Clinical and imaging considerations in primary immunodeficiency disorders: an update.

HHS Public Access Author manuscript Author Manuscript

Pediatr Radiol. Author manuscript; available in PMC 2017 November 01. Published in final edited form as: Pediatr Radiol. 2016 November ; 46(12): 1630–1644. doi:10.1007/s00247-016-3684-x.

Clinical and imaging considerations in primary immunodeficiency disorders: an update Eveline Y. Wu1, Lauren Ehrlich2, Brian Handly3, Donald P. Frush4, and Rebecca H. Buckley5,6 Eveline Y. Wu: [email protected] 1Department

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of Pediatrics, University of North Carolina at Chapel Hill, 030 MacNider Hall, CB#7231, Chapel Hill, NC 27599, USA

2Department

of Diagnostic Radiology, Yale School of Medicine, New Haven, CT, USA

3Department

of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

4Division

of Pediatric Radiology, Duke University Medical Center, Durham, NC, USA

5Department

of Pediatrics, Duke University Medical Center, Durham, NC, USA

6Department

of Immunology, Duke University School of Medicine, Durham, NC, USA

Abstract Author Manuscript

Primary immunodeficiencies are a group of genetically determined disorders with diverse presentations. The purpose of this review is to provide a practical and brief description of a select number of these diseases and to discuss the important role the radiologist can have in making an early diagnosis and in detecting and following disease complications. The role of diagnostic imaging and informed performance and interpretation are vital in the diagnosis, surveillance and management of all primary immunodeficiency disorders.

Introduction

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Primary immunodeficiency diseases (PIDDs) comprise a spectrum of more than 300 distinct disorders characterized by defects in the development of specific components of the immune system. They are classified according to which functional compartment of the immune system is impaired and broadly include humoral, primary cellular or combined, complement, and phagocytic disorders (Table 1). Since there is no screening for most of these conditions, the diagnosis of a PIDD is not usually made until the patient develops one or multiple infections. The diverse nature and variable presentation of PIDDs also make diagnosis a challenge. Early diagnosis therefore requires a high index of suspicion in combination with a detailed clinical history, thorough physical examination, and supportive ancillary studies.

Correspondence to: Eveline Y. Wu, [email protected]. CME activity This article has been selected as the CME activity for the current month. Please visit the SPR Web site at www.pedrad.org on the Education page and follow the instructions to complete this CME activity. Compliance with ethical standards Conflicts of interest None

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Often times, imaging findings can either indicate the presence of or confirm the diagnosis of a PIDD. The radiologist’s familiarity with PIDDs is therefore paramount. We last published a comprehensive review of the clinical features and imaging findings of PIDDs in children more than a decade ago [1]. In the last 10 years, remarkable progress has been made in the discovery of the genetic basis, diagnosis and treatment of PIDDs (Table 2). Our objective is to review the spectrum of PIDD disorders, providing relevant imaging features and emphasizing notable advancements in selected immunodeficiency disorders.

Humoral immunodeficiency disorders

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Primary humoral immunodeficiencies are characterized by defective antibody production and include X-linked agammaglobulinemia (XLA), common variable immunodeficiency (CVID), selective immunoglobulin A (IgA) deficiency, hyper-IgM syndromes (HIGM) and others [2, 3]. The most common primary antibody deficiency is selective immunoglobulin A (IgA) deficiency, characterized by an isolated absence of serum or secretory IgA. A closely related condition, CVID, is defined by recurrent sinopulmonary infections, low levels of most or all serum immunoglobulin classes, and impaired antibody responses. However, in contrast to XLA, where B cells are few or absent, the number of circulating B cells is often normal in CVID. XLA patients are also panhypogammaglobulinemic, as are many with CVID. Due to molecular defects resulting in failure of immunoglobulin class switch recombination, HIGM syndromes have normal or elevated levels of serum IgM and absent or very low concentrations of IgG, IgA and IgE [4].

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Patients with primary humoral immunodeficiencies generally present with recurrent bacterial infections, especially those involving the upper and lower respiratory tracts (Fig. 1). Other significant clinical manifestations include autoimmune disease (Fig. 2), particularly autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura, lymphoid hyperplasia, and endocrine abnormalities [5]. CVID and selective IgA deficiency patients are also at increased risk of malignancy, particularly lymphoma and gastrointestinal cancers.

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Imaging findings can aid in the diagnosis of primary humoral immunodeficiencies. Radiographically, children with XLA classically have sparse lymphoid tissue so the tonsillar and adenoidal tissues are reduced in amount. Antibody-deficient patients demonstrate both upper and lower airway abnormalities, including pansinusitis, bronchiectasis, bronchial wall thickening and atelectasis [1]. Bronchiectasis is more typical in the middle and lower lobes than in the upper lobes (Fig. 3) [6]. In contrast to XLA and CVID, bronchiectasis is not a common complication in selective IgA deficiency because functioning IgG antibodies are usually available [7]. Magnetic resonance imaging performed for central nervous system infection in humoral immunodeficiency may demonstrate diffuse leptomeningeal thickening and enhancement when contrast media is administered [1]. Other sequelae include cerebral atrophy (Fig. 4) and abscesses (Fig. 5). With imaging, children and adults with CVID may be distinguished from other humoral immunodeficiency patients in that they may have normal amounts of tonsillar and adenoidal tissue, and up to 25% develop lymphadenopathy and splenomegaly [8]. Patients with CVID

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may also develop lymphoid interstitial pneumonia, characterized on chest CT by the presence of ground-glass attenuation, poorly defined centrilobular nodules and thickening of the interstitium along the lymphatic vessels (Fig. 6) [9]. Nodular lymphoid hyperplasia of the gastrointestinal tract is also frequently observed in this population (Fig. 7) [10].

