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Primary Immunodeficiencies
Tomás Franquet, MD, PhD
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KEY FACTS

  • Terminology

    • Imaging

      • Top Differential Diagnoses

        • Clinical Issues

          • Diagnostic Checklist

            TERMINOLOGY

            • Abbreviations

              • Primary immunodeficiency disorders (PIDD)
            • Definitions

              • Heterogeneous group of genetic diseases involving immune system
                • > 300 distinct disorders described
              • Disorders of antibody function
                • Selective IgA deficiency (SIgAD)
                  • Most common of all inborn defects of humoral immunity
                  • Isolated absence or near absence of serum and secretory IgA
                    • Serum IgA < 5 mg/dL
                  • > 1% of recurrent infections in children
                    • Pneumonia: Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma species, enterovirus species
                    • Asthma and bronchiectasis
                  • Other complications
                    • Interstitial lung disease: Lymphoid interstitial pneumonia, organizing pneumonia
                    • Lymphoma: Hodgkin lymphoma, non-Hodgkin lymphoma (B-cell origin)
                    • Autoimmunity: Immune thrombocytopenic purpura, hemolytic anemia, rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, vasculitis
                • Common variable immunodeficiency (CVID)
                  • Most frequent symptomatic primary immunodeficiency
                  • Familial but not strictly X-linked or autosomally inherited
                  • Increased risk of lymphoreticular tumors and autoimmune diseases
                    • 20-30% of patients with CVID have autoimmune diseases
                    • Thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, primary biliary cirrhosis
                  • Associated pulmonary diseases
                    • Lung infections
                    • Interstitial lung disease: Granulomatous-lymphocytic interstitial lung disease (GLILD), organizing pneumonia, lymphoproliferative disorders
                    • Chronic airway disease
                  • GLILD
                    • 10-30% of patients with CVID
                    • Diffuse lung involvement by granulomas with benign lymphoproliferative infiltrates
                  • Symptoms: Early or late childhood or adulthood
                    • Acute: Productive cough, change in sputum, and increased dyspnea (should suggest infection)
                    • Chronic: Fever and lymphadenopathy (should suggest lymphoproliferative disorder)
                • X-linked agammaglobulinemia (XLA)
                  • Autosomal recessive: Interruption of normal B-cell maturation by defect in tyrosine kinase production
                    • Small adenoids, tonsils, and lymph nodes
                  • Recurrent otitis: Most common infection prior to diagnosis
                  • Pulmonary infections shortly after birth
                    • Secondary complications: Sinopulmonary infections (Staphylococcus aureus, S. pneumoniae, H. influenzae)
                  • Up to 30% of affected patients have autoimmune diseases
                  • 5% of affected patients may develop lymphoma and other lymphoreticular malignancies
              • Cellular and combined immunodeficiency disorders
                • DiGeorge syndrome (thymic hypoplasia)
                  • Gene defects on chromosome 22
                    • Impaired function of thymus and parathyroid glands
                    • Cardiovascular anomalies: Right-sided aortic arch, interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, and atrial or ventricular septal defects
                  • Degree of thymic hypoplasia: Highly variable T-cell number
                    • Severe immunodeficiency (complete DiGeorge syndrome): Susceptible to viral or Pneumocystis jirovecii infections
                • Severe combined immunodeficiency (SCID)
                  • Absence of T- and B-cell (and sometimes natural killer cell) function
                  • Recurrent severe pneumonia
                    • Most common pathogens: P. jirovecii, parainfluenza 3, respiratory syncytial virus, adenovirus, cytomegalovirus, bacteria
                • Autosomal dominant hyper-IgE syndrome (AD-HIES)
                  • Otherwise called Job syndrome
                  • Usually diagnosed in infancy
                    • Classic triad: Staphylococcal infections of skin, cyst-forming pneumonias, and IgE levels at least 10 times normal
                  • Recurrent pyogenic pneumonias
                    • Most common pathogens: S. aureus, S. pneumoniae, H. influenzae, Aspergillus fumigatus, Pseudomonas, and P. jirovecii
                    • Complications: Empyema, pneumatocele formation, bronchiectasis
                    • Single or multiple pneumatoceles: May expand when superinfected with bacteria and fungi
                • Wiskott-Aldrich syndrome (WAS)
                  • X-linked recessive immunodeficiency disorder: Eczema, thrombocytopenia with small defective platelets, recurrent infections
                    • Prolonged bleeding from circumcision site, bruising, or bloody diarrhea during infancy
                  • Pyogenic infections before 1st year of age: Meningitis, otitis media, pneumonia, sepsis
                    • Most common pathogens: S. pneumoniae, P. jirovecii, and herpes viruses
                  • Massive bleeding, infection, vasculitis, autoimmune cytopenias, or lymphoreticular malignancies are common causes of death
              • Phagocytic defects
                • Chronic granulomatous disease (CGD)
                  • Defect in membrane-associated nicotinamide adenine dinucleotide phosphate oxidase in phagocytic cells
                  • Onset in infancy, childhood, or, less commonly, early adolescence
                    • Male:female ratio of 6:1
                  • Recurrent bronchopneumonia, empyema, and lung abscess
                    • Most common pathogens: S. aureus, Klebsiella, Pseudomonas, Aspergillus, and Candida
                • Chédiak-Higashi syndrome (CHS)
                  • Rare autosomal recessive defect
                    • Impaired microbicidal activity of phagocytes
                  • Up to 30% of affected patients have segmental or lobar pneumonia
                    • S. aureus, H. influenzae, group A streptococcus, and gram-negative organisms (Klebsiella, Pseudomonas)
                  • Acute respiratory failure
                    • Extensive histiocytic infiltration of lungs
              • Other immunodeficiencies
                • Chronic mucocutaneous candidiasis (CMC)
                  • Phenotypic manifestation of complex immunodeficiency
                  • Recurrent or persistent Candida infections of skin, nails, oropharynx, and lung
                  • Risk of developing bronchiectasis in early childhood

