AJR 2001; 176:1541-1552
© American Roentgen Ray Society
Primary Immunodeficiency Disorders in Pediatric Patients
Clinical Features and Imaging Findings
Emma Zi Yin1,
Donald P. Frush2,
Lane F. Donnelly3 and
Rebecca H. Buckley4
1
Department of Medicine, Duke University Medical Center, Durham, NC
27710.
2
Division of Pediatric Radiology, Rm. 1905, McGovern-Davison Children's Health
Center, Box 3808, Department of Radiology, Duke University Medical Center,
Erwin Rd., Durham, NC 27710.
3
Department of Radiology, Children's Hospital and Medical Center, 3333 Burnet
Ave., Cincinnati, OH 45229.
4
Department of Pediatrics, Duke University Medical Center, Durham, NC
27710.
Received October 2, 2000;
accepted after revision December 4, 2000.
Address correspondence to D. P. Frush.
Introduction
For radiologists, a review of the primary immunodeficiencies in children
that emphasizes clinical features and radiologic findings is practical for
several reasons. First, the radiologist can be the physician who suggests the
presence of an immune disorder after recognizing certain radiologic features
(Fig. 1). Second, the
radiologist may be involved in the examination of patients with known primary
immune disorders and should be familiar with the potential imaging
manifestations such as opportunistic infection or malignancy
[1]. Moreover, many
radiologists may be unfamiliar with the various primary immune disorders.
Finally, the understanding of genetic causes of primary immunodeficiencies is
rapidly evolving, and much information from even a few years ago, including
classification schemes and categorization of various disorders, is already
obsolete.
View larger version (126K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 1. —Oral and IV contrast-enhanced axial CT scan of mid abdomen of
2-month-old male infant with failure to thrive shows mixed attenuation
adenopathy (arrows) that infiltrates mesentery. Diagnosis of chronic
granulomatous disease was established after laparoscopic biopsy of nodal mass
and culture that yielded Candida.
|
|
Our review will focus on the pediatric population because most of these
disorders present during infancy or childhood. Information covered includes a
contemporary categorization of immune disorders based on the immune system
defect (Appendix). These categories consist of humoral, cellular, phagocytic,
or complement deficiencies, or a combination of these disorders. Although this
classification is not inclusive of all immunodeficiencies, it lists those
immunodeficiencies that radiologists are more likely to encounter or those in
which radiologic imaging plays an important role in diagnosis or surveillance.
Discussion of each disorder includes the specific defect or defects, clinical
manifestations, contemporary therapeutic considerations, and radiologic
manifestations.
Humoral Immunodeficiency Disorders
Humoral immunodeficiency comprises a heterogeneous group of disorders
characterized by impaired antibody production. Humoral immunodeficiencies are
common, accounting for about 70% of all primary immunodeficiency disorders
[2,
3]. Clinically, affected
individuals are prone to recurrent pyogenic infections especially with
encapsulated bacteria such as Haemophilus influenzae, Streptococcus
pneumoniae, and staphylococci. Recurrent pneumonia, otitis media,
sinusitis, and septicemia are the most common clinical manifestations.
Successful host defense against bacterial infection requires collaboration of
antibodies, complement, and phagocytes. Therefore, all these components should
also be investigated thoroughly in those patients with increased
susceptibility to bacterial infections. Most patients with defects
predominantly involving humoral immunity are able to recover from viral
infections because of their normal T-cell responses.
IgA Deficiency
The most common primary immunodeficiency disorder, IgA deficiency affects
an estimated 1:600 in the general population
[4]. Caucasians are affected
much more frequently than Asians or African Americans. Both genetic and
environmental factors contribute to the pathogenesis of this disorder. Some
children with IgA deficiency may be clinically healthy, whereas others are
susceptible to respiratory and gastrointestinal infections, allergies,
autoimmune diseases, and malignancies
[5]. Imaging findings are
predominantly caused by bacterial infections. Treatment of this disorder is
supportive.
Common Variable Immunodeficiency
Common variable immunodeficiency represents a group of undifferentiated
disorders characterized by impaired antibody production of all major classes.
Common variable immunodeficiency has an estimated incidence of up to 1:10,000
in the general population [2,
6]. Diagnosis is usually made
by the finding that levels of serum immunoglobulins are low or absent although
numbers of circulating B cells are in the normal range. Both males and females
are affected equally with no obvious pattern of inheritance. In contrast with
X-linked agammaglobulinemia in which onset is always in early childhood, the
onset of symptoms in common variable immunodeficiency may occur in early or
late childhood or adulthood
[6], and, unlike X-linked
agammaglobulinemia, circulating B cells are usually normal in quantity and
phenotype. During antigen stimulation, these B cells do respond and
proliferate but fail to differentiate into antibody-secreting plasma cells
[2]. T-cell—mediated
immunity is often intact; however, T-cell abnormalities have also been noted
in up to 60% of patients [3,
6].
Clinically, patients with common variable immunodeficiency and X-linked
agammaglobulinemia share such susceptibilities as increased risk of recurrent
pyogenic sinopulmonary infection, gastrointestinal involvement, and fatal
enteroviral meningoencephalitis, although this disease is seen less often in
patients with common variable immunodeficiency than in those with X-linked
agammaglobulinemia. Unlike patients with X-linked agammaglobulinemia, patients
with common variable immunodeficiency have a healthy amount of tonsillar
tissue, and 15-25% patients with this immunodeficiency develop lymphadenopathy
or splenomegaly [3,
5]. Nodular lymphoid
hyperplasia of the gastrointestinal tract is frequently observed as a part of
a generalized lymphoproliferative process
[2]. Common variable
immunodeficiency is also associated with an increased cancer risk,
predominantly with lymphoreticular tumors. Approximately 20% of patients with
this immunodeficiency will develop autoimmune diseases
[2,
5]. Standard treatment for
patients with this group of disorders consists of IV immunoglobulin
replacement.
