Pulmonary Complications of Immune Deficiencies
Girish Vitalpur, MD, FAAP, and Clement L. Ren, MD, MS
•More than 200 primary immune deficiency disorders (PIDDs) are recognized.
•PIDDs affect 1 in 2,000 children in the United States and 1 in 1,200 children worldwide.
•More than 60% of PIDDs are diagnosed in childhood.
•Many PIDDs are caused by X-linked recessive disorders: They are ≤4 times more common in boys <16 years of age.
•PIDDs are detected in 16% of non–cystic fibrosis bronchiectasis cases in children.
•See Figure 86-1 for the etiologic origins of PIDDs.
•B cell defects and/or antibody disorders (50%–60% of PIDD cases)
—Common variable immune deficiency (CVID)
▪This is a heterogeneous group of disorders characterized by low immunoglobulin (Ig) levels, with normal or decreased levels of B cells.
Although some gene mutations have been associated with CVID (eg, mutations in the gene for transmembrane activator and calcium- modulating cyclophilin ligand interactor, or TACI), the genetic basis for most CVID is unknown.
—X-linked agammaglobulinemia (XLA)
▪About 85% of cases are caused by a mutation in the Bruton tyrosine kinase (BTK) gene, leading to a lack of BTK and a block in B cell maturation at the pre–B cell stage.
—Selective IgA deficiency (polygenic)
▪This is defined as a serum IgA level <5 or7 mg/dL (<50 or 70 g/L), with normal levels of other Igs, at ≥4 years of age.
▪It is the most common antibody defect, occurring in 1 in 400–600 births in the U.S. population.
▪Ninety percent of cases are asymptomatic.
▪Patients may have enough secretory IgA or IgG to compensate for low serum IgA levels.
▪The deficiency can resolve over time and can be associated with development of normal IgA levels but may also precede the onset of CVID.
—Specific antibody deficiency (usually pneumococcal antibody deficiency)
—Transient hypogammaglobulinemia of infancy (THI)
▪Usually not associated with clinically significant immune dysfunction
▪Resolves on its own by 2–4 years of life
—IgG subclass deficiency
▪Low levels of IgG subclasses IgG1, IgG2, and/or IgG3 or IgG4, with normal total IgG levels
▪Can be associated with IgA deficiency and/or autoimmunity
▪Subclass levels vary with age; may be asymptomatic
—Chronic granulomatous disease (CGD)
▪More than 50% of cases are caused by X-linked recessive deficiency; otherwise, CGD is autosomal recessive.
▪A defect in nicotinamide adenine dinucleotide phosphate oxidase production leads to defective microbicidal function.
▪Caused by a mutation in the LYST gene
▪Results in impaired bacteriolysis in lysosomes
—Leukocyte adhesion defects (LADs)
▪Because of a lack of adhesive proteins (CD11/CD18) on white blood cell (WBC) surfaces, WBCs cannot adhere to the endo-thelium or travel to sites of infection.
▪Bacterial and fungal skin infections, delayed umbilical cord separation, recurrent pneumonias, and ear infections
▪Autosomal recessive; 3 forms
—Severe neutropenia (<0.5 × 109/L)
▪Congenital (Kostmann syndrome, severe congenital neutropenia)
▪Associated with other PIDDs (severe combined immune deficiency [SCID], CVID, Chédiak-Higashi disease, etc)
▪Associated with other disorders (Schwachman-Diamond syndrome, glycogen storage disease, etc)
▪Acquired by infection, drug effect, or vitamin B12 or folate deficiency
•T cell defects (5%–10% of PIDDs)
▪A defect in Wiskott-Aldrich syndrome protein causes impaired B cell and T cell signaling
▪Mutations in genes on 22q11, 10p13, or others
▪Thymic hypoplasia; associated with hypoparathyroidism and conotruncal heart defects
▪Inheritance usually sporadic
—Interleukin-12 receptor (IL12R) mutations cause lack of interleukin-12 activity, leading to lack of interferon-γ production from T cells and natural killer cells.
▪If X-linked—CD40 ligand defect
▪If autosomal recessive—CD40 defect
▪Both lead to failure of B cells to switch from making IgM to making IgG and other Ig isotypes
▪IgM levels increased; IgG, IgA, and IgE levels decreased or absent
▪Affects 1 in 58,000 live births in the United States
▪More than 14 genetic causes have been identified. Common examples include
~Adenosine deaminase deficiency
♦Adenosine and deoxyadenosine accumulates in T cells, leading to their death
~Interleukin-2 receptor γ chain deficiency
♦T cells cannot respond to interleukin-2, a cytokine critical for T cell activation
▪Defects in T cell precursors or T cell maturation cause a lack of T cells, with lack of or nonfunctioning B cells (with or without natural killer cells).
