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or radiologists, a review of the pri-mary immunodeficiencies in chil-dren that emphasizes clinical

features and radiologic findings is practical forseveral reasons. First, the radiologist can be thephysician who suggests the presence of an im-mune disorder after recognizing certain radio-logic features (Fig. 1). Second, the radiologistmay be involved in the examination of patientswith known primary immune disorders andshould be familiar with the potential imagingmanifestations such as opportunistic infectionor malignancy [1]. Moreover, many radiologistsmay be unfamiliar with the various primary im-mune disorders. Finally, the understanding ofgenetic causes of primary immunodeficienciesis rapidly evolving, and much information fromeven a few years ago, including classificationschemes and categorization of various disor-ders, is already obsolete.

Our review will focus on the pediatric popu-lation because most of these disorders presentduring infancy or childhood. Information cov-ered includes a contemporary categorization ofimmune disorders based on the immune systemdefect (Appendix). These categories consist ofhumoral, cellular, phagocytic, or complementdeficiencies, or a combination of these disor-ders. Although this classification is not inclusiveof all immunodeficiencies, it lists thoseimmunodeficiencies that radiologists are morelikely to encounter or those in which radiologicimaging plays an important role in diagnosis or

surveillance. Discussion of each disorder in-cludes the specific defect or defects, clinicalmanifestations, contemporary therapeutic con-siderations, and radiologic manifestations.

Humoral Immunodeficiency Disorders

Humoral immunodeficiency comprises a het-erogeneous group of disorders characterized byimpaired antibody production. Humoral immuno-deficiencies are common, accounting for about70% of all primary immunodeficiency disorders[2, 3]. Clinically, affected individuals are prone torecurrent pyogenic infections especially with en-capsulated bacteria such as

Haemophilus influen-zae

,

Streptococcus pneumoniae

, andstaphylococci. Recurrent pneumonia, otitis me-dia, sinusitis, and septicemia are the most com-mon clinical manifestations. Successful hostdefense against bacterial infection requires col-laboration of antibodies, complement, andphagocytes. Therefore, all these componentsshould also be investigated thoroughly in thosepatients with increased susceptibility to bacterialinfections. Most patients with defects predomi-nantly involving humoral immunity are able torecover from viral infections because of theirnormal T-cell responses.

IgA Deficiency

The most common primary immunodefi-ciency disorder, IgA deficiency affects an esti-mated 1:600 in the general population [4].Caucasians are affected much more frequently

than Asians or African Americans. Both geneticand environmental factors contribute to the patho-genesis of this disorder. Some children with IgAdeficiency may be clinically healthy, whereas oth-ers are susceptible to respiratory and gastrointesti-nal infections, allergies, autoimmune diseases,and malignancies [5]. Imaging findings arepredominantly caused by bacterial infections.Treatment of this disorder is supportive.

Common Variable Immunodeficiency

Common variable immunodeficiency repre-sents a group of undifferentiated disorders char-acterized by impaired antibody production of allmajor classes. Common variable immunodefi-ciency has an estimated incidence of up to1:10,000 in the general population [2, 6]. Diag-nosis is usually made by the finding that levelsof serum immunoglobulins are low or absent al-though numbers of circulating B cells are in thenormal range. Both males and females are af-fected equally with no obvious pattern of in-heritance. In contrast with X-linkedagammaglobulinemia in which onset is alwaysin early childhood, the onset of symptoms incommon variable immunodeficiency may occurin early or late childhood or adulthood [6], and,unlike X-linked agammaglobulinemia, circulat-ing B cells are usually normal in quantity andphenotype. During antigen stimulation, these Bcells do respond and proliferate but fail to differ-entiate into antibody-secreting plasma cells [2].T-cellmediated immunity is often intact; how-

Primary Immunodeficiency Disorders in PediatricPatients:

Clinical Features and Imaging Findings

Emma Zi Yin

1

, Donald P. Frush

2

, Lane F. Donnelly

3

, Rebecca H. Buckley

4

Received October 2, 2000; accepted after revision December 4, 2000.

1

Department of Medicine, Duke University Medical Center, Durham, NC 27710.

2

Division of Pediatric Radiology, Rm. 1905, McGovern-Davison Childrens Health Center, Box 3808, Department of Radiology, Duke University Medical Center, Erwin Rd., Durham, NC 27710. Address correspondence to D. P. Frush.

3

Department of Radiology, Childrens Hospital and Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229.

4

Department of Pediatrics, Duke University Medical Center, Durham, NC 27710.

AJR

2001;176:15411552 0361803X/01/17661541 American Roentgen Ray Society

Review

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ever, T-cell abnormalities have also been notedin up to 60% of patients [3, 6].

