukocytes (Monocytes/Macrophages, Neutophils
)
Dendritic cells.
Natural killer (NK) cells.
Circulating plasma proteins (Antimicrobial peptides, complements, Cytokines)
Adaptive Immune system:
Humoral immunity (Antibodies): B-Lymphocytes.
Cellular Immunity: T-Lymphocytes.
Slide4Child with Recurrent Infection
Normal Child
Child with Underlying Disorder
Slide5“Normal Child” with more than the average of viral infections
Child with underlying disease that mimics infection
Child with underlying disease predispose him to certain infections
Secondary immune system dysfunction
Primary immune system dysfunction
Child with Recurrent Infection
Slide6How to differentiate the child with recurrent infection due to immunodeficiency from “Normal Child
”
?
Slide7Normal Child
Half of children with recurrent infections.
6-8 upper respiratory tract infections (URTI)/year
The mean duration of viral URTI is 1 week (some beyond 2 weeks)
Normal growth and development
Respond quickly to treatment/complete recovery.
Well health status between infections.
Normal physical exam
Normal screening lab tests.
Slide8Risk Factors
Exposure:
Day-care attendance.
School aged siblings
Size of the family
Second-hand smoke
Physical Factors: Obstruction, Foreign bodies, broken barriersChildren with atopic diseases
Slide9Children with atopic diseases:
Allergic Rhinitis,
Atopic Dermatitis
Asthma
Third of children with recurrent infections
Slide10Child with chronic illness:
Cystic Fibrosis
Cerebral palsy
Chronic aspiration
Child with immunodeficiency:
Secondary versus primary
Slide11Types of immunodeficiency
Primary
Secondary
< 10 %
90%
Manifest since early age
Manifest in any age
Slide12P
rimary
(congenital) immunodeficiency:Genetic disorders that results in defects in development or function of the immune system.
S
econdary
(acquired)
immunodeficiency
:
Exposure to factors resulting in suppression of normal immune system.
Slide13Secondary immunodeficiency
Infection
: Congenital rubella, HIV infection, Infectious mononucleosis.
Immunosuppressive agents:
Corticosteroids, Radiation, Antimetabolites.
Malignancy:
Leukemia, Hodgkin disease.
Disruption of barrier protection:
Burns, severe eczema, catheters.
Metabolic problems:
Diabetes mellitus, uremia, Zinc & vitamin deficiency, Malnutrition
.
Protein-losing enteropathy.
Nephrotic syndrome.
Prematurity
When to suspect immunodeficiency?
Clinical
features suggestive of a primary immunodeficiency
10 Warnings Signs of PID created by the Jeffrey Modell Foundation
Slide15Clinical features suggestive of a primary immunodeficiency
Two
or more serious sinus infections or pneumonias within one yearFour or more new ear infections within one yearSix or more ear or respiratory tract infections within one year
Two or more episodes of sepsis or meningitis in a lifetime
Two or more months of antibiotics with little
effect
Slide16Clinical features suggestive of a primary immunodeficiency
Recurrent
or resistant oral or cutaneous candidiasisRecurrent deep skin or organ abscessesFamily history of immunodeficiency or unexplained early death
Failure to gain weight or grow normally (failure to thrive)
Need for intravenous antibiotics and/or hospitalization to clear infections
Slide17Clinical features suggestive of a primary immunodeficiency
Infection
caused by an unusual microbial organism Complications from a live vaccine.Chronic
diarrhea
Non-healing
wounds
Extensive
skin lesions
Unexplained autoimmunity or feversFeatures typical of syndromic PIDs
Slide18History
Age of onset
Type of the infections and pathogensSite of
infections
Frequency, Duration of illnesses
Responses to the previous treatments.
Severity of illnesses, Needs for hospitalization,
Clinical Approach to Suspected Immunodeficiency
Slide19Complete Systemic review:
Associated
conditions:
Failure
to thrive
Chronic Diarrhea, Malabsorption
Autoimmune disease
Congenital heart disease (
DiGeorge syndrome)
Abnormal gait (Ataxia-telangiectasia
)
Delayed separation of the umbilical cord, Poor wound healing (Phagocytic defect)
Atopic dermatitis (hyper-
IgE
syndrome, WAS)
Easy bruising/bleeding tendency (WAS)
Slide20Immunization
history
Presence of chronic illnessesDrug history
Family history
Consanguinity
.
