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The Role ofImmunity
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intheDevelopment ofOtitis Media
SaraConcha andRodrigoHoyos-Bachiloglu
8
Part I: TheRole ofInnate andAdaptive
Immunity inOtitis Media
The term “immunity” comes from the Latin word immunitas,
which refers to the protection from legal prosecution offered
to Roman senators during their tenures in ofce. The immune
system is responsible for protecting an organism against foreign substances, especially infectious microbes, and also
products of damaged cells [1].
A normal immune response against microbes involves
sequential and coordinated responses by different branches
of the immune system (Table8.1). Innate immunity is essential for the defense against microbes during the rst few
hours or days after infection, is mediated by mechanisms
that are in place even before an infection occurs, facilitates
rapid responses to the invading microbes, and stimulates
adaptive immunity. Innate immunity detects microbial infections using pattern recognition receptors (PRRs) that are specic to molecules shared by groups of related microbes
(pathogen-associated molecular patterns (PAMPs)).
Adaptative immunity is stimulated by exposure to infectious
agents and generates pathogen-specic immune responses,
and it also has signicant receptor diversity and memory.
Immunological memory allows the adaptive system to
increase in magnitude and defensive capabilities with each
successive exposure to a particular agent.
Innate Immunity
The innate system is composed of cellular and chemical barriers such as the skin, mucosal epithelia, antimicrobial peptides, blood proteins, including the complement system, and
cells like macrophages and neutrophils.
S. Concha (*) · R. Hoyos-Bachiloglu
Department of Pediatric Immunology and Infectious Diseases,
Ponticia Universidad Católica de Chile, Santiago, Chile
e-mail: sconcha1@uc.cl; rhoyos@med.puc.cl
Table 8.1 Components of innate and adaptive immunity
Innate Adaptive
Epithelial and
chemical
barriers
Blood proteins Complement Antibodies
Cells • Neutrophils
• Mucociliary apparatus
• Mucous glycoproteins
• Surfactants
• Defensins, interferons,
lactoferrin, and nitric
oxide
• Middle ear epithelial
cells
• Macrophages
• Mast cells
• Dendritic cells
Epithelial
lymphocytes and
antibodies
• Lymphocytes T
– CD4
Th1
Th2
Th17
– CD8
• Lymphocytes B
Epithelial andChemical Barriers
Mucosal immunity constitutes the rst line of defense against
respiratory pathogens in the respiratory tract. Epithelial cells
of the middle ear contain several key defense mechanisms
such as the mucociliary apparatus, the trapping function of
mucous glycoproteins and surfactants, and the ability to
secrete innate defense molecules such as defensins, interferons, lactoferrin, and nitric oxide [2].
Mucins are high-molecular-weight glycoproteins responsible for the viscous properties of middle ear effusion [3].
Although mucins are important components of innate immunity in the respiratory tract, they can also play a pathological
role. Abnormally high levels of mucins have been demonstrated in middle ear effusions of chronic suppurative otitis
media (OM) patients, preventing the transmission of sound
waves and leading to conductive hearing loss. The upregulation of some mucin genes such as MUC2, MUC5AC, and
MUC5B plays an important role in the pathogenesis of otitis
media [2].
Surfactant proteins (SPs) such as SP-A are expressed in
the middle ear and Eustachian tube and play an important
role in innate responses through opsonization and comple-
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
M. V. Goycoolea et al. (eds.), Textbook of Otitis Media, https://doi.org/10.1007/978-3-031-40949-3_8
75
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S. Concha and R. Hoyos-Bachiloglu
ment activation. SP-A opsonizes Gram-negative bacteria and
modulates the expression of pro-inammatory cytokines like
interleukin (IL)-1β, IL-6, and tumor necrosis alpha (TNF-α).
The immune function of SP-A invivo has been studied using
mouse models of otitis media, which demonstrated its role in
enhancing bacterial phagocytosis and modulating middle ear
inammation [4].
Defensins are cationic proteins, whose main antimicrobial
mechanisms are forming a pore in the microbial membrane
and stimulating the production of pro-inammatory cytokines
and chemokines. Human B-defensin 2 and 3 are upregulated
in the middle ear in response to bacteria and play a critical role
in eliminating Haemophilus inuenzae (Hi) [5, 6].
Middle ear epithelial cells express PRRs such as Toll-like
receptors (TLRs) that detect infections by recognizing
PAMPs and activate the innate immune response.
Peptidoglycans such as those on the surface of Haemophilus
inuenzae (Hi) are recognized by TLR2; upon biding to its
ligand, TLR2 initiates nuclear factor kappa B (NF-κB)-
dependent cascades that activate the immune response and
upregulate TLR2 expression in a positive feedback loop [7,
8]. Polymorphisms of the TLR4 gene are associated with
recurrent acute OM.When infected with Hi, TLR4 knockout
mice had a worse mucosal immune response, with impairment of phagocytosis and phagosome maturation of polymorphonuclear cells as compared to wild-type mice [9].
Additional genes involved in the innate immunity have been
found to be differentially regulated in acute otitis media
(AOM)-prone children compared to healthy-age appropriate
controls. Downregulation of TLR adaptor molecule 2 was
found in middle ear uid of 24 children with acute otitis
media [10]. TLRs are not the only PRRs involved in the
pathogenesis and recovery of otitis media; Nod-like receptors (NLRs) have also been shown to initiate and support
robust immune responses through the production of inammatory cytokines and recruitment of leukocytes to the middle ear [11].
