Keywords
common variable immunodeficiency disorders - bronchiectasis - primary immunodeficiency
- secondary immunodeficiency - pulmonary disease
With increased attention directed toward bronchiectasis in recent years, there has
been a recognition that the underlying pathogenesis of this syndrome is more complex
than the traditionally accepted vicious cycle.[1] Although the circular events of repeated infections that incite inflammation that
injure and disrupt the integrity of the airway thereby allowing for repeated infections
are still relevant, a new, revised version of the traditional cycle, referred to as
vortex,[2] has been proposed. The vortex model more adequately describes the complexity of
the underlying inflammation and remodeling steps that have much more complex interactions
with each other. While immunodeficiency as a defined cause of bronchiectasis has fit
nicely with the traditional vicious cycle model over the years, it too is now understood
to be far more complex than once thought. Immunodeficiency is now known to involve
complex autoinflammatory and autoimmunity mechanisms. Putting these two together,
with an increased understanding of immune deficiencies related to bronchiectasis,
our understanding of the pathogenesis of bronchiectasis may be enhanced as well.
Within the enormous landscape of immunodeficiency, both primary and secondary immune
deficiencies are at play in the pathogenesis of bronchiectasis. International guidelines[3]
[4]
[5] recommend investigation into the etiology bronchiectasis, to include evaluation
for immunodeficiency as the potential cause of bronchiectasis.
Primary Immunodeficiency
Primary immune deficiencies (PIDs), also called inborn errors of immunity, result
in inadequate or maladaptive immune response to the environment and to internal stimuli.[6] The result is an increased susceptibility to infection, autoimmunity, autoinflammatory
diseases, allergy, and malignancy. There are over 400 distinct types of PIDs and this
number, which has grown remarkably over the last two decades, is likely to continue
to increase.
The International Union of Immunological Societies (IUIS) Expert Committee on human
inborn errors of immunity organizes PIDs into 10 groups: combined immunodeficiencies;
combined immunodeficiencies with syndromic features; predominantly antibody deficiencies;
diseases of immune dysregulation; congenital defects of phagocytes; defects in intrinsic
and innate immunity; autoinflammatory diseases; complement deficiencies; genes that
cause bone marrow failure; and phenocopies of inborn errors of immunity. National
and international registries have been established in the United States and Europe
to improve knowledge of these disorders and aid in clinical research. In both the
United States and European registries, common variable immunodeficiency (CVID) is
the most common PID.[7]
[8]
Common Variable Immunodeficiency
Common Variable Immunodeficiency
Common variable immunodeficiency is a diagnosis of exclusion, to be assigned only
after more well-defined syndromes with Mendelian inheritance have been considered
and ruled out.[9] Since it was first named by the World Health Organization in 1971,[10] the International Union of Immunological Societies Expert Primary Immunodeficiency
Committee renamed CVID as “CVID disorders,”[11] which retains the familiar acronym but additionally acknowledges the tremendous
heterogeneity that is inherent in the diagnosis. There is more than one set of diagnostic
criteria for the diagnosis CVID,[12]
[13]
[14] but basic tenets of the diagnosis include a marked decrease in immunoglobulin G
(IgG) along with a decrease in either IgA or IgM, the absence of an alternative cause
for hypogammaglobulinemia, and a poor response to vaccination. It should be noted
that diagnostic criteria are frequently evolving, and the diagnosis can be murky even
for immunologists. Intravenous immunoglobulin (IV Ig), an effective therapy for CVID,
is expensive and subject to supply versus demand shortage. This has led some to propose
more stringent diagnostic criteria that include histological markers of CVID[13] to best determine the most appropriate recipients of IV Ig. A detailed description
of the diagnosis of CVID according to the International Consensus Document (ICON)
is shown in [Table 1]. CVID disorders can manifest from childhood to old age. Often there is confusion
from other causes of hypogammaglobulinemia that may be transiently present at younger
age. Furthermore, clinical manifestations and laboratory abnormalities do not always
occur concomitantly. To accommodate for these complicating factors, it is recommended
to refrain from the diagnosis of CVID until at least 4 years of age.