▪A defect in the ataxia telangiectasia mutated (ATM) gene causes impaired DNA repair and regulation of cell growth.
•Complement defects, innate immunity defects, inflammasome defects (<2% of PIDDs)—complement component 2 and mannose-binding lectin deficiencies can result in recurrent lower respiratory tract infections.
The clinical features of PIDDs are provided in Table 86-1.
—Number, type, site, and severity of infections
—Family history of severe infections or immune disorders
—Delayed umbilical cord separation (suggestive of LAD)
—Response to antibiotics or otolaryngological procedures
—Assess growth parameters (often subnormal with PIDDs)
—Absence of tonsils (suggestive of XLA)
—Crackles, wheezes, clubbing
—Initial assessment is shown in Table 86-2. Secondary assessment is shown in Box 86-1.
|Table 86-1. Clinical Features of Primary Immune Deficiency Disorders|
|Immune Defect||Infectious Complications||Noninfectious Complications|
|B cell defects (often may not present in the first 6 months of life, as maternal antibodies are still offering protection the first 6 months of life)||Recurrent pneumonias, sinusitis, upper respiratory infections due to|
• Encapsulated organisms (eg, Streptococcus pneumoniae, Haemophilus influenzae)
•Enteroviruses (mainly with CVID and XLA)
Patients with XLA are also more susceptible to Pneumocystis jirovecii pneumonia
|Obstructive lung disease (bronchiectasis, asthma), ILD, lymphoma, and autoimmunity (mainly with CVID)|
•Associated with Aspergillus spp and/or catalase-producing bacteria
— Staphylococcus aureus
— Serratia marcescens
— Burkholderia cepacia
|ILD, mainly with CGD|
T cell defects (often present within the first 6 months after birth)
Most patients with SCID present with chronic cough, pneumonia, failure to thrive, and/or diarrhea
• P jirovecii
• Candida spp
• Aspergillus spp
• Coccidioides Viruses
• Herpes simplex virus
• Epstein-Barr virus
• Varicella-zoster virus
Bronchiolitis with organizing pneumonias Lymphoma
Combined B cell and T cell defects
Those due to B cell and T cell defects as noted
Due to treatments of SCIDs, as discussed ILD
Leukemias and lymphomas (especially with ataxia telangiectasia) Thrombocytopenia (WAS)
With mannose-binding lectin deficiency: URIs and pneumonia
CGD, chronic granulomatous disease; CVID, common variable immune deficiency; ILD, interstitial lung disease; SCID, severe combined immune deficiency; URI, upper respiratory infection; WAS, Wiskott-Aldrich syndrome; XLA, X-linked agammaglobulinemia. Adapted from Nonas S. Pulmonary manifestations of primary immunodeficiency disorders. Immunol Allergy Clin N Am. 2015;35(4):753–766. Copyright 2015, with permission from Elsevier.
|Table 86-2. Laboratory Studies for Initial Assessment in the Diagnosis of Primary Immune Deficiency Disorders|
|Complete blood count with differential||B cell, T cell, B cell and T cell, neutropenias|
|Quantitative Ig levels (IgG, IgA, IgM, IgE)a||B cell, T cell, B cell and T cell|
|Specific antibody titers (pneumococcal antibody titers, to 14 or 23 serotypes)b||B cell, T cell, B cell and T cell|
|Specific antibody titers (diphtheria and tetanus antigens)b||B cell, T cell, B cell and T cell|
|IgG subclass levels||Role in PIDD assessment is controversial, and interpretation of results may be difficult|
|Oxidative burst assaysc||Phagocyte defects (eg, CGD): flow cytometry assays with nitroblue tetrazolium or dihydrorhodamine dyes to test for the ability to generate an oxidative burst|
|Total complement hemolytic activity (CH50); mannose-binding lectin levelc||Complement defects (CH50 is used to assess the presence of a classic pathway)|
CGD, chronic granulomatous disease; Ig, immunoglobulin; PIDD, primary immune deficiency disorder.
a Values vary with age.
b Values vary with age and immunization status.
c Tests are indicated by specific histories or concerns.
Vaccinate with polysaccharide pneumococcal vaccine and assess pneumococcal titers 4 weeks later to assess immune responses and antibody production .
Use flow cytometry to assess lymphocyte subsets .
Perform lymphocyte stimulation assays to mitogens and antigens .
Genetic testing is available for specific PIDDs, such as interleukin-2 receptor deficiency and leukocyte adhesion defects .
Nutritional deficiencies are associated with PIDD: vitamins A, B6, B12, C, and E; copper; folic acid; iron; selenium; and zinc .