Chest radiographs or CT scans may reveal pulmonary infection, including
atelectasis and bronchial wall thickening or more advanced bronchiectasis
(Fig. 2). Radiologic findings
in patients with common variable immunodeficiency differ from those in
patients with X-linked agammaglobulinemia because of the presence of normal or
increased amounts of lymphoid tissue, lymphadenopathy, or splenomegaly
(Fig. 3).
View larger version (114K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 3. —Common variable immunodeficiency in 25-year-old man. IV
contrast-enhanced axial CT scan in mid abdomen reveals splenomegaly and
several prominent mesenteric and retroperitoneal lymph nodes
(arrows).
|
|
X-Linked Agammaglobulinemia
X-linked agammaglobulinemia is also referred to as Bruton's
agammaglobulinemia. This disorder was the first recognized primary
immunodeficiency, described by Bruton in 1952
[7]. Incidence of the condition
is unknown, but it is less common than IgA deficiency or common variable
immunodeficiency. Affected patients have markedly decreased numbers of mature
B cells and plasma cells in the circulation and consequently have reduced
lymphoid tissue. Serum immunoglobulins of all isotypes are almost completely
undetectable. T-cell number and function remain intact. There is a block in
differentiation at all stages of B-cell development
[2]. The gene responsible for
X-linked agammaglobulinemia has been identified as Bruton's tyrosine kinase
gene, a key regulator of B-cell maturation, located on the X chromosome
[8,9,10,11].
During the first 6-9 months of life, patients with X-linked
agammaglobulinemia are protected from infections by maternally derived IgG
antibodies. As this source of antibodies diminishes, patients begin to develop
pyogenic bacterial infections, with recurrent sinopulmonary infections being
most common [5]. Although most
pediatric patients develop recurrent bacterial infections during infancy, 20%
of patients do not present until approximately 3-5 years
[2,
5,
6], probably because of the
widespread use of antibiotics. Less common complications include chronic
conjunctivitis; chronic intestinal protozoal infection, especially giardiasis;
malabsorption; and persistent central nervous system enteroviral infections
with resultant chronic meningoencephalitis, dermatomyositis, rheumatoidlike
arthritis, and an increased cancer risk
[12,
13].
The standard treatment for X-linked agammaglobulinemia is IV immunoglobulin
replacement therapy. Despite apparently adequate treatment with IV
immunoglobulin, however, many patients still develop pansinusitis or
postinfectious chronic lung diseases, most commonly bronchiectasis.
On chest radiography or CT, bronchiectasis is most commonly found in the
middle or lower lobes (Fig. 4);
upper lobe distribution is very uncommon
[14]. Splenomegaly is not
seen, and lymphoid tissue (i.e., adenoids) is typically extremely small
[3]. MR imaging may reveal
infectious involvement of the central nervous system with diffuse
leptomeningeal thickening and enhancement, or encephalitis
[15,
16] (Fig.
5A,5B).
View larger version (134K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 4. —2-year-old boy with X-linked hypogammaglobulinemia and
recurrent pulmonary infections. CT scan at lung base shows scattered
bronchiectasis in basilar regions of lower lobes, lingula, and middle lobe
(arrows). Findings for upper lobes were normal (not shown).
|
|
View larger version (150K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 5A. —11-month-old male infant with X-linked agammaglobulinemia and
vaccine-type polio encephalomyelitis. Axial T1-weighted MR image (TR/TE,
500/20) at level of mid brain shows regions of low signal intensity
(arrows) in white matter tracts of cerebral peduncles.
|
|
View larger version (157K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 5B. —11-month-old male infant with X-linked agammaglobulinemia and
vaccine-type polio encephalomyelitis. Axial T2-weighted MR image (2000/80)
shows increased signal intensity (arrows) in regions that showed low
signal intensity in A. Abnormal signal intensity extended into
substantia nigra and was seen in thalami bilaterally (not shown).
|
|
Other Humoral Deficiencies
Other defects characterized by antibody deficiency include both X-linked
and non—X-linked hyper-IgM, which are both characterized by recurrent
bacterial infections [3].
Primary Cellular and Combined Immunodeficiency Disorders
Cellular immunodeficiency is characterized by disseminated viral
infections, particularly with herpes viruses such as herpes simplex,
varicella-zoster, and cytomegalovirus; superficial and systemic fungal
infections; and parasitic infections. Overwhelming viremia; severe
mucocutaneous candidiasis; and progressive pneumonia caused by parainfluenza,
respiratory syncytial virus, cytomegalovirus, varicella, and Pneumocystis
carinii are common presentations in patients with this immunodeficiency.
Cellular deficiency is also almost always accompanied by some abnormality of
antibody responses because antibody production is T-cell—dependent.
DiGeorge Syndrome
DiGeorge syndrome, which is also called thymic aplasia or hypoplasia, is a
typical example of a primary T-cell deficiency. DiGeorge syndrome is most
often caused by gene defects on chromosome 22, which lead to abnormal
development of the third and fourth pharyngeal pouches during early
embryogenesis [17]. As a
result, the organs that develop from these structures—the most important
being the thymus, parathyroid glands, and heart—can be affected.
Impaired functions of these organs account for a unique constellation of
clinical presentations. The most common are T-cell deficiencies of varying
severity caused by hypoplasia or aplasia (or agenesis) of the thymus. Other
presentations are neonatal hypocalcemic tetany stemming from
hypoparathyroidism and congenital cardiovascular anomalies, especially of the
great vessels and septa. Another distinctive abnormality associated with this
syndrome is facial dysmorphology, which presents as micrognathia, low-set
ears, shortened philtrum of the upper lip, and hypertelorism
[18]
(Fig. 6). B cells are present
in normal numbers. Nevertheless, antibody responses may still be affected
because of an inadequate number of T cells, which varies greatly depending on
the degree of thymic hypoplasia. In up to 80% of patients, the
immunodeficiency is mild (partial DiGeorge syndrome) and can even be transient
[3,
6,
17]. However, those patients
with more severe forms of this disease (complete DiGeorge syndrome) may
resemble children with severe combined immunodeficiency. These children, as is
the case for all children with cellular immunodeficiencies, are susceptible to
infections with opportunistic organisms, such as acid-fast bacteria, viruses,
fungi, and P. carinii, and to graft-versus-host disease from
nonirradiated blood or blood-product transfusions
[3].