Table 1
Diagnosis of common variable immunodeficiency disorders[14]
[32]
|
Criteria
|
|
Value for diagnosis
|
Comment
|
|
Laboratory data
|
IgG
|
Lower than the age-adjusted reference range
Absolute lower limit = 4.5 g/L, but the diagnostic criteria can be fulfilled with
higher levels
|
Must be repeated in at least 2 measurements more than 3 weeks apart[a]
Normal values are typically reported as 2 SDs above or below the mean or the 5th–95th
percentile intervals
|
|
IgA or IgM
|
Low[b]
If IgM is high in the setting of low IgG and IgA, consider hyper-IgM syndrome or defects
of class switch
|
|
IgE
|
|
Low IgE is not necessary to diagnose CVID, but elevated IgE should prompt consideration
and workup of alternative diagnosis of immune dysregulation
|
|
Vaccine response
|
Pre-vaccine measurement and post-vaccine response (4 wk after vaccine if pre-vaccination
levels are low):
✓ T-dependent (protein or glycoprotein) antigens:
- Tetanus or
- Diphtheria toxoids or
- Haemophilus influenza type B
and
Post-vaccination[c] response to:
✓ T-independent (polysaccharide) antigens:
- Pneumococcal
- Conjugate polysaccharide
- Prevnar-13 (United States)
- Prevenar-13 (Europe)
- Pure polysaccharide
- Pneumovax (PPV23)
|
Tetanus toxoids < 0.15 IU/mL
Haemophilus influenzae type B < 1 μg/mL
Titers for assessing response to pneumococcal conjugate vaccine have not been established
Pure pneumococcal polysaccharide:
Impaired memory: > 70% protective titers (>1.3 μg/mL) for adults but lose this response
within 6 mo
Mild: ≤ 1.3 μg/mL in multiple serotypes or failure to generate a twofold increase
in ≥70% of the serotypes (patients aged 6–65 y)
Moderate: <70% of the serotypes are ≥1.3 μg/mL, but at least three serotypes are >1.3 μg/mL
Severe: no more than two serotypes show protective serotypes (>1.3 μg/mL) and the
protective titers are low (1.3–2.0 μg/mL)
|
Vaccine response must be measured prior to initiation of immunoglobulin replacement
therapy. Some experts may forego vaccine testing in the setting of characteristic
phenotype with low IgG and IgA levels to facilitate more rapid initiation of therapy
Vaccine responses may be impaired by prolonged use of systemic corticosteroids
|
|
Exclusion of other causes
|
|
Immune globulin loss:
- Nephrotic syndrome
- Protein-losing enteropathy
- Severe burns
- Lymphangiectasia
Medications:
- Antiepileptics (carbamazepine, phenytoin)
- Antimalarial agents
- Captopril
- Fenclofenac
- Glucocorticoids (systemic)
- Gold salts
- Penicillamine
- Rituximab
- Sulfasalazine
Malignancy:
- Chronic lymphocytic leukemia
- Lymphomas
- Good's syndrome (thymoma with immunodeficiency)
- Monoclonal gammopathy
Viral infections
Known immune defects
|
|
|
Gene sequencing
|
|
|
Not required or recommended for diagnosis especially in the setting of infection as
the only clinical manifestation.
In the presence of autoimmunity, malignancy, or other noninfectious complication,
consider molecular genetic evaluation
|
|
Additional diagnostic notes
|
|
|
In the majority of patients, a characteristic clinical manifestation (infection, autoimmunity,
lymphoproliferation) will be present at the time of diagnosis, but CVID can be diagnosed
in asymptomatic individuals if the laboratory criteria are met, vaccine response is
inadequate, and other causes have been excluded
Consider CVID a temporary designation until additional clinical and genetic information emerges
|
Abbreviations: CVID, common variable immunodeficiency; Ig, immunoglobulin.
a May forego repeat measurement in patients with IgG <100–300 mg/dL to facilitate more
rapid initiation of therapy.
b The scenario of normal IgA and IgM with low IgG should be called “unspecified IgG
deficiency” or “unspecified hypogammaglobulinemia” but should not be called CVID.
c Preimmunization levels may be falsely elevated. High titers of naturally occurring
cross-reactive antipolysaccharide and antibodies may be present. These antibodies
correlate poorly with functional activity.
Epidemiology of Common Variable Immunodeficiency
Epidemiology of Common Variable Immunodeficiency
Globally, the physician reported prevalence of CVID is 11,996 with the highest areas
in the United States at 4,833 and western Europe at 3,439.[15] Detection of PID as a whole has increased over recent years, by 32.7% from 2013
to 2018 in the United States and by 12% in the western Europe over the same time period.
Men and women are equally affected, but there may be a racial difference. CVID appears
to be less common in African Americans, although this observation is based largely
on European American study populations. Although adult patients often provide history
of childhood symptoms suggestive of an immune disorder, the diagnosis is most often
made during adulthood, between the ages of 20 and 45 years. Some studies note that
diagnosis is delayed up to 15 years.[16]
Clinical Spectrum of Common Variable Immunodeficiency
Clinical Spectrum of Common Variable Immunodeficiency
The clinical spectrum of CVID consists of two main phenotypes: primarily recurrent
infections and recurrent infections with autoimmune and/or inflammatory features.
[Table 2] summarizes recurrent infections and autoimmune and inflammatory features of patients
with CVID. The autoimmune or inflammatory manifestations of CVID may predate detection
of CVID and can mimic other inflammatory or autoimmune diseases such as sarcoidosis
or celiac disease. In a U.S. study of 455 CVID patients, granulomas were present in
8.1% of the patients and were identified 1 to 18 years before the diagnosis of CVID.[17] Sinopulmonary infections are most often cited in large case studies of patients
with CVID.[16]
[18] A 12-month prospective study of 12 patients with primary hypogammaglobulinemia depicts
the dominance of respiratory infections in these patients. The patients, all of who
were receiving immune globulin replacement, underwent nasal swabs and induced sputum
at the onset of respiratory tract infections and every 3 months thereafter. The 12
patients had 65 episodes of acute respiratory infections versus only 12 acute episodes
noted in the 11 spouses who served as controls. The most common bacteria identified
in patients were Moraxella catarrhalis (29%) and Haemophilus influenzae (22%). Rhinovirus was the most common respiratory virus identified. It was identified
in the sputum in 54% of patient infection episodes. Viral PCR was additionally performed
every 2 weeks after a viral infection episode and revealed the extended persistence
of virus in these patients. Rhinoviral PCR was positive for 8 weeks in seven patients
with CVID and for 5 months in a patient with X-linked agammaglobulinemia (XLA).