Early
childhood deaths
.Positive family history of known immunodeficiency disorder or unusual, chronic, or recurrent infections
Slide21Physical Exam:
Growth parameters/Nutritional status.
Evidence of ongoing infection/Signs of infections:
Sinopulmonary infections
Oral thrush
Skin abscesses
Evidence of chronic infections (scarring tympanic membranes, crackles
Absence of lymphoid tissue (e.g., tonsils) Or increased size of lymphoid tissue
(lymphadenopathy)
Slide22Hepatomegaly, splenomegaly
.
Rheumatologic conditions (CVID, IgA deficiency)
Ataxia
and telangiectasia (ataxia-telangiectasia)
Eczema
(Wiskott-Aldrich Syndrome, SCID, CGD, Hyper IgE syndrome).
Petechiae
or bruises
suggest
(Wiskott-Aldrich
Syndrome).
Slide23DIFFERENTIAL DIAGNOSIS
Secondary immunodeficiency
Underlying
disease states,
Medications
Injury
P
revious
surgical procedures, Prematurity
Classification of
P
rimary Immunodeficiency Disorders
Slide28X-linked agammaglobulinemia.
Common
variable immunodeficiency (CVID).IgA deficiency.
Hyper-IgM syndrome.
Selective IgG subclass deficiencies.
Transient hypogammaglobinemia of infancy.
Primary Antibody Deficiency Diseases:
Slide29T-cell and Combined Immunodeficiency Diseases:
Severe combined immunodeficiency (SCID).
Hyper-IgE syndrome.
DiGeorge syndrome.
Wiskott-Aldrich syndrome (WAS).
Ataxia-telangiectasia (AT).
Complement Deficiency
:
Proximal
complement
deficiency
Distal
complement
deficiency.
Properdin
deficiency
Slide30Phagocytic/Neutrophil Disorders:
Disorders of Neutrophil Numbers:
Severe congenital neutropenia.
Cyclic neutropenia.
Shwachman-Diamond syndrome.
Benign congenital neutropenia.
Autoimmune neutropenia.
Disorders of Neutrophil Function/Migration:
Chronic granulomatous disease (CGD).
Leukocyte adhesion defect (LAD).
Slide31Laboratory
Evaluation
Complete
blood count
with differential
Chemistry panel
:
E
lectrolytes, glucose, blood urea nitrogen (BUN), creatinine,
albumin
Serum immunoglobulin
levels:
IgG
, IgA, IgM, IgE
levels,
(
vary with age)
Antibody titers to vaccine
antigens:
tetanus
,
diphtheria/pneumococcus, Haemophilus
Test for cellular immunity:
Delayed-type
hypersensitivity skin tests:
Tetanus, Candida, mumps. For presence of antigen-specific T cells & functional
Slide32Flow cytometry:
T-cell, B-cell, and NK-cell subsets. (CD markers
)
T-cell proliferation
assays
Complement studies
:
Total complement activity (CH50)
Individual
complement components
(
Tests
for neutrophil function:
N
itroblue tetrazolium, (NBT), Dihydrorhodamine
123 (DHR
)
Flow
cytometry
adhesion molecules on neutrophil
:
CD18, CD15
Genetic testing
Diagnostic
Imaging
:
Chest x-ray, absence of a thymus (
DiGeorge Syndrome)
MRI, Abnormalities in cerebellum (
A
taxia-telangiectasia)
Slide33Slide34Characteristic Features of Primary Immunodeficiency
B-CELL DEFECT
T-CELL DEFECT
PHAGOCYETE DEFECT
COMPLEMENT DEFECT
Age of onset
After maternal
Abs diminish,
after 5-7 mo of age,
Later childhood to adulthood
Early onset
, usually 2-6 mo
of age
Early onset
Onset at
any age
Slide35B-CELL DEFECT
T-CELL DEFECT
PHAGOCYETE DEFECT
COMPLEMENT DEFECT
Specific pathogens
involved
Encapsulated Bacteria
;
S.Pneumonia, Meningoccus
Haemophilus.
Less:
Fungi
Viruses:
Enteroviruses
Parasites:
giardia,
Cryptosporidia
Intracellular Bacteria
:
common Gram +ve & Gram -ve
Mycobacteria
Viruses
:
CMV, EBV
Fungi
:
Candida
Pneumocystis jiroveci
.
Protozoa
Staph.