Clinically, patients with common variableimmunodeficiency and X-linked agammaglob-ulinemia share such susceptibilities as increasedrisk of recurrent pyogenic sinopulmonary infec-tion, gastrointestinal involvement, and fatal en-teroviral meningoencephalitis, although thisdisease is seen less often in patients with com-mon variable immunodeficiency than in thosewith X-linked agammaglobulinemia. Unlikepatients with X-linked agammaglobulinemia,patients with common variable immunodefi-ciency have a healthy amount of tonsillar tissue,and 1525% patients with this immunodefi-ciency develop lymphadenopathy or splenomeg-aly [3, 5].

Nodular lymphoid hyperplasia of thegastrointestinal tract is frequently observed as apart of a generalized lymphoproliferative pro-cess [2]. Common variable immunodeficiencyis also associated with an increased cancer risk,predominantly with lymphoreticular tumors.Approximately 20% of patients with this immu-nodeficiency will develop autoimmune diseases[2, 5]. Standard treatment for patients with thisgroup of disorders consists of IV immunoglob-ulin replacement.

Chest radiographs or CT scans may revealpulmonary infection, including atelectasis andbronchial wall thickening or more advancedbronchiectasis (Fig. 2). Radiologic findings inpatients with common variable immunodefi-

ciency differ from those in patients with X-linkedagammaglobulinemia because of the presence ofnormal or increased amounts of lymphoid tissue,lymphadenopathy, or splenomegaly (Fig. 3).

X-Linked Agammaglobulinemia

X-linked agammaglobulinemia is also re-ferred to as Brutons agammaglobulinemia. Thisdisorder was the first recognized primary immu-nodeficiency, described by Bruton in 1952 [7].Incidence of the condition is unknown, but it isless common than IgA deficiency or commonvariable immunodeficiency. Affected patientshave markedly decreased numbers of mature Bcells and plasma cells in the circulation and con-sequently have reduced lymphoid tissue. Serumimmunoglobulins of all isotypes are almost com-pletely undetectable. T-cell number and functionremain intact. There is a block in differentiationat all stages of B-cell development [2]. The generesponsible for X-linked agammaglobulinemiahas been identified as Brutons tyrosine kinasegene, a key regulator of B-cell maturation, lo-cated on the X chromosome [811].

During the first 69 months of life, patientswith X-linked agammaglobulinemia are pro-tected from infections by maternally derived IgGantibodies. As this source of antibodies dimin-ishes, patients begin to develop pyogenic bacterialinfections, with recurrent sinopulmonary infec-tions being most common [5]. Although mostpediatric patients develop recurrent bacterial in-

fections during infancy, 20% of patients do notpresent until approximately 35 years [2, 5, 6],probably because of the widespread use of antibi-otics. Less common complications includechronic conjunctivitis; chronic intestinal protozoalinfection, especially giardiasis; malabsorption;and persistent central nervous system enteroviralinfections with resultant chronic meningoenceph-alitis, dermatomyositis, rheumatoidlike arthritis,and an increased cancer risk [12, 13].

The standard treatment for X-linked agam-maglobulinemia is IV immunoglobulin re-placement therapy. Despite apparentlyadequate treatment with IV immunoglobulin,however, many patients still develop pansi-nusitis or postinfectious chronic lung dis-eases, most commonly bronchiectasis.

On chest radiography or CT, bronchiectasis ismost commonly found in the middle or lowerlobes (Fig. 4); upper lobe distribution is very un-common [14]. Splenomegaly is not seen, andlymphoid tissue (i.e., adenoids) is typically ex-tremely small [3]. MR imaging may reveal infec-tious involvement of the central nervous systemwith diffuse leptomeningeal thickening and en-hancement, or encephalitis [15, 16] (Fig. 5).

Other Humoral Deficiencies

Other defects characterized by antibodydeficiency include both X-linked and nonX-linked hyper-IgM, which are both character-ized by recurrent bacterial infections [3].

Fig. 1.Oral and IV contrastenhanced axial CT scan of mid abdomen of 2-month-old male infant with failure tothrive shows mixed attenuation adenopathy (arrows) that infiltrates mesentery. Diagnosis of chronic granulo-matous disease was established after laparoscopic biopsy of nodal mass and culture that yielded Candida.

Fig. 2.Common variable immune deficiency in 37-year-old woman. Axial high-resolution CT scan at mid lung levelshows scattered regions of mild bronchiectasis (arrows).