Table 2
Clinical manifestations of common variable immunodeficiency disorders
|
Location
|
Infection
|
Autoimmunity
|
Inflammation
|
Malignancy
|
|
Lung
|
Bacteria
Viral
|
|
Lymphocytic and/or granulomatous infiltrates (granulomatous lymphocytic interstitial
lung disease)[a]
|
Lung cancer
|
|
Gastrointestinal tract
|
|
Antienterocyte antibodies
|
Lymphocytic and/or granulomatous infiltrates
Noninfectious enteropathy:
- Colitis
- Gastritis
|
Colorectal cancer
Esophageal cancer
|
|
Liver
|
|
Nodular regenerative hyperplasia
Primary biliary cirrhosis
|
Lymphocytic and/or granulomatous infiltrates
|
|
|
Hematologic:
- Lymph nodes
- Bone marrow
|
|
Immune-mediated thrombocytopenia
Hemolytic anemia
Pernicious anemia
Autoimmune neutropenia
|
Lymphocytic and/or granulomatous infiltrates[a] of the lymph nodes, bone marrow, and spleen
|
Lymphoma, most often B cell origin (non-Hodgkin's lymphoma most frequent)
Mucosa-associated lymphoid tissue lymphomas
|
|
Connective tissue:
- Joints
- Skin
|
Septic arthritis
|
Sjogren's disease
Sicca
Juvenile and rheumatoid arthritis
Juvenile spondyloarthritis
Undifferentiated arthritis
Vitiligo
Alopecia
|
Granulomas
|
Melanoma and other skin cancer
|
|
Brain
|
|
|
Lymphocytic and/or granulomatous infiltrates
|
|
|
Kidneys
|
|
|
Lymphocytic and/or granulomatous infiltrates
|
|
|
Thyroid
|
|
Thyroiditis
|
|
Thyroid cancer
|
|
Retinas
|
|
|
Granulomas
|
|
|
|
|
|
Other: breast uterine, ovary, vaginal, and neurogenic malignancies have been reported
|
a Lung and lymphoid tissue are the most frequent locations for granulomatous inflammation
in common variable immunodeficiency.
Common Variable Immunodeficiency and Bronchiectasis
Common Variable Immunodeficiency and Bronchiectasis
Of all PIDs, pulmonary complications are most prevalent in CVID. An analysis of 1,937
PID patients registered in the U.S. Immunodeficiency Network (USIDNET) found that
61.7% of patients with CVID were reported as having pulmonary disease.[19] The study further narrowed pulmonary disease by type and revealed that the highest
prevalence of airway disease was in CVID patients. Nearly 58% of CVID patients were
reported to have airway disease (which included bronchiectasis). Thus, bronchiectasis
is common in CVID. Other studies have suggested that there are factors other than
antibody level that allow for the development of bronchiectasis in CVID patients.
In a separate analysis of the USIDNET registry, pulmonary complications were compared
between CVID and XLA.[20] Respiratory infections, pneumonia, and bronchiectasis were more common in CVID patients
than in XLA patients despite a higher IgG levels. At the same time, CVID patients
manifested lower levels of CD4+ and CD8+ T cells compared with XLA patients. This follows a previous observation correlating
bronchiectasis with low CD4+ T cells.[21] A variety of interstitial lung diseases are also seen in CVID patients and similar
to the prevalence of bronchiectasis, they are more common in CVID patients compared
with XLA patients despite the profoundly lower antibody level in XLA.[20]
Shifting focus from bronchiectasis within PID communities to PID within bronchiectasis
communities can be additionally informative. National and international bronchiectasis
registries provide insight. The U.S. Bronchiectasis Research Registry was established
in 2008 and currently includes 18 sites and approximately 3,800 registered bronchiectasis
patients. As of 2017, when the registry included 2,710 patients, CVID accounted for
2.9% of the population.[22] These patients were 64 (SD 12.5) years of age at diagnosis of bronchiectasis and
66.9 (SD 10.5) at the time of enrollment in the registry. Sixty-one percent experienced
bronchiectasis exacerbations within the prior 2 years and 44.4% had been hospitalized
during the same time. Lung function in this group as measured by percent forced expiratory
volume in 1 second (FEV1%) predicted was 75 (SD 20.9). Microbiologic culture analysis
revealed that 25% grew Pseudomonas aeruginosa and 43% grew nontuberculous mycobacteria. These data expose the late age in which
some immunodeficient patients are diagnosed with bronchiectasis and reveal the severity
of their disease as measured by pathogenic organisms and hospitalizations that correlate
with more severe disease.[23]
[24] Interestingly, in the United States, the prevalence of only 2.9% of the bronchiectasis
population is lower than other areas. Other areas seem to capture a higher prevalence:
5.8% of 1,258 patients enrolled in various European centers were identified as having
immunodeficiency-related cause of bronchiectasis.[25] In China, the proportion of bronchiectasis attributed to immunodeficiency varies
according to location. In the northeastern coastal region, 3.8% of bronchiectasis
is attributed to immunodeficiency[26] and in southern China the percentage is 8.8.[27] In Singapore, immunodeficiency was identified in 7.7% of a cohort of 181 bronchiectasis
patients.[28] Using the Australian Bronchiectasis Registry, Visser et al reported immunodeficiency
in 3.7% of a cohort of 589 with mostly moderate to severe bronchiectasis patients
from six centers across the states of New South Wales and Queensland.[29] Only India reports a smaller percentage of immunodeficiency compared with the United
States at less than 1% of their population.[30]
It is not clear to what degree of stringency immunodeficiency has been diagnosed within
the international bronchiectasis community. Most registries report “immunodeficiency”
as the cause of bronchiectasis rather than referring to a more specific etiology.
