Download PRIMARY IMMUNODEFICIENCY

PRIMARY
IMMUNODEFICIENCY
Yackov Berkun
Recurrent infections
Common
– respiratory 6 - 8/y
– otitis 6/y
– gastroenteritis 2/y
Day care more
Respiratory infections


Allergy
Asthma
–
–

Atelectasis
Viral infection
Aspiration



Cystic fibrosis
Gastroesophageal
Reflux
Tracheoesophageal
fistula
Recurrent otitis




0 - 3 year
66% - one
33% - three and
more
Eustachian tube
Secondary Immune
Deficiency
Severe malnutrition
 Nephrotic syndrome
 Protein loosing enteropathy
 Intestinal lymphangiectasia
 Irradiation
 Drugs, toxins

Secondary Immune
Deficiency

Chromosomal
–
–

21 trisomy
8 trisomy
Viral
–
–
–
–
HIV
CMV, EBV
Rubella
Toxoplasma
Secondary Immune
deficiency
 Malignancy
 Foreign body
 Central line
 Ventriculoperitoneal shunt
 Heart valve
 Barrier
 Burn
Secondary
Hypogammaglobulinemia
 Drug







antimalarial
corticosteroids
gold
penicillamine
sulfa
Captopril
carbamazepin, phenytoin
Primary Immune deficiency
Rare
 Inherited
 Genetic
 Importance of early diagnosis
 None in current screening

Primary immune
Deficiency Incidence
1:10,000
 IgA 1:400
 M/ F = 5
 100 syndromes

Innate /acquired immunity
RBC plt
PMN
mφ
CD8+
NK
CTL
CD4+
thymus
TH2
myeloid
lymphoid
Pre-B
TH1
Components of the Immune
System
Nonspecific/innate
Humoral
Cellular
complement,
interferon
TNF etc.
macrophages,
PMN, NK cell,
eosinophils
Specific
Humoral
antibodies
Cellular
T cells; other
effectors cells
Characteristics of Innate and
Adaptive Immunity
Innate Immunity
Adaptive Immunity
Antigen independent
Antigen dependent
No time lag
A lag period
Not antigen specific
Antigen specific
No Immunologic
memory
Development
of memory
Physical Barriers to Resistance
NELSON
1 or more systemic bacterial infections
(sepsis, meningitis)
 2 or more serious respiratory or
documented bacterial infections
(cellulitis, abscesses, draining otitis
media, pneumonia, lymphadenitis)
within 1 yr

NELSON
serious infections occurring at unusual
sites (liver, brain abscess)
 infections with unusual pathogens

(Pneumocystis jiroveci, Aspergillus,
Serratia marcescens, Nocardia,
Burkholderia cepacia)

infections with common childhood
pathogens but of unusual severity
Additional clues
failure to thrive with or without chronic
diarrhea
 persistent infections after receiving live
vaccines
 chronic oral or cutaneous moniliasis

When? How? Cont.

Unusual site
– Osteomyelitis, liver,
brain abscess
When? How? Cont.
Unusual pathogen
– PCP, Aspergillus, Serratia marcescens,
Nocardia, Burkholderia cepacia
Chronic infections
Common pathogen - unusual severity
When? How? Cont.

Structural
damage
(bronchiectasis)
Incidence
Antibody deficiency 50%
Phagocytic 18%
Combined 20%
T cell 10%
Complement 2%
Severe Combined ID
Diverse genetic mutations
 Absence of all adaptive immune
function
 Some - lack of natural killer (NK) cells
 Most severe immunodeficiency

Severe Combined ID





Early ( 4 - 5 mnt)
Diarrhea, pneumonia,
otitis media, sepsis,
cutaneous infections
Persistent
Every pathogen
Opportunistic
–
–
–
PCP
BCG fatal
live vaccine
SCID clinical
 Persistent Candida
 Seborrhea
 GVHD
– Maternal
immunocompetent T
cells crossing placenta
– T lymphocytes in
nonirradiated blood
products or allogeneic
bone marrow
SCID clinical


FTT
Chronic diarrhea
SCID features
 No lymphoid tissue
– nodes, thymus
 Hypogammaglobulinemia
 Impaired T cell function
 Lymphocyte count <2800
 CD3<20%
SCID