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Primary Cellular and Combined Immunodeficiency Disorders

Cellular immunodeficiency is character-ized by disseminated viral infections, particu-larly with herpes viruses such as herpessimplex, varicella-zoster, and cytomegalovi-rus; superficial and systemic fungal infec-tions; and parasitic infections. Overwhelmingviremia; severe mucocutaneous candidiasis;and progressive pneumonia caused by parain-fluenza, respiratory syncytial virus, cytomeg-alovirus, varicella, and

Pneumocystis carinii

are common presentations in patients withthis immunodeficiency. Cellular deficiency isalso almost always accompanied by some ab-normality of antibody responses because an-tibody production is T-celldependent.

DiGeorge Syndrome

DiGeorge syndrome, which is also called thy-mic aplasia or hypoplasia, is a typical example ofa primary T-cell deficiency. DiGeorge syndromeis most often caused by gene defects on chromo-some 22, which lead to abnormal developmentof the third and fourth pharyngeal pouches dur-ing early embryogenesis [17]. As a result, the or-gans that develop from these structuresthemost important being the thymus, parathyroidglands, and heartcan be affected. Impairedfunctions of these organs account for a uniqueconstellation of clinical presentations. The mostcommon are T-cell deficiencies of varying sever-ity caused by hypoplasia or aplasia (or agenesis)of the thymus. Other presentations are neonatalhypocalcemic tetany stemming from hypopara-

thyroidism and congenital cardiovascular anom-alies, especially of the great vessels and septa.Another distinctive abnormality associated withthis syndrome is facial dysmorphology, whichpresents as micrognathia, low-set ears, shortenedphiltrum of the upper lip, and hypertelorism [18](Fig. 6). B cells are present in normal numbers.Nevertheless, antibody responses may still be af-fected because of an inadequate number of Tcells, which varies greatly depending on the de-gree of thymic hypoplasia. In up to 80% of pa-tients, the immunodeficiency is mild (partialDiGeorge syndrome) and can even be transient[3, 6, 17]. However, those patients with more se-vere forms of this disease (complete DiGeorgesyndrome) may resemble children with severecombined immunodeficiency. These children, as

Fig. 3.Common variable immunodeficiency in 25-year-old man. IV contrast-en-hanced axial CT scan in mid abdomen reveals splenomegaly and several prominentmesenteric and retroperitoneal lymph nodes (arrows).

Fig. 4.2-year-old boy with X-linked hypogammaglobulinemia and recurrent pulmonaryinfections. CT scan at lung base shows scattered bronchiectasis in basilar regions of lowerlobes, lingula, and middle lobe (arrows). Findings for upper lobes were normal (not shown).

Fig. 5.11-month-old male infant with X-linked agamma-globulinemia and vaccine-type polio encephalomyelitis.A, Axial T1-weighted MR image (TR/TE, 500/20) at levelof mid brain shows regions of low signal intensity(arrows) in white matter tracts of cerebral peduncles. B, Axial T2-weighted MR image (2000/80) shows in-creased signal intensity (arrows) in regions thatshowed low signal intensity in A. Abnormal signal in-tensity extended into substantia nigra and was seen inthalami bilaterally (not shown).

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is the case for all children with cellular immuno-deficienicies, are susceptible to infections withopportunistic organisms, such as acid-fast bacte-ria, viruses, fungi, and

P. carinii

, and to graft-ver-sus-host disease from nonirradiated blood orblood-product transfusions [3].

Treatment is usually supportive. Thymic epi-thelial transplants or unfractionated human

luekocyte antigenidentical sibling bone marrowtransplantation are recommended only for thosewith the complete DiGeorge syndrome [19].

Chest radiography may reveal narrow uppermediastinal contour and retrosternal lucency at-tributable to absence of the thymus. Cardiovas-cular anomalies such as abnormalities of thegreat vessels (Fig. 7), including right-side aorticarch, interrupted aortic arch, and truncus arterio-sus; tetralogy of Fallot; or atrial or ventricularseptal defects are frequently present [17, 18].

Severe Combined Immunodeficiency Syndromes

Severe combined immunodeficiency repre-sents a group of genetically determined immuno-deficiency disorders characterized by the absenceof T- and B-cell (and sometimes natural killercell) function. Many defects have been identifiedthat involve cytokine receptors and enzyme defi-ciencies. The main inheritance patterns are eitherautosomal recessive or X-linked patterns, whichare caused by mutations in the gene that encodesthe common cytokine receptor gamma chain [2,20]. The X-linked type accounts for about 46%of all severe combined immunodeficiency disor-ders. Autosomal recessive forms include aden-osine deaminase (ADA) deficiency (15%), Januskinase 3 (Jak 3) deficiency (7%), interleukin-7(IL-7) receptor alpha chain deficiency (2%), re-combinase activating gene (RAG) 1 and 2, orcluster of differentiation 45 (CD 45) deficiencies(

