Allergy/Immunology 3

Question 1

What is an immunodeficiency? (4)

Answer 1

1. A failing of one or more of the body’s defensive mechanisms resulting in morbidity or mortality.
2. Any part of the immune system can be deficient- cells, proteins, signaling mechanisms…….
3. The body is susceptible to infection by organisms that meet with little or no resistance.
4. Severity is variable.

Question 2

Immunologic response (3)

Answer 2

1. Principle underlying pediatric immunizations
2. Immunodeficiency
   a. >140 inherited immunodeficiency disorders identified
   b. Worldwide pandemic of HIV infection- heightened awareness of immunology and immune deficiency disorder
3. Can be divided into secondary and primary immunodeficiency
   a. HIV can cause a secondary immunodeficiency (ex: viral infection causing neutropenia)

Question 3

Distribution of primary immunodeficiency (5)

Answer 3

1. B cell: 50%
2. T cell: 10%
3. T & B cell: 20%
4. Phagocyte: 18%
5. Complement: 2%

Question 4

Secondary immunodeficiency (5)

Answer 4

1. Infection (HIV)
2. Renal failure, or protein losing enteropathy (malnutrition)
3. Leukemia or Lymphoma
4. Certain Drug Therapies
5. Others

Question 5

Common B-cell immunodeficiencies (4)

Answer 5

a. Selective IgA deficiency (1:500)
b. IgG2 subclass / Selective antibody deficiency
c. Transient hypogammaglobulinemia of infancy
d. DiGeorge anomaly

Question 6

Jeffery Modell Criteria (10)

Answer 6

MUST KNOW ALL OF THESE; two or more requires a work-up

1. Four or more new ear infections within 1 year.
2. Two or more serious sinus infections within 1 year.
3. Two or more months on antibiotics with little effect.
4. Two or more pneumonias within 1 year.
5. Failure of an infant to gain weight or grow normally.
6. Recurrent, deep skin or organ abscesses.
7. Persistent thrush in mouth or fungal infection on skin.
8. Need for intravenous antibiotics to clear infections.
9. Two or more deep-seated infections including septicemia.
10. A family history of PI.

Question 7

Clinical Manifestations that Raise Suspicion of Primary Immune Deficiency (4)

Answer 7

1. Warts (human papilloma virus recurrent infections)
   a. WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis)
   b. Epidermodysplasia verruciformis
   c. DOCK8 deficiency (hyper-IgE syndrome)
   d. GATA2 deficiency (Mono MAC syndrome, DCML deficiency)
   e. IRF8 deficiency
   f. Combined immunodeficiencies
2. Ataxia
   a. Ataxia-telangiectasia
   i. When you look at the whites of the eye there are swirly vessels in them
   b. Ataxia-telangiectasia like disease (ATLD) ! PNP deficiency Microcephaly
   c. Cernunnos deficiency
   d. Ligase IV deficiency
   e. Ligase I deficiency
   f. Nijmegen breakage syndrome
   g. Dyskeratosis congenita
3. Deafness
   a. Reticular dysgenesis
   b. ADA deficiency
4. Partial albinism
   a. Immunodeficiencies with immune dysregulation and hypopigmentation
   i. Griscelli syndrome
   ii. Chediak-Higashi syndrome
   iii. Hermansky-Pudlak syndrome

Question 8

Autoimmunity (2)

Answer 8

1. Occurs when the immune system begins attacking self components of the body aberrantly
2. Autoimmune diseases include multiple sclerosis, rheumatoid arthritis, lupus and type I diabetes

Question 9

Alloimmunity (2)

Answer 9

1. Immune system reacts against antigens on tissues of other members of the same species
   a. Neonatal diseases where maternal immune system becomes sensitized against antigens expressed by fetus
   b. Transplant rejection and transfusion reactions when immune system of recipient of organ transplant or blood transfusion reacts against antigens on donor cells
2. Fetus affected by maternal antibodies
   a. Rh and ABO alloimmunization
   b. Graves disease: Maternal antibody against TSH receptor causes neonatal hyperthyroidism

Question 10

Disorders of immune system (2)