Malignancy
Fatal < 2y
SCID, X-linked


Common γ-chain of IL-2 Receptor
IL-4, -7, -9,-11,-15, -21
SCID, recessive 1

ADA 15%
– apoptosis,
– <500 lymphocytes
– chondro-osseous
dysplasia

Jak 3 deficiency 6%
– B+,NK– signal

IL-7 receptor 10%
– B+,NK+
SCID, recessive 2
 Artemis
– V(D)J
recombination/DNA
repair factor
 RAG recombinase
activating genes
– B-, NK+
 CD45 Deficiency
– protein tyrosine
phosphatase
– T- and B-cell antigen
receptor signal
transduction
SCID management
 BMT is standard of care
– 3 mnt – 95%
– HLA-identical or T-cell–depleted haploidentical
related bone marrow stem cells
– without pretransplant chemoablation or posttransplant GVHD prophylaxis
 Isolation
 PCP prophylaxis
 IVIG
 Suspected infections aggressive treatment
SCID management
 Research
 Gene therapy
– X-SCID
 PEG-ADA
– ADA deficiency

Screening for SCID (T-cell lymphopenia)
has become incorporated as part of the
newborn screening programs in a few
states
Combined Immunodeficiency
(CID)





Low but not absent T-cell function
Recurrent or chronic pulmonary infections,
failure to thrive, oral or cutaneous
candidiasis, chronic diarrhea, recurrent skin
infections, gram-negative sepsis, urinary tract
infections, and severe varicella in infancy
Survive longer than SCID
Fail to thrive and die early in life
Neutropenia and eosinophilia are common
CID

Purine nucleoside phosphorylase
deficiency
– serum and urinary uric acid low
– neurologic abnormalities
– autoimmune diseases
Interleukin 2 Receptor a chain mutation
 Cartilage hair hypoplasia

– short-limbed dwarfism
CID, bare lymphocyte
syndrome

MHC class I (HLA-A,
-B, and -C) antigens
– CD8 -, CD4 + T cells
– chromosome 6 –
encode peptide
transporter proteins
TAP1 and TAP2
CID, MHC class II
deficiency
HLA-DR, -DQ, -DP
 4 genes
 expression of MHC class II molecules on
the surface of B cells and macrophages
 Low CD 4, high CD 8
 hypogammaglobulinemic

Humoral B
Later (>7mnt)
 Sinopulmonary infections
 Septicemia
 Encapsulated bacteria
 No fungal or viral – usually
 No growth failure - usually
 Replacement IVIG therapy- almost
normal life

XLA
Bruton, 1952
 8 year boy
 Recurrent infections
 Protein electrophoresis: no g globulin
 Replacement therapy

Immunoglobulins
Glycoprotein molecules produced by plasma
cells in response to an immunogen and
function as antibodies
+
Amount of protein

albumin
globulins
a
b
g
Immune serum
Ag adsorbed serum
Mobility
Molecular basis
1993: gene on Xq23.3
 Protein: 659 aminoacids cytoplasmic
Tyrosine Kinase, Bruton
 Signal transduction molecule
 Expressed in B until plasma cells, mono,
myeloid, platelets, not T cells

B-cell Differentiation
Bone marrow
Peripheral lymphoid tissue
Antigen-independent
Stem cell
Pro-B
Pre-B
Antigen-dependent
IgM
IgM
IgM + IgD
IgG
IgM
m+d
IgM + IgA
IgA
Immature
Mature
IgM + IgE
IgE
Germinal
center cells
Plasma
cells
B cells
Sell S, Max EE. Immunology, Immunopathology, and Immunity; 2001.
Molecular basis, cont.
>500 mutation
 New mutations are common
 Pro+, pre- B
 No genotype- phenotype correlation
 In same family different severity
 1:200.000

XLA
Presentation after 6 month
 Milder phenotypes later
 1.5 year- 90% symptomatic
 Encapsulated pyogenic bacteria

– Hemophylus influenza type b
– Streptococcus pneumoniae

Mycoplasma
XLA
Lungs, ears (sinuses not developed)
 Chronic diarrhea, FTT
 Neutropenia

XLA
Meningitis
 Meningoencephaliis
(echo, coxackie)

XLA
Skin infections
Myositis
Arthritis
– Septic staph,
mycoplasma,
ureaplasma
XLA, late clinical


Bronchiectasis
Sinusitis
Diagnosis
Male
 History, family
 Absent Ig (all)
 Hypoplastic lymph nodes without
germinal centers
 No tonsils and adenoids

Diagnosis
B cell low-absent
 Normal T, NK
 Normal pro B cell (CD 34+19+)
 No pre B cell (CD 34-19+)