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1545

also be caused by multiple organisms. Pneu-mocystis typically produces interstitial infiltrates,which progress to alveolar infiltrates. However,viral pneumonitis can be indistinguishable frompneumocystis pneumonia or other opportunisticinfections (Fig. 9). An important feature to recog-nize in children with severe combined immuno-deficiency syndrome, as opposed toimmunocompetent children or children withother immunodeficiencies with an acute pulmo-nary infection, is the absence of the thymicshadow [24] (Figs. 9 and 10). A recent review ofchest radiographs in more than 130 patients with

severe combined immunodeficiency in infancyand early childhood revealed thymic absence inevery patient (Frush DP et al., unpublished data).

The adenosine deaminase deficiency type isnoteworthy from a radiologic standpoint be-cause of skeletal abnormalities and because in-fants and children with this disorder usuallyhave more profound lymphopenia than infantsand children with other severe combined im-munodeficiency disorders [25]. Skeletalabnormalities, although not present in allpatients, are unique to this type of severe com-bined immunodeficiency and are usually lim-

ited to the axial skeleton. These abnormalitiesinclude cupping and flaring at the costochon-dral junctions anteriorly, metaphyseal cupping,and irregularity at the costovertebral junctionwith increased separation between the rib headand vertebral body. In addition, a bone-in-bone appearance of the vertebral bodies andsquaring of the scapula tip have also been re-ported [23, 25, 26] (Fig. 11). In a recent reviewof radiographic changes in more than 130 in-fants and children with severe combined im-munodeficiency, 45% (10/22) of patients withadenosine deaminase deficient form had at least

Fig. 9.Posteroanterior chest radiograph of 6-month-old male infant with X-linked se-vere combined immunodeficiency shows bilateral nodular opacities caused by diffuseCandida infection. Note absence of thymus.

Fig. 10.Anteroposterior chest radiograph of 4-month-old male infant with X-linked agammaglobulinemia and unusual presentation of acute Pneumocystiscarinii pneumonia reveals diffuse granular opacities. Presence of thymus(straight arrows), partly outlined by pneumomediastinum (curved arrow), indi-cates that patient does not have severe combined immunodeficiency.

Fig. 11.4-month-old male infant with severe combined immunodeficiency, adenosinedeaminase form, and typical skeletal abnormalities. Posteroanterior chest radiograph showsflaring of anterior ribs most evident at right costochondral junctions (curved arrows). Notealso squared inferior scapula (straight arrows). Narrow mediastinum is caused by absenceof thymus. Viral pneumonitis is responsible for hyperinflation and right upper lobe atelectasis.

Fig. 12.Axial IV contrastenhanced CT scan of upper abdomen of 8-year-old boywith Wiskott-Aldrich syndrome and small-bowel lymphoma shows aneurysmal dil-atation (arrows) of proximal small bowel, accompanied by wall thickening.

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one of these osseous changes visible on chestradiographs; 27% (6/22) had two or morechanges, and 18% (4/22) had three or morechanges. No patient with nonadenosine deami-nase deficient severe combined immunodefi-ciency had any visible thoracic osseouschanges (Frush DP et al., unpublished data).

In Omenns syndrome, another severe im-munodeficiency, patients present withdesquamating erythroderma, adenopathy,hepatosplenomegaly, severe infections, and fail-ure to thrive. In approximately half of the pa-tients, the syndrome is caused by recombinaseactivating gene (RAG) 1 and 2 mutations. Lym-phocyte counts may be normal or elevated. TheT lymphocytes are clonal and cytotoxic butfunction poorly otherwise. There is an absenceof B cells, and serum levels of IgG, IgM, andIgA range from low to absent. Paradoxically, thelevel of IgE is elevated, and there is eosinophilia.A number of organs such as the liver, spleen,skin, and gastrointestinal tract become targets ofattack for cytotoxic T cells [3]. The disorder isfatal in infancy unless patients undergo bonemarrow transplantation [3].

Partial Combined Immunodeficiency Syndromes

Partial combined immunodeficiency syn-dromes include Wiskott-Aldrich syndrome, car-tilage-hair hypoplasia, ataxia-telangiectasia,purine-nucleoside phosphorylase deficiency,and X-linked lymphoproliferative disease.

