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. structural brain abnormality,seizures Genitourinary malformation.

• Neurological abnormalities •

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 CATALASEPOSTIVE 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