Answer 10

1. Immune deficiencies
   a. Defects of the Adaptive immune system
   i. T lymphocytes (cellular) immune function
   ii. B lymphocytes (humoral) immune function
2. Defects of the Innate immune system
   a. Considered as group
   i. Primarily cellular abnormalities
   ii. Soluble protein defects

Question 11

Clinical presentations of immune deficiency (14)

Answer 11

1. Cellular immune defect
2. Humoral immune defect
3. Neutrophil defect
4. Interferon gamma/ interleukin 12 pathways defect
5. Complement defect
6. Early component
7. Terminal component
8. Recurrent opportunistic infection
9. Recurrent sinopulmonary infection with encapsulated bacteria
10. Recurrent bacterial and fungal infections involving the skin and organs
11. Recurrent atypical mycobacterial
12. Salmonella infections
13. Recurrent sinopulmonary infections
14. Recurrent Neisseria infections

Question 12

Immunodeficiency lab values (7)

Answer 12

1. Low Lymphocyte count
2. Low neutrophil count
3. Low leukocyte count
4. IgA deficiency is probably most common
5. Cellular immunity tends to be looked at first
6. Humoral immunity: Quantitate immune globulins
7. Do total neutrophil count

Question 13

Clinical Presentation of Patient with T cell dysfunction (7)

Answer 13

Infections with intracellular “opportunistic” microorganisms

a. Viruses (HSV, V-Z, CMV, EBV)
b. Protozoa (Cryptosporidium, toxoplasma)
c. Mycobacteria
d. Fungal (Candida, Pneumocystis carinii)
e. Bacteria, gram negative enteric (T-cell)
f. Bacteria, polysaccharide encapsulated (B-cell)
g. DiGeorge will present with opportunistic infections

Question 14

DiGeorge Syndrome (6)

Answer 14

1. Congenital thymic hypoplasia
2. Dysmorphogenesis of 3rd and 4th pharyngeal pouches
3. Hypoplasia of thymus
4. Other issues: Congenital heart disease and Hypoparathyroidism
5. Deletion of several genes on chromosome 22
   * Cardiac diseases are associated with chromosome 22
6. Syndrome – variable
   a. Hypoplasia versus aplasia of parathyroid and thymus
   i. Thymic hypoplasia can lead to cellular immunodeficiency
   b. B cell numbers normal
   i. antibody response can be intact if sufficient T-cell function for T-cell help
   c. If thymic hypoplasia partial, few or no life threatening infections

Question 15

Antibody deficiency (3)

Answer 15

1. Occurs later due to maternal transfer of antibodies
2. 3-6 month lag time before they present
3. Child will usually not present until after 6months due to maternal protection
   a. No tonsils

Question 16

IgA deficiency (3)

Answer 16

1. May not be symptomatic
2. Clinical features: Recurrent sinopulmonary infections, Gastrointestinal disorders, Allergy, Cancer and Autoimmune disease.
3. Pathogenesis: block in B cell differentiation is due to intrinsic B cell defect or abnormal T cell help such as production of cytokine (TGF-beta,IL-5) or in B cell responses to these cytokines.

Question 17

X-Linked Agammaglobulinemia (8)

Answer 17

1. Described by the IUIS committee as the ‘prototypical antibody deficiency’.
2. First immunodeficiency described.
3. Defect on the X chromosome affecting the Btk gene. (only affects males)
4. Results in an absence or severe reduction in B lymphocytes and hence immunoglobulin of all types.
5. Absence of mature B cells
6. Patients lack lymphoid tissue and fail to develop plasma cells
7. Germinal centers where B cells proliferate and differentiate are poorly developed in all lymphoid tissue, including the spleen.
8. Tonsils, adenoids, peripheral lymph nodes, and Peyer patches in the intestines are all small or absent

Question 18

X-linked Agammaglobulinemia patho (8)

Answer 18

1. Infections begin at 4 - 6 months of life when transplacental maternal IgG wanes
2. Absent circulating mature B-cells
3. All major classes of immunoglobulin affected (IgG, IgM, IgA)
4. Lack of ability to make an antibody response to antigen
5. Pyogenic infections prominent
   * Pyogenic infections = pus containing infections
6. Viral infections (enteroviruses) possible
7. Recurrent otitis media, pneumonia, and sinusitis before age 1 year.
8. By mid childhood, chronic sinusitis becomes prevalent, and the prevalence of otitis media decreases.