Wiskott-Aldrich syndrome is an X-linkedrecessive immunodeficiency disorder charac-terized by a triad of eczema, thrombocytopeniawith small defective platelets, and recurrent in-fections [2, 3]. The gene on the X chromosomeresponsible for the condition encodes a proteincalled the Wiskott-Aldrich syndrome protein[3] and is expressed in lymphocytes, mega-karyocytes, spleen, and thymus. The functionof this protein is still unclear, but it is thought tohave a major role in actin polymerization. Im-munologically, antibody responses to polysac-charide antigens are consistently impaired.Therefore, such patients are particularly sus-ceptible to infection with polysaccharide-en-capsulated organisms, such as pneumococci,

H. influenzae

, and meningococci. Serum levelsof IgA and IgE are elevated. IgM level is de-creased, and IgG remains normal or is slightlydecreased. T-cell function may initially appearto be normal, but it is not.

Clinically, affected infants often first presentwith prolonged bleeding from the circumci-sion site, bruising, or bloody diarrhea [3]. Pyo-genic infections usually appear during the firstyear of the patients life and may include men-

ingitis, otitis media, pneumonia, and sepsis. In-fections with agents such as

P. carinii

andherpes viruses are also common. Patientsrarely survive beyond their teenage years with-out bone marrow transplantation. Death usu-ally results from massive bleeding, infection,or lymphoreticular malignancy [3].

Therapy includes transfusions of fresh irra-diated platelets for acute bleeding episodesand bone marrow transplantation, which hascompletely corrected both the hematologicand immunologic abnormalities in many pa-tients. If no sibling donor with identical humanleukocyte antigen is available, splenectomymay improve platelet count. Because of the an-tibody deficiency, monthly IV immunoglobu-lin replacement is indicated [3].

Imaging findings include recurrent pneu-monia, sinusitis, and mastoiditis; absence oflymphoid tissue in the nasopharynx; hemor-rhage; or malignancy [24] (Fig. 12).

Cartilage-hair hypoplasia, also known aschondrometaphyseal dysplasia, McKusickstype, is an autosomal recessive disorder withmorphologic and immunologic abnormalitiesranging from humoral to cellular to com-bined immunodeficiencies [3]. The disorder,characterized by short-limbed dwarfism andsevere infections, was first described in theAmish population in Pennsylvania. Character-istic morphologic features of patients includeshort limbs, short pudgy hands, and fine andsparse hair on the face and scalp. Patients withmilder forms of the syndrome may only re-quire conservative therapy, whereas bone mar-row transplantation has been effective forsome patients with the severe combined im-munodeficiency phenotype [3].

Imaging findings of the immunodefi-ciency with cartilage-hair hypoplasia aresimilar to those of other humoral, cellular, orcombined immunodeficiencies with the ex-ception of skeletal manifestations [27]. Pa-

tients with cartilage-hair hypoplasia haveshort-limb skeletal dwarfism with metaphysealdysplasia consisting of sclerosis and cupping(Fig. 13). These findings are in contrast tothose in patients with adenosine deaminasedeficient severe combined immunodefi-ciency whose skeletal changes are found pre-dominantly in the axial skeleton.

Ataxia-telangiectasia is an autosomal reces-sive disorder also known as the Louis-Barrssyndrome. A mutation in the ataxia-telangiecta-sia gene compromises DNA repair mechanismsthus rendering the affected cells highly suscepti-ble to radiation-induced chromosomal damage[2, 3, 28]. Immunologic features include selec-tive IgA deficiency or hypogammaglobuline-mia. The thymus is markedly hypoplastic, andT-cell dysfunction is moderately severe.

The most prominent clinical features ofataxia-telangiectasia are progressive cerebellarataxia that becomes evident when the child be-gins to walk, oculocutaneous telangiectasia thatfirst becomes evident when the child is between3 and 6 years, recurrent bronchopulmonary in-fections affecting approximately 80% of pa-tients, and a high incidence of malignancy [2, 3,28]. The degree of immunodeficiency is highlyvariable. Children that survive the first decadeare at high risk for both solidadenocarci-nomaand lymphoproliferative malignancies[2, 3]. Patients usually die by early adulthoodfrom chronic pulmonary disease, neurologic de-terioration, or malignancy. Ataxia-telangiectasiaand Wiskott-Aldrich syndrome have the highestmalignancy rates of all of the primary immuno-deficiencies [2] (Fig. 12).

Treatment is limited to supportive care,and no cure is available. Bone marrow trans-plantation has not been successful and wouldlikely not correct the neurologic defect.

Imaging findings include lymphoid hy-poplasia, the absence of thymic shadow, re-current sinopulmonary infections with

Fig. 13.5-year-old boy with carti-lage-hair hypoplasia. Anteroposte-rior radiograph of both kneesreveals tibial and femoral metaphys-eal irregularity and sclerosis(curved arrows) but sharply definedmetaphyseal margin. Epiphyseshave normal appearance. Note alsocup-shaped metaphyses (straightarrows ) in distal femurs.