Treatment is usually supportive. Thymic epithelial transplants or
unfractionated human luekocyte antigen—identical sibling bone marrow
transplantation are recommended only for those with the complete DiGeorge
syndrome [19].
Chest radiography may reveal narrow upper mediastinal contour and
retrosternal lucency attributable to absence of the thymus. Cardiovascular
anomalies such as abnormalities of the great vessels
(Fig. 7), including right-side
aortic arch, interrupted aortic arch, and truncus arteriosus; tetralogy of
Fallot; or atrial or ventricular septal defects are frequently present
[17,
18].
View larger version (132K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 7. —Posteroanterior chest radiograph of 6-month-old male infant
with partial DiGeorge syndrome (thymic hypoplasia) shows cardiomegaly with
elevation of cardiac apex (arrow) caused by right ventricular
hypertrophy occurring after severe pulmonary stenosis. Narrow mediastinum is
due to hypoplastic thymus. Costovertebral anomalies present are not
characteristic of DiGeorge syndrome.
|
|
Severe Combined Immunodeficiency Syndromes
Severe combined immunodeficiency represents a group of genetically
determined immunodeficiency disorders characterized by the absence of T- and
B-cell (and sometimes natural killer cell) function. Many defects have been
identified that involve cytokine receptors and enzyme deficiencies. The main
inheritance patterns are either autosomal recessive or X-linked patterns,
which are caused by mutations in the gene that encodes the common cytokine
receptor gamma chain [2,
20]. The X-linked type
accounts for about 46% of all severe combined immunodeficiency disorders.
Autosomal recessive forms include adenosine deaminase (ADA) deficiency (15%),
Janus kinase 3 (Jak 3) deficiency (7%), interleukin-7 (IL-7) receptor alpha
chain deficiency (2%), recombinase activating gene (RAG) 1 and 2, or cluster
of differentiation 45 (CD 45) deficiencies (<2%), as well as unknown forms
(30%) [2,
20]. Not surprisingly, severe
combined immunodeficiency is observed much more commonly in male infants.
Patients with either type of inheritance are similar in their clinical and
histopathologic features.
Affected children frequently start to develop severe infections with
opportunistic organisms soon after the neonatal period. Typical presenting
features include failure to thrive, chronic diarrhea, persistent oral thrush,
severe diaper rash or other skin rashes, pneumonia, and sepsis. Because they
lack graft-rejection capability, these infants are also at risk for severe
graft-versus-host disease from transfusion of nonirradiated blood products and
transplacentally acquired maternal T cells. Immunization with live attenuated
viruses, such as poliovirus, bacille
Calmette-Guérin, or measles virus, must be
avoided because of the risk of severe or systemic infection that can be
fatal.
Without immune reconstitution, severe combined immunodeficiency is fatal.
Whereas previous treatment focused on having the patients avoid contact with
potential infections—resulting in the so-called bubble
babies—current therapy for these patients is most commonly bone marrow
transplantation, which has been highly successful
[21]. The first successful
gene therapy for this condition was recently reported
[22]. All forms of severe
combined immunodeficiency share certain radiologic features, but individual
variations may also be present.
Radiologic manifestations include severe or recurrent pneumonia or other
complex infections [23]
(Fig. 8). Pathogens include
P. carinii, parainfluenza 3, respiratory syncytial virus,
cytomegalovirus, and bacterial organisms; infection may also be caused by
multiple organisms. Pneumocystis typically produces interstitial infiltrates,
which progress to alveolar infiltrates. However, viral pneumonitis can be
indistinguishable from pneumocystis pneumonia or other opportunistic
infections (Fig. 9). An
important feature to recognize in children with severe combined
immunodeficiency syndrome, as opposed to immunocompetent children or children
with other immunodeficiencies with an acute pulmonary infection, is the
absence of the thymic shadow
[24] (Figs.
9 and
10). A recent review of chest
radiographs in more than 130 patients with severe combined immunodeficiency in
infancy and early childhood revealed thymic absence in every patient (Frush DP
et al., unpublished data).
View larger version (125K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 8. —6-month-old male infant with autosomal recessive severe
combined immunodeficiency of unknown molecular cause and Candida
organism chest wall infection. Axial contrast-enhanced CT scan of upper chest
shows mixed attenuation mass consisting of abscess containing air and fluid in
lung (large arrows) with invasion of anterior chest wall (small
arrows).
|
|
View larger version (101K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 9. —Posteroanterior chest radiograph of 6-month-old male infant
with X-linked severe combined immunodeficiency shows bilateral nodular
opacities caused by diffuse Candida infection. Note absence of
thymus.
|
|
View larger version (129K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 10. —Anteroposterior chest radiograph of 4-month-old male infant
with X-linked agammaglobulinemia and unusual presentation of acute
Pneumocystis carinii pneumonia reveals diffuse granular opacities.
Presence of thymus (straight arrows), partly outlined by
pneumomediastinum (curved arrow), indicates that patient does not
have severe combined immunodeficiency.
|
|
The adenosine deaminase deficiency type is noteworthy from a radiologic
standpoint because of skeletal abnormalities and because infants and children
with this disorder usually have more profound lymphopenia than infants and
children with other severe combined immunodeficiency disorders
[25]. Skeletal abnormalities,
although not present in all patients, are unique to this type of severe
combined immunodeficiency and are usually limited to the axial skeleton. These
abnormalities include cupping and flaring at the costochondral junctions
anteriorly, metaphyseal cupping, and irregularity at the costovertebral
junction with increased separation between the rib head and vertebral body. In
addition, a "bone-in-bone" appearance of the vertebral bodies and
squaring of the scapula tip have also been reported
[23,
25,
26]
(Fig. 11). In a recent review
of radiographic changes in more than 130 infants and children with severe
combined immunodeficiency, 45% (10/22) of patients with adenosine deaminase
deficient form had at least one of these osseous changes visible on chest
radiographs; 27% (6/22) had two or more changes, and 18% (4/22) had three or
more changes. No patient with nonadenosine deaminase deficient severe combined
immunodeficiency had any visible thoracic osseous changes (Frush DP et al.,
unpublished data).
