IMMUNODEFICIENCIES

JANUARY 28, 2008

PRIMARY
IMMUNODEFICIENCIES
• INHERITED DEFECTS OF THE IMMUNE
SYSTEM

• CLASSIFIED BASED ON THE SITE OF

THE LESION IN THE PATHWAY

• INCREASED SUSCEPTIBILITY TO
INFECTION
10 warning signs of Primary
Immune Deficiency
• 8 or more new ear infections within one
year.
• 2 or more serious sinus infections within 1
year.
• 2 or more months on antibiotics with little
effect.
• 2 or more pneumonias within 1 year.
• Failure of an infant to gain weight or grow
normally.
• Recurrent, deep skin or organ abscesses.
• Persistent thrush in mouth or elsewhere on
skin, after age 1.
• Need for intravenous antibiotics to clear
infections.
• Two or more deep-seated infections such
as sepsis, meningitis or cellulitis.
• A family history of primary immune
diseases.
ADENOSINE DEAMINASE
DEFICIENCY
• 1 IN 100,000 BIRTHS

• DEFECTIVE ADA GENE, CHR 20

• LACK ADENOSINE DEAMINASE

ADENOSINE DEAMINASE
ENZYME
• BREAKS DOWN TOXIC BYPRODUCTS

• ADA DEOXYADENOSINE
DEOXYINOSINE

• T CELLS HAVE SHORT LIVE SPAN

• AFFECTS B CELLS AS WELL
• LEADS TO SCID
• MOSTLY SEEN AT AGE 1
• RARELY, ADULTS
• AUTOSOMAL RECESSIVE
S/SX OF ADA

• INFANTILE TYPE:
INFECTIONS, RIB FLARING
VERTEBRAL ABNORMALITIES
SCAPULAR DEFECTS
• DELAYED ONSET TYPE( <2 YRS OLD)
INFECTIONS
• LATE ONSET
RECURRENT BACTERIAL
SINOPULMONARY INFECTIONS,
LYMPHOPENIA
EOSINOPHILIA
• ADULT TYPE
PERSISTENT CONDYLOMA
RECURRENT HSV
ITP
LYMPHOPENIA
P.E.

• PERIPHERAL LN PAUCITY
• NORMAL OR ENLARGED LIVER
• SMALL THYMIC SHADOW IN
NEONATES
• DEVELOPMENTAL DELAY,
HYPERTONIA, SPASTICIY, TREMORS
• FAILURE TO THRIVE
LABS

• PROFOUND LYMPHOPENIA >500

CELLS/MCL
• T-, B-,NK- TYPICAL PICTURE
• CD3, CD4, CD 8 DECREASED
• CD4/CD8 RATIO <1
• DECREASED Ig
TREATMENT

• BONE MARROW TRANSPLANT

• 90% SUCCESS RATE IN M.S.D. AND
M.F.D.
• 63% M.U.D.
• RECONSTITUTED T CELL FUNCTIONS,
NUMBERS
• B CELLS VARIED
TREATMENT

• PEG-ADA
PEGADEMASE
CONJUGATE OF THE ENZYME ADA
1 INJECTION Q WEEKLY IM
2-6 MONTHS:IMPROVEMENT
TREATMENT ADA

• GENE THERAPY
• RETROVIRAL VECTORS TRANSFECT
AUTOLOGOUS CD 34+ STEM CELLS
WITH THE ADA GENE
INCREASE T, B AND NK CELLS
• COGNITIVE , BEHAVIORAL NO
CHANGES
• HOSPITALIZED, HEPA FILTER
• NO LIVE VACCINES
• TMP-SMZ FOR P. CARINII
• FLUCONAZOLE FOR CANDIDIASIS
RETICULAR DYSGENESIS

• COMBINED IMMUNODEFICIENCY,
NEUTROPENIA
• SEEN IN NEWBORN
• SIMILAR FINDINGS IN SCID, ADA
• NORMAL ERYTHROID PRECURSORS,
MEGAKARYOCYTES
• NONFUNCTIONAL T CELLS
• MACROPHAGES PRESENT
• B CELLS MAY NOT BE AFFECTED
• 1 IN 3-5 MILLION
• TREATMENT: STEM CELL
TRANSPLANT
PNP DEFICIENCY
• PURINE NUCLEOTIDE
PHOSPHORYLASE DEFICIENCY
• LYMPHOPENIA, DECREASED CD3+ ,
NORMAL NUMBER OF B CELLS
• TREATMENT: HLA-MATCHED BONE
MARROW TRANSPLANT
• UNSUCCESSFUL:PEG-PNP
• GENE THERAPY
DISORDERS OF T CELLS:
DiGEORGE’S SYNDROME
• CONGENITAL THYMIC
APLASIA/HYPOPLASIA
• IMMUNODEFICIENCY WITH
HYPOPARATHYROIDISM
• NO CHROMOSOMAL ASSOCIATION
CLEAR, BUT MAYBE CHR 22
• 1 IN 3000
DiGEORGE’S SYNDROME