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Recurrent infections are a major cause of significant morbidity and sometimes early mortality in primary humoral immunodeficiency. Early recognition and diagnosis is imperative, as prompt initiation of appropriate therapy can significantly improve patient outcome and survival. Early detection and effective treatment of acute infections are also vital. The cornerstone in the management of primary antibody deficiency is immunoglobulin replacement therapy. In recent years, there has been increased use of subcutaneous immunoglobulin replacement therapy. Studies have shown that subcutaneous immunoglobulin is equal to intravenous immunoglobulin therapy in effectiveness [5]. Adequate immunoglobulin replacement not only lowers the frequency and severity of infections, but also increases life expectancy. Management of primary antibody deficiency also requires vigilant monitoring for associated complications, including autoimmunity, granulomatous disease, lymphoproliferation and malignancy [11–13].

Primary cellular and combined immunodeficiency disorders

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Primary cellular and combined immunodeficiencies comprise a heterogeneous group of disorders resulting from defects affecting various stages of T cell development or function and include severe combined immunodeficiency (SCID), DiGeorge anomaly, WiskottAldrich syndrome, cartilage-hair hypoplasia, ataxia-telangiectasia and purine nucleoside phosphorylase deficiency [14]. These defects may also be associated with decreased numbers of other lymphocyte populations, such as B cells and natural killer (NK) cells. Though these syndromes share molecular defects causing T cell dysfunction, they differ enough to justify being discussed separately. Severe combined immunodeficiency

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Severe combined immunodeficiency (SCID) is a fatal syndrome characterized by profound deficiencies of both T cell number and function and, as a consequence, also B cell function, since antibody production is T cell dependent. Depending on the underlying molecular defect, patients may also have deficiencies of B cells and/or NK cells. In the past 20 years, significant progress has been made in identifying molecular causes of SCID. It is now known that SCID can be caused by mutations in at least 13 different genes (Table 2), and more are likely to be discovered. These include cytokine receptor genes and antigen receptor genes, among others [14–16]. Inheritance may be either X-linked or autosomal recessive or from de novo mutations. Patients with primary cellular immunodeficiencies suffer from recurrent and severe infections, and suspicion should be raised by infections with opportunistic organisms such as Pneumocystis jiroveci pneumonia, Candida albicans and viral pathogens. Infants with SCID may also contract infections from live attenuated vaccines including rotavirus, varicella, and bacillus Calmette-Guerin (BCG). A history of chronic diarrhea and skin rash may also be


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present. These patients also exhibit poor growth and failure to thrive. On physical examination, there is an absence of tonsillar and other lymphoid tissues [5]. Because T cells comprise 70% of normal circulating lymphocytes, SCID is almost always associated with significant lymphopenia due to the absence of T cells [5, 16]. Diagnosis is confirmed by the findings of low or absent T cell numbers and absent T cell function in vitro. Other characteristic findings include impaired specific antibody responses and low serum immunoglobulin levels, though IgG levels may be normal in early infancy due to the presence of maternal IgG. Evaluation of all lymphocyte subsets should be performed by flow cytometry. Identification of a genetic cause is important, but it is not required to proceed with treatment.

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A defining radiologic feature of SCID and other severe T cell deficiencies, such as complete DiGeorge anomaly, is the absence of thymus [17]. For example, chest radiography demonstrates a narrow upper mediastinal contour and retrosternal lucency caused by the lack of normal thymic tissue (Fig. 8) [1, 17]. Other radiographic manifestations include severe and/or recurrent pneumonias [18]. Pneumocystis typically produces diffuse interstitial infiltrates that eventually progress to alveolar infiltrates. Viral pneumonia may be radiographically indistinguishable from Pneumocystis pneumonia. Patients with SCID due to adenosine deaminase (ADA) deficiency, a subtype characterized by the most profound lymphopenia, demonstrate unique skeletal imaging abnormalities including cupping and flaring at the costochondral junctions anteriorly, irregularity at the costovertebral junction, and an increased separation of the rib head and vertebral body [19]. A “bone-in-bone” appearance of the vertebral bodies (Fig. 9) has also been described, but this can be a normal appearance in young infants [19]. Infants eventually diagnosed with SCID will often present with chest radiographic abnormalities including linear opacities, bronchiectasis, air trapping, nodular and ground glass opacities, and interstitial thickening likely related to past, often opportunistic, infections prior to the diagnosis of SCID. Patients suspected of having SCID should be placed in protective isolation and avoid contact with potentially ill individuals. Other requirements in the medical management of patients with SCID include immunoglobulin replacement therapy, antibiotic prophylaxis against Pneumocystis jiroveci pneumonia and early treatment of infections. They should only receive irradiated, leukoreduced and cytomegalovirus-negative blood products given the risks of lethal graft-versus-host disease (GVHD) and transmission of infections. Live attenuated vaccines should be avoided. Perhaps one of the most important determinants of long-term outcome is early diagnosis, referral to an immunologist for rapid confirmation of the diagnosis and expedited definitive therapy [20].