            IMAGING

            • Radiographic Findings

              • CT Findings

                DIFFERENTIAL DIAGNOSIS

                  CLINICAL ISSUES

                  • Presentation

                    • Demographics

                      DIAGNOSTIC CHECKLIST

                      • Consider

                        • Image Interpretation Pearls

                          Selected References

                          1. Freeman AF et al: Hyper-IgE syndromes and the lung. Clin Chest Med. 37(3):557-67, 2016
                          2. Wu EY et al: Clinical and imaging considerations in primary immunodeficiency disorders: an update. Pediatr Radiol. 46(12):1630-1644, 2016
                          3. Nonas S: Pulmonary Manifestations of primary immunodeficiency disorders. Immunol Allergy Clin North Am. 35(4):753-66, 2015
                          4. Touw CM et al: Detection of pulmonary complications in common variable immunodeficiency. Pediatr Allergy Immunol. 21(5):793-805, 2010
                          5. Tanaka N et al: Lung diseases in patients with common variable immunodeficiency: chest radiographic, and computed tomographic findings. J Comput Assist Tomogr. 30(5):828-38, 2006
                          Related Anatomy
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                          Related Differential Diagnoses
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                          References
                          Tables

                          Tables

                          KEY FACTS

                          • Terminology

                            • Imaging

                              • Top Differential Diagnoses

                                • Clinical Issues

                                  • Diagnostic Checklist

                                    TERMINOLOGY

                                    • Abbreviations

                                      • Primary immunodeficiency disorders (PIDD)
                                    • Definitions