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bronchiectasis, and fibrosis. MR images andCT scans of the central nervous system canshow diffuse cerebellar atrophy, particularly inthe vermis [29, 30]. Because of these patientsincreased risk of cancer from radiation expo-sure, imaging studies using ionizing radiationshould be performed sparingly.

Purine-nucleoside phosphorylase is an en-zyme deficiency affecting lymphocyte functionin a way that is somewhat similar to the mecha-nism in adenosine deaminase deficiency. Clini-cal presentations vary in patients withimmunodeficiency associated with purine-nu-cleoside phosphorylase deficiency. Childrenwith milder forms may present later with di-verse neurologic findings such as developmen-tal delay, hypotonia, and spasticity. However,purine-nucleoside phosphorylase deficiency isuniformly fatal in childhood. Unlike adenosinedeaminase deficiency, this disorder is not asso-ciated with skeletal anomalies.

X-linked lymphoproliferative disease (aninadequate response to Epstein-Barr viral in-fection) results acute infectious mononucleo-sis, malignancy, or immunodeficiency [3].

Disorders of Phagocytic Cells and Adhesion Molecules

Phagocytes comprised mainly of neutro-phils, monocytes, and macrophages are ofgreat importance in host defense against pyo-genic bacteria and fungi as well as other in-tracellular microorganisms. Defects inphagocyte production or function predisposeaffected patients to recurrent pyogenic andfungal infections. Common organisms in-clude bacteria such as

Pseudomonas

,

Serra-tia marcescans,

and

Staphylococcus aureus

,

and fungi such as

Aspergillus

and

Candida

.

Phagocytic disorders are not associated withincreased susceptibility to viral or protozoalinfections, or increased risk for malignancy.Disorders include chronic granulomatousdisease, leukocyte adhesion deficiency, andChdiak-Higashi syndrome.

Chronic Granulomatous Disease

Chronic granulomatous disease is the mostcommon phagocytic disorder, occurring in ap-proximately one in every 125,000 live births[31]. In two thirds of patients, this disorder is in-herited in an X-linked fashion, but three forms ofautosomal recessive chronic granulomatous dis-ease exist as well. Diagnosis of this disorder isestablished with a respiratory burst assay.Chronic granulomatous disease is actually a col-lection of four different molecular defects that

result in defective and reduced activity of nicoti-nomide adenine dinucleotide oxidase in leuko-cytes [31]. This oxidase catalyzes a reactionproducing important bacteriocidal products afterphagocytosis: superoxide radical, singlet oxy-gen, and hydrogen peroxide. Catalase-negativeorganisms such as streptococci and pneumo-cocci provide oxidative products and are therebykilled. However, catalase-positive bacteria suchas

S. aureus

,

S. marcescens

, and some fungisuch as

Aspergillus

organisms destroy the veryoxygen radicals they produce. Prolonged intra-cellular existence of these catalase-positivemicroorganisms in chronic granulomatous dis-ease triggers a cell-mediated response, resultingin granuloma formation.

The onset of symptoms usually occurs dur-ing the patients first year of life. In a recentreview of a chronic granulomatous diseaseregistry [31], the researchers cited pulmonaryinfection as the most frequent symptom, af-fecting 79% of patients, and fungal organismsaccounted for most of these infections. Othersymptoms included suppurative adenitis(53%), subcutaneous abscess (42%), liver ab-scess (27%), osteomyelitis (25%), and sepsis(18%). Gastric outlet obstruction, urinary tractobstruction, and enteritis or colitis occur in1017% of patients [31]. Trimethoprim sul-famethoxazole prophylaxis and recombinanthuman interferon gamma, in addition tochronic antifungal therapy, are standards ofcare for this disorder.

Radiologic findings include chest radio-graphs or CT scans showing chronic or re-current pneumonia, including abscess,pleural reaction, osteomyelitis, and chestwall invasion by organisms such as

As-pergillus

or

Candida

; hilar or mediastinaladenopathy; and esophagitis or esophagealstricture [3235] (Fig. 14). In the abdomen,chronic granulomatous disease manifesta-tions amenable to sonography, CT, or MRimaging include focal abscess or granulomaformation in the liver and spleen, adenopa-thy, antral narrowing, duodenal fold thick-ening, enteric fistulas or sinus tracts, renalinfections, ureteral or urethral strictures, andthickened bladder wall caused by granulo-matous cystitis [31, 32, 36] (Figs. 14 and15). Osteomyelitis can be evaluated usingradiography, CT, or MR imaging (Fig. 16).Radionuclide imaging is indicated for pa-tients in whom clinical signs of infection arepresent with no evident source. Sedimenta-tion rate is a useful clinical barometer be-cause it becomes elevated with developing(including occult) or persistent infection.

