Recurrent infections in children - PowerPoint Presentation

Slide1

Recurrent infections in children

Immunodeficiency Diseases

Slide2

Innate Immune System

Adaptive Immune System

Slide3

Innate 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.

Slide4

Child 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

Slide6

How to differentiate the child with recurrent infection due to immunodeficiency from “Normal Child

”

?

Slide7

Normal 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.

Slide8

Risk 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

Slide9

Children with atopic diseases:

Allergic Rhinitis,

Atopic Dermatitis

Asthma

Third of children with recurrent infections

Slide10

Child with chronic illness:

Cystic Fibrosis

Cerebral palsy

Chronic aspiration

Child with immunodeficiency:

Secondary versus primary

Slide11

Types of immunodeficiency

Primary

Secondary

< 10 %

90%

Manifest since early age

Manifest in any age

Slide12

P

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.

Slide13

Secondary 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

Slide14

When to suspect immunodeficiency?

Clinical

features suggestive of a primary immunodeficiency

10 Warnings Signs of PID created by the Jeffrey Modell Foundation

Slide15

Clinical 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

Slide16

Clinical 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

Slide17

Clinical 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

Slide18

History

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

Slide19

Complete 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)

Slide20

Immunization

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

Slide21

Physical 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)

Slide22

Hepatomegaly, 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).

Slide23

DIFFERENTIAL DIAGNOSIS

Secondary immunodeficiency

Underlying

disease states,

Medications

Injury

P

revious

surgical procedures, Prematurity

 

Slide24

Slide25

Slide26

Slide27

Classification of

P

rimary Immunodeficiency Disorders

Slide28

X-linked agammaglobulinemia.

Common

variable immunodeficiency (CVID).IgA deficiency.

Hyper-IgM syndrome.

Selective IgG subclass deficiencies.

Transient hypogammaglobinemia of infancy.

Primary Antibody Deficiency Diseases:

Slide29

T-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

Slide30

Phagocytic/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).

Slide31

Laboratory

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

Slide32

Flow 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)

Slide33

Slide34

Characteristic 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

Slide35

B-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,

Slide36

B-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

Slide37

Slide38

Selective 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)

Slide39

2/3 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

Slide40

X-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

.

Slide41

Age 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.

Slide42

Autosomal

recessive

Agammaglobulinemia

Flow cytometry: absence of circulating B cells (

CD19, CD20).

Tx: Igs replacement therapy.

Chronic Antibiotics therapy.

Slide43

Common 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

Slide44

Later 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)

Slide45

Recurrent

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

Slide46

Transient 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.

Slide47

Hyper-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.

Slide48

Hyper-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

Slide50

AR

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

Slide51

Tx:

Stem cell transplant

Ig replacement therapy

Prophylactic treatment with trimethoprim-sulfamethoxazole

(P. jiroveci pneumonia

)

Granulocyte

colony-stimulating factor

Slide52

Early 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.

Slide53

Terminal 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

Slide54

Congenital 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

Slide55

Severe 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)

Slide56

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)

Slide57

Skin

, 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

Slide58

Leukocyte 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)

Slide59

Slide60

Severe 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

Slide61

1st 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.

Slide62

T-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.

Slide63

Hyper-

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.

Slide64

Asymmetrical face, prominent forehead and chin,

deep-set

eyes, broad nose,

thickened

facial

skin &

high arched palate.

Slide65

DiGeorge 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

Slide66

Slide67

Wiskott-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

Slide68

Wiskott-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.

Slide69

Ataxia-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

Slide70

Thank you