                                      • Heterogeneous group of genetic diseases involving immune system
                                        • > 300 distinct disorders described
                                      • Disorders of antibody function
                                        • Selective IgA deficiency (SIgAD)
                                          • Most common of all inborn defects of humoral immunity
                                          • Isolated absence or near absence of serum and secretory IgA
                                            • Serum IgA < 5 mg/dL
                                          • > 1% of recurrent infections in children
                                            • Pneumonia: Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma species, enterovirus species
                                            • Asthma and bronchiectasis
                                          • Other complications
                                            • Interstitial lung disease: Lymphoid interstitial pneumonia, organizing pneumonia
                                            • Lymphoma: Hodgkin lymphoma, non-Hodgkin lymphoma (B-cell origin)
                                            • Autoimmunity: Immune thrombocytopenic purpura, hemolytic anemia, rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, vasculitis
                                        • Common variable immunodeficiency (CVID)
                                          • Most frequent symptomatic primary immunodeficiency
                                          • Familial but not strictly X-linked or autosomally inherited
                                          • Increased risk of lymphoreticular tumors and autoimmune diseases
                                            • 20-30% of patients with CVID have autoimmune diseases
                                            • Thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, primary biliary cirrhosis
                                          • Associated pulmonary diseases
                                            • Lung infections
                                            • Interstitial lung disease: Granulomatous-lymphocytic interstitial lung disease (GLILD), organizing pneumonia, lymphoproliferative disorders
                                            • Chronic airway disease
                                          • GLILD
                                            • 10-30% of patients with CVID
                                            • Diffuse lung involvement by granulomas with benign lymphoproliferative infiltrates
                                          • Symptoms: Early or late childhood or adulthood
                                            • Acute: Productive cough, change in sputum, and increased dyspnea (should suggest infection)
                                            • Chronic: Fever and lymphadenopathy (should suggest lymphoproliferative disorder)
                                        • X-linked agammaglobulinemia (XLA)
                                          • Autosomal recessive: Interruption of normal B-cell maturation by defect in tyrosine kinase production
                                            • Small adenoids, tonsils, and lymph nodes
                                          • Recurrent otitis: Most common infection prior to diagnosis
                                          • Pulmonary infections shortly after birth
                                            • Secondary complications: Sinopulmonary infections (Staphylococcus aureus, S. pneumoniae, H. influenzae)
                                          • Up to 30% of affected patients have autoimmune diseases
                                          • 5% of affected patients may develop lymphoma and other lymphoreticular malignancies
                                      • Cellular and combined immunodeficiency disorders
                                        • DiGeorge syndrome (thymic hypoplasia)
                                          • Gene defects on chromosome 22
                                            • Impaired function of thymus and parathyroid glands
                                            • Cardiovascular anomalies: Right-sided aortic arch, interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, and atrial or ventricular septal defects
                                          • Degree of thymic hypoplasia: Highly variable T-cell number
                                            • Severe immunodeficiency (complete DiGeorge syndrome): Susceptible to viral or Pneumocystis jirovecii infections
                                        • Severe combined immunodeficiency (SCID)
                                          • Absence of T- and B-cell (and sometimes natural killer cell) function
                                          • Recurrent severe pneumonia
                                            • Most common pathogens: P. jirovecii, parainfluenza 3, respiratory syncytial virus, adenovirus, cytomegalovirus, bacteria
                                        • Autosomal dominant hyper-IgE syndrome (AD-HIES)
                                          • Otherwise called Job syndrome
                                          • Usually diagnosed in infancy
                                            • Classic triad: Staphylococcal infections of skin, cyst-forming pneumonias, and IgE levels at least 10 times normal
                                          • Recurrent pyogenic pneumonias
                                            • Most common pathogens: S. aureus, S. pneumoniae, H. influenzae, Aspergillus fumigatus, Pseudomonas, and P. jirovecii
                                            • Complications: Empyema, pneumatocele formation, bronchiectasis
                                            • Single or multiple pneumatoceles: May expand when superinfected with bacteria and fungi
                                        • Wiskott-Aldrich syndrome (WAS)
                                          • X-linked recessive immunodeficiency disorder: Eczema, thrombocytopenia with small defective platelets, recurrent infections
                                            • Prolonged bleeding from circumcision site, bruising, or bloody diarrhea during infancy
                                          • Pyogenic infections before 1st year of age: Meningitis, otitis media, pneumonia, sepsis
                                            • Most common pathogens: S. pneumoniae, P. jirovecii, and herpes viruses
                                          • Massive bleeding, infection, vasculitis, autoimmune cytopenias, or lymphoreticular malignancies are common causes of death
                                      • Phagocytic defects
                                        • Chronic granulomatous disease (CGD)
                                          • Defect in membrane-associated nicotinamide adenine dinucleotide phosphate oxidase in phagocytic cells
                                          • Onset in infancy, childhood, or, less commonly, early adolescence
                                            • Male:female ratio of 6:1
                                          • Recurrent bronchopneumonia, empyema, and lung abscess
                                            • Most common pathogens: S. aureus, Klebsiella, Pseudomonas, Aspergillus, and Candida
                                        • Chédiak-Higashi syndrome (CHS)
                                          • Rare autosomal recessive defect
                                            • Impaired microbicidal activity of phagocytes
                                          • Up to 30% of affected patients have segmental or lobar pneumonia
                                            • S. aureus, H. influenzae, group A streptococcus, and gram-negative organisms (Klebsiella, Pseudomonas)
                                          • Acute respiratory failure
                                            • Extensive histiocytic infiltration of lungs
                                      • Other immunodeficiencies
                                        • Chronic mucocutaneous candidiasis (CMC)
                                          • Phenotypic manifestation of complex immunodeficiency
                                          • Recurrent or persistent Candida infections of skin, nails, oropharynx, and lung
                                          • Risk of developing bronchiectasis in early childhood

                                    IMAGING

                                    • Radiographic Findings

                                      • CT Findings

                                        DIFFERENTIAL DIAGNOSIS

                                          CLINICAL ISSUES

                                          • Presentation

                                            • Demographics

                                              DIAGNOSTIC CHECKLIST

                                              • Consider

                                                • Image Interpretation Pearls

                                                  Selected References

                                                  1. Freeman AF et al: Hyper-IgE syndromes and the lung. Clin Chest Med. 37(3):557-67, 2016
                                                  2. Wu EY et al: Clinical and imaging considerations in primary immunodeficiency disorders: an update. Pediatr Radiol. 46(12):1630-1644, 2016
                                                  3. Nonas S: Pulmonary Manifestations of primary immunodeficiency disorders. Immunol Allergy Clin North Am. 35(4):753-66, 2015
                                                  4. Touw CM et al: Detection of pulmonary complications in common variable immunodeficiency. Pediatr Allergy Immunol. 21(5):793-805, 2010
                                                  5. Tanaka N et al: Lung diseases in patients with common variable immunodeficiency: chest radiographic, and computed tomographic findings. J Comput Assist Tomogr. 30(5):828-38, 2006