Treatment
Early
 IVIG 0.4 - 0.6 gr/kg/3-4 week
 Aim- normal levels > 600 mg/dl
 Prompt, early, effective antibiotics
 No live vaccine (esp polio)

B cell
B cell disorders
X Linked Agammaglobulinemia
(Bruton’s)
 Common Variable Immunodeficiency
 IgA deficiency
 IgG subclasses
 Transient Hypogammaglobulinemia of
infancy

B cell disorders, rare
X Linked HyperIgM
 Mu chain deficiency

m
chain
 Ig a
– CD 79, BCR receptor signal
Common Variable ID
A group of undifferentiated disorders
with defective antibody formation
 Incidence 1:25,000
 Normal number of defective B cells
 Low serum IgG and IgA

Common Variable ID
Females=males
 Later onset
 Autoimmune disorders
 Lymphoreticular and gastrointestinal
malignancies

Hyper-IgM syndrome
Recurrent infections
 Low IgA, IgG, IgE, normal-elevated IgM
 1960- dysgammaglobulinemia
 1980- intrinsic B defect in Ig isotype
switch
 1993- CD40 ligand

HIGM, clinical
Upper and lower respiratory tract
pyogenic infections
 Second year
 Pneumocystis carini pneumonia
 Protracted diarrhea

– Cyptosporidum parrum
HIGM, clinical,
cont.
Sclerosing cholangitis
 Liver disease

– later tumors
Chronic neutropenia in 50%
 Thrombocytopenia- some

HIGM, clinical,

Lymphoid hyperplasia
– hepatosplenomegaly
– lymphadenopathy
– enlarged tonsils
cont.
HIGM, laboratory
Normal circulating B cells
 IgM levels increase with age
 Normal specific IgM
 No specific IgG
 T cells number and subsets normal
 Proliferation:

– normal to mitogens
– reduced to antigens
HIGM, prognosis
IVIG
 Worse prognosis
 <30% alive at 25 year

– PCP early
– liver disease and malignancy later

Transplantation bone marrow
– liver
HIGM, molecular

T cell signal for B activation
Phagocytes
Gingivitis
 Skin (furunculosis)

Phagocytes
Visceral abscesses
 Lymphadenitis
 Low virulence

– S. Aureus
– gram –
– Aspergillus
Phagocytes
 Killing
defect
– Persistent
abscess
– Granuloma
Phagocytes
 Adhesion,
chemotaxis
– Healing
– Cold abscess – no pus
– Delayed umbilicus
Chronic granulomatous
disease (CGD)
Primary immunodeficiency phagocytic cells
 PMN, eosinophils, monocytes,
macrophages
 mutation in one of 4 subunits of the
NADPH oxidase complex
 Defective superoxide generation
 Catalase + bacteria and fungi

Chronic granulomatous
disease (CGD)
Recurrent life-threatening bacterial and
fungal infections
 Exuberant inflammatory responsesgranuloma formation
 Autoimmune
 Poor wound healing and dehiscence
 1 in 200,000 persons

CGD

400 Mutations
– membrane-bound
– gp91 phox (phagocyte
oxidase) and p22 phox
– cytoplasmic p47 phox
and p67 phox
CGD clinical features


< 5 y (75%)
soft tissues infections
– cellulitis and subcutaneous
abscess

Recurrent pneumonia, lung
abscess, sinusitis, otitis
CGD clinical features


Suppurative lymphadenitis
Abscesses
– skin, lymph node, liver, CNS, perianal
CGD clinical features




Severe, resistant facial
acne
painful inflammation of
the nares
severe gingivitis
aphthous ulcers
CGD clinical features
Catalase-producing pathogens
 degrade ambient hydrogen peroxide

– Staph Aureus
– Burkholderia
– gram-negative enteric bacilli Serratia
marcescens, Klebsiella, Proteus,
Salmonella, Aerobacter
– Aspergillus
CGD Inflammatory Complications

Granuloma
– gastrointestinal and genitourinary
obstruction

Autoimmune diseases
– SLE, discoid lupus, pneumonitis, IBD
– systemic steroid therapy, Cyclosporine,
sulfasalazine
CGD, clinical manifestations
Lymphadenopathy (75.6%)
 Pulmonary infections (65.9%)
 Skin involvement (63.4%)
 Gastrointestinal (56.1%)
 Skeletal (29.3%)
 Central nervous system (2.4%)

CGD X-linked

onset is earlier
– 81% vs 19%<10y
obstructive granulomas and infections
are more frequent
 mortality rate is higher

Diagnosis
Dyes - reactive oxygen production
 Nitroblue tetrazolium, rhodamine,
dichlorofluorescein
 Chemiluscency (single oxigen- light

emission)
Management
Fever and leukocytosis rare even in
severe infections- only ESR
 Discovery on CXR or brain CT
 Aggressive management with surgical
debridement of infection

Management

Prophylactic
– co-trimoxazole
– itraconazole some benefit
 g interferon

BMT
Immunocompetence Evaluation
thorough history, physical examination,
and family history
 Most immunologic defects can be
excluded at minimal cost with the
proper choice of screening tests, which
should be broadly informative, reliable,
and cost-effective

Evaluation, history

Age
– 4-5 month SCID
– 7-9 month B cell


Recurrent pneumonia- asthma?
Where
– Foreign body
– Aspiration


Growth?
Diarrhea?
Evaluation, history
Thrush?
 Medications
 Blood transfusion
 Past

– neonatal hypocalcemia
– TEF

Immunisation - live
Evaluation, history

Family
– consanquinity
– death
– infection
– addict
Evaluation, examination




Ill
Growth
Mucosal- thrush
Hair
Evaluation, examination
 Skin
– rash
– eczema
Evaluation, examination
 Skin
– telangiectasia
Evaluation, examination

Lymph nodes
– Peripheral, tonsils
– Hepatomegaly
(CVID, Omenn)
Evaluation, site




Skin
Lymphadenitis
Gingivitis
Abscess
–
phagocyte
Evaluation, site




Otitis
Sinus
Pulmonary
Meningitis
–
B cell
Pathogen

Virus
–
–

T cell
Enterovirus- B cell
Fungi
–
–
T cell
Aspergillusphagocyte

Parasite
–
–

Pathogen
T cell
Giardia- B cell
Bacteria
–
–
–
–
encapsulated- B cell, complement
mycobacterial- T cell
Pneumocystis Carini – T cell
low virulence- phagocyte
Workup 1: CBC


Normal lymphocyte counts are higher in
infancy and early childhood than later in life
Lymphopenia
–

<1000, infant<1,5 - 2000
T cell, combined
Leucocytosis
LAD, HyperIgE
Ommen
Workup 1: CBC

Neutropenia
Congenital, acquired
 Lysosomal
inclusion
– Chediac Higashi Syndrome
Workup 1: CBC

RBC Howell-Jolly
bodies
– Congenital asplenia

Small platelets
– Wiskott-Aldrich
syndrome

ESR is normal, chronic bacterial or
fungal infection is unlikely
Workup 2: Ig





Normal- no humoral
IgG - 6 year
IgA - adolescent
IgM  - HyperIgM
IgE   – HyperIgE Job

IgE  - T cell
– DiGeorge, Ommen, WAS
Workup 3: T cell
CXR ( Thymus, lung)
 Delayed hypersensitivity

– Candida
most cost-effective test of T-cell function
– Trychophyton
– Mumps
– PPD
Workup 4: special
CD 19, 20 (- XLA, + CVID)
 CD 2,3,4,8,CD40L,TCR
 Proliferation to mytogen:

– T: PHA, con A, Candida, Tetanus
– B T dep: fungi, RWM
– B T indep: LPS, Staph, EBV
Workup 4: special, cont
Subclasses
 Isohemagglutinin

– antibodies to type A and B red blood cell
polysaccharide antigens
– IgM antibodies
– may be normally absent < 2 yr
– always absent if blood type AB
Workup 4: special, cont

Special response
– diphtheria, tetanus, H. influenzae
polyribose phosphate, pneumococcal
antigens

Pre and 2-3 wk post vaccine
– DT- protein (T dependent)
– Pneumococcal- polysaccharide (T
independ.)
Workup 5: phagocyte
CD11,18
 CD15 (LAD2)
 Chemotaxis (LAD, CHS, HyperIgE)
 Nitrobluetetrazoline (NADPH)

Workup 5: phagocyte, cont
 Intracellular
killing
 Chemiluscency
(single oxigenlight emission)
 Peroxidase staining
Workup 6: Complement
CH50
 Sheep RBC+anti
sheep RBC
antibody

Recurrent infections
Most recurrent infections - no
identifiable immunodeficiency disorder
 Major reason - excessive exposure of
infants to infectious agents
 Excessive use of antibiotics masked
classic presentation