Klebsiella
Pseudomonas
Encapsulated Bacteria
;
Streptococcus
Haemophilus
Pnemococcus
Neisseria,
Slide36B-CELL DEFECT
T-CELL DEFECT
PHAGOCYETE DEFECT
COMPLEMENT DEFECT
Site of Infections
Sinopulmonary,
Chronic
Gastrointestinal
Symptoms
Arthritis,
Enteroviral
Meningoencephalitis
Non-specific.
all types of
Infections
opportunistic organisms
Extensive
candidiasis,
Failure to thrive
Chronic diarrhea
Poor survival beyond infancy/early childhood
Skin
(abscesses, impetigo,
Cellulitis
)
Lymph nodes
:
suppurative
Adenitis
Oral cavity:
gingivitis, mouth ulcers
Internal organs:
abscesses,
Osteomyelitis
Sinopulmonary
Skin
Infections
Meningitis,
Arthritis, Septicemia
Autoimmune disease
Slide37Slide38Selective IgA deficiency
Isolated Absence/Low serum IgA level
(<5 mg/dL
)
The diagnosis cannot be made until about 4
yr
of
age.
N
ormal IgG & IgM levels.
The basic
defect:
Unknown.
Familial
inheritance: 20
% of cases
(CVID
and
THI)
Slide392/3 of the patients
= Asymptomatic.
Sinopulmonary
infections,
GI
(Intestinal giardiasis)
CVID, IgG subclass
deficiency
(long-term
follow-up
).
Autoimmune
disease, Celiac disease, Malignancy
,
Allergy
.
Tx
:
treatment
of specific
infections
IVIG
is
not indicated
Antibiotic
prophylaxis
Slide40X-linked
Agammaglobulinemia (XLA)
Mutation of Bruton's tyrosine kinase (Btk) gene (
C
h. Xq22).
B cells Maturation in the BM
(pre-B cells).
Profound
deficiency of B
cells
(Absent or
<
1%)
Severe hypogammaglobinemia,
total
Igs
<100
mg/
dL
A
ntibodies to
antigens given during routine immunizations
are
low
Absence
of lymphoid
tissue
T
cells: Normal
The
thymus
is normal
.
Slide41Age of 6 - 12 mo of life.
Recurrent
bacterial:
respiratory infections
,
sepsis, meningitis
Encapsulated bacteria:
Strep
. pneumoniae, H. influenzae type b, Staph. aureus, Pseudomonas.
Giardiasis
Enteroviral infections:
Enteroviral meningoencephalitis, vaccine-associated
poliomyelitis
Small size or absence of LNs and tonsils.
Slide42Autosomal
recessive
Agammaglobulinemia
Flow cytometry: absence of circulating B cells (
CD19, CD20).
Tx: Igs replacement therapy.
Chronic Antibiotics therapy.
Slide43Common variable immunodeficiency (CVID)
Hypogammaglobinemia with low or normal number of B-cells.
B
cells
differentiation into
plasma
cells
Low
IgG levels
<2 standard deviations below the age-adjusted
norms
(<
500 mg/
dL
),
Low
IgA and/or low IgM.
Abs
titers to protein
and polysaccharide antigens are
low or
absent
Slide44Later age onset, ≥ four years of age
Peak
onset in the second and third decades of life
T-cells: variable Number/function.
M=F
Gene defects, Sporadic
10-20% is Familial inheritance (AD, AR)
Slide45Recurrent
or
chronic pulmonary
infections:
pneumonia
, sinusitis, otitis media, bronchiectasis
.
GI
infections:
diarrhea (bacterial, giardiasis
).
Sepsis
and meningitis with
encapsulated bacteria.
Normal to enlarged tonsils and lymph nodes.
Splenomegaly 25
%.
Autoimmunity:
(Autoimmune hemolytic anemia,
thrombocytopenia)
Malignancy
(lymphoma).
Granulomatous disease:
Lungs, GI
,
liver
Slide46Transient H
ypogammaglobinemia
of infancy (THI)
IgG level
is
less
than 2
SDs from
age-appropriate levels in infants older than 6 months of age in the first years of
life.
(
< 200 mg/
dL
)
With
or without
decreased IgA and IgM levels.
Normal B
and T cells
counts.
Normal
IgG
antibody responses to vaccines.
Risk for
sinopulmonary infections.
Ig levels increase
to
normal
by 2-4 years of age.
Slide47Hyper-IgM
syndromes (
HIGM)
Inability of B cells
to switch from the production
of
IgM
to IgG
, IgA or IgE.
