| How are primary immunodeficiencies involving known molecular
defects classified? |
- Antibody/B cell deficiencies [Bruton's X-linked agammaglobulinemia, AR
agammaglobulinemia, CVID (ICOS and TACI deficiencies), HIM (AR), ICF syndrome]
- Cellular deficiencies (IFN-γ/IL-12 axis, APS type 1, defective NK function)
- Combined [SCID, Wiskott-Aldrich, DiGeorge, ataxia telangiectasia, HIM (AR),
XLP syndrome, WHIM syndrome, caspase 8 deficiency]
- Complement
- Phagocytic (CGD, Chediak-Higashi syndrome, LAD, specific granule deficiency,
cyclic neutropenia, X-linked neutropenia)
|
| What are some common primary immunodeficiencies with no known
molecular defect? |
- Selective IgA deficiency
- CVID
- SADNI
- Hyper-IgE syndrome
- Cartilage hair hypoplasia
- Idiopathic CD4 lymphocytopenia (Nezelof syndrome)
|
| What are common causes of secondary immunodeficiency? |
- Immunosuppression (chemotherapy, steroids, immunomodulators, antilymphocyte
antibodies)
- Infections (HIV, herpes, parasites)
- Malignancy (Hodgkin's, leukemia, myeloma)
- Autoimmune disease (diabetes, lupus)
- Malnutrition
- Environmental exposure (radiation, chemical)
- Other (uremia, intestinal lymphangiectasia, pregnancy, aging, stress,
hyposplenism)
|
| In general, what does a history of contact dermatitis (e.g.,
poison ivy) suggest? |
Intact cellular immunity |
| What is a simple test for T-cell function? |
The “anergy†panel skin test (e.g., PPD, Candida,
Trichophyton, tetanus toxoid, saline control) is a measure of delayed-type
hypersensitivity; a positive test requires intact T-cell function. |
| What interferes with an anergy panel? |
- Corticosteroids (topical or higher-dose systemic)
- Anticoagulants (induration is the result of fibrin deposition)
- Technique (failure to place antigen intradermally)
- Infection (HIV, EBV, TB, leprosy)
- Autoimmune disease (sarcoid, lupus, rheumatoid arthritis)
- Malnutrition
- Pregnancy
- Malignancy (e.g., Hodgkin's lymphoma)
|
| What assays are available to test for T cells? |
Flow cytometry for CD3, CD4, CD8, CD45, T-cell receptor |
| What assays are available to test for B cells? |
CD19, CD20, CD21, Ig-associated |
| What assays are available to test for NK cells? |
CD16/CD56 |
| What assays are useful in the evaluation of patients with
borderline IgG levels or recurrent sinopulmonary bacterial infections? |
Pre- and postimmunization pneumococcal, diphtheria, tetanus
titers, isohemagglutinins |
| What is the treatment for IgA deficiency? |
Antibiotics for specific infections and, sometimes, prophylactic
antibiotics. IgA-deficient patients who are unable to mount a response to
polysaccharide vaccines are occasionally given IVIg. |
| Are blood transfusions safe in patients with IgA
deficiency? |
No. Some IgA-deficient patients with anti-IgA antibodies are at
increased risk of a severe reaction to trace IgA from IVIg and from blood
transfusions (washed packed cells should be given if transfusion is
needed). |
| What constitutes the diagnosis of CVID? |
Total serum IgGs are reduced to >2 standard deviations below
the age-adjusted mean as well as impaired production of specific antibodies
(isohemagglutinins or poor response to vaccines above). |
| What infections are seen in IgG deficiencies? |
Most common, sinopulmonary infections
Common, central nervous
system, joint, and gastrointestinal tract infections |
| What organisms are the most common causes of infection in
patients with IgG deficiencies? |
Most common, encapsulated bacteria such as Haemophilus
influenzae or Streptococcus pneumoniae
Common, Staphylococcus
aureus, meningococci, Pseudomonas, Campylobacter, Ureaplasma, and
Mycoplasma, Giardia |
| Are persons with IgG deficiencies more susceptible to viral
infections? |
As a rule, no. However, IgG-deficient patients are susceptible to
polioviruses (and should not receive live virus vaccine) and to hepatitis B and
C. In patients with XLA (but not CVID or HIM), a chronic meningoencephalitis,
which is ultimately fatal, can develop with enteroviruses (echovirus or
coxsackie) infection. |
| What are the laboratory and radiographic findings in
CVID? |
Low IgG, IgA, IgE, variable IgM. B cells (CD19) are present in
the peripheral blood and sometimes in exuberant lymphoid tissue. Commonly these
patients (25%) have bronchiectasis on high-resolution computed tomography (CT)
of the chest. |
| When are patients with agammaglobulinemia first seen? |
Generally, boys with XLA are seen after the first 6 months of
life (after maternal antibodies are gone) and within the first 2 years of
life. |
| What are laboratory and radiographic findings in
agammaglobulinemia? |
XLA patients have essentially no B cells (CD19) in circulation
and no discernible lymphoid tissue (a lateral neck view showing no adenoidal
tissue is a diagnostic test in children). |