The seemingly small number and percentage of CVID patients within international registries
suggest that not all CVID patients with bronchiectasis have found their way into bronchiectasis
registries. One explanation for this may be that many CVID cases are not recognized.
Specific Antibody Deficiency
Specific Antibody Deficiency
Specific antibody deficiency (SAD) refers to a reduced ability to produce antibodies
to polysaccharide (pneumococcal) in the setting of normal immunoglobulins.[31] SAD can occur in combination with a defined primary or secondary immunodeficiency
or it can be the only immunologic abnormality present in a patient. SAD is also referred
to as “impaired polysaccharide responsiveness,” “selective antibody deficiency with
normal immunoglobulins,” and “antibody deficiency with near-normal immunoglobulins.”
It is unknown if a genetic defect or inheritance pattern is involved in this syndrome.[31] Clinically, patients with SAD manifest with recurrent sinopulmonary infections.
It appears that clinical symptoms may be more severe as the severity of antibody nonresponsiveness
increases. Antibody response to polysaccharide has been stratified in a working group
report into memory, mild, moderate, and severe[32] ([Table 1]). In an analysis of 595 patients with chronic rhinosinusitis, 40.2% were identified
as having SAD.[33] Within the population, mild, moderate, and severe SADs were present in 39.8, 50.2,
and 10%, respectively. The clinical characteristics of these patients were then compared
according to severity of their response to polysaccharide responses. The investigators
found that patients with moderate and severe SAD were more likely to have a history
of pneumonia and they required more courses of antibiotics in the 2-year period after
vaccination than patients with mild SAD. Of note, the study also analyzed a healthy
control population and found SAD to be present in 20.4% of the healthy cohort using
the same working group report stratification. In the healthy population with SAD,
mild, moderate, and severe SADs were present in 45, 40, and 15%, respectively.
Regarding SAD in bronchiectasis, Vendrell and colleagues analyzed antibody responses
to both the 23-valent pneumococcal vaccine and the Hib-conjugate vaccine in 107 patients
with idiopathic bronchiectasis who had normal IgG levels.[34] They found that 11% of the population failed to respond to either the pneumococcal
vaccine or the H. influenzae type B vaccine. These patients were deemed to have antibody production deficiency.
In addition, 20 patients (19%) did not respond to the pneumococcal vaccine only. Sputum
microbiology, extent of bronchiectasis, pulmonary function, and pneumonia history
did not differ between bronchiectasis patients with and without an antibody production
deficiency. These data suggest that SAD prevalence in bronchiectasis may be similar
to the healthy population and that the presence of SAD, at least in bronchiectasis,
does not seem to correlate with clinical features as it does in chronic rhinosinusitis
patients. In contrast, van Kessel and colleagues[35] analyzed antipneumococcal antibody responses in 26 idiopathic bronchiectasis patients,
all of who had normal total immunoglobulin levels. Four patients (15.3%) demonstrated
abnormal responses to the 23-valent pneumococcal vaccine (“total nonresponders”).
The investigators further analyzed the same group using more stringent criteria. They
analyzed isotype-specific antibodies (IgA, IgG1, and IgG2), serotypes 4, 6B, 9V, 14,
19F, and 23F. Using these more strenuous criteria, they found that 50% of their idiopathic
bronchiectasis cohort demonstrated inadequate response to the vaccination. This group
of patients was deemed “isotype nonresponders.” The authors showed a trend toward
more infections per year in the overall nonresponders (both isotype and total) compared
with the normal responders to pneumococcal vaccination. These data suggest that interpretation
of vaccination responses within the idiopathic bronchiectasis cohort may require a
more analytical protocol than for the healthy population.
Primary Immunodeficiencies Involving High Serum Immunoglobulin E
Primary Immunodeficiencies Involving High Serum Immunoglobulin E
In addition to its role in providing defense during parasite infection, IgE is also
well known for its mechanistic role in asthma, allergic bronchopulmonary aspergillosis,
and eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome). Three
distinct hyper-IgE syndromes (HIESs) are more recently described. They are STAT3 (signal
transducer and activator 3), DOCK8 (dedicator of cytokinesis 8), and PGM3 (phosphoglucomutase
3).[36] These three entities all share skin manifestations, sinopulmonary infections (including
bronchiectasis), and elevated IgE, but each has specific nuances. Because these conditions
require gene sequencing for diagnosis, specific attention is given to the clinical
features to aid the clinician in recognition and referral to a specialty center.
Autosomal Dominant Hyper-IgE Syndrome
Autosomal Dominant Hyper-IgE Syndrome
Autosomal dominant hyper-IgE syndrome (AD-HIES) is a syndrome of skin abscesses and
recurrent pyogenic pneumonias caused by dominant (or sporadic then passed down in
an autosomal dominant pattern) mutations in STAT3. STAT3 is required for naive T lymphocytes
to differentiate in Th17 lymphocytes. Th17 cells secrete cytokines (IL-17 and IL-22)
that upregulate antimicrobial peptides at the mucosal level. A typical AD-HIES patient
manifests head and upper body rash during infancy. The rash is initially diagnosed
as neonatal acne or erythema toxicum neonatorum but eventually progressed to eczematous
dermatitis that becomes chronically infected with Staphylococcus aureus. The moniker “Job's syndrome” was given to AD-HIES because the recurrent skin abscesses
resembled boils described in the Bible that affected the prophet Job.[37] Pneumonias from S. aureus and H. influenza occur during in the first several years of life, but diagnosis can delayed because
of a diminished inflammatory response that accompanies this syndrome. Pneumatoceles,
empyema, and bronchiectasis eventually develop in the majority of AD-HIES patients,
suggesting that impaired epithelial repair is part of the pathogenesis. [Fig. 1] depicts an AD-HIES patient with a large pneumatocele. With recurrent pneumonias
and the attendant changes to the lung architecture (bronchiectasis and pneumatoceles),
the pathogenic organisms evolve to include Aspergillus fumigatus, P. aeruginosa, and nontuberculous mycobacteria. Patients with AD-HIES manifest a typical facial
appearance of a prominent forehead and facial asymmetry, deep-set eyes, broad nasal
bridge, a high arched palate, and rough skin. Characteristically, the majority of
patients retain primary teeth which can lead to dental crowding without surgical intervention.
Significant scoliosis, minimal trauma skeletal fractures (e.g., rib fractures from
coughing), and flexible joints are also present in the majority of patients. Management
of AD-HIES involves systemic prophylactic antimicrobial therapy, antiseptic baths
(bleach baths) for skin lesions, and airway clearance (nebulized hypertonic saline)
for bronchiectasis. A special consideration is the frequent hemoptysis seen in these
patients due to the architectural distortion of pulmonary parenchyma.[38] Vigilance for this complication as well as a plan for its occurrence is indicated.
In some instances, surgical resection for hemoptysis or large infected pneumatoceles
is necessary, but this is uniquely challenging due to the high complication rate caused
by impaired healing. Bronchopleural fistula is the most common surgical complication
in these patients and may require further surgery or valve insertion.[39]
Fig. 1 Representative axial image from a computed tomography of the chest of a 28-year-old
man with STAT3 mutated autosomal dominant hyper-IgE syndrome. (Photo courtesy of Kenneth
N. Olivier, MD, MPH, National Heart Lung Blood Institute, National Institutes of Health,
Bethesda, MD.)
DOCK8 Immunodeficiency Syndrome
DOCK8 Immunodeficiency Syndrome
DOCK8 (dedicator of cytokinesis 8) encodes a protein that is important in both innate
and adaptive immunity. It regulates actin cytoskeleton-dependent immune responses
and is involved in migration of immune cells.[40] DOCK8 immunodeficiency syndrome (DIDS) has an autosomal recessive inheritance pattern
and is the result of homozygous or compound heterozygous deletions in DOCK8. Similar
to AD-HIES, the condition presents during early childhood with a rash and frequent
sinopulmonary infections. Bronchiectasis presumably results from recurrent bacterial
and viral pneumonias. [Fig. 2] depicts bronchiectasis in a patient with DIDS. Atopy, severe food allergies leading
to anaphylaxis, and asthma are more common in these patients than in AD-HIES patients.[41] DOCK8 patients usually have elevation of IgE, a typically normal IgG and low IgM.
Over time, DOCK8-deficient patients develop lymphopenia. A notable feature of DOCK8
deficiency that separates it from AD-HIES is the particular susceptibility to viral
skin infections. DOCK8 deficiency makes lymphocytes unable to maintain cell shape
during migration from skin lesions to lymph nodes, an event called cytothripsis.[42] This also results in impaired tumor surveillance, leading to viral-mediated malignancy
seen in this population. Vasculitis of the middle and large size blood vessels is
infrequently seen in DIDS patients at much younger age than in the general population.[41] The mainstay of therapy for DOCK8-deficient patients are prophylactic antimicrobials
and immune supplementation. Hematopoietic stem cell transplantation reverses the key
underlying immune defect and improves clinical features.[43] Early referral for transplantation is important to avoid end-organ damage. A pilot
study of reduced-intensity hematopoietic cell transplantation (HCT) for DOCK8 deficiency
patients is currently underway with an estimated completion date of December 2023
(NCT01176006).
Fig. 2 Representative axial images from a computed tomography of the chest of a 44-year-old
woman with DOCK8 deficiency.
PGM3 Deficiency
PGM3 (phosphoglucomutase 3) is an enzyme required for glycosylation of proteins, a
process required for adequate function of the majority of proteins in the body. PGM3
deficiency can result from hypomorphic (partial loss of function) homozygous and compound
heterozygous mutations.[44]
[45] The phenotype of PGM3 deficiency is broad ranging and can result in early-onset
bone marrow failure, skeletal abnormalities, and cognitive delay[46] to a more indolent hyper-IgE phenotype of allergies, atopic dermatitis, and recurrent
sinopulmonary infections leading to bronchiectasis.[47] Patients with PGM3 deficiency have an elevated IgE, neutropenia, and CD8+ lymphopenia.[46]
Supportive care with antimicrobial prophylaxis is indicated. Stem cell transplantation
reverses the infection susceptibility but does not impact the neurocognitive dysfunction
or skeletal abnormalities.