View larger version (123K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 11. —4-month-old male infant with severe combined
immunodeficiency, adenosine deaminase form, and typical skeletal
abnormalities. Posteroanterior chest radiograph shows flaring of anterior ribs
most evident at right costochondral junctions (curved arrows). Note
also squared inferior scapula (straight arrows). Narrow mediastinum
is caused by absence of thymus. Viral pneumonitis is responsible for
hyperinflation and right upper lobe atelectasis.
|
|
In Omenn's syndrome, another severe immunodeficiency, patients present with
desquamating erythroderma, adenopathy, hepatosplenomegaly, severe infections,
and failure to thrive. In approximately half of the patients, the syndrome is
caused by recombinase activating gene (RAG) 1 and 2 mutations. Lymphocyte
counts may be normal or elevated. The T lymphocytes are clonal and cytotoxic
but function poorly otherwise. There is an absence of B cells, and serum
levels of IgG, IgM, and IgA range from low to absent. Paradoxically, the level
of IgE is elevated, and there is eosinophilia. A number of organs such as the
liver, spleen, skin, and gastrointestinal tract become targets of attack for
cytotoxic T cells [3]. The
disorder is fatal in infancy unless patients undergo bone marrow
transplantation [3].
Partial Combined Immunodeficiency Syndromes
Partial combined immunodeficiency syndromes include Wiskott-Aldrich
syndrome, cartilage-hair hypoplasia, ataxia-telangiectasia, purine-nucleoside
phosphorylase deficiency, and X-linked lymphoproliferative disease.
Wiskott-Aldrich syndrome is an X-linked recessive immunodeficiency disorder
characterized by a triad of eczema, thrombocytopenia with small defective
platelets, and recurrent infections
[2,
3]. The gene on the X
chromosome responsible for the condition encodes a protein called the
Wiskott-Aldrich syndrome protein
[3] and is expressed in
lymphocytes, megakaryocytes, spleen, and thymus. The function of this protein
is still unclear, but it is thought to have a major role in actin
polymerization. Immunologically, antibody responses to polysaccharide antigens
are consistently impaired. Therefore, such patients are particularly
susceptible to infection with polysaccharide-encapsulated organisms, such as
pneumococci, H. influenzae, and meningococci. Serum levels of IgA and
IgE are elevated. IgM level is decreased, and IgG remains normal or is
slightly decreased. T-cell function may initially appear to be normal, but it
is not.
Clinically, affected infants often first present with prolonged bleeding
from the circumcision site, bruising, or bloody diarrhea
[3]. Pyogenic infections
usually appear during the first year of the patient's life and may include
men-ingitis, otitis media, pneumonia, and sepsis. Infections with agents such
as P. carinii and herpes viruses are also common. Patients rarely
survive beyond their teenage years without bone marrow transplantation. Death
usually results from massive bleeding, infection, or lymphoreticular
malignancy [3].
Therapy includes transfusions of fresh irradiated platelets for acute
bleeding episodes and bone marrow transplantation, which has completely
corrected both the hematologic and immunologic abnormalities in many patients.
If no sibling donor with identical human leukocyte antigen is available,
splenectomy may improve platelet count. Because of the antibody deficiency,
monthly IV immunoglobulin replacement is indicated
[3].
Imaging findings include recurrent pneumonia, sinusitis, and mastoiditis;
absence of lymphoid tissue in the nasopharynx; hemorrhage; or malignancy
[24]
(Fig. 12).
View larger version (135K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 12. —Axial IV contrast-enhanced CT scan of upper abdomen of
8-year-old boy with Wiskott-Aldrich syndrome and small-bowel lymphoma shows
aneurysmal dilatation (arrows) of proximal small bowel, accompanied
by wall thickening.
|
|
Cartilage-hair hypoplasia, also known as chondrometaphyseal dysplasia,
McKusick's type, is an autosomal recessive disorder with morphologic and
immunologic abnormalities ranging from humoral to cellular to combined
immunodeficiencies [3]. The
disorder, characterized by short-limbed dwarfism and severe infections, was
first described in the Amish population in Pennsylvania. Characteristic
morphologic features of patients include short limbs, short pudgy hands, and
fine and sparse hair on the face and scalp. Patients with milder forms of the
syndrome may only require conservative therapy, whereas bone marrow
transplantation has been effective for some patients with the severe combined
immunodeficiency phenotype
[3].
Imaging findings of the immunodeficiency with cartilage-hair hypoplasia are
similar to those of other humoral, cellular, or combined immunodeficiencies
with the exception of skeletal manifestations
[27]. Patients with
cartilage-hair hypoplasia have short-limb skeletal dwarfism with metaphyseal
dysplasia consisting of sclerosis and cupping
(Fig. 13). These findings are
in contrast to those in patients with adenosine deaminase deficient severe
combined immunodeficiency whose skeletal changes are found predominantly in
the axial skeleton.
View larger version (95K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 13. —5-year-old boy with cartilage-hair hypoplasia.
Anteroposterior radiograph of both knees reveals tibial and femoral
metaphyseal irregularity and sclerosis (curved arrows) but sharply
defined metaphyseal margin. Epiphyses have normal appearance. Note also
cup-shaped metaphyses (straight arrows) in distal femurs.
|
|
Ataxia-telangiectasia is an autosomal recessive disorder also known as the
Louis-Barr's syndrome. A mutation in the ataxia-telangiectasia gene
compromises DNA repair mechanisms thus rendering the affected cells highly
susceptible to radiation-induced chromosomal damage
[2,
3,
28]. Immunologic features
include selective IgA deficiency or hypogammaglobulinemia. The thymus is
markedly hypoplastic, and T-cell dysfunction is moderately severe.