• abnormal facies
• congenital heart defects
• hypoparathyroidism with
hypocalcemia
• cognitive, behavioral, and psychiatric
problems
• Increased susceptibility to infections.
•
• Pathological hallmarks
conotruncal abnormalities

absence or hypoplasia of thymus

and parathyroid glands

ABNORMAL T-CELL FUNCTION

OTHER S/SX
• growth retardation.
• Behavioral and psychiatric
ADHD
Anxiety, affective disorders
• Adults:schizophrenia
• 25% of children with 22q11 deletion syndrome
develop schizophrenia in late adolescence or
adulthood.

• Neurological abnormalities
structural brain abnormality,seizures
• Genitourinary malformation.
SYNDROMES RELATED TO CHR
22
• CATCH-22
CARDIAC
ABNORMAL FACIES
THYMIC HYPOPLASIA
CLEFT PALATE
HYPOCALCEMIA
• velocardiofacial syndrome (VCFS or
Shprintzen syndrome)
• Conotruncal anomaly face syndrome
• Cayler syndrome
• Opitz-GBBB syndrome
• CHARGE (coloboma [eye], heart anomaly,
atresia [choanal], retardation [mental and
growth], genital anomaly, ear anomaly)
syndrome.
• ABNORMAL DEVELOPMENT OF 3RD
AND 4TH PHARYNGEAL POUCHES
• HYPOCALCEMIA
TETANY
CONVULSIONS
COMMON CAUSE OF
MORTALITY
• CARDIAC ABNORMALITIES
TETRALOGY OF FALLOT
VSD
INTERRUPTED AORTIC ARCH
PULMONARY ATRESIA
TRUNCUS ARTERIOSUS
DiGEORGE’S FACIES
• Facies
hypertelorism
micrognathia
short philtrum with fish-mouth appearance
antimongoloid slant
telecanthus with short palpebral fissures
• Otolaryngic
low-set ears, defective pinna
cleft palate
velopharyngeal insufficiency.
LABS

• FLOW CYTOMETTRY
T-CELL FUNCTION
• INCREASED PTH
• HYPOCALCEMIA
• ABSENT THYMIC SHADOW ON CXR,
MRI
• KARYOTYPING
TREATMENT

• VIT D, CALCIUM SUPPLEMENTS

• BONE MARROW, THYMUS
TRANSPLANT
• SURGICAL CORRECTION OF CARDIAC
ANOMALIES
• INFECTION PRECAUTIONS
T CELL DEFICIENCIES WITH
VARIABLE DEGREES OF B CELL
DEFICIENCY
• ATAXIA-TELANGECTASIA
• WISKITT-ALDRICH SYNDROME
• SHORT-LIMBED DWARFISM
• MHC DEFICIENCY
ATAXIA-TELANGECTASIA

• CHR 14
• LOW T CELLS, NORMAL B CELLS
• LOW TO NORMAL IgM
• LOW IgG, IgA
• HIGH INCIDENCE OF LEUKEMIAS
WISKOTT-ALDRICH
SYNDROME
• INITALLY NORMAL T CELL NUMBERS, THEN
REDUCES
• LOW IgM, NORMAL IgG
• ELEVATED IgA, ELEVATED IgE
• PLATELET DEFECT, LOW COUNT
• DEFECTIVE WASp
CYTOSKELETAL REORGANIZATION
• EZCEMA, PETECHIA, PYOGENIC
INFECTIONS
SHORT-LIMBED DWARFISM

• T CELL DEFICIENCY, RARELY B CELLS

INVOLVED
• SKELETAL DYSPLASIA, THIN HAIR
MHC DEFICIENCY

• BARE LEUKOCYTE SYNDROME

• DEFECTIVE MHC CLASS II GENES
• DECREASED CD4+, DECREASE Th
FUNCTION
• INFECTION-PRONE
DISORDERS OF B
LYMPHOCYTES
• X-LINKED INFANTILE
HYPOGAMMAGLUBULINEMIA
• TRANSIENT
HYPOGAMMAGLOBULINEMIA
• COMMON VARIABLE
IMMUNODEFICIENCY
HYPOGAMMAGLOBULINEMIA
X-LINKED INFANTILE
HYPOGAMMAGLOBULINEMIA
• BRUTON’S HYPOGAMMAGLOBULINEMIA,
AGAMMAGLOBULINEMIA
• XLA
• MOST SEVERE B CELL IMMUNODEFICIENCY
• DECREASES/ABSENT B CELLS
• LOW/ABSENT IG
• DEFECTIVE B CELL TYROSINE KINASE GENE
(btk GENE)
• 1 IN 100,000
S/SX

