Primary Immunodeficiency Diseases_Jackson

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Blood and Lymph exam II

Primary immunodeficiency diseases

- disorders associated with genetic defects and mutations
- secondary immunodeficiencies are more common (infection, drugs, malnutirtion)
- More commonly manifest in children

What are the warning signs of Primary Immunodeficiency?

1. 8 + ear infections/yr
2. 2+ serious sinus infections/yr
3. 2+ monts of abx w/ no effect
4. 2+ pneumonias/yr
5. Failur of infant to gain wt or grow normally
6. Recurrent, deep skin or organ abscesses
7. Persistent thrush in mouth or elsewehere on skin, post 1y/o
8. Need IV abx to clear infection
9. 2+ deep seated infections
10. Family hx of PID
11. Chronic diarrhea, malabsorption

Need to Examin the possiblity of other common causes of recurrent infections in children

1. chilhood itself
2. immature immune system
3. Passive cigarette smoke exposure
4. anatomic abnormality
5. asthma, allergic rhinits
6. CF
7. Gastroesophageal reflux
8. Malnutrition
9. immunodeficiency

A defect in _____Lymphocyte leads to intracellular pathogen diseases?

T cell

A defect in ________ lymphocytes leads to extracellular pathogen diseases?

B cell

Itracellular pathogens are most commonly?

Viruses

Extracellular pathogens are most commonly?

Bacteria

Fungi are what type of pathogens (Intra or extrall - cellular)?

Both

Complement defects are associated with _______ pathogens?

Extracellular

Immune system of the fetus and neonates

- the immune system of the newborn is somewhat funcation, but still maturing
- Maternal IgG is protective until 3 to 6 months
- Neutrophil responses are sub par at birth but quickly become adequate

What are the 4 Ab immunodeficiencies discussed in class?

1. IgA deficiency
2. X - linked agammaglobulinemia
3. Immunodeficiency with Hyper - IgM
4. Common variable immunodificiency (CVI)

General Presentation of immunodeficiency will be...

A __________ year old __________ patients presents with a _________ infection. Histroy reveals severe infections and ....

Selective IgA deficiency: General Presentation

A WHATEVER year old m/f patient presents with a BACTERIAL SINUS infection. History reveals several severe infections and SERUM IgA LEVELS < 7mg/dL
- normal serum IgA ~ 200mg/dL

Seletive IgA deficiency

- Common; 1:500
- Most are ASYMPTOMATIC
- recurrent sinopulmonary infections, GI infections and GI problems
- Caution for anaphylacit transfusion rxns (transfusion will have IgA abs)

X - Linked Aggamaglobulinemia (Bruton's Aggamaglobulinemia)

- 1: 200K M births
- mutated btk gene on x chromosome
- low levels of CD19+ cells; low serum ab; normal T cells
- low ab response to vaccines
- infections with extracellular bacteria; pneuomonia

X Linked Immunodeficiency with Hyper IgM: General Presentation

A 6 Month OLD M patient presents with a BACTERIAL PNEUMONIA infection. History reveals several severe infections and low serum IgG and IgA, but high levels of IgM

X Linked Immunodeficiency with Hyper IgM

~ 1 per 1 million births
- deficient CD40 ligand on T helper cells
- impaired ab class switching and neutropenia
- infections with various pathogens
- increased autoimmunity and malignancy

Common Variable Immunodeficiency (CVID): General Presentation

A 25 y/o M/F patient presents with a BACTERIAL RESPIRATORY infection. history reveals several severe infecitons and BELOW NORMAL LEVELS OF SERUM IMMUNOGLOBULIN

CVID

-" lane onset hypogammalglobulinemia
- may present at any age but mean age ~25 y/o
- 1:25K
- recurrent sinopulmonary infections, GI infections and GI problems
- serum Ig levels not as low as XLA
- increased incidence of autoimmunity and malignancy

What were the T cell and combined immunodeficiencies discussed in class?

1. DiGeorge Syndrome
2. Wiskott - Aldrich Syndrome
3. Severe Combined Immunodeficiency (SCID)

DiGeorge Syndrome

- abnormality in chromosome 22
Clnical symptoms described by "CATCH - 22"
C - cardiac abnormality (tetralogy of Fallot)
A - abnormal facies
T - - Thymus
C - Cleft palate
H - hypocalcemia/hypothyroidism
22 - chromosome mutation
- Patient generally have hx of multiple severe infections of VIRAL or FUNGAL origin
- X-ray --> Thymic shadowing
- Decrease in circulating T cells.

Wiskott - Aldrich Syndrome: class triad

1. x linked immnodeficiency (abnormal Ig and t cells)
2. thrombocytopenia with small platelets
3. Eczema

Wiskott - Aldrich Syndrome: Common characteristics

- ~1/3 pts have triad
- dx with in first 2 years of life
- recurrent sinopulmonary bacterial infections
- mutation in WAS gene on x chromosome (cytoskeletal regulator protein)
- low serum IgM and IgG; possibly elevated IgE and IgA
- increased autoimmunity and malignancy

Severe Combined Immunodeficiency (SCID)

"bubble boy"
- Both T and B cells severely affected
- early severe infections, diarrhea and failure to thrive
- many different genetic defects; x linked C gamma chain most common
- Tx --> bone marrow/stem cell transplant, + gene therapy

What conditions related to defects in phagocytic and complement activity discussed in class?