The most prominent clinical features of ataxia-telangiectasia are
progressive cerebellar ataxia that becomes evident when the child begins to
walk, oculocutaneous telangiectasia that first becomes evident when the child
is between 3 and 6 years, recurrent bronchopulmonary infections affecting
approximately 80% of patients, and a high incidence of malignancy
[2,
3,
28]. The degree of
immunodeficiency is highly variable. Children that survive the first decade
are at high risk for both solid—adenocarcinoma—and
lymphoproliferative malignancies
[2,
3]. Patients usually die by
early adulthood from chronic pulmonary disease, neurologic deterioration, or
malignancy. Ataxia-telangiectasia and Wiskott-Aldrich syndrome have the
highest malignancy rates of all of the primary immunodeficiencies
[2]
(Fig. 12).
Treatment is limited to supportive care, and no cure is available. Bone
marrow transplantation has not been successful and would likely not correct
the neurologic defect.
Imaging findings include lymphoid hypoplasia, the absence of thymic shadow,
recurrent sinopulmonary infections with bronchiectasis, and fibrosis. MR
images and CT scans of the central nervous system can show diffuse cerebellar
atrophy, particularly in the vermis
[29,
30]. Because of these
patients' increased risk of cancer from radiation exposure, imaging studies
using ionizing radiation should be performed sparingly.
Purine-nucleoside phosphorylase is an enzyme deficiency affecting
lymphocyte function in a way that is somewhat similar to the mechanism in
adenosine deaminase deficiency. Clinical presentations vary in patients with
immunodeficiency associated with purine-nucleoside phosphorylase deficiency.
Children with milder forms may present later with diverse neurologic findings
such as developmental delay, hypotonia, and spasticity. However,
purine-nucleoside phosphorylase deficiency is uniformly fatal in childhood.
Unlike adenosine deaminase deficiency, this disorder is not associated with
skeletal anomalies.
X-linked lymphoproliferative disease (an inadequate response to
Epstein-Barr viral infection) results acute infectious mononucleosis,
malignancy, or immunodeficiency
[3].
Disorders of Phagocytic Cells and Adhesion Molecules
Phagocytes comprised mainly of neutrophils, monocytes, and macrophages are
of great importance in host defense against pyogenic bacteria and fungi as
well as other intracellular microorganisms. Defects in phagocyte production or
function predispose affected patients to recurrent pyogenic and fungal
infections. Common organisms include bacteria such as Pseudomonas,
Serratia marcescans, and Staphylococcus aureus, and fungi such
as Aspergillus and Candida. Phagocytic disorders are not
associated with increased susceptibility to viral or protozoal infections, or
increased risk for malignancy. Disorders include chronic granulomatous
disease, leukocyte adhesion deficiency, and
Chédiak-Higashi syndrome.
Chronic Granulomatous Disease
Chronic granulomatous disease is the most common phagocytic disorder,
occurring in approximately one in every 125,000 live births
[31]. In two thirds of
patients, this disorder is inherited in an X-linked fashion, but three forms
of autosomal recessive chronic granulomatous disease exist as well. Diagnosis
of this disorder is established with a respiratory burst assay. Chronic
granulomatous disease is actually a collection of four different molecular
defects that result in defective and reduced activity of nicotinomide adenine
dinucleotide oxidase in leukocytes
[31]. This oxidase catalyzes a
reaction producing important bacteriocidal products after phagocytosis:
superoxide radical, singlet oxygen, and hydrogen peroxide. Catalase-negative
organisms such as streptococci and pneumococci provide oxidative products and
are thereby killed. However, catalase-positive bacteria such as S. aureus,
S. marcescens, and some fungi such as Aspergillus organisms
destroy the very oxygen radicals they produce. Prolonged intracellular
existence of these catalase-positive microorganisms in chronic granulomatous
disease triggers a cell-mediated response, resulting in granuloma
formation.
The onset of symptoms usually occurs during the patient's first year of
life. In a recent review of a chronic granulomatous disease registry
[31], the researchers cited
pulmonary infection as the most frequent symptom, affecting 79% of patients,
and fungal organisms accounted for most of these infections. Other symptoms
included suppurative adenitis (53%), subcutaneous abscess (42%), liver abscess
(27%), osteomyelitis (25%), and sepsis (18%). Gastric outlet obstruction,
urinary tract obstruction, and enteritis or colitis occur in 10-17% of
patients [31]. Trimethoprim
sulfamethoxazole prophylaxis and recombinant human interferon gamma, in
addition to chronic antifungal therapy, are standards of care for this
disorder.
Radiologic findings include chest radiographs or CT scans showing chronic
or recurrent pneumonia, including abscess, pleural reaction, osteomyelitis,
and chest wall invasion by organisms such as Aspergillus or
Candida; hilar or mediastinal adenopathy; and esophagitis or
esophageal stricture
[32,33,34,35]
(Fig.
14A,14B,14C,14D,14E).
In the abdomen, chronic granulomatous disease manifestations amenable to
sonography, CT, or MR imaging include focal abscess or granuloma formation in
the liver and spleen, adenopathy, antral narrowing, duodenal fold thickening,
enteric fistulas or sinus tracts, renal infections, ureteral or urethral
strictures, and thickened bladder wall caused by granulomatous cystitis
[31,
32,
36] (Figs.
14A,14B,14C,14D,14E
and 15). Osteomyelitis can be
evaluated using radiography, CT, or MR imaging (Fig.
16A,16B).
Radionuclide imaging is indicated for patients in whom clinical signs of
infection are present with no evident source. Sedimentation rate is a useful
clinical barometer because it becomes elevated with developing (including
occult) or persistent infection.
View larger version (127K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 14A. —Multiple radiologic manifestations of chronic granulomatous
disease in a male. At 7 years, patient presented with urinary frequency.
