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About
Primary Immune Deficiency
IDF PATIENT/FAMILY HANDBOOK | CHAPTER II
Common Variable Immunodeficiency
Common Variable Immune Deficiency is a disorder characterized
by low levels of serum immunoglobulins (antibodies) and an
increased susceptibility to infections. The genetic causes of the
low levels of serum immunoglobulins are not known in most cases.
It is a relatively common form of immunodeficiency, hence, the
word “common.” The degree and type of deficiency of serum
immunoglobulins, and the clinical course, varies from patient to
patient, hence, the word “variable.”
 Definition of Common Variable Immune Deficiency
Common Variable Immune Deficiency (CVID) is
a disorder characterized by low levels of serum
immunoglobulins (antibodies) and an increased
susceptibility to infections. The exact cause
of the low levels of serum immunoglobulins is
usually not known. It is a relatively common
form of immunodeficiency, hence, the word
“common.” The degree and type of deficiency of
serum immunoglobulins, and the clinical course,
varies from patient to patient, hence, the word
“variable.” In some patients, there is a decrease in
both IgG and IgA; in others, all three major types
(IgG, IgA and IgM) of immunoglobulins may be
decreased. The clinical signs and symptoms also
vary from severe to mild. Frequent and unusual
infections may first occur during early childhood,
adolescence or adult life. In the majority of
patients, the diagnosis is not made until the 3rd or
4th decade of life. However, about 20% of patients
have symptoms of disease or are found to be
immunodeficient under the age of 16.
Due to the relatively late onset of symptoms
and diagnosis, other names that have been
used for this disorder include “acquired”
agammaglobulinemia, “adult onset”
agammaglobulinemia, or “late onset”
hypogammaglobulinemia. The term “acquired
immunodeficiency” is now used to refer to a
syndrome caused by the AIDS virus (HIV) and
should not be used for individuals with CVID as
these two disorders are very different.
The causes of CVID are largely unknown although
recent studies have shown the involvement of
a small group of genes in some of the patients
(see chapter titled Inheritance). Over the past
few decades, studies on the cells of the immune
system in patients with CVID have revealed a
spectrum of lymphocyte abnormalities. Most
patients appear to have normal numbers of
B-lymphocytes, but they fail to undergo normal
maturation into plasma cells capable of making the
different types of immunoglobulins and antibodies.
Other patients lack enough function from helper
T-lymphocytes necessary for a normal antibody
response. A third group of patients have excessive
numbers of cytotoxic T-lymphocytes, although the
role of these cells in the disease is unclear.
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Clinical Presentation of Common Variable
Immune Deficiency:
Both males and females may have CVID. Some
patients have symptoms in the first few years of life
while many patients may not develop symptoms
until the second or third decade, or even later. The
presenting features of most patients with CVID
are recurrent infections involving the ears, sinuses,
nose, bronchi and lungs. When the lung infections
are severe and occur repeatedly, permanent
damage to the bronchial tree may occur and
a chronic condition of the bronchi (breathing
tubes) develops, causing widening and scarring
of these structures. This condition is known as
bronchiectasis. The organisms commonly found in
these infections are bacteria that are widespread
in the population and that often cause pneumonia
(Haemophilus influenzae, pneumococci, and
staphylococci). The purpose of treatment of lung
infections is to prevent their recurrence and the
accompanying chronic damage to lung tissue.
A regular cough in the morning that produces
yellow or green sputum may suggest the presence
of chronic infection or bronchiectasis (widening,
scarring and inflammation of the bronchi).
Patients with CVID may also develop enlarged
lymph nodes in the neck, the chest or abdomen.
The specific cause is unknown, but enlarged
lymph nodes may be driven by infection, immune
dysregulation, or both. Similarly, enlargement of
the spleen is relatively common, as is enlargement
of collections of lymphocytes in the walls of the
intestine called Peyer’s patches.
Although patients with CVID have a depressed
antibody response and low levels of immunoglobulin
in their blood (hypogammaglobulinemia), some of
the antibodies that are produced by these patients
may attack their own tissues (autoantibodies).
These autoantibodies may attack and destroy
blood cells (e.g. red cells, white cells or platelets).
Although, most individuals with CVID present first
with recurrent bacterial infections, in about 20% of
cases the first manifestation of the immune defect
is a finding of very low platelets in the blood, or
perhaps severe anemia due to destruction of red
cells. The autoantibodies may also cause arthritis
or endocrine disorders, such as thyroid disease.
Some patients with CVID who may not be
receiving optimal immunoglobulin replacement
therapy may also develop a painful inflammation
of one or more joints. This condition is called
polyarthritis. In the majority of these cases, the
joint fluid does not contain bacteria. To be certain
that the arthritis is not caused by a treatable
infection; the joint fluid may be removed by
needle aspiration and studied for the presence of
bacteria. In some instances, a bacterium called
Mycoplasma may be the cause and can be difficult
to diagnose. The typical arthritis associated with
CVID may involve the larger joints such as knees,
ankles, elbows and wrists. The smaller joints (i.e.
the finger joints) are rarely affected. Symptoms
of joint inflammation usually disappear with
adequate immunoglobulin therapy and appropriate
antibiotics. In some patients, however, arthritis
may occur even when the patient is receiving
adequate immunoglobulin replacement.
