Pulmonary Complications of Immune Deficiencies

Chapter 86


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Pulmonary Complications of Immune Deficiencies


Girish Vitalpur, MD, FAAP, and Clement L. Ren, MD, MS


Introduction


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.


Etiology


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.


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Figure 86-1. Etiologic origins of primary immune deficiency disorders.


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)


Commonly observed


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


Phagocyte disorders (10%–15% of PIDDs)


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.


Chédiak-Higashi disease


Autosomal recessive


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)


Wiskott-Aldrich syndrome


X-linked recessive


A defect in Wiskott-Aldrich syndrome protein causes impaired B cell and T cell signaling


DiGeorge syndrome


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.


Hyper-IgM syndrome


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


Combined B cell and T cell defects (20% of PIDDs)


SCID


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


Autosomal recessive


Adenosine and deoxyadenosine accumulates in T cells, leading to their death


~Interleukin-2 receptor γ chain deficiency


X-linked recessive


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).


Ataxia telangiectasia


Autosomal recessive


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.


Clinical Features


The clinical features of PIDDs are provided in Table 86-1.


Diagnostic Considerations


History


Number, type, site, and severity of infections


Frequent diarrhea


Family history of severe infections or immune disorders


Delayed umbilical cord separation (suggestive of LAD)


Response to antibiotics or otolaryngological procedures


Physical examination


Assess growth parameters (often subnormal with PIDDs)


Absence of tonsils (suggestive of XLA)


Crackles, wheezes, clubbing


Severe eczema


Laboratory studies


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)


Mycoplasma


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)
Phagocyte defects

Necrotizing pneumonia


Lung abscess


Empyema


Associated with Aspergillus spp and/or catalase-producing bacteria


Staphylococcus aureus


Nocardia


Serratia marcescens


Klebsiella


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


Bacteria


Pseudomonas spp


H influenzae


S pneumoniae


Mycobacteria


Fungi


P jirovecii


Candida spp


Aspergillus spp


Coccidioides Viruses


Cytomegalovirus


Herpes simplex virus


Epstein-Barr virus


Varicella-zoster virus


Bronchiectasis


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)


Complement defects


Encapsulated bacteria


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
Initial Assessment PIDD
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
HIVc  
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.


Aug 22, 2019 | Posted by in PEDIATRICS | Comments Off on Pulmonary Complications of Immune Deficiencies
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