Sagittal sonogram of bladder shows asymmetric wall thickening
(arrows) of superior and posterior bladder caused by granulomatous
cystitis.
|
|
View larger version (117K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 14B. —Multiple radiologic manifestations of chronic granulomatous
disease in a male. At 9 years, patient presented with fever and right-sided
pulmonary mass on chest radiograph (not shown). Axial CT scan of mid lung
shows round pneumonia (arrows) caused by coagulase-positive
Neisseria species.
|
|
View larger version (108K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 14C. —Multiple radiologic manifestations of chronic granulomatous
disease in a male. At 11 years, patient presented with fever without source.
Axial IV contrast—enhanced CT scan at level just inferior to main
pulmonary artery reveals subcarinal adenopathy (arrows) with
low-attenuation central region; culture yielded Aspergillus
organisms.
|
|
View larger version (90K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 14D. —Multiple radiologic manifestations of chronic granulomatous
disease in a male. At 21 years, patient presented with dysphagia.
Single-contrast barium esophagram shows marked narrowing of mid esophagus
(straight arrows). Small traction diverticulum (curved
arrow) distal to stricture is caused by chronic mediastinal adenopathy
(not shown).
|
|
View larger version (115K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 14E. —Multiple radiologic manifestations of chronic granulomatous
disease in a male. At 22 years, patient presented with elevated sedimentation
rate. Axial IV contrast—enhanced CT scan of upper abdomen reveals
multiple small low-attenuation lesions (arrows). Sonographically
guided biopsy was subsequently performed, but no organisms were isolated.
Patient responded to more aggressive antifungal and antibacterial therapy.
|
|
View larger version (152K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 15. —26-year-old man with chronic granulomatous disease and early
satiety. Anteroposterior view of upper gastrointestinal tract obtained during
single-contrast gastrointestinal study shows marked antral narrowing
(arrows) caused by granulomatous gastric involvement.
|
|
View larger version (107K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 16A. —6-year-old girl with chronic granulomatous disease and
vertebral osteomyelitis after extension of pulmonary Aspergillus
infection. Anteroposterior radiograph of lower thoracic spine shows vertebra
plana of T11 vertebral body (large straight arrow) and mottled
lucency (small straight arrows) caused by contiguous involvement of
T12 vertebral body. Opacities in paraspinal regions bilaterally (curved
arrow) are attributable to mediastinal fungal infection.
|
|
View larger version (142K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 16B. —6-year-old girl with chronic granulomatous disease and
vertebral osteomyelitis after extension of pulmonary Aspergillus
infection. Axial proton density—weighted MR image (TR/TE, 2000/40) at
level of T11 shows increased marrow signal intensity as well as increased
signal intensity (arrows) extending into prevertebral and paraspinal
regions.
|
|
Leukocyte Adhesion Defect
Leukocyte adhesion deficiency is caused by mutations in the gene encoding
CD18, a component of three different leukocyte adhesion molecules necessary
for cell adhesion and migration
[37,
38]. Phagocytes, in particular
neutrophils, cannot migrate out of the blood vessels into areas of infection.
Common clinical features in leukocyte adhesion deficiency include impaired
wound healing, severe periodontal disease, and recurrent widespread pyogenic
infections, such as otitis media, pneumonia, peritonitis, and cellulitis,
later in childhood. The severity of symptoms can vary greatly, depending on
the nature of the gene defect. Treatment options for leukocyte adhesion
deficiency include aggressive antibiotic therapy and bone marrow
transplantation.
Chédiak-Higashi Syndrome
Chédiak-Higashi syndrome is a rare
autosomal recessive disorder with an immunodeficiency caused by impaired
chemotaxis and bacterial-killing functions
[2]. Other features include
large intracytoplasmic granulations, partial oculocutaneous albinism,
recurrent bacterial infections, peripheral neuropathy, and an increased
incidence of malignancy [27,
39]. In particular, recurrent,
aggressive lymphoproliferation with diffuse organ infiltration is associated
with an accelerated phase of the disease
[40]. The treatment of choice
is bone marrow transplantation
[39].
Radiologic findings are often nonspecific and include hilar and mediastinal
adenopathy, hepatosplenomegaly, brain atrophy, diffuse decreased
periventricular density on CT, and increased T2-weighted signal intensity in
periventricular white matter and corona radiata on MR images
[16,
40]
(Fig. 17).
View larger version (142K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 17. —10-year-old girl with
Chédiak-Higashi syndrome. Axial T2-weighted MR
image (TR/TE, 2300/80) reveals mildly diffuse cerebral atrophy with increased
periventricular white-matter T2-weighted signal intensity
(arrows).
|
|
Complement Deficiencies
Complement disorders represent the rarest form of primary
immunodeficiencies, accounting for only 1-3% of these disease
[41]. Deficiencies associated
with all the components of the complement cascade have been identified, with
complement 2 deficiency occurring most often. These disorders, which may
involve any one of the complement components, are usually transmitted in an
autosomal recessive mode. An increased incidence of autoimmune disease and
pyogenic infections is associated with a deficiency of early components
(complements 1-4) of the classic pathway. Deficiencies of the terminal
complement components (complements 5-9) are associated with increased
susceptibility to serious infections from Neisseria species
[41]. Complement 3 deficiency
usually results in serious complications such as recurrent pneumonia,
meningitis, and peritonitis. Its clinical presentations often mimic those of
the antibody deficiency disorders. On the other hand, some patients with
deficiencies in complement 2, 4, or 9 can remain completely asymptomatic.
Treatment usually involves prophylactic antibiotics and specific vaccination
against encapsulated organisms. Complement replacement therapy is not
effective in treating these disorders.