Lack of memory
responses/Antigen specificity
Low
or absent IgG, IgA & IgE.
Normal or elevated
IgM.
Slide48Hyper-IgM
syndromes (
HIGM)
Immunoglobulins isotype
switching:
CD40 ligand (CD40L)
on CD4 T
cells
CD40
on B
cells
Signaling molecules/transcription factors
nuclear
factor
κB
(
NF-
κB
)
activation-induced
cytidine deaminase
(
AID)
uracil-DNA glycosylase
(UNG)
Slide49- X-linked HIGM
Defect
of
CD40 ligand
on
the surface of activated Th cells.
Defective cellular immunity/combined immunodeficiency
Susceptibility
to all kinds of infections,
Pneumocystis
jiroveci
pneumonia
, Cryptosporidium
enteritis
&
malignancy
.
N
eutropenia
Slide50AR
HIGM:Primary (intrinsic) B cell defect.
Defects
in genes involved in the CD40 signaling
pathway:
CD40
: similar to X-linked HIGM/ susceptibility to P. jiroveci
pneumonia
Activation-Induced
Cytidine Deaminase
AID
Uracil
DNA Glycosylase
UNG
Less
likely to have
opportunistic
infections, cancer or neutropenia
BUT tendency to develop
autoimmune and inflammatory disorders
Slide51Tx:
Stem cell transplant
Ig replacement therapy
Prophylactic treatment with trimethoprim-sulfamethoxazole
(P. jiroveci pneumonia
)
Granulocyte
colony-stimulating factor
Slide52Early complements deficiency
:
Deficiency of C1, C2 and C4:
Increased susceptible to autoimmune diseases:
(SLE, GN, JRA)
Deficiency of C3:
Recurrent bacterial infection, particularly encapsulated bacteria.
Slide53Terminal complement deficiency :
C5 through C9:
Associated with infections due to
N.meningitidis, N.gonorrheae,
& chronic meningococcemia
Properdin deficiency:
Recurrent infections, fatal meningococcemia.
Prophylactic antibiotics
Immunization
of patients
and close
contacts with pneumococcal and meningococcal vaccines
Slide54Congenital neutropenia:
Neutropenia: Absolute
neutrophil count (ANC) <
1,500/mm3
Severe neutropenia: ANC < 500/mm3
.
Very rare PID.
Early
onset recurrent bacterial infections.The most common presenting features:
Cellulitis, pharyngitis, gingivitis
Abscesses, lymphadenitis, Omphalitis,
Typhlitis
,
Pneumonia
, Otitis media
Granulocyte
colony-stimulating factor (G-CSF)
Prophylactic antibiotics and antifungal medications
Slide55Severe congenital neutropenia (
Kostmann
syndrome):
AR
Maturation arrest of myeloid differentiation at promyelocyte stage.
Monocytosis
Cyclic neutropenia
AR, AD or sporadic disorder.
Stem
cell
disorder.
Decrease production/excessive apoptosis
Neutropenia very three weeks, monocytosis
Shwachman-Diamond
syndrome
AR , pancreatic insufficiency
Bone
marrow
dysfunction
Chédiak
-Higashi
syndrome
AR
Giant
granules: Neutrophils, lymphocytes
, platelets,
melanocytes
.
Partial
oculocutaneous
albinism, bleeding tendency
Hemophagocytic lymphohystocytosis (HLH)
Chronic Granulomatous Disease (CGD):
X-linked (65-70% of cases)
Autosomal recessive.
Genetic defect in NADPH oxidase:
R
esponsible for the phagocyte
oxidative burst:
forming
the reactive oxygen compounds
(superoxide radical)
Defective intracellular
killing of bacteria and catalase-positive
pathogens
Staph.
aureus, Burkholderia
cepacia
complex
Serratia
marcescens, salmonella,
klebsiella
Fungi
(Aspergillus fumigatus, Candida
albicans)
Slide57Skin
, bone, lungs LNs, & liver.
Osteomyelitis and perianal abscesses or fissures are common.
Non-infectious
manifestations:
Formation
of Granulomas.
Dx:
DHR flow cytometry test (dihydrorhodamine123, DHR123)
Nitroblue tetrazolium (NBT)
Tx:
Prophylactic
antibiotics and antifungal medications
Recombinant interferon-γ
Stem cell transplantation
Slide58Leukocyte adhesion disorders (LAD):
Failure of neutrophil adhesion and migration to site of infection.