| What infections are common in patients with
agammaglobulinemia? |
Sinopulmonary bacterial infections, enterovirus
meningoencephalitis |
| Can a patient have an antibody deficiency with a normal total
IgG level? |
Yes, there have been reports of patients with B-cell
immunodeficiency in spite of a normal total IgG level. |
| How are patients with B-cell immunodeficiency and normal total
IgG level recognized? |
Most of these patients have an inability to mount a response to
polysaccharide antigens (pneumococcus or unconjugated
Haemophilus). |
| How should patients with recurrent pneumonia or other serious
bacterial infections be evaluated? |
The patient should receive vaccination with unconjugated
pneumococcal vaccine and tetanus toxoid; then prevaccination and postvaccination
(3 to 4 weeks) titers of antibodies to at least 14 pneumococcal serotypes
assayed simultaneously. An adequate response is a fourfold increase in antibody
titers between the paired serums. Vaccination with H. influenzae (type b)
conjugated to a protein may be useful for protecting these patients but is
usually not helpful in diagnosis. |
| What is the treatment for IgG deficiencies? |
Monthly infusions of pooled IVIg. The dose is generally begun at
200 to 400 mg/kg and is titrated to maintain an IgG trough level of >400
mg/dL obtained immediately before the next infusion (or sometimes to an adequate
clinical response). Despite IgG infusions, many patients with CVID require
prophylactic antibiotics. |
| Name some of the different types of SCID. |
ADA deficiency (most common)
PNP deficiency
RAG1, RAG2
(Omenn syndrome)
Defective cytokine signaling
X-linked (common gamma
chain)
Autosomal recessive (IL2, IL7 receptor) |
| For each of the following, list the lymphocyte
defect and major abnormalities: |
| DiGeorge syndrome |
T cell; cardiac defects (great vessels) and hypocalcemia (failure
of development of the parathyroids), absent thymus, abnormal ears, shortened
philtrum, micrognathia, and hypotelorism |
| Idiopathic CD4 lymphocytopenia (Nezelof syndrome) |
T cell; DiGeorge syndrome without the associated congenital
anomalies; resembles HIV (failure to thrive, candidiasis, anemia,
thrombocytopenia, cancer) |
| SCID |
T and B cell; may be X-linked or autosomal recessive. Affected
infants rarely survive the severe immunodeficiency state beyond 1 year. They
often present with failure to thrive, diarrhea, respiratory infection, and
disseminated infection. |
| ADA |
Most common type of SCID; T and B cells; a form of SCID with
deficient purine metabolism (adenosine deaminase) |
| PNP |
Type of SCID; T cells; similar to ADA with deficient purine
metabolism leading to toxic intracellular levels of deoxyguanosine
triphosphate |
| Wiskott-Aldrich syndrome |
T and B cell; low serum levels of IgM and increased levels of
IgE; eczema, thrombocytopenia, repeated infections (encapsulated organisms),
lymphoreticular malignancies, and anergy |
| Ataxia-telangiectasia |
T and B cells; cerebellar ataxia and oculocutaneous
telangiectasia (butterfly rash over the sclera, face, and ears), truncal ataxia,
ovarian agenesis, sinopulmonary infections leading to bronchiectasis and
lymphomas, and high levels of α-fetoprotein and carcinoembryonic
antigen; highly susceptible to radiation-induced chromosomal injury and
subsequent tumors. |
| Chronic mucocutaneous candidiasis (autoimmune polyglandular
syndrome type I) |
T cell; superficial candidiasis (not systemic) associated with
single or multiple endocrinopathies, iron deficiency, and anergy; molecular
defect in AIRE |
| Hyperimmunoglobulin E |
Uncertain, with increased serum levels of IgE (up to 10 times
normal); recurrent infections of the skin and sinopulmonary tract with S.
aureus, H. influenzae, and Aspergillus; coarse facial features;
delayed shedding of primary teeth; and chronic eczematous rashes |
| Do any of the T- and B-cell primary immunodeficiencies
discussed occur in adults? |
CVID; chronic mucocutaneous candidiasis and hyperimmunoglobulin E
are disorders compatible with living to adulthood; the other T-cell or combined
immunodeficiencies listed above are severe and generally present early in life;
without bone marrow transplantation, they are generally fatal. |
| In general, how are T-cell and combined immunodeficiencies
treated? |
Bone marrow, fetal liver, and thymus transplantation may have a
role. Gamma globulin infusions ± antibiotics may be given for patients who are
IgG deficient or with SADNI. Fresh frozen plasma may be given for other
immunoglobulin-deficient states. Good postural drainage helps prevent
sinopulmonary infections. Live vaccines, blood transfusions, and x-rays avoided
in patients with T-cell deficiencies. Splenectomy, chemotherapy,
immunomodulators, antifungals, and antivirals are needed in rare
cases. |