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Hematopoietic stem cell transplantation (HSCT) offers the potential for a permanent cure and is currently the standard of treatment for SCID. Though the treatment of choice is an allogeneic HSCT from a human leukocyte antigen (HLA)-identical sibling, chances of amatched donor are small. Advances in the past 3 decades have improved outcomes of patients with SCID undergoing rigorously T cell-depleted, HLA half-matched parental HSCT [15, 16, 21]. Immune reconstitution is achieved and survival rates are high, especially if a related donor transplant is performed in the first 3.5 months of life without pre-transplant


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conditioning [15, 16]. Moreover, the vestigial thymus in infants with SCID is functional, as evidenced by increasing thymic size post-transplantation and long-term maintenance of thymic output [22]. Because patients with SCID lack cellular immunity, HSCT does not require pre-transplant chemotherapeutic conditioning. Post-transplant GVHD prophylaxis is also not necessary even in the HLA half-matched parental HSCT, since the T cells are removed from the graft prior to administration. If GVHD occurs, reactions are usually mild and self-limited [15]. Patients with SCID due to ADA deficiency may also receive enzyme replacement therapy with PEGylated bovine ADA, but its use is limited by its failure to provide adequate or sustained immune reconstitution. An exciting prospect is gene therapy, with promising preliminary results in ADA-SCID [23]. Results from trials for gene therapy for X-linked SCID were initially promising, but have been complicated by development of leukemic transformation due to insertional mutagenesis [24].

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It is intuitive and evident that infants with SCID have a better outcome with earlier diagnosis, avoidance of infections and prompt restoration of immune function. The Secretary of Health and Human Services’ 2010 recommendation that newborn screening for SCID be added to the list of conditions routinely performed. The screening test is for T cell lymphopenia and is performed on dried blood spots. Thirty-nine states have now initiated newborn screening using this method and almost all have detected SCIDs as well as complete DiGeorge anomaly in patients and those with other causes of T cell lymphopenia [25, 26]. DiGeorge anomaly

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DiGeorge anomaly results from defective development of the third and fourth pharyngeal pouches and the classic presentation is a triad of thymic hypoplasia or aplasia, conotruncal anomalies, and hypoplasia or absence of the parathyroid glands. Complete DiGeorge anomaly due to athymia results in profound T cell defects; however, a majority of patients have partial DiGeorge anomaly with some thymic function and varying degrees of T cell deficiency [5, 27]. Complete DiGeorge anomaly may be further divided into typical or atypical phenotypes. Atypical complete DiGeorge anomaly is characterized by an expansion of oligoclonal peripheral T cells that infiltrate organs and is therefore often accompanied by rash and lymphadenopathy [28, 29]. Patients with DiGeorge anomaly have a heterogeneous presentation and may not present with the classic triad of features, emphasizing the need for a high index of suspicion.

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Approximately 75% of patients with DiGeorge anomaly have congenital heart disease, most commonly tetralogy of Fallot, interrupted aortic arch, ventricular septal defects and truncus arteriosus (Fig. 10) [27]. Patients may present with seizures during the neonatal period due to hypocalcemia resulting from absence of the parathyroid glands. Other associated attributes include facial dysmorphism with hooded and down-slanting eyes, low-set ears, short philtrum with fish-mouth appearance, micrognathia, palatal defects, feeding difficulties, gastroesophageal reflux, speech delay and mental retardation. Other syndromes associated with DiGeorge anomaly include CHARGE (coloboma, heart defects, atresia of the choanae, retarded growth and development, genitourinary abnormalities and ear anomalies) and diabetic embryopathy [27, 28].


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There is a continuum of immunodeficiency in DiGeorge anomaly, ranging from a profound T cell immunodeficiency to entirely normal immune function. Fewer than 1% of DiGeorge anomaly patients have complete athymia, so immunodeficiency is less commonly the initial manifestation. Those with complete DiGeorge anomaly and profound T cell deficiency may present similarly to SCID patients, with chronic diarrhea, skin rash, failure to thrive, an absence of tonsillar or lymph tissue on exam, and absence of thymus on imaging (Fig. 11). Moreover, they are also susceptible to infections with opportunistic pathogens and are at significant risk of contracting infections from live attenuated vaccines. Early diagnosis is critical as these patients will not survive without immune reconstitution. Patients with partial DiGeorge anomaly have variable decreases in T cell numbers, but T cell function is normal or only marginally reduced and no immune therapy is required [5, 27].

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The diagnosis of DiGeorge anomaly is based on a combination of clinical characteristics and ancillary studies. As with SCID, complete DiGeorge anomaly may also be associated with significant lymphopenia due to the absence of T cells. Infants with complete DiGeorge anomaly will therefore also benefit from instituting newborn screening and earlier diagnosis. In vitro evaluations of T cell function and specific antibody responses should also be performed. Though B cell function may be compromised from limited T cell help, B cells and NK cells are typically present [5]. In addition, patients suspected of having DiGeorge anomaly should undergo assessments for cardiac disease and abnormal parathyroid function.

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Many, but not all, patients with DiGeorge anomaly have a heterozygous deletion of chromosome 22q11.2 detectable by fluorescent in situ hybridization (FISH). Conversely, not all patients with hemizygous deletion of 22q11.2 have DiGeorge anomaly [27]. An additional molecular defect associated with DiGeorge anomaly is deletion of chromosome 10p13-14 [5]. Again, genetic analysis should not interfere with or postpone pursuit of definitive treatment.

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Treatment of DiGeorge anomaly requires a multidisciplinary approach given the wide range of clinical features. Correction of hypocalcemia and repair of cardiac defects may be critical shortly after birth. Patients with complete DiGeorge anomaly should be placed in protective isolation and require antimicrobial prophylaxis. In these patients, administration of live attenuated vaccines should be avoided and blood products should be irradiated, leukoreduced, and cytomegalovirus negative. Allogeneic thymus transplantation has proven to be a promising, life-saving cure with good survival rates and evidence of functional immune reconstitution [29]. There is also early interest in parental parathyroid grafts to correct the hypoparathyroidism, but further prospective study is needed to optimize success of engraftment and function [30]. Patients may otherwise require lifelong calcium and vitamin D supplementation.