Some patients with CVID report gastrointestinal
complaints such as abdominal pain, bloating,
nausea, vomiting, diarrhea and weight loss. Careful
evaluation of the digestive organs may reveal
malabsorption of fat and certain sugars. If a small
sample (biopsy) of the bowel mucosa is obtained,
characteristic changes may be seen. These
changes are helpful in diagnosing the problem and
treating it. In some patients with digestive problems,
a small parasite called Giardia lamblia has been
identified in the biopsies and in the stool samples.
Eradication of these parasites by medication may
eliminate the gastrointestinal symptoms.
Finally, patients with CVID may have an increased
risk of cancer, especially cancer of the lymphoid
system, skin and gastrointestinal tract.
Patients with CVID do not have physical
abnormalities unless complications have
developed. Some patients with CVID may have
an enlarged spleen and lymph nodes. If chronic
lung disease has developed, the patient may have
a reduced ability to exercise and decreased vital
capacity (the maximum amount of air that can
be taken into the lung voluntarily). Involvement of
the gastrointestinal tract may, in some instances,
interfere with normal growth in children or lead to
weight loss in adults.
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Diagnosis of Common Variable
Immune Deficiency:
CVID is suspected in children or adults who
have a history of recurrent infections involving
ears, sinuses, bronchi, and lungs. The diagnosis
is confirmed by finding low levels of serum
immunoglobulins, including IgG, IgA and usually
IgM. Patients who have received complete
immunizations against polio, measles, diphtheria
and tetanus will usually have very low or absent
antibody levels to one or more of these vaccines.
Immunization with other vaccines, such as the
pneumococcal vaccine, is done to define the
degree of immunodeficiency. In some instances,
these tests help the physician decide if the patient
will benefit from immunoglobulin replacement
therapy. The number of T-lymphocytes may also
be determined and their function tested in samples
of blood. With special laboratory techniques, it is
possible to determine if B-lymphocytes produce
antibody in a test tube (tissue culture) and if
T-lymphocytes have normal functions.
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Genetics and Inheritance of Common Variable
Immune Deficiency:
Due to the unclear genetic nature of CVID, a clear
pattern of inheritance has not been defined. In
some instances, more than one family member
is found to be deficient in one or more types of
immunoglobulins. For example, it is not unusual
for one family member to have CVID while another
may have selective IgA deficiency (see chapter
titled Selective IgA Deficiency).
In the past few years, mutations in several different
genes have been found to be associated with
CVID. These include inducible co-stimulatory
(ICOS) in one family and a protein on B-cells
(CD19) in several families as causes of autosomal
recessive CVID. Mutations in a cell receptor (TACI)
for two factors (BAFF or APRIL) needed for normal
growth and regulation of B-cells have also been
found in about 10% of patients with CVID. A
causative role of these mutations in the immune
defect is not yet clear since some of these
mutations can be found in people with normal
immunoglobulins.
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Treatment for Common Variable
Immune Deficiency:
The treatment of CVID is similar to that of
other disorders characterized by low levels
of serum immunoglobulins. In the absence
of a significant T-lymphocyte defect or organ
damage, immunoglobulin replacement therapy
almost always brings improvement of symptoms.
Immunoglobulin is extracted from a large pool
of human plasma consisting mostly of IgG and
containing all the important antibodies present in
the normal population (see chapter titled Specific
Medical Therapy).
Patients with chronic sinusitis or chronic lung
disease may also require long-term treatment
with broad-spectrum antibiotics. If mycoplasma
or chlamydia infections are suspected, antibiotics
specific for those organisms may be indicated. If
bronchiectasis has developed, physical therapy
and daily postural drainage are needed to remove
the secretions from the lungs and bronchi.
Patients with gastrointestinal symptoms and
malabsorption are evaluated for the presence of
Giardia lamblia, rotavirus and a variety of other
gastrointestinal infections.
Most patients with immunodeficiency and
arthritis respond favorably to treatment with
immunoglobulin replacement therapy.
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Expectations for Common Variable
Immune Deficiency Patients:
Immunoglobulin replacement therapy combined
with antibiotic therapy has greatly improved the
outlook of patients with CVID. The aim of the
treatment is to keep the patient free of infections
and to prevent the development of chronic lung
disease. The outlook for patients with CVID
depends on how much damage has occurred
to their lungs or other organs before diagnosis
and treatment with immunoglobulin replacement
therapy and how successfully infections can be
prevented in the future by using immunoglobulin
and antibiotic therapy.
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