Finally, impairment of epithelial and chemical barriers in
otitis-prone children has been observed. They have lower
capacity for epithelial repair, lower pro-inammatory neutrophil chemoattractants such as macrophage inammatory
protein-1β (MIP-1β), IL-8, and CXCL5 [12], and proinammatory cytokines of higher levels such as IL-2 and
lower levels such as IL-7, IL-6, and IL-10in nasal washes,
thus showing that middle ear cytokine responses mirror those
of the nasal mucosa versus the peripheral blood and suggesting that proximal mucosal sites may better predict the quality
of middle ear responses compared to peripheral blood [13].
The Complement System
The complement system consists of several plasma proteins
that work together to opsonize microbes, promote recruit-
ment of phagocytes to the sites of infection, and, in some
cases, directly kill the microbes [1]. There are three pathways of complement activation, among which the most
important for responding to capsulated bacteria is the classical pathway, which is one of the major effector mechanisms
of the humoral arm of adaptive immune responses.
Cells
Neutrophils are the most abundant leukocytes and the rst
line of defense against invading pathogens in the middle ear,
experiencing roughly a 600-fold increase during acute otitis
media [14]. They express multiple TLRs and play a crucial
role in eradicating middle ear infections [2]. Upon activation, they form neutrophil extracellular traps (NETs) that are
positively correlated with higher bacterial loads within middle ear uids and surface-attached bacteria and contribute to
effusion viscosity, thus leading to chronic suppurative otitis
media [15].
Macrophages are also present in middle ear effusions, and
their role in infection depends on the causative agent.
Streptococcus pneumoniae serotypes 14 and 19F were found
to be resistant to phagocytosis that can lead to bacterial antigens being trapped in the middle ear, thus promoting effusion [2]. Haemophilus inuenzae utilizes a system of
phase-variable epigenetic regulation, to facilitate adaptation
and survival by evading opsonization, the process by which
it is marked for destruction by macrophages [16].
Mast cells are distributed throughout the tubotympanum, predominantly in the pars accida, and can trigger
allergic rhinitis, thus causing persistent inammation that
can lead to tube dysfunction and also impediment of mucociliary function that can lead to recurrent otitis media with
effusion [17]. A possible role of mast cells and their cytokines in the pathogenesis of chronic serous otitis media
has been suggested as these cells are increased in the
patient’s adenoid tissue and in thymic stromal lymphopoietin [18].
A normal tympanic membrane also contains abundant
dendritic cells that have the potential to migrate and activate
T cells. A signicant increase in the number of these cells
has been found in tubotympanic disease and in atticoantral
disease, with the difference being more pronounced in the
latter form of otitis media [19].
Adaptive Immune Responses
The adaptive immune system is composed of T and B lymphocytes and their products. There are two branches of adaptive immunity, namely, humoral immunity, which is mediated
by antibodies and B cells, and cell-mediated or cellular
immunity mediated by T cells.
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Humoral Immunity
A humoral immune response combats microbes in many
ways. Antibodies bind to microbes and prevent them from
infecting cells, thus neutralizing the microbes. In fact,
antibody- mediated neutralization is the only mechanism
of adaptive immunity that stops an infection before it is
established; this is why eliciting the production of potent
antibodies is the key goal of vaccination. Immunoglobulin
(Ig)G antibodies coat microbes and target them for phagocytosis because phagocytes (neutrophils and macrophages) express receptors for parts of IgG molecules.
Both IgG and IgM activate the complement system, and
complement products promote phagocytosis and destruction of microbes. IgA is secreted from mucosal epithelia
and neutralizes microbes in the lumens of mucosal tissues, such as the respiratory and gastrointestinal tracts,
thus preventing inhaled and ingested microbes from
infecting the host [1].
There are differences between children and adult’s
humoral immunity, and the susceptibility of infants to
AOM wanes with age due to immunological maturation.
During pregnancy, IgG antibodies are passively transferred
to the infant and progressively decrease during extrauterine life, reaching their lowest point at 6months of life. The
production of IgM and IgA begins progressively from
birth. The capacity to respond to protein antigens is
approximately 80% at birth and achieves levels like those
of adults around 3 months of life. The ability to respond to
polysaccharide antigens is not optimal until 2 years of life
due to the absence of B cells in the marginal zone of the
spleen [1].
For the normal development of humoral immunity, a correct development of B cells and a normal interaction of these
with circulating T lymphocytes is necessary. Developing
antibody-mediated immunity to Streptococcus pneumoniae
and non-typeable Hi (NTHi), the two most common pathogens causing AOM, is a cardinal step in preventing recurrent
infections in young children. Upon receiving T cell help, B
lymphocytes that recognized an antigen proliferate and differentiate into plasma cells that secrete different classes of
antibodies with distinct functions. Polysaccharides and lipids stimulate secretion mainly of the antibody class called
immunoglobulin M (IgM). Protein antigens induce the production of antibodies of different classes (IgG, IgA, IgE)
from a single clone of B cells.
Otitis prone children have lower serum bactericidal antibody titers against pneumococcal proteins: histidine triad
protein D (PhtD), pneumococcal choline binding protein A
(PcpA) and pneumolysin (PlyD1) compared with nonotitis
prone children after nasