Pulmonary Complications of Immune Deficiencies

Chapter 86


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.


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)


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


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)


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


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


Pseudomonas spp

H influenzae

S pneumoniae



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)

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
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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