Activated PI3 Kinase Delta Syndrome
Activated PI3 Kinase Delta Syndrome
Phosphoinositide 3-kinase delta (PI3Kδ) is a lipid kinase that engages with B cells,
T cells, and cytokine and costimulatory receptors. PI3Kδ contains a regulatory subunit
(p85α) and a catalytic subunit (p110δ). Mutations in the genes that encode these subunits
can result in increased PI3Kδ activity.[48]
[49] Increased PI3Kδ activity causes both immunodeficiency and immune dysregulation.[50] Clinically, the result includes recurrent respiratory infections, recurrent herpes
family virus infections, benign and malignant lymphoproliferation, immune cytopenias,
solid-organ autoimmunity, and, in some cases, developmental delays.[50] The “gain-of-function” gene mutations that occur in the PI3Kδ subunits are autosomal
dominant. They were discovered by using whole-exome sequencing to analyze PID patients
of unknown etiology from unrelated families.[48]
[49] Activated PI3Kδ syndrome (APDS) is also referred to as PASLI (p110δ-activating mutation
causing senescent T cells, lymphadenopathy, and immunodeficiency). Two characteristic
phenotypes of APDS (APDS 1 and APDS 2) have been observed.[51]
[52]
[53] Both phenotypes universally experience repeated respiratory infections, but the
APDS 1 phenotype seems to manifest more bronchiectasis than the APDS 2 phenotype (60
vs. 18%, respectively) despite having normal IgG levels. The fact that IgG levels
are normal in the context of this bona fide PID is an important reminder to the nonimmunologist
clinician to look beyond Ig levels when evaluating a seemingly idiopathic bronchiectasis
case. Importantly, a majority of APDS patients have elevated IgM and some have been
reported as being misdiagnosed as hyper-IgM syndrome.[48]
Like other PIDs, APDS is treated with airway clearance for bronchiectasis, prophylactic
antibiotics, and immunoglobulin replacement therapy. Hematopoietic stem cell transplantation
has been described as a therapy in young patients, but longer follow-up is needed
to confirm initial successful results.[52]
[53] Rapamycin, an mTOR inhibitor, has been reported to reduce lymphadenopathy and splenomegaly
in APDS patients. However, multiple other regulating pathways that are involved in
the relationship between mTOR and PI3Kδ make rapamycin a less-than-ideal therapy.
The identification of the gene mutations that cause APDS and their role in increasing
PI3Kδ activity has allowed for the development of more targeted therapies. PI3Kδ inhibitors
are currently being studied in APDS patients. A phase II clinical trial of leniolisib
(CDZ173), an oral PI3Kδ inhibitor, is currently enrolling and has an expected completion
date of June 2021 (NCT02435173). A separate phase II trial of nemiralisib, a PI3Kδ
inhibitor via dry powder inhaler, has recently completed (NCT02593539).
X-Linked Agammaglobulinemia
X-Linked Agammaglobulinemia
X-linked agammaglobulinemia was the first described immunoglobulin deficiency. In
1952, Dr. Ogden Bruton described a case of complete absence of IgG in an otherwise
normal 8-year-old boy.[54] XLA is now known to result from a defective gene located on the X chromosome that
encodes a protein-tyrosine kinase that is critical for the development of B cells.[55]
[56] The gene has now been renamed the Bruton tyrosine kinase or BTK gene. XLA patients have severe reduction in all immunoglobulins and profoundly decreased
B cells.[55]
[56] XLA is relatively uncommon. In a 2006 report, the estimated U.S. prevalence was
1/190,000 live male births from 1988 to 1997.[57] More recently, the United Kingdom reported 0.3 per 100,000 from the UK Primary Immunodeficiency
registry in which XLA made up 4.4% of the registered patients as of 2017.[58]
A minority of patients are diagnosed at birth based on family history. The majority
are diagnosed only after recurrent infections manifest.[58] Clinical symptoms of XLA manifest between 3 and 18 months of age after the protective
effects of maternal immunoglobulins diminish.[57] The most common clinical symptoms in these patients result from bacterial infections.[59] In particular, Streptococcus pneumoniae, H. influenzae type B, Streptococcus pyogenes, and Pseudomonas species are reported.[57] The respiratory and gastrointestinal tracts are frequent sites of infection. Unfortunately,
respiratory infections continue to be recurrent despite adequate immunoglobulin therapy.[57]
[60]
[61] In a study of 73 patients aged 2 to 33 years, chronic lung disease was present in
33% of the cohort and was more likely to be present with delayed diagnosis.[60] The authors calculated that XLA patients have a 25-year post diagnosis risk of 92%
to develop chronic lung disease. Regrettably, once bronchiectasis has developed in
XLA patients, it progresses despite IgG replacement therapy.[61] The progression of bronchiectasis may be due to the fact that the XLA patients remain
IgM and IgA deficient despite IgG replacement. In addition, inflammatory mechanisms
in the airway that have yet to be identified may be contributing as well. The lack
of B lymphocytes and their regulation of inflammatory regulation has been proposed
as a mechanism of inflammatory and autoimmunity complications in these patients.[62]
Secondary Immunodeficiencies
Secondary Immunodeficiencies
Chronic Graft versus Host Disease
Chronic graft versus host disease (cGVHD) is a significant complication that typically
presents at least 100 days after, but within 3 years of allogeneic HCT.[63] The pathogenesis of cGVHD is not completely understood, but it resembles more of
an autoimmune phenomenon rather than an immunodeficiency. It is included in this section,
as HCT patients are generally considered in the context of immune-suppressed state.
In the absence of biopsy-proven bronchiolitis obliterans (the only diagnostic manifestation
of cGVHD), the diagnosis can be made by a constellation of clinical findings that
must include airflow obstruction (FEV1/forced vital capacity <0.7 and FEV1 <75% of
predicted) and high-resolution computed tomography evidence of air trapping, small
airway thickening, or bronchiectasis.[63] These criteria must exist in the absence of respiratory infection. Bronchiectasis
that occurs in the context of cGVHD can be severe and rapidly progressive,[64] and has been described as resulting in severe cystic bronchiectasis over only 2
years.[65] Airway infection with S. aureus and P. aeruginosa is described. Although the mortality associated specifically with bronchiectasis
in these patients is unknown, in HCT recipients who survive longer than 2 years, those
who have pulmonary dysfunction been identified as having a 15-fold increased risk
of late deaths[66] compared with the general population. This underscores the need for close monitoring
and aggressive interventions in patients who manifest decline in lung function. Patients
with early pulmonary cGVHD may be asymptomatic or manifest nonspecific symptoms.[67] As such, screening with routine pulmonary function, surveillance for infection,
and elimination of exacerbating factors such as gastroesophageal reflux is recommended.[68] Some studies have shown benefit from inhaled corticosteroids in cGVHD patients with
obstructive airway disease.[69]
[70] However, this benefit must be balanced by recent data pointing toward an increased
risk of pneumonia[71] and nontuberculous mycobacterial infection[72] in patients with chronic obstruction pulmonary disease who receive inhaled corticosteroids.
For patients with life-threatening pulmonary cGVHD, lung transplantation is performed
with similar survival at 1, 3, and 5 years as matched controls with other end-stage
lung diseases.[73]
Malignancy
Bronchiectasis that develops in patients with hematologic malignancy is presumably
related to the immunodeficiency caused by the malignancy itself or chemotherapy administered
during the disease. Hematologic malignancies, such as multiple myeloma and chronic
lymphocytic leukemia, result in reduced levels of immunoglobulin levels[74]
[75] and attendant risk of infection. In a description of patients with combined bronchiectasis
and hematologic malignancy, 27% of who had not received HCT, bronchiectasis demonstrated
progression over time in terms of airway dilation and bronchial wall thickening. P. aeruginosa was grown from 30% of sputum cultures. Immunoglobulin deficiency was not ubiquitous,
present in 59%, and all but one patient had received chemotherapy. The constellation
of findings in this report makes it difficult to implicate the exact cause of bronchiectasis.
Taking the influence of chemotherapy out of the equation, a radiographic analysis
of 49 patients with adult T-cell leukemia (ATL) at the time of diagnosis and before
any therapeutic intervention revealed CT findings bronchiectasis in 22% of the population.[76] Further analysis comparing aggressive and indolent ATL showed no significant difference
in bronchiectasis prevalence between the two types of disease. In an earlier retrospective
review of CT scans performed at the time of diagnosis of ATL, bronchiectasis was identified
in 21.7% of the 60 patients.[77] Surgical biopsy from one patient's area of bronchiectasis revealed atypical lymphocytes
infiltrating the wall of respiratory bronchioles and extending into the peribronchiolar
interstitium. This provocative finding could suggest that bronchiectasis results from
the influence of malignant cells rather than immunosuppression that accompanies malignancy.
One malignancy that may be a lesser known association with bronchiectasis is thymoma
in the context of hypogammaglobulinemia. Thymomas typically present in adults in the
fifth and sixth decades of life and commonly incite paraneoplastic autoimmune complications
that affect bone marrow precursors and the nervous system. Good's syndrome is thymoma
accompanied by destruction of bone marrow precursors by CD8 T lymphocytes that result
in pure B cell aplasia (hypogammaglobulinemia) and thymoma. Seventy-eight patients
with Good's syndrome who were registered in the UK-Primary Immune Deficiency Registry
reviewed for clinical and laboratory features.[78] Forty-five percent of the cohort overall had bronchiectasis. The prevalence of bronchiectasis
was further analyzed by histologic type; type AB thymomas (those with higher content
of immature T cells) had the highest prevalence of bronchiectasis at 59% (vs. 25,
0, and 22% in types A, B, and C, respectively).
Thus far, the discussion has focused primarily on bronchiectasis identified in the
patient with known malignancy. Importantly, bronchiectasis has been noted to be the
clinical presentation of malignancy such as relapsed B-cell lymphoma.[79] This highlights the importance of following guidelines[3] which recommend performing a thorough workup for etiology in a patient who presents
with bronchiectasis to ensure the successful identification of a previously unidentified
malignancy.