Other Immunodeficiencies
The hyperimmunoglobulinemia E syndrome is a condition characterized by
staphylococcal abscesses of the skin, lungs, viscera, or other sites beginning
in infancy with markedly elevated serum levels of IgE. The underlying
molecular defect is unknown
[42]. The mode of inheritance
appears to be autosomal dominant with variable penetrance
[42,
43]. No gender or racial
discrepancy in incidence has been noted. The most common infectious agent is
staphylococci. Eczema, mucocutaneous candidiasis, and coarse facial features
(Fig. 18) are frequently
associated with this syndrome
[42,
43]. Delayed eruption of
teeth, scoliosis, osteopenia, and insufficiency fractures are also unique
features of this immune disorder
[43]. Treatment is usually
supportive, with an emphasis on long-term antistaphylococcal antibiotic
prophylaxis.
View larger version (143K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 18. —Photograph of 6-year-old boy with hyperimmunoglobulinemia E
syndrome shows some of facial characteristics of the syndrome, such as
prominent forehead and facial pores. Other characteristics such as facial
asymmetry, broad nasal bridge, and deep-set eyes are not evident.
|
|
Imaging findings include recurrent pneumonia with subsequent and usually
persistent pneumatocele formation
[44]. The presence of
persistent single or multiple pneumatoceles is the most striking radiographic
feature of this syndrome (Fig.
19A,19B).
These lung cysts may persist, expand, and become superinfected with bacteria
and fungi, and may require surgical excision
[44]. Osteoporosis
predominantly affecting the spine and, to a lesser degree, the limbs in the
epiphyseal—metaphyseal regions may also occur with recurrent
insufficiency fractures [43,
45] (Fig.
19A,19B).
The mechanism responsible for this osteoporosis is not known.
View larger version (141K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 19A. —14-year-old boy with hyperimmunoglobulinemia E syndrome.
Posteroanterior chest radiograph shows multiple large left-sided chronic
pneumatoceles with air—fluid levels. Note associated rightward shift of
heart and mediastinum (arrows).
|
|
View larger version (117K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 19B. —14-year-old boy with hyperimmunoglobulinemia E syndrome.
Lateral lumbar spine radiograph obtained 1 year after A shows multiple
vertebral compression fractures attributable to osteopenia.
|
|
Conclusion
Primary immunodeficiency represents a broad spectrum of disorders with
enormously diverse intrinsic defects involving one or multiple components of
the immune system. Immunodeficiency is characterized clinically by the
patient's increased susceptibility to infection, malignancy, and autoimmunity,
for which imaging is important in diagnosis and treatment. Therefore, in
treating the child with a primary immunodeficiency, the radiologist can play
an important role, one that is facilitated by a familiarity with the
classification and mechanisms of the deficiencies, their clinical
manifestations, and their imaging features.
References
-
Manson DE, Sikka S, Reid B, Roifman C. Primary immunodeficiencies:
a pictorial immunology primer for radiologists. Pediatr
Radiol 2000;30:501
-510[Medline]
-
[No authors listed]. Primary immunodeficiency diseases.
Clin Exp Immunol
1999;118[suppl 1]:1
-28
-
Buckley RH. Primary immunodeficiency diseases. In: Paul WE, ed.
Fundamental immunology. Philadelphia:
Lippincott-Raven, 1999:1427
-1453
-
Schaffer FM, Monteiro RC, Volanakis JE, Cooper MD. IgA deficiency.
Immunodefic Rev
1991;3:15
-44[Medline]
-
Heraszewsli RA, Webster ADB. Primary hypogammaglobulinemia: a
survey of clinical manifestations and complications. Q J
Med 1993;86:31
-42[Abstract/Free Full Text]
-
Sneller MC, Strober W, Eisenstain E, Jaffe JS, Cunningham-Rundles
C. New insights into common variable immunodeficiency. Ann Intern
Med 1993;118:720
-730[Abstract/Free Full Text]
-
Bruton OC. Agammaglobulinemia. Pediatrics
1952;9:722
-726[Abstract/Free Full Text]
-
Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression of
a B-cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia.
Cell
1993;72:279
-290[Medline]
-
Vetrie D, Vorechovsky I, Sideras P, et al. The gene involved in
X-linked agammaglobulinemia is a member of the src family of protein-tyrosine
kinases. Nature
1993;361:226
-233[Medline]
-
Rawlings DJ, Witte ON. Bruton's tyrosine kinase is a key regulator
in B-cell development. Immunol Rev
1994;138:105
-119[Medline]
-
Smart BA, Ochs HD. The molecular basis and treatment of primary
immunodeficiency disorders. Curr Opin Pediatr
1997;9:570
-576[Medline]
-
Lavilla P, Gil A, Rodriguez MCG, Dupla ML, Pintado VP, Fontan G.
X-linked agammaglobulinemia and gastric adenocarcinoma.
Cancer
1993;72:1528
-1533[Medline]
-
Huo YK, Wang Z, Ji-Hong H, et al. Radiosensitivity of
ataxia-telangiectasia, X-linked agammaglobulinemia, and related syndromes
using a modified colony survival assay. Cancer Res
1994;54:2544
-2547[Abstract/Free Full Text]
-
Curtin JJ, Webster ADB, Farrant J, Katz D. Bronchiectasis in
hypogammaglobulinemia—a computed tomography assessment. Clin
Radiol 1991;44:82
-84[Medline]
-
Lerner EJ, Bilaniuk LT. Bruton-type (congenital X-linked)
agammaglobulinemia: MR imaging of unusual intracranial complications.
AJNR
1992;13:976
-980[Abstract]
-
Taybi H, Lachman RS. Radiology of syndromes, metabolic
disorders, and skeletal dysplasias, 4th ed. St. Louis: Mosby,
1996: 13
-
Demczuk S, Aurias A. DiGeorge syndrome and related syndromes
associated with 22q11.2 deletions: a review. Ann Genet
1995;38:59
-76[Medline]
-
Greenberg F. DiGeorge syndrome: an historical review of clinical
and cytogenetic features. J Med Genet
1993;30:803
-806[Free Full Text]
-
Markert ML, Boeck A, Hale LP, et al. Transplantation of thymus
tissue in complete DiGeorge syndrome. N Engl J Med
1999;341:1180
-1189[Abstract/Free Full Text]
-
Buckley RH, Schiff RI, Schiff SE, et al. Human severe combined
immunodeficiency: genetic, phenotypic, and functional diversity in one hundred
eight infants. J Pediatr
1997;130:378
-387[Medline]
-
Buckley RH, Schiff SE, Schiff RI, et al. Hematopoietic stem-cell
transplantation for the treatment of severe combined immunodeficiency.
