Acquired and Innate Immune Deficiencies

Question 1

Discuss the warning signs of primary immunodeficiency.

Answer 1

• 4+ ear infections/yr
• 2+ sinus infections/yr
• 2+ pneumonias/yr
• failure to thrive
• recurrent deep skin abscesses
• persistent fungal (mouth/skin)
• IV antibiotics/2+ mon. w/o effect
• 2+ infections w/septicemia

Question 2

B cell Immune Deficiency: common infections

Answer 2

• recurrent sinopulmonary (decreased IgA)
infections or sepsis
• usually encapsulated organisms
• chronic meningoencephalitis

Question 3

B cell Immune Deficiency: lab tests

Answer 3

Ig levels
specific Ig titers
flow cytometry (B cell #)

Question 4

B cell Immune Deficiency: examples

Answer 4

X-linked agammaglobulinemia
common variable immunodeficiency
selective IgA deficiency

Note: antibody deficiencies = 65% of innate immunologic disorders

Question 5

T cell Immune Deficiency: common infections

Answer 5

• opportunistic infections
• recurrent + severe common infections
• failure to thrive, diarrhea

Question 6

T cell Immune Deficiency: lab tests

Answer 6

CBC w/ differential
flow cytometry
T cell functional study
Ig levels

Question 7

T cell Immune Deficiency: examples

Answer 7

DiGeorge syndrome
Wiskott Aldrich syndrome
SCID (B + T cell)

Question 8

Phagocytic immune deficiency: common infections

Answer 8

• soft tissue abscesses or lymphadenitis
• infections w/catalase (+) organisms [S.
aureus, Serratia, Aspergillus]
• poor wound healing

Question 9

Phagocytic immune deficiency: lab tests

Answer 9

CBC w/differential
PMN oxidative burst assay
flow cytometry

Question 10

Phagocytic immune deficiency: examples

Answer 10

chronic granulomatous disease
leukocyte adhesion defect

Note: phagocytic deficiencies = 10% of primary immunodeficiencies

Question 11

Complement immune deficiency: common infections

Answer 11

• recurrent disseminated Neisseria
• autoimmune disease
• bacterial sepsis

Question 12

Complement immune deficiency: lab tests

Answer 12

CH50 measures

classical complement cascade

Question 13

Complement immune deficiency: examples

Answer 13

terminal complement deficiency

Question 14

Innate defects in immune system: common infections

Answer 14

• septicemia

* poor inflammatory response

Question 15

Innate defects in immune system: lab tests

Answer 15

TLR signaling

Question 16

Innate defects in immune system: examples

Answer 16

IRAK4 mutation
NEMO mutation
MyD88 mutation

Question 17

Severe Combined Immunodeficiency (SCID)

Answer 17

18+ genes

• early detection + TX [newborn screening]
• ≠ normal T cell #s (look for TRECs = biomarker for T cell development)
• fatal within 1st year if no immune reconstitution (bone marrow transplant, gene therapy, PEG-ADA, thymic transplant)

Question 18

DiGeorge Syndrome

Answer 18

22q11.2: microdeletion (1:3k-6k)
- classic triad: hypocalcemia, ♥ defect, thymic dysfunction
o Tetralogy of Fallot, decreased lymphocytes [lymphs made = good, do well]
o can do thymus transplant if thymus absent/incomplete

Question 19

Common Variable Immunodeficiency (CVID)

Answer 19

~Relatively common (1:65k)

• Inherited primary immunodeficiency = bimodal presentation: 10 years and 30 years.

A defect in B cell differentiation and/or function

• Dx: marked decrease in IgG and at IgM or IgA; and has:
  1) onset greater than 2 years old
  2) absence of isohemagglutinins and/or poor response to vaccines (functional defect)
  3) exclude defined causes of hypogammaglobulinemia

• Increased incidence of lymphoid malignancy, autoimmune disease, and atopy.
• Incidence of autoimmune disease in CVID patients = 25%
TX: IVIG (long-term), antibiotics, suppress immune system

Question 20

Wiskott Aldrich syndrome (WAS)

Answer 20

Spectrum, X-linked recessive

• present w/ recurrent infections, decreased platelets, eczema => increased risk of autoimmunity + malignancy
• WAS protein expressed in blood cells = functions to modulate actin cytoskeleton
• actin cytoskeleton has role in immune function

o ID + TX: genotype-phenotype relationships + clinical scoring system

TX:  IVIG, replace immune system w/ bone marrow transplant, gene therapy

Question 21

X-linked lymphoproliferative disorder (XLP)

Answer 21

• mutation in SH2D1A gene (encodes SLAM-associated protein)
  = involved in NK cell development + CD8+ responses in EBV infection

Typical presentation:
after EBV infection = fulminant liver failure
-due to severe immune dysregulation
–> fatal mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoma, aplastic anemia

Tx: bone marrow transplant, B cell depletion therapy early in EBV infection course

Question 22

Chronic Granulomatous Disease (CGD)

Answer 22

X-linked + autosomal recessive

• disruption of NADPH oxidase complex function
  o inability of PMNs to kill w/ ROS
  o esp. catalase (+): S. aureus, Klebsiella, Aspergillus, Burkholeria, Serratia
• Increased WBCs, Increased Ig, (-) HIV

TX: antibiotics prophylaxis, IFN-γ prophylaxis, corticosteroids, bone marrow transplant, gene therapy

Question 23

Define secondary or acquired immunodeficiency and distinguish from primary immunodeficiency

Answer 23

Primary immunodeficiencies are caused by defects which originate in the immune system itself.

Secondary immunodeficiencies are due to insufficiency of a supporting component of the immune system or an external or “secondary” depleting factor.

Question 24

Explain that a large variety of conditions have a negative impact on immune function

Answer 24

Endocrine/physiologic
Gastrointestinal
Hematologic/Oncologic
Infectious
Rheumatologic
Renal
Iatrogenic/environmental/toxic

Question 25

Describe several examples of infections with worse outcomes in pregnant women

Answer 25

* Hepatitis A and B * Influenza * Herpes viruses * Chlamydia/GC * Listeria * Campylobacter * Tuberculosis * Malaria

Question 26

Explain the specific risk of infection with the use of TNF inhibitors.

Answer 26

Patients at risk for Granulomatous infections | Ex: mycobacterial infection, endemic fungal infections (histoplasmosis)

Question 27

MOA of immune deficiency: aging

Answer 27

"Immune senescence" Associated changes: - progressive decrease in size and function of thymus - decrease in suppressor cell function --> increase in auto reactivity - changes in lymphocyte development and function = higher risk of latent virus reactivation (ex: VZV to cause shingles)

Question 28

MOA of immune deficiency: malnutrition

Answer 28

-impaired cellular and humoral immunity -MOS relates to: Global metabolic disturbances low levels of leptin deficient intake of protein, fat, vitamins, minerals deficiencies in zinc, iron, folate, pyridoxine, Vitamin A

Question 29

MOA of immune deficiency: protein losing conditions

Answer 29

Ex: nephrotic syndrome or protein loosing enteropathy; IBD, Celiac's, burns, peritoneal dialysis -can result in hypo-gammaglobulinemia

Question 30

MOA of immune deficiency: pregnancy

Answer 30

Modulated immune condition: - Progesterone = inhibits lymphocyte proliferation in vitro - Uromodulin = pregnancy specific serum factor that inhibits B cell activity - Depressed T cell response

Question 31

MOA of immune deficiency: diabetes

Answer 31

- impair function of cells involved in cellular and/or humoral immunity - --MOST prominent: neutrophil dysfunction -Type I: more immune dysregulation (autoimmune disease) -Hyperglycemia = makes neutrophil function worse -Other factors: co-existing vascular disease = poor circulation/neuropathy = ulceration = poor wound healing = infection = difficulty clearing infection = complications -CV compromise

Question 32

MOA of immune deficiency: malignancy

Answer 32

- impaired cell-mediated and humoral responses - bone marrow involvement = interferes with growth and development lymphocytes - tumors may produce substances that interfere with lymphocyte development or function ``` B cell deficiencies have been noted in: • Multiple myeloma • Waldenstrom's macroglobulinemia • Chronic lymphocytic leukemia • Well differentiated lymphomas ``` T cell deficiencies have been noted in: • Hodgkin's disease • Advanced solid tumors

Question 33

MOA of immune deficiency: rheumatologic disease

Answer 33

- immune dysregulation = autoimmunity - increased susceptibility to infection ``` Includes: Lupus RA Granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) IBD ```

Question 34

Summarize some important infections associated with the secondary immune deficiency of cirrhosis

Answer 34

MOA: - Shunting of portal blood so decreased ability of Kupffer cells to clear organisms - hypocomplementemia = reduces serum opsonic activity - reduced hepatic metabolism of endogenous gluccocorticoids = immune suppressive Most common complications: - sepsis - bacterial peritonitis Unusual infections associated with cirrhosis: • Cryptococcal infection • Candidal infection • Infection with Vibrio vulnificus

Question 35

Summarize some important infections associated with the secondary immune deficiency of diabetes

Answer 35

Common infections of increased frequency and severity: • Pneumonias ( viral, strep pneumo) • UTI ( including pyelonephritis) • Cellulitis • Diabetic foot infections • Infections with candida (superficial) Vaginitis, thrush Some unusual infectious complications of diabetes include: • Infections with candida (deep) • Rhinopulmonary zygomycosis (mucormycosis) • Malignant otitis externa due to P. aeruginosa.