Human Immunodeficiency Virus
In the acute infection stage, human immunodeficiency virus (HIV) binds to macrophages[80] and dendritic cells,[81] typically in epithelium and then fuses with CD4+ T cells. The infected T cells spread to lymph nodes and into plasma at which point
there is widespread dissemination to peripheral organs.[82] At this stage of highest host susceptibility, viral replication is rapid and CD4+ T cells decline precipitously. The low CD4+ cell count that is characteristic of the disease is an undeniable risk factor in
the development of respiratory infections.[83] Recurrent pneumonias and pulmonary Mycobacterium tuberculosis are AIDS-defining conditions, but at the same time they are dominant etiologies of
bronchiectasis independent of HIV.[26]
[27]
[84]
[85] This suggests that bronchiectasis in HIV patient may be the sequelae of pneumonias
contracted early in the course of their HIV infection rather than an on-going process
acquired later in the course of HIV status. Even in studies of children with bronchiectasis
and HIV, bronchiectasis was much more likely to develop in children who had a history
of recurrent pneumonia.[86] Moving beyond the CD4 level and its accompanying burden of respiratory infection
risk, HIV also results in neutropenia and aberrant neutrophil functions, including
neutrophil chemotaxis, phagocytosis, bactericidal activity, and oxidative burst activity.[87] In a study of HIV patients on antiretroviral therapy with viral load less than 20
RNA copies and CD4 count greater than 350 cells/mm3, neutrophils were found to exhibit hyperactivation and deregulated apoptosis. This
mirrors recent discovery of the underpinnings of bronchiectasis pathophysiology in
non-HIV individuals. Bedi and colleagues have shown that neutrophil dysfunction such
as prolonged survival and impaired bacterial phagocytosis and killing is important
driver of bronchiectasis pathophysiology in idiopathic bronchiectasis.[88]
[89]
Unfortunately, description of concomitant bronchiectasis and HIV is relatively sparse.
Much of the literature is based on retrospective case series and is often hindered
by variable patient follow-up and adherence to therapy. Furthermore, description of
workup for an alternative etiology other than HIV in the patient cohort is typically
not available. For example, a case series from two urban U.S. centers of individuals
who ranged in age from 12 to 77 included three congenitally acquired cases of HIV
on antiretroviral therapy. No workup of alternative causes for bronchiectasis was
available despite some descriptions included features that were suggestive of primary
ciliary dyskinesia. This highlights the need for registries and prospective studies
that follow up patients over time. These studies may not only clarify the connection
of bronchiectasis and HIV but also reveal pathophysiologic mechanisms that drive bronchiectasis
even in the non-HIV patient.
Immunoglobulin Replacement Therapy
Immunoglobulin replacement therapy is used in a vast number of clinical entities from
to infection to autoimmunity to neurologic disorders and beyond.[90] For certain diseases, immunoglobulin replacement is an absolute essential aspect
of therapy. For many other diseases, it provides supplemental clinical benefit by
way of anti-inflammatory and immunomodulating effects. Regarding bronchiectasis, immunoglobulin
replacement should be used in the setting of absent or deficient antibody production
([Table 1]). Immunoglobulin replacement consists of liquid concentrates of IgG recovered from
plasmapheresis of human donors. Multiple steps including donor screening, pooled plasma
nucleotide testing, nanofiltration, and treatment with inactivating detergents are
utilized to reduce the risk of viral transmission to near zero.
The primary goal of IgG therapy is to improve the patient's frequency of infections.
The specific trough IgG level required to achieve this outcome will vary from patient
to patient.[91] Therefore, the patient's frequency of infection should be the primary parameter
for increasing the maintenance dose. Bronchiectasis patients seem to require higher
doses than patients without bronchiectasis. In a 22-year prospective study of 90 clinically
phenotyped patients with CVID, the relationship between IgG dose, trough IgG level,
and infection rates was analyzed.[91] Bronchiectasis patients received a mean dose of 0.70 (±0.29) g/kg/mo compared with
0.53 (±0.20) g/kg/mo for patients without bronchiectasis to achieve equivalent IgG
trough levels and similar infection score per patient-period. The regression coefficient
for trough IgG levels against replacement dosing for bronchiectasis patients was also
analyzed. Every 0.1 g/kg/mo increase in replacement dose yielded an increase in trough
by 0.41 g/L. This regression coefficient was much lower than for patients without
bronchiectasis. In practice, an initial starting dose of 0.6 mg/kg/mo can be used
and then adjusted according to clinical outcomes. Many intravenous and subcutaneous
formulations of IgG are available. These products are proprietary and not interchangeable.
Replacement therapy can be administered in a hospital, infusion center, outpatient
office, or home setting. The frequency of administration depends on the route of delivery
and ranges from days (subcutaneous form) to every 3 to 4 weeks (intravenous form).
The exact product should be selected based on the patient's clinical variables and
preferences. Additional considerations when using IgG products include an awareness
of maltose-containing products in the setting of diabetics; the presence of isohemagglutinins
in IV IgG which may contribute to hemolysis[90]; and varying levels of IgA, sodium, and osmolality unique to each product. Some
common side effects of IgG therapy include headache, myalgia, arthralgia, chills,
malaise, fatigue, fever, rash, nausea, hypo- or hypertension, tachycardia, and fluid
overload.[90] Side effects may be infusion rate related and more common with higher doses.
Conclusion
Immunodeficiency is an important cause of bronchiectasis and is probably more prevalent
than currently recognized. All patients with idiopathic bronchiectasis should undergo
thorough evaluation for possible immunodeficiency. The identification of an immunodeficiency
in this group impacts therapeutic management and provides an opportunity to improve
clinical outcomes. In recent years, several distinct PIDs with characteristic bronchiectasis
have been identified. Careful analysis and phenotyping of these groups has expanded
understanding of immunodeficiency, especially about the relationship between immunodeficiency,
autoimmunity, and autoinflammatory disease. As both PID and bronchiectasis registries
have grown in number and size, so can the opportunity to learn more about underlying
pathophysiology that links these two syndromes together.