1. Chronic granulomatous disease
2. Deficient Complement proteins
3. Hereditary Angioedema

Chronic granulomatous dz: General presentation

A 1 y/o M patient presents with a SEVERE BACTERIAL infection. History reveals several severe infections and skin abscesses caused by STAPHYLOCOCCUS AUREUS

Chronic granulomatous dz

- x linked form is most common
- granuloma formation is common
- defective subunit of NADPH oxidase --> diminished intracellular killing by Macs and PMNs
- age < 2y/o
- dx with nitroblue tetrazolium (NBT) or dihydrhodamine tests

Compliment Protein Deficiency: Imporntance of C3

- Defect in the activation of C3 cause ppl to more susceptible to a wide range of pyogenic infections, emphasizing the important role of c3 as an OPSONIIN that promotes phagocytosis of bacteria by macs nad PMNs

defects in C5 - C9 have increased susceptibility to _______?

Neisseria

Hereditary Angioedema

- recureent attacks of edema; subcutaneous and submucosal tissues
- respiratory obstruction may occur
- DEFICIENCY IN C1 INHIBITOR OF COMPLEMENT
- excess production of C2 Kinin and bradykinin --> increased inflammation

Katie is a 22 y/o being evaluated for severe prolonged diarrhea. History reveals numerous respiratory and GI infections throughout her life. She has been hospitalized several times with pneuomonia and previous episodes of diarrhea due to Giardia lamblia. You suspect...

IgA deficiency

What are the treatment options for immundeficiency diseases?

1. Replacement of immunoglobulin (IVIG, SCIG)
2. Prohylactic and prompt abx tx
3. Stem cell transplantation
4. Gene therapy and gene repair
5. Defective protein replacement

Ataxia telangiectasia

- rare, progressive MULTI SYSTEM diorder of CHILDHOOD
- First signs --> Delayed development of motor skills, ataxia at 12 - 18 months
- cerebellar defect
- " Wobbly Baby"
- Defect involes mutation in a gene that codes for a kinase involed in DNA repair
- Patients very susceptible to radiation damage
MUST USE CAUTION IF ORDERING X-RAYS
- 20% develop cancer

Leukocyte Adhesion Deficiency I: General Presentation

A 1 y/o M/F patietn presents with a BACTERIAL SKIN infection. History revelas several severe infections and a DELAYED UMBILICAL CORD SEPARATION AFTER BIRTH.

Leukocyte Adhesion Deficiency I

- B 2 integrin is deficient or defective (CD 18)
W/out PMN cna not bind to membrane and leave circulation
- AR inheritance
- Delayed separation of umbilical cord; omphalitis
- Recureent bacterial skin and mucosal infections
- lack of pus formation and impaired wound healing
- Periodontal disease
- Neutrophilia (increased PMNs)

Transient Hypogammaglobulinemia of Infancy (THI): general presentation

An infant w/ recurring episodes of otitis media and sinusitis that began at age 6 months
- generally normal birth and physical
- normal growth paramaters
- Ab titers to vaccines appear normal, but total serum IgG is below normal

THI

- Dx based on IgG levels at least 2 SD below the mean for age matched controls, that persist beyond 6 months of age and occurs in the absence of other immunodeficiency conditions
- Famy hx of immunodeficiency dz
- exact cause unknown but may represent a maturational defect in B cells, T cells or APC
- Abx tx or prophylaxis may be warranted
- Spontaneous recovery by age 2 - 4

Your patient Tommy is a 4y/o who presents with severe sinusitis. His mother reports a history of several severe infections, including pneumonia caused by Pneumocytosis jiroveci. tommy's WBC count is normal. Further testing revealed a deficiency in the CD 40 ligand of T cells. Which immunoglobulin isotype would you expect to fine in ecess in Tommy's serum?

IgM

Baby Omar was born at term, but with low birth wt. he had abnormal facial features, low set ears, relatively small mouth and lower jaw. Omar was evaluated due to a serious infection and a history of several severe viral infections. A chest x ray revealed a complete lack of thymus shadow and in interrupted aortic arch was seen with echocardiogram. What other finding would be consistent with this situation and most likely in this patient?

Tetany or siezure

Parents bring their 2 y/o son to your clinic for severe skin abscess. His history is significant for two similar infectious episodes, all involving Gram + and catalase + bacteria. Further tests revealed normal serum ab levels, T cell numbers, and complement activity. A special test revealed that this patient's neutrophils did not generate reactive oxygen species. What other finding would be consistent with this patient's situation?

Multiple lung granulomas

What laboratory test should you order if suspected immunodeficiency?

1. CBC with differential
2. Analyze lymphocyte subset
3. Serum Ig levels, including subclasses
4. Serum ab titers to vaccines
5. Othere tests depend upon suspicions
a. CD 40 ligand
b. Complement proteins/CH50
c. NBT/DHR

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