Leukocyte Adhesion Defect

Leukocyte adhesion deficiency is causedby mutations in the gene encoding CD18, acomponent of three different leukocyte adhe-sion molecules necessary for cell adhesionand migration [37, 38]. Phagocytes, in par-ticular neutrophils, cannot migrate out of theblood vessels into areas of infection. Com-mon clinical features in leukocyte adhesiondeficiency include impaired wound healing,severe periodontal disease, and recurrentwidespread pyogenic infections, such as oti-tis media, pneumonia, peritonitis, and cellu-litis, later in childhood. The severity ofsymptoms can vary greatly, depending on thenature of the gene defect. Treatment optionsfor leukocyte adhesion deficiency includeaggressive antibiotic therapy and bone mar-row transplantation.

Chdiak-Higashi Syndrome

Chdiak-Higashi syndrome is a rare auto-somal recessive disorder with an immunode-ficiency caused by impaired chemotaxis andbacterial-killing functions [2]. Other featuresinclude large intracytoplasmic granulations,partial oculocutaneous albinism, recurrentbacterial infections, peripheral neuropathy,and an increased incidence of malignancy[27, 39]. In particular, recurrent, aggressivelymphoproliferation with diffuse organ infil-tration is associated with an acceleratedphase of the disease [40]. The treatment ofchoice is bone marrow transplantation [39].

Radiologic findings are often nonspecificand include hilar and mediastinal adenopa-thy, hepatosplenomegaly, brain atrophy, dif-fuse decreased periventricular density on CT,and increased T2-weighted signal intensityin periventricular white matter and coronaradiata on MR images [16, 40] (Fig. 17).

Complement Deficiencies

Complement disorders represent the rarestform of primary immunodeficiencies, account-ing for only 13% of these diseases [41]. Defi-ciencies associated with all the components ofthe complement cascade have been identified,with complement 2 deficiency occurring mostoften. These disorders, which may involve anyone of the complement components, are usuallytransmitted in an autosomal recessive mode. Anincreased incidence of autoimmune disease andpyogenic infections is associated with a defi-ciency of early components (complements 14)of the classic pathway. Deficiencies of the termi-nal complement components (complements

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ED

Fig. 14.Multiple radiologic manifestations of chronic granulomatous disease in a male. A, At 7 years, patient presented with urinary frequency. Sagittal sonogram of bladder shows asymmetric wall thickening (arrows) of superior and posterior bladder causedby granulomatous cystitis.B, 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.C, At 11 years, patient presented with fever without source. Axial IV contrastenhanced CT scan at level just inferior to main pulmonary artery reveals subcarinal adeno-pathy (arrows) with low-attenuation central region; culture yielded Aspergillus organisms.D, At 21 years, patient presented with dysphagia. Single-contrast barium esophagram shows marked narrowing of mid esophagus (straight arrows). Small traction diver-ticulum (curved arrow) distal to stricture is caused by chronic mediastinal adenopathy (not shown).E, At 22 years, patient presented with elevated sedimentation rate. Axial IV contrastenhanced CT scan of upper abdomen reveals multiple small low-attenuation le-sions (arrows ). Sonographically guided biopsy was subsequently performed, but no organisms were isolated. Patient responded to more aggressive antifungal andantibacterial therapy.

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59) are associated with increased susceptibilityto serious infections from

Neisseria

species [41].Complement 3 deficiency usually results in seri-ous complications such as recurrent pneumonia,meningitis, and peritonitis. Its clinical presenta-tions often mimic those of the antibody defi-ciency disorders. On the other hand, somepatients with deficiencies in complement 2, 4, or9 can remain completely asymptomatic. Treat-ment usually involves prophylactic antibioticsand specific vaccination against encapsulated or-ganisms. Complement replacement therapy isnot effective in treating these disorders.

Other Immunodeficiencies

The hyperimmunoglobulinemia E syn-drome is a condition characterized by staphy-lococcal abscesses of the skin, lungs, viscera,or other sites beginning in infancy with mark-

Fig. 15.26-year-old man with chronic granulomatous disease and early satiety. Anteroposterior view of uppergastrointestinal tract obtained during single-contrast gastrointestinal study shows marked antral narrowing(arrows) caused by granulomatous gastric involvement.