Question 19

X-linked Agammaglobulinemia infectious agents (5)

Answer 19

1. S pneumonia or H influenzae type B.; extracellular encapsulated bacteria.
2. In childhood, encapsulated bacteria continue and staphylococcal infections
3. Neisseria meningitidis and Moraxella catarrhalis (not encapsulated) are other bacteria whose portal of entry is the respiratory tract.
4. A chronic cough in a patient may indicate a risk for chronic pulmonary disease, which may be restrictive, obstructive, or both.
5. Infections due to Mycoplasma and Ureaplasma species have been reported in both adolescents and adults.

Question 20

Diarrhea and other manifestations with X-linked Agammaglobulinemia (3)

Answer 20

1. Diarrhea that is not completely explained by frequent antibiotic use.
   a. Giardia or Campylobacter
   b. Susceptible to certain viruses that replicate in the gastrointestinal tract and then spread to the CNS.
   i. enteroviruses - Poliovirus, echovirus, and coxsackievirus
2. Short stature
3. High mutation rate with X linked disorders

Question 21

Sub-class deficiency (6)

Answer 21

1. Total serum IgG levels are normal
2. One or more subclasses are below normal.
3. IgG3 deficiency is the most common subclass in adults.
4. IgG2 deficiency associated with IgA deficiency in children.
5. Pathogenesis: abnormal B cell differentiation.
6. Some individual have recurrent bacterial infection.

Question 22

Common Variable Immunodeficiency (CVID) (7)

Answer 22

1. CVID is a heterogenous group of disorders with intrinsic B-cell defect or a B-cell dysfunction related to abnormal T-cell B-cell interaction.
2. No circulating B lymphocytes
3. Ranges from frequent GI symptoms including malabsorption and chronic diarrhea
4. Nodular lymphoid hyperplasia
5. Higher incidence of autoimmune disease
6. Systemic granulomatous disease
7. Malignancy rate is higher

Question 23

X-linked hyper-IgM (9)

Answer 23

1. Underlying defect is in an encoding protein CD 40 ligand needed for switching from IgM to IgG, IgA or IgE production
2. Can make IgM, but not IgG, IgA, or IgE
3. Normal IgM, but very low IgG, IgA, and IgE
4. Presents with recurrent sinopulmonary infection with encapsulated bacteria
5. Neutropenia
6. Liver disease
7. Development of malignancy more common
8. Treated with IgG replacement and P. jiroveci prophylaxis
9. CBC dif and gamma globulins can pick this up

Question 24

Combined Immunodeficiencies (4)

Answer 24

1. Combined immunodeficiency (CID)
2. Severe combined immunodeficiency (SCID)
3. Ataxia-Telangiectasia syndrome (AT)
4. Wiskott -Aldrich syndrome (WAS)

Question 25

Severe Combined Immunodeficiency (SCID) (5)

Answer 25

1. Presents early in life a. DIARRHEA AND FTT i. Recurrent infections with fungi, viruses (parainfluenza, CMV, adeno virus ii. Life threatening 2. Without bone marrow transplant, patient will die by age 2 ! Susceptible to infections by opportunistic organisms 3. Absence of T cell function 4. Has no Thymus 5. Absolute lymphocyte count * Infancy is higher (lower limit is 2,500 to 3,000)

Question 26

Clinical features of SCID (7)

Answer 26

1. Failure to thrive 2. Onset of infections in the neonatal period 3. Opportunistic infections 4. Chronic or recurrent thrush 5. Chronic rashes 6. Chronic or recurrent diarrhea 7. Paucity of lymphoid tissue

Question 27

Wiskott-Aldrich Syndrome (6)

Answer 27

1. X-linked disorder a. Eczema b. Thrombocytopenia with small platelets 2. Immunodeficiency 3. Excessive bleeding following 4. Opportunistic infections are more common as child ages 5. Defect in gene encoding the WAS protein involved in polymerization 6. IVIG or cure with bone marrow transplant

