Primary Immune Deficiency Syndromes

1. X-linked agammaglobulinemia of Bruton a. Definition: inherited immunodeficiency characterized by a developmental failure to produce mature B cells and plasma cells, resulting in agammablobulinemia b. Genetics: mutation of B-cell Bruton tyrosine kinase (btk)

c. Clinical findings i. Male infants ii. Recurrent infections beginning at 6 months of fife iii. Common infections: pharyngitis, otitis media, bronchitis, and pneumonia iv. Organisms: H. Influenza, S. pneumococcus, and S. aureus

2. Common variable immunodeficiency a. Definition: group of disorders characterized by a B-cell maturation defect and hypogam maglobulmemia b. Clinical findings i. Both sexes are affected ii. Onset is in childhood iii. Recurrent bacterial infections iv. Increased susceptibility to Giardia lamblia c. Complications i. Increased frequency of developing autoimmune diseases ii. Increased risk of lymphoma and gastric cancer

3. DiGeorge syndrome a. Definition: embryologic failure to develop the 3rd and 4th pharyngeal pouches, resulting in the absence of the parathyroid glands and thymus b. Clinical findings i. Hypocalcemia and tetany ii. T-cell deficiency iii. Recurrent infections with viral and fungal organisms

4. Severe combined immunodeficiency (SCID)

a. Definition: combined deficiency of cell-mediated and humoral immunity often caused by a stem-cell defect b. Modes of inheritance i. X-linked (mutation of the chemokine receptor)

ii. Autosomal recessive (deficiency of adenosine deaminase)

c. Clinical features i. Recurrent infections with bacteria, fungi, viruses, and protozoa ii. Susceptible to Candida, cytomegalovirus (CMV), and Pneumocystis carinii infection iii. Have adverse reactions to live virus immunizations d. Treatment i. Bone marrow transplant ii. Gene therapy (experimental)

e. Prognosis: without treatment most infants die of infection within a year

5. Wiskott-Aldrich syndrome a. Genetics i. X-linked recessive inheritance ;

ii. Mutation in the gene for Wiskott-Aldrich syndrome protein (WASP)

b. Clinical triad i. Recurrent infections ii. Severe thrombocytopenia iii. Eczema c. Treatment: bone marrow transplant d. Complications i. Increased risk of lymphoma ii. Death due to infection or hemorrhage D. Secondary Immune Deficiency Syndromes

1. Systemic diseases a. Diabetes mellitus b. Collagen vascular disease (e.g., SLE)

c. Alcohol abuse

2. Renal transplantation a. Patients are immunocompromised due to the immunosuppressive drugs required to prevent rejection of the transplanted organ b. Hyperacute rejection i. Mediated by preformed antibodies ii. Occurs immediately after transplantation iii. Micro: neutrophilic vasculitis with thrombosis c. Acute rejection i. Occurs weeks or months after organ transplantation ii. Abrupt onset of oliguria and azotemia iii. Micro: neutrophilic vasculitis and interstitial lymphocytes iv. Treated with increased doses of immunosuppressive drugs d. Chronic rejection Note i. Occurs months or years after organ transplantation ii. Gradual onset of oliguria, hypertension (HTN), and azotemia iii. Micro: intimai fibrosis of vessels and interstitial lymphocytes iv. Poor response to treatment

Cardiac Transplantation

The major complication in patients is accelerated graft arteriosclerosis.

long- term cardiac transplant

3. Acquired immunodeficiency syndrome (AIDS)

a. Definition: HIV positive and CD4 count <200 or HIV positive and an AIDS-defining disease b. Epidemiology i. Males > females ii. Occurs in all ages and ethnic groups iii. All areas of the country are affected

There is no evidence that AIDS is transmitted by casual contact.

Clinical Correlate

IVM r L Hn _m medical 61


Macrophages and follicular dendritic cells are reservoirs for the virus.

c. Transmission of HIV

i. Sexual contact

• Homosexuals

• Increasing rate of heterosexual transmission

• Cofactors: herpes and syphilis ii. Parenteral transmission

• Intravenous drug abuse (IVDA)

■ Hemophiliacs

• Blood transfusions

• Accidental needle sticks in hospital workers iii. Vertical transmission d. Human immunodeficiency virus (HIV)

i. Enveloped RNA retrovirus ii. Reverse transcriptase iii. HIV infects CD4-positive cells

■ CD4+ T-cell lymphocytes

■ Macrophages

• Lymph node follicular dendritic cells

■ Langerhans cells iv. Binding of CD4 by gpl20

v. Entry into cell by fusion requires gp41 and coreceptors

• CXCR4 (a-chemokine receptor)

e. Diagnosis i. HIV antibody ELISA test ii. Western blot confirmation f. Monitoring i. CD4 count ii. HIV-1 RNA viral load by PCR

g. Treatment i. Combination antiretroviral treatment ii. Reverse transcriptase inhibitors iii. Protease inhibitors iv. Prophylaxis for opportunistic infections based on CD4 count h. Acute phase i. Initial infection ii. Viremia with a reduction in CD4 count iii. Mononucleosis-like viral symptoms and adenopathy iv. Seroconversion i. Latent phase i. Asymptomatic or persistent generalized lymph adenopathy ii. Continued viral replication in reservoir sites

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