Fig. 16.6-year-old girl with chronic granulomatousdisease and vertebral osteomyelitis after extension ofpulmonary Aspergillus infection.A, Anteroposterior radiograph of lower thoracic spineshows vertebra plana of T11 vertebral body (large straightarrow) 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.B, Axial proton densityweighted MR image (TR/TE, 2000/40) at level of T11 shows increased marrow signal intensityas well as increased signal intensity (arrows) extendinginto prevertebral and paraspinal regions.

BA

Fig. 17.10-year-old girl with Chdiak-Higashi syn-drome. Axial T2-weighted MR image (TR/TE, 2300/80)reveals mildly diffuse cerebral atrophy with increasedperiventricular white-matter T2-weighted signal in-tensity (arrows).

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edly elevated serum levels of IgE. The under-lying molecular defect is unknown [42]. Themode of inheritance appears to be autosomaldominant with variable penetrance [42, 43].No gender or racial discrepancy in incidencehas been noted. The most common infectiousagent is staphylococci. Eczema, mucocutane-ous candidiasis, and coarse facial features (Fig.18) are frequently associated with this syn-drome [42, 43]. Delayed eruption of teeth,

scoliosis, osteopenia, and insufficiency frac-tures are also unique features of this immunedisorder [43]. Treatment is usually supportive,with an emphasis on long-term antistaphylo-coccal antibiotic prophylaxis.

Imaging findings include recurrent pneu-monia with subsequent and usually persistentpneumatocele formation [44]. The presenceof persistent single or multiple pneumatoce-les is the most striking radiographic feature of

this syndrome (Fig. 19). These lung cystsmay persist, expand, and become superin-fected with bacteria and fungi, and may re-quire surgical excision [44]. Osteoporosispredominantly affecting the spine and, to alesser degree, the limbs in the epiphysealmetaphyseal regions may also occur with re-current insufficiency fractures [43, 45] (Fig.19). The mechanism responsible for this os-teoporosis is not known.

Fig. 18. Photograph of 6-year-old boy with hyperimmunoglobulinemia E syndrome shows someof facial characteristics of the syndrome, such as prominent forehead and facial pores. Othercharacteristics such as facial asymmetry, broad nasal bridge, and deep-set eyes are not evident.

Fig. 19.14-year-old boy with hyperimmunoglobulinemia E syndrome.A, Posteroanterior chest radiograph shows multiple large left-sided chronic pneumatoceles with airfluid levels. Note associated rightward shift of heart and mediastinum (arrows). B, Lateral lumbar spine radiograph obtained 1 year after A shows multiple vertebral compression fractures attributable to osteopenia.

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Conclusion

Primary immunodeficiency represents abroad spectrum of disorders with enormouslydiverse intrinsic defects involving one or mul-tiple components of the immune system. Im-munodeficiency is characterized clinically bythe patients increased susceptibility to infec-tion, malignancy, and autoimmunity, for whichimaging is important in diagnosis and treat-ment. Therefore, in treating the child with aprimary immunodeficiency, the radiologist canplay an important role, one that is facilitated bya familiarity with the classification and mecha-nisms of the deficiencies, their clinical mani-festations, and their imaging features.

References

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APPENDIX: Primary Immunodeficiencies Relevant for Radiologists

Predominantly Humoral (B Cell) Defects with Antibody DeficiencySelective immunoglobulin A deficiencyCommon variable immunodeficiencyX-linked agammaglobulinemia (Brutons agammaglobulinemia)NonX-linked hyperimmunoglobulin M

Predominantly Cellular (T Cell) DefectsThymic hypoplasia or aplasia (DiGeorge) syndromeOther T-cell defects (X-linked hyperimmunoglobulin M, X-linked lymphoproliferative disease)

Combined DefectsSevere combined immunodeficiency

X-linked severe combined immunodeficiencyAutosomal recessive severe combined immunodeficiency

Adenosine deaminase (ADA) deficiencyJanus kinase 3 (Jak 3) deficiencyInterleukin-7 (IL-7) receptor alpha chain deficiencyRecombinase activating gene (RAG) 1 or 2 deficiencyUnknown forms

Omenns syndromePartial Combined Immunodeficiency

Wiskott-Aldrich syndromeCartilage-hair hypoplasia Ataxia-telangiectasiaPurine-nucleoside phosphorylase deficiencyCluster of differentiation (CD) 3 deficiencyZeta-associated protein (ZAP) 70 deficiencyMajor histocompatibility complex deficiencies

Phagocyte DefectsChronic granulomatous disease Leukocyte adhesion deficiencyChdiak-Higashi syndrome

Complement DeficienciesComplement component deficiencies

Other ImmunodeficienciesHyperimmunoglobulin E syndrome

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