(LAD-1), 2 (LAD-2), and 3 (LAD-3
)
Recurrent deep bacterial infections of skin, periodontitis
Absent pus formation, Impaired wound healing.
Staph. Aureus or gram –ve bacilli.
Marked Neutrophilia.
Delayed separation of the umbilical cord.
Dx: Flow cytometry for the presence of adhesion molecules (CD18 or CD15)
Slide59Slide60Severe combined immunodeficiency (SCID)
The most severe form of PIDs.
Profound lack of T-cell numbers/function
B-cell dysfunction
.
Variable numbers of B cells and natural killer (NK) cells
Serum immunoglobulin concentrations are low or absent.
Mutations in any genes that involved are in
lymphoid cell development
Slide611st few mo of life
C
hronic diarrhea, pneumonia, otitis media, sepsis, and chronic candidiasis and other
fungal infections
,
Infections with common viral pathogens
Infections with opportunistic
organisms (Pneumocystis
jirovecii
)
Failure to thrive
S
kin
rash/eczema
Hypoplasia
of lymphatic tissues.
No
thymic
shadow on chest x-ray.
Slide62T-B+ SCID
= The most frequently observed phenotype.
X-linked
(AR)
(
T-B+NK- SCID)
(
ɣc
and JAK3 deficiency)
(T-B+NK+ SCID)
(IL-7 receptor
ɑ deficiency & CD45 deficiency
)
T-B-NK+ SCID
=20-30% of SCID
AR
Ig replacement therapy
Antibiotic
prophylaxis
(Pneumocystis), Anti fungi
prophylaxis
S
tem
cell transplantation.
Slide63Hyper-
IgE
syndrome:
Skin rash/eczema
Skin abscesses and lung infections
Eosinophilia
and high serum levels of
IgE
Recurrent
severe
staphylococcal abscesses
of the
skin & lungs
.
Candida albicans is
the 2nd
most common pathogen.
Humeral
and cell mediated immunity defect
.
osteopenia = Recurrent Fractures
Autosomal dominant
and
AR
AD-HIES
: defect in transcription
factor
STAT3 gene
Pneumatoceles/bronchiectasis
Distinctive
coarse facial appearance.
Anti-staphylococcal medications prophylaxis.
Slide64Asymmetrical face, prominent forehead and chin,
deep-set
eyes, broad nose,
thickened
facial
skin &
high arched palate.
Slide65DiGeorge Syndrome
:
Deletion
of Ch. 22q11.2 (90
%)
Abnormal Developmental of third and fourth pharyngeal pouches
.
Hypoplasia
or aplasia of the thymus
and parathyroid glands
Congenital T-cell immunodeficiency.
Variable severity of clinical phenotype.
Cardiac anomalies
(
conotruncal, atrial and ventricular septal defects)
Abnormal faces:
(
micrognathia, thin upper lip hypertelorism, malformed ears, high and broad nasal bridge)
Thymic hypoplasia
Cleft palate
Hypocalcemia
Slide66Slide67Wiskott-Aldrich syndrome (WAS)
X-linked disorder
.
WASP defect (in
lymphocytes,
monocytes & megakaryocytes
).
WASP controls
the assembly
of actin filaments required for cell migration and cell-cell
interactions
Birth-1st
year of
life.
Low IgM
, elevated IgA and
IgE
, and a normal
or slightly
low IgG
Slide68Wiskott-Aldrich syndrome (WAS)
Thrombocytopenia, Bleeding tendency
(bloody diarrhea, purpura, prolonged bleeding from circumcision)
Atopic dermatitis.
Cellular and humoral immunity are affected.
Recurrent encapsulated bacteria infection, Opportunistic infections
Autoimmune diseases and malignancy.
Slide69Ataxia-telangiectasia
(AT).
Complex syndrome with immunologic, neurologic, endocrinology, hepatic, and cutaneous abnormalities.
Ataxia-telangiectasia mutated
(ATM) gene on chromosome
11 (AR
)
Defect in cell division control and DNA repair = unstable cells
Progressive cerebellar
ataxia
(early childhood)
Oculocutaneous
telangiectasia
(3-6
yr
).
M
alignancy: Leukemia, Lymphoma
variable humoral and cellular immunodeficiency
.
Chronic sinopulmonary
disease
Very sensitive to the effect of radiation exposure
Slide70Thank you