N Engl J Med
1999;340:508
-516[Abstract/Free Full Text]
-
Cavazzana-Calvo M, Hacein-Bey S, deSaint Basile G, et al. Gene
therapy of human severe combined immunodeficiency (SCID)-X1 disease.
Science
2000;288:669
-672[Abstract/Free Full Text]
-
Kuhn JP, Slovis TL, Silverman FN, Kuhns LR. The neck and
respiratory system. In: Silverman FN, Kuhn JP, eds. Caffey's
pediatric x-ray diagnosis, 9th ed. St. Louis: CV Mosby,
1993: 563-566
-
Hedlund GL, Griscom NT, Cleveland RH, Kirks DR. Respiratory system.
In: Kirks DR, ed. Practical pediatric imaging.
Philadelphia: Lippincott-Raven, 1998:756
-757
-
Hirschhorn R. Adenosine deaminase deficiency.
Immunodefic Rev
1990;2:175
-198[Medline]
-
Chakravarti VS, Borns P, Lobell J, Douglas SD. Chondroosseous
dysplasia in severe combined immunodeficiency due to adenosine deaminase
deficiency (chondroosseous dysplasia in ADA deficiency SCID).
Pediatr Radiol
1991;21:447
-448[Medline]
-
Ming JE, Stiehm ER, Graham JM. Immunodeficiency as a component of
recognizable syndromes. Am J Med Genet
1996;66:178
-198
-
Gatti RA, Boder E, Vinters HV, Sparks RS, Norman A, Lange K.
Ataxia-telangiectasia: an interdisciplinary approach to pathogenesis.
Medicine
1991;70:99
-117[Medline]
-
Assencio-Ferreira VJ, Bancovsky I, Diament AJ, Gherpelli JL,
Moreira FA. Computed tomography in ataxia-telangiectasia. J Comput
Assist Tomogr 1981;5:660
-661[Medline]
-
Farina L, Uggetti C, Ottolini A, et al. Ataxia-telangiectasia: MR
and CT findings. J Comput Assist Tomogr
1994;18:724
-727[Medline]
-
Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic
granulomatous disease: report on a national registry of 368 patients.
Medicine
2000;79:155
-169[Medline]
-
Stricof DD, Glazer GM, Amendola MA. Chronic granulomatous disease:
value of newer imaging modalities. Pediatr Radiol
1984;14:328
-331[Medline]
-
Kenney PJ, Brinsko RE, Patel DV. Gastric involvement in chronic
granulomatous disease of childhood: demonstration by computed tomography and
upper gastrointestinal studies. J Comput Assist Tomogr
1985;9:563
-565[Medline]
-
Renner WR, Johnson JF, Lichtenstein JE, Kirks DR. Esophageal
inflammation and stricture: complication of chronic granulomatous disease of
childhood. Radiology
1991;178:189
-191[Abstract/Free Full Text]
-
Hiller N, Fisher D, Abrahamov A, Blinder G. Esophageal involvement
in chronic granulomatous disease: case report and review. Pediatr
Radiol 1995;25:308
-309[Medline]
-
Kopen PA, McAlister WH. Upper gastrointestinal and ultrasound
examinations of gastric antral involvement in chronic granulomatous disease.
Pediatr Radiol
1984;14:91
-93[Medline]
-
Springer TA, Thompson WS, Miller LJ, Schmalstieg FC, Anderson DC.
Inherited deficiency of the Mac 1, LFA-1, p150/95 glycoprotein family and its
molecular basis. J Exp Med
1984;160:1901
-1918[Abstract/Free Full Text]
-
Fischer A, Lisowska-Grospierre B, Anderson DC, Springer TA.
Leukocyte adhesion deficiency: molecular basis and functional consequences.
Immunodefic Rev
1988;1:39
-54[Medline]
-
Haddad E, Le Deist F, Blanche S, et al. Treatment of
Chédiak-Higashi syndrome by allogenic bone
marrow transplantation: report of 10 cases. Blood
1995;85:3328
-3333[Abstract/Free Full Text]
-
Ballard R, Tien RD, Nohria V, Juel V. The
Chédiak-Higashi syndrome: CT and MR findings.
Pediatr Radiol
1994;24:266
-267[Medline]
-
Colten HR, Rosen FS. Complement deficiencies. Annu Rev
Immunol 1992;10:809
-834[Medline]
-
Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E
and undue susceptibility to infection. Pediatrics
1972;49:59
-70[Abstract/Free Full Text]
-
Grimbacher B, Holland SM, Gallin JI, et al. Hyper-IgE syndrome with
recurrent infections—an autosomal dominant multisystem disorder.
N Engl J Med
1999;340:692
-702[Abstract/Free Full Text]
-
Merten DF, Buckley RH, Pratt PC, Effmann EL, Grossman H.
Hyperimmunoglobulinemia E syndrome: radiographic observations.
Radiology
1979;132:71
-78[Abstract]
-
Kirchner SG, Sivit CJ, Wright PF. Hyperimmunoglobulinemia E
syndrome: association with osteoporosis and recurrent fractures.
Radiology
1985;156:362[Abstract/Free Full Text]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
M. C. B. Godoy, P. M. Vos, P. L. Cooperberg, C. P. Lydell, P. Phillips, and N. L. Muller
Chest Radiographic and CT Manifestations of Chronic Granulomatous Disease in Adults
Am. J. Roentgenol.,
November 1, 2008;
191(5):
1570 - 1575.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Introduction
Humoral Immunodeficiency...