Question 28

Ataxia Telangiectasia

Answer 28

1. Autosomal recessive 2. Depressed IgA, Decreased IgG, T lymphocyte deficiency 3. Increased risk of malignancy 4. Increased sensitivity to radiation

Question 29

Ataxia Telangiectasia manifestations (5)

Answer 29

1. Recurrent sinopulmonary infection 2. Neurologic i. Regression in motor milestones 3. Cutaneous i. Telangiectasia in the eye, ear, cheek 4. Endocrine * Mild diabetes 5. Delayed puberty

Question 30

Complement System (4)

Answer 30

1. 10% of plasma proteins are complements 2. Activated components can destroy pathogen directly 3. Activates or collaborates with other components 4. Activates by three different ways—all converge at C3

Question 31

Complement system defect (2)

Answer 31

1. Terminal components defects leads to an increased susceptibility to Neisseria species 2. Membrane Attack Complex component defect (MAC) a. Increased risk for systemic meningococcal infections b. 15% of patients with one episode of meningococcal disease c. 40% of patients with more than one episodes d. Family history (sib have 1 in 4 risk) Autosomal recessive

Question 32

Mimics of Immune Deficiency (6)

Answer 32

1. Nephrotic syndrome 2. Protein losing enteropathy a. Protein losing enteropathy can be a complication of cardiac transplant 3. Losing cells through GI tract a. Intestinal lymphangiectasia 4. Cow s milk protein allergy a. May have immunodeficiency due to loss of protein from GI tract 5. Does the patient have antibodies against vaccine preventable diseases? 6. Response to Prevnar is a positive sign

Question 33

Neutrophil disorders (3)

Answer 33

1. Skin 2. Bacterial and Fungal infection a. Typically involve skin, lung, bone, liver and oral cavity b. Congenital neutropenia c. Chronic granulomatous disease (CGD) i. Classically involve skin, lung, liver, and bone ii. Staphylococcus aureus, serratia marcescens, Burkholderia cepacia, nocardia species, aspergillus 3. Leukocyte adhesion deficiency (LAD)

Question 34

Screening Laboratory Tests (4)

Answer 34

1. Cellular immune defect a. Absolute lymphocyte count b. HIV 2. Humoral immune defect: recurrent infection with encapsulated organisms a. Quantitative immunoglobulins b. Natural antibodies c. HIV test 3. Neutrophil defect a. Absolute neutrophil count X 2 b. Neutrophil morphology 4. Complement defect a. Total hemolytic complement (CH 50)

Question 35

Immunological Testing for Primary Immunodeficiency: Stage 1 (3)

Answer 35

a. History and physical b. CBC with differential c. Quantitative immunoglobulins i. IgG ii. IgA iii. IgM

Question 36

Immunological Testing for Primary Immunodeficiency: Stage 2 (3)

Answer 36

1. Specific antibody responses (tetanus, diphtheria) * ANERGY PANEL 2. Response to pneumococcal vaccine (pre/post for ages 3 and up) 3. IgG subclass analysis

Question 37

Immunological Testing for Primary Immunodeficiency: Stage 3 (4)

Answer 37

a. Candida and tetanus skin tests b. Lymphocyte surface markers i. CD3/CD4/CD8/CD19/CD 16/CD 15 c. Mononuclear lymphocyte proliferation studies (mitogen and antigen stimulation) d. Neutrophil oxidation burst

Question 38

Immunological Testing for Primary Immunodeficiency: Stage 4 (9)

Answer 38

a. Complement screening CH50, C3, C4 b. Enzyme measurements (adenosine deaminase, purine nucleoside phosphorylase) c. Phagocyte studies (surface glycoproteins, mobility, phagocytosis) d. NK cytotoxicity studies e. Further complement studies AH50 f. Neo antigen to test antibody production g. Other surface / cytoplasmic molecules h. Cytokine receptor studies i. Family / genetic studies

Question 39

Final words (4)

Answer 39

1. Use the 10 warning signs as an initial screen for immunodeficiency. 2. Utilize 1st stage testing for patients that screen positive above. 3. Consider allergy/immunology referral for further workup (e.g. recurrent otitis is often linked with allergic or non- allergic rhinitis as well). 4. Unusual organisms and abnormal laboratories should always trigger a follow-up evaluation