• PNEUMONIAS
• SINOPULMONARY INFECTIONS
• DELAYED DIAGNOSIS:
CHRONIC PULMONARY
INFECTIONS
POOR GROWTH
S.PNEUMONIAE, H.INFLUENZAE
IgA DEFICIENCY

• MOST COMMON
• 1 IN 700 CAUCASIANS
• AUTO DOMINANT OR RECESSIVE
• MAY BE DUE TO DEFECT IN CHR 18
OR TO AUTOIMMUNE ANTIBODIES
AGAINST IgA
S/SX
• 80% ASYMPTOMATIC
•recurrent sinopulmonary
infections,
•atopic disorders (atopic asthma,
allergic rhinitis, atopic dermatitis,
IgE-mediated food allergy)
•GI disease ,celiac disease
•neurologic diseases
•autoimmunity
•malignancy.
DEFECTS OF THE PHAGOCYTIC
SYSTEM
• CYCLIC NEUTROPENIA
• CHRONIC GRANULOMATOUS DISEASE
• LEUKOCYTE ADHESION DEFICIENCY
• CHEDIAK-HIGASHI SYNDROME
• RECURRENT PULMONARY
INFECTIONS WITH CATALASE-
POSTIVE ORGANISMS
• FUNGAL
ASPERGILLUS, CANDIDA
S/SX

• 1ST FIVE YEARS OF LIFE

Skin infections
Pneumonia
Lung abscesses
Suppurative lymphadenitis
Diarrhea secondary to enteritis
Perianal or perirectal abscesses
Hepatic or splenic abscesses
• MOST FREQUENT:
RECURRENT OTITIS MEDIA
LABS

• SERUM IgA <7MG/DL IN PATIENTS >

4 YEARS OLD
• NORMAL IgG, ESP TO VACCINATION
TREATMENT

• PROPHYLACTIC ANTIBIOTICS, WINTER

• IVIG
• PNEUMOCOCCAL VACCINE
CHRONIC GRANULOMATOUS
DISEASE
• DEFECT IN NADPH OXIDASE
• INABILITY TO PRODUCE SUPEROXIDE
IONS
• MUTATION OF THE CYBB GENE ON
THE X-CHROMOSOME-80%
• MUTATION OF THE NCF1 GENE IN
CHR 7
• GRANULOMAS
nodular masses of inflammatory
tissue, form in response to
persistent antigenic stimulus
(chronic infections) or because
of lack of negative feedback by
oxygen radicals on
proinflammatory cytokines
• GIT, GUT GRANULOMA MAY BE
PRESENTING S/SX
DYSPHAGIA
N&V
OBSTRUCTION (ESOPHAGUS,
DUODENUM)
ABDOMINAL PAIN
• PERIANAL ABSCESSES, FISTULAS
• ESOPHAGEAL DYSMOTILITY
• URINARY RETENTION
• DYSURIA
• INCONTINENCE
NBT TEST

• NITROBLUE TETRAZOLIUM TEST

• (+) RESULT: BLUE INCLUSIONS IN
PHAGOCYTES DUE TO BLUE
FORMAZAN
TREATMENT

• DAILY TMP-SMZ
160/800 MG TAB BID PO
• ITRACONAZOLE
200MG QID PO
• PREDNISONE

• STEM CELL TRANSPLANT

CHEDIAK-HIGASHI DISEASE

• AUTO RECESSIVE
• OCULOCUTANEOUS ALBINISM
• NYSTAGMUS
• INCREASED INFECTIONS(SKIN)

• REDUCED INTRACELLULAR KILLING;

CHEMOTACTIC MOVEMENT
• DEFECT IN CHS1 GENE
• AFFECTS SYNTHESIS/STORAGE OF
SECRETORY GRANULES IN VARIOUS
CELLS
Lysosomes of leukocytes and fibroblasts,
dense bodies of platelets, azurophilic
granules of neutrophils, and melanosomes
of melanocytes are generally larger in size
and irregular in morphology
TREATMENT

• BONE MARROW TRANSPLANT

• MICROTUBULE DRUGS
• ACYCLOVIR
• IG