Combined immunodeficiency disorders Combined immunodeficiency disorders (CIDs) are a spectrum of diseases characterized by reduced, but not absent, T cell function and include (among others) Wiskott-Aldrich syndrome, cartilage-hair hypoplasia, ataxia-telangiectasia and purine nucleoside phosphorylase deficiency [16]. Though the number of circulating B cells is typically normal,


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reduced antibody function is often present. CIDs have heterogeneous clinical presentations, but there are often distinctive features that serve as diagnostic clues. Wiskott-Aldrich syndrome is characterized by the clinical triad of eczema, thrombocytopenia with small platelets and immunodeficiency [5, 31]. Clinical manifestations include bloody diarrhea, excessive bleeding from a circumcision site and easy bruising. Sinopulmonary infections with common pathogens occur most frequently in Wiskott-Aldrich syndrome, though severe infections with opportunistic pathogens, such as Pneumocystis jiroveci and herpes simplex, also occur. Patients with AT exhibit progressive cerebellar ataxia and deterioration of motor skills, oculocutaneous telangiectasia and immunodeficiency [8, 32]. Opportunistic infections are rare, but recurrent infections involving the respiratory tract may lead to chronic lung disease. Cartilage-hair hypoplasia is a genetic form of metaphyseal chondrodysplasia associated with short stature, redundant skin folds of the neck and extremities, and sparse hair [5, 33]. Immunodeficiency is also common, and potentially lethal or fatal infections with varicella, vaccinia and poliovirus have been described. Wiskott-Aldrich syndrome, cartilage-hair hypoplasia and ataxia-telangiectasia also all share a significantly increased risk of malignancy.

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CIDs are associated with reduced cellular and humoral immune function [5, 31–33]. Decreased numbers or percentages of T cells and depressed proliferative responses to mitogens are common. There is also often defective antibody-mediated immunity with high variability in the concentrations of immunoglobulins. In addition, Wiskott-Aldrich syndrome patients typically have thrombocytopenia, and cartilage-hair hypoplasia patients often exhibit lymphopenia, anemia, neutropenia or a combination of cytopenias. If a CID is suspected, confirmatory testing by mutation analysis can be performed. Wiskott-Aldrich syndrome is caused by mutations in the Wiskott-Aldrich syndrome protein (WASP) gene, mapped to Xp11.22-11.23 [8, 27]. AT and cartilage-hair hypoplasia are both autosomal recessive conditions. The mutated gene in ataxia-telangiectasia (ATM) is located on chromosome 11q22-23 [8, 28]. The abnormal gene in cartilage-hair hypoplasia encodes the ribonucleic acid (RNA) component of the mitochondrial RNA processing endoribonuclease (RMRP) and is located on chromosome 9p21-23 [5, 33].

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Imaging studies can often aid in the establishment of a CID. Noteworthy findings are related to infectious complications or sequelae and may include otitis media, sinusitis, mastoiditis and pneumonia. Imaging findings in Wiskott-Aldrich syndrome include recurrent pneumonia, sinusitis and mastoiditis as well as hemorrhage related to thrombocytopenia [17]. ataxia-telangiectasia patients demonstrate diffuse cerebellar atrophy, with predilection for the cerebellar vermis (Fig. 12) [34]. Patients with Wiskott-Aldrich syndrome and ataxiatelangiectasia share the highest incidence of malignancy (Fig. 13). Of particular importance to ataxia-telangiectasia patients and some types of SCID patients is that imaging studies using ionizing radiation must be minimized as possible due to the increased risk of malignancy resulting from altered repair mechanisms following deoxyribonucleic acid (DNA) damage from radiation exposure. Imaging findings in cartilage-hair hypoplasia are similar to those of other CIDs with added skeletal manifestations of short-limbed dwarfism. The skeletal dysplasia is characterized by widening, scalloping, and sclerosis of the metaphyses of tubular bones (Fig. 14) [35, 36].


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Patients with milder degrees of immunodeficiency do not require immune reconstitution for survival, but patients with more severe defects in immunity may require definitive therapy. Unfortunately, there is currently no curative treatment option for ataxia-telangiectasia and outcome is poor. The most common causes of death are malignancy and advancing neurological disease [5]. For other CIDs, HSCT has had good long-term results because of improvements in donor selection and post-transplant care in the past decade. Though an HLA-identical sibling donor is ideal, comparable results have recently been achieved using closely matched related and unrelated donors [31, 33]. In contrast to patients with absent cellular immunity, patients with a CID require reduced intensity pre-transplant conditioning to ensure successful donor engraftment. Patients should only receive leukoreduced, irradiated, and cytomegalovirus-negative blood products. Live attenuated vaccines should not be given. In addition, immunoglobulin replacement therapy and antimicrobial prophylaxis may also be indicated. Patients with Wiskott-Aldrich syndrome who do not get transplantation may need a splenectomy for persistent thrombocytopenia.

Disorders of phagocytic cells and adhesion molecules

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Primary phagocytic immunodeficiencies may be divided into disorders associated with defects in phagocyte numbers, adhesion, signaling or function [37]. Leukocyte adhesion deficiency (LAD) results from genetic mutations affecting molecules essential for neutrophil and lymphocyte adhesion to blood vessel walls, with resultant defective chemotaxis and lymphocyte killing. The interferon-gamma (IFN-γ) and interleukin-12 (IL-12) pathway is pivotal in innate immunity and defects in this axis result in severely impaired defense against intracellular pathogens. Chronic granolumatous disease (CGD) is also characterized by defective intracellular killing due to mutations involving components of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an enzyme instrumental in the generation of reactive oxygen species. Disorders involving defective neutrophil granule formation and function are rare and include myeloperoxidase deficiency, the ChédiakHigashi syndrome and neutrophil-specific granule deficiency.

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Phagocyte disorders may have variable presentations, but all share an increased susceptibility to infection with bacteria, primarily those on the skin and gut mucosa, and fungi. The infections can be severe and refractory to conventional treatment, often a clue of an underlying immunodeficiency. In addition to an increased risk of infections, congenital neutropenias are characterized by either a chronic or intermittent decrease in neutrophil counts. In contrast, LAD is associated with an increase in circulating neutrophil numbers, even in the absence of infection, due to abnormal trafficking and inability to egress from the vascular system. LAD type I is the most common and is manifested by delayed umbilical cord separation, poor pus formation, poor wound healing, periodontal disease and recurrent skin infections. Diagnosis may be established by performing flow cytometry to evaluate for expression of CD18, which is deficient in LAD type I. LAD types II and III have been described in only few patients, but they also present with leukocytosis and recurrent infections [38]. Mutations in the IFN-γ and IL-12 pathway are also rare, and patients are uniquely susceptible to primarily disseminated mycobacterial and Salmonella species infections [5].


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CGD is characterized by recurrent and refractory infections with catalase-positive bacteria and fungi, most commonly Staphylococcus aureus, Serratia marescens, Burkholderia cepacia, Nocardia and Aspergillus species. In recent years, a novel bacterium Granulibacter bethesdensis has been discovered and characterized as a cause of significant infection in CGD [39]. In decreasing order of frequency, types of infection include pneumonia, abscess formation, suppurative adenitis and osteomyelitis. Frequent sites of abscess involvement include subcutaneous tissue, liver, lymph nodes, lung and perirectal area [40]. There is also tissue granuloma formation. Diagnosis is confirmed by an abnormal assay of oxidase function in the dihydrorhodamine test. Genetic testing is available to confirm presence of mutation in an NADPH oxidase subunit. CGD has either an autosomal recessive or, more commonly, an X-linked recessive inheritance pattern.

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Imaging findings include recurrent and chronic pneumonia, often resulting in pleural reaction/thickening or lung abscess (Fig, 15) [41]. Aspergillus infection manifests in a variety of radiographic patterns, such as segmental or lobar infiltrates, nodular opacities and cavitation [42]. Suppurative lymphadenitis, subcutaneous and chest wall abscesses, and osteomyelitis are all known complications of CGD. Esophagitis and esophageal strictures have been described in this population [43, 44]. In the abdomen, CGD patients often develop hepatic (Fig. 16) and splenic (Fig. 17) abscesses, renal infections and granuloma formation leading to bronchial, esophageal and gastric antral narrowing, duodenal fold thickening, enteritis and colitis, enteric fistulas and sinus tracts, bladder wall thickening, and ureteral and urethral strictures [40, 45–47].

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Patients with Chédiak-Higashi syndrome demonstrate nonspecific hilar and mediastinal lymphadenopathy and hepatosplenomegaly. Brain imaging demonstrates cerebral atrophy, CT hypodensity, and MR T2-hyperintensity in periventricular white matter and corona radiata [48]. Early diagnosis and appropriate antimicrobial therapy are the mainstay in the treatment of acute infections in patients with phagocytic immunodeficiencies. Long-term antimicrobial prophylaxis is also important. The increase in the antifungal armamentarium during the past decade with the introduction of voriconazole and posaconazole has contributed to improved survival. Abscesses may require invasive surgical drainage. HSCT is a potential curative treatment for both LAD and CGD, and available data show promising long-term outcome results [49–51]. Filgastrim, a granulocyte colony-stimulating factor analogue, is used in chronic neutropenia syndromes and other phagocyte disorders when neutropenia is present.

Other immunodeficiencies Author Manuscript

Hyper IgE syndrome Hyper-IgE syndrome (HIES), also known as Buckley syndrome, is characterized by recurrent infections involving the skin and lower respiratory tract, eczematous rash, bone and teeth anomalies, and elevated serum IgE levels [5, 52]. Patients invariably suffer from recurrent skin abscesses and pneumonias, most commonly due to Staphylococcus aureus. Chronic infections with candida and gram-negative bacteria are also frequent. Recurrent and chronic infections of the lung often result in pneumatoceles. Musculoskeletal abnormalities


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include osteopenia with recurrent fractures. Delayed shedding of the primary teeth is also a consistent finding. In addition, patients have coarse facial features with a prominent forehead, deep set eyes and broad nasal bridge with fleshy nasal tip.

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Though elevated IgE levels are typical, they do not correlate with disease severity. IgD levels are also elevated in majority of hyper-IgE patients. In addition, blood and sputum eosinophils are frequently increased [5]. No specific immune defect occurs consistently in patients with HIES, but poor recall antibody responses are most common. Deficiencies involving cellular immunity have also been described [5, 52]. Only in the past 5 years have the genetic etiologies of HIES been discovered and correlated with clinical phenotype. Mutations in signal transducer and activator of transcription 3 (STAT3) are the cause of the autosomal dominant form of HIES (AD-HIES). An autosomal recessive form of HIES (ARHIES) has recently been described and is due to mutations involving the dedicator of cytokinesis 8 (DOCK8) gene [52]. AR-HIES shares certain clinical features with AD-HIES, including eczema, recurrent sinopulmonary infections, elevated IgE levels and eosinophilia. In contrast to AD-HIES, musculoskeletal and dental abnormalities and development of pneumatoceles are rare in AR-HIES [52]. Perhaps the most striking and distinctive feature of AR-HIES is the propensity for recurrent cutaneous viral infections, including widespread Molluscum contagiosum, warts caused by human papilloma virus, and recurrent herpes simplex virus and varicella zoster. Moreover, neurological complications, such as central nervous system bleeding and infarction, have been described [52]. Mutations in the gene encoding tyrosine kinase 2 (Tyk2) has also been reported in two individuals with AR-HIES [52].

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Imaging findings in patients with HIES include persistent pneumatocele formation from recurrent staphylococcal pneumonias (Fig. 18). These pneumatoceles may become extremely large, superinfected and require surgical excision [53]. Fractures after minimal trauma are also associated with this syndrome, related to osteoporosis (Fig. 19) [54].

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Regardless of the underlying genetic etiology, treatment of HIES requires early detection and treatment of infections. Measures to prevent bacterial colonization include antiseptic treatments of the skin and continuous antibiotic prophylaxis. Antifungal prophylaxis may also be necessary. Patients require resection of pneumatoceles and even pneumonectomy. Patients with AD-HIES often survive into adulthood and lead full lives with adequate prevention and treatment of infections, though successful allogeneic HSCT has been described in two cases [55]. Allogeneic HSCT has also been reported in two patients with DOCK8 deficiency [56, 57]. Hyper-IgE patients are at increased risk of malignancy, particularly lymphoma. In addition, patients with AR-HIES have an increased rate of squamous cell carcinoma likely associated with chronic HPV infection [52].

Conclusion Primary immunodeficiencies result from a wide variety of molecular defects that adversely affect the development and function of the immune system. The variability of the clinical features among patients with a primary immunodeficiency demands a high degree of suspicion. Many recent advances in the diagnosis and clinical care of these PIDDs have


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contributed significantly to improved outcome and survival. Timely diagnosis and early institution of appropriate therapy, however, is always critical. A radiologist’s familiarity with these PIDDs and associated imaging findings is also essential, as imaging plays an integral role in both diagnosis and surveillance.

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A 14-year-old girl with hyper-IgM syndrome. Coronal CT image through the midface reveals mucosal thickening of the maxillary sinuses as well as near complete opacification of the ethmoid air cells. Marked thickening of the nasopharyngeal mucosa is also evident


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Fig. 2.

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A 32-year-old man with X-linked agammaglobulinemia complicated by Crohn disease with enterocutaneous fistula. a Intravenous and oral contrast-enhanced axial CT image through the pelvis demonstrates punctate foci of air extending through the anterior abdominal wall musculature into the subcutaneous fat (arrow). The fat also has increased attenuation due to inflammation. Punctate low attenuation focus in the left rectus muscle (arrowhead) probably represents a small abscess. b Higher attenuation within the same region in the anterior subcutaneous fat represents oral contrast media. Associated bowel wall thickening is also present (arrows)


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Fig. 3.

Intravenous contrast-enhanced CT examination in a 13-year-old boy with common variable immunodeficiency. a Axial image at the level of the lower thorax and (b) coronal reformation demonstrate lower lobe bronchiectasis (arrows) with atelectasis seen in the right middle lobe (arrowheads). Note also areas of air trapping likely from small airways inflammation. c Coronal reconstruction from the abdomen and pelvis CT demonstrate multiple prominent lymph nodes (arrows)


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Fig. 4.

MRI of the brain in a 22-month-old boy with X-linked agammaglobulinemia. a T2-weighted axial image at the level of the lateral ventricles demonstrates normal appearance of the lateral ventricles and periventricular white matter. b MRI performed two years later at a similar level shows diffuse volume loss, advanced for age, which has markedly progressed in the interval. Interval increase in the size of the lateral ventricles is likely secondary to progressive volume loss. There is now also scattered T2 prolongation throughout the


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supratentorial white matter (arrows) that is believed to be secondary to encephalitis. The patient now has a ventricular shunt in place (arrowhead)

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Fig. 5.

MRI of the brain in a 2-year-old boy with X-linked agammaglobulinemia. Post-contrast axial T1-weighted (a) and 3-D spoiled gradient echo (b) images demonstrate a rimenhancing lesion in the right cerebellum (arrows), representing an abscess


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Fig. 6.

Unenhanced CT chest at the level of the heart using lung window and levels in a 28-year-old man with common variable immunodeficiency and lymphoid interstitial pneumonia shows diffuse bronchiectasis that was predominately distributed in the lower lobes, with nodular opacities due to lymphocytic infiltration, and small bilateral pleural effusions (better seen with soft-tissue window and level)


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Fig. 7.

A 13-year-old boy with common variable immunodeficiency and lymphoproliferation in the abdomen. Coronal enhanced CT image demonstrates enlarged lymphoid tissue in the porta hepatis and retroperitoneal regions (arrows). The spleen is markedly enlarged


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Fig. 8.

A 7-month-old boy with severe combined immunodeficiency. a Frontal chest radiograph demonstrates a narrow mediastinal contour. b Absent thymic tissue is evident as a prominent anterior clear space on the lateral view. Hyperinflation is present and there are patchy areas of heterogeneous opacification, most likely representing atypical infection, which is often both chronic and acute with small airways disease and air trapping


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Fig. 9.

A 2-month-old boy with severe combined immunodeficiency due to adenosine deaminase deficiency. a Frontal chest radiograph demonstrates narrow superior mediastinum, and (b) lateral view shows prominent anterior clear space due to thymic absence. Anterior rib cupping at the costochondral junctions is particularly evident on the right side (arrows in a)


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Author Manuscript Author Manuscript Author Manuscript Fig. 10.

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IV contrast-enhanced chest CT in a 2-year-old boy with complete DiGeorge anomaly status post repair of pulmonary atresia and unrepaired ventricular septal defect. a Axial image at the level of the aortic arch demonstrates a right-side arch with an aberrant left subclavian artery (arrow) and no thymic tissue. b Axial image at the midventricular level shows the large ventricular septal defect (*), a small right ventricle (RV) and the right-side descending thoracic aorta (arrow)


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Fig. 11.

A 2-month-old boy with DiGeorge anomaly. Sagittal volumetric interpolated breath-hold examination (VIBE) post-contrast image shows cardiac tissue directly apposed to the chest wall without intervening thymus


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Fig. 12.

A 6-year-old girl with ataxia telangiectasia. Three-dimensional axial T1 acquisition in coronal (a) and sagittal (b) planes. The cerebellum is atrophic, with thinning of the cerebellar cortex both laterally as well as in the vermis


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Fig. 13.

Same patient as in Fig. 12 with ataxia telangiectasia, now 8 years old and with mucosaassociated lymphoid tissue (MALT) lymphoma. a Coronal maximum intensity projection image from 18-Fluorodeoxyglucose positron emission tomography (FDG-PET)/CT examination demonstrates abnormal radiotracer uptake in the stomach. b Axial CT image from FDG-PET/CT examination demonstrates wall thickening of the stomach (arrow) correlating with FDG avidity


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Fig. 14.

A 10-month-old boy with cartilage-hair hypoplasia. Frontal radiographs of the lower extremities demonstrate bowing and metaphyseal flaring and growth plate irregularity


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Author Manuscript Author Manuscript Author Manuscript Fig. 15.

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A 14-year-old boy with chronic granolumatous disease. Axial image (a) and coronal reformation (b) from noncontrast enhanced CT of the chest (lung window and level images) demonstrate right lower and middle lobe consolidation and cavitation [arrows in (a) and (b)] due to pneumonia. Right pleural effusion was better seen on soft-tissue window and level. There is also scarring and some cavitary change seen in the left upper lobe in (b) due to prior infection


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Fig. 16.

A 19-month-old boy with chronic granolumatous disease and liver abscesses. a Coronal half-Fourier acquired single-shot turbo spin echo (HASTE) from an MRI of the abdomen and pelvis demonstrates targetoid T2 hyperintense foci representing abscesses in the right and left lobes of the liver. b Corresponding focused transverse US image of the left lobe of the liver demonstrates an ill-defined, septated hypoechoic abscess


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Fig. 17.

A 32-year-old boy with chronic granolumatous disease and splenic abscesses. Axial intravenous contrast-enhanced images at the level of the splenic hilum superiorly (a) and more inferiorly (b), show innumerable tiny low attenuation splenic lesions representing microabscesses. There is also marked splenomegaly


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Fig. 18.

A 17-year-old girl with hyper-IgE syndrome. Axial CT image demonstrates thin-walled cystic lucencies in the bilateral lower lobes representing pneumatoceles


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Fig. 19.

Sagittal reformatted CT image of the lower thoracic and lumbar spine in a 27-year-old man with hyper-IgE syndrome. Compression deformity of the T12 vertebral body is likely due to syndrome-related osteoporosis


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Table 1

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Clinical findings in the major subgroups of primary immunodeficiency disorders

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Subgroup

Patterns of infections

Other notable features

Humoral immunodeficiency disorders X-linked agammaglobulinemia Common variable immunodeficiency Selective IgA deficiency Hyper-IgM syndromes

Recurrent bacterial sinopulmonary infections with encapsulated organisms (Haemophilus influenzae, pneumococci, streptococci) Chronic or recurrent gastroenteritis (enterovirus, Giardia lamblia) Chronic enteroviral meningoencephalitis Septic arthritis (mycoplasma, ureaplasma)

Autoimmunity, including AIHA, ITP, IBD Nodular lymphoid hyperplasia Bronchiectasis

Primary cellular and combined immunodeficiency disorders Severe combined immunodeficiency DiGeorge anomaly Wiskott-Aldrich syndrome Cartilage-hair hypoplasia Ataxia-telangiectasia PNP deficiency

Severe or unusual viral infections Fungal infections, including oral thrush (Candida albicans) Pneumocystis jiroveci pneumonia Post-vaccination disseminated BCG infection

Failure to thrive Chronic diarrhea and malabsorption Graft-versus-host disease Congenital heart disease (DiGeorge anomaly) Cytopenias

Phagocytic disorders Leukocyte adhesion deficiency Chronic granulomatous disease IFN-γ/IL-12 pathway Myeloperoxidase deficiency Chédiak-Higashi syndrome Neutrophil-specific granule deficiency

Skin abscesses and lymphadenitis Bacterial pneumonia Recurrent infections with catalase positive organisms and fungi (CGD) (Staphylococcus aureus, Serratia marescens,

Chronic periodontal disease Delayed separation of the umbilical cord (LAD)

Burkholderia cepacia Nocardia and Aspergillus)

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Complement disorders

Recurrent Neisserial infections Pyogenic bacterial infections with encapsulated organisms

Autoimmunity, including RA and SLE Hereditary angioedema

Other immunodeficiencies Hyper IgE syndrome

Recurrent bacterial pneumonias (Staphylococcus aureus, Haemophilus influenzae, pneumococci) Staphylococcal skin abscesses Pneumatoceles (may be suprainfected with Pseudomonas and Aspergillus) Chronic mucocutaneous candidiasis Cutaneous viral infections (Molluscum contagiosum, HPV, HSV, VZV)

Severe eczema Osteopenia and pathological fractures Delayed shedding of primary teeth Elevated serum IgE levels and eosinophilia CNS bleeding and infarction

AIHA autoimmune hemolytic anemia, BCG bacillus Calmette-Guérin, CGD chronic granulomatous disease, CNS central nervous system, HPV human papillomavirus HSV herpes simplex virus, IBD inflammatory bowel disease, IFN interferon, Ig immunoglobulin, IL interleukin, ITP idiopathic thrombocytopenic purpura, LAD leukocyte adhesion deficiency, PNP purine nucleoside phosphorylase, RA rheumatoid arthritis, SLE systemic lupus erythematosus. VZV varicella zoster virus


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Table 2

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Genetic defects leading to primary immunodeficiency diseases Chromosome

Primary immunodeficiency disease

Humoral immunodeficiency disorders X-linked agammaglobulinemia (XLA) and agammaglobulinemia 10q23.2-q23.33

Agammaglobulinemia due to BLNK deficiency

19p13.2

Agammaglobulinemia caused by mutations in Iga gene

22q11.2

Agammaglobulinemia caused by mutations in λ5 surrogate lightchain gene

Xq22

XLA caused by Bruton tyrosine kinase (Btk) deficiency

Common variable immunodeficiency (CVID)

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2q33

Autosomal recessive CVID due to ICOS deficiency

6p21.3

(?) CVID and selective IgA deficiency

16p11.2

CVID due to CD19 deficiency

17p11.2

CVID or selective IgA deficiency due to TACI deficiency

22q13.1-q13.3

CVID due to BAFF-R deficiency

Hyper-IgM syndrome 12

Hyper-IgM caused by deficiency of uracil-DNA glycosylase

12p13

Hyper-IgM caused by deficiency of activation-induced cytidine deaminase

20q12-q13.2

Hyper-IgM due to CD40 deficiency

Xq26

Hyper-IgM caused by CD154 (CD40 ligand) deficiency

Primary cellular and combined immunodeficiency disorders Severe combined immunodeficiency (SCID)

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1q22-q25

SCID due to CD3 δ-chain deficiency

1q31-q32

SCID due to CD45 deficiency

5p13

SCID or Omenn syndrome due to IL-7 receptor α-chain deficiency

10p13

SCID (Athabascan, radiation sensitive) due to mutations in the Artemis gene

11p13

SCID or Omenn syndrome caused by RAG-1 or RAG-2 deficiencies

11q23

SCID or non-SCID due to CD3 γ- δ-, or ε- chain deficiencies

19p13.1

SCID due to Janus kinase 3 (Jak3) deficiency

20q13.2-q13.11

SCID due to adenosine deaminase (ADA) deficiency

Xq13.1-q13.3

X-linked SCID due to common γ-chain (γc) deficiency

2q35

CID with microcephaly due to Cernunnos deficiency

DiGeorge anomaly

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10p13

DiGeorge anomaly/velocardiofacial syndrome

22q11.2

DiGeorge anomaly/velocardiofacial syndrome

Combined immunodeficiency disorders Xp11.22

Wiskott-Aldrich syndrome (WAS) caused by WAS protein (WASP) deficiency

9p13

Cartilage-hair hypoplasia due to deficiency of RNA component of


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Chromosome

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Primary immunodeficiency disease mitochondrial RNA-processing endoribonuclease

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11q22.3

Ataxia-telangiectasia (AT), attributable to AT mutation, causing deficiency of DNA-dependent kinase

14q13.1

Purine nucleoside phosphorylase (PNP) deficiency

Disorders of phagocytic cells and adhesion molecules Leukocyte adhesion deficiency (LAD) 21q22.3

LAD type 1 (LAD-1) caused by CD18 deficiency

11q14.3-q21

LAD-2 due to deficiency of sialyl LewisX

Interferon-gamma (IFN-γ) and interleukin-12 (IL-12) pathway defects

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5q31.1-q33.1

IL-12 p40 deficiency

19p13.1

IL-12R β-chain deficiency

6q23-q24

IFN-γ receptor 1 deficiency due to α-chain deficiency

21q22.1-q22.2

IFN-γ receptor 2 deficiency due to β-chain deficiency

Chronic granulomatous disease (CGD) 1q25

CGD caused by gp67phox deficiency

7q11.23


16q24


Xp21.1


BLNK B-cell linker, CID combined immunodeficiency disorder, DNA deoxyribonucleic acid, gp gene product, ICOS inducible T-cell costimulator, IFN interferon, Ig immunoglobulin, IL interleukin, phox phagocytic oxidase, RAG recombination-activating gene, RNA ribonucleic acid, TACI transmembrane activator and CAML (calcium-modulator and cyclophilin ligand) interactor

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Primary and acquired immunodeficiency disorders.

Dose and outcomes in primary immunodeficiency disorders.

Biologic response modifiers in primary immunodeficiency disorders.

Vaccine use in primary immunodeficiency disorders.

Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency.

Pituitary apoplexy: an update on clinical and imaging features.

Primary immunodeficiency disorders in Iran: update and new insights from the third report of the national registry.

Prostate Imaging--An Update.

An update on the use of immunoglobulin for the treatment of immunodeficiency disorders.

Sleep and substance use disorders: an update.

Primary immunodeficiency update: Part I. Syndromes associated with eczematous dermatitis.

Diagnosing endometriosis in primary care: clinical update.

Gestational Trophoblastic Disorders: An Update in 2015.

The value of family history in diagnosing primary immunodeficiency disorders.

Primary Immunodeficiency Disorders in India-A Situational Review.

Pulmonary manifestations of primary immunodeficiency disorders in children.

Primary immunodeficiency diseases and Epstein-Barr virus-induced lymphoproliferative disorders.

Poliovirus Excretion in Children with Primary Immunodeficiency Disorders, India.

Spectrum of primary immunodeficiency disorders in Sri Lanka.

Safety Considerations with Dual Bronchodilator Therapy in COPD: An Update.

Hormone therapy in menopause: An update on cardiovascular disease considerations.

Primary ovarian insufficiency: an update.

[Primary CNS lymphoma--an update].

Pharmacogenetic considerations for HIV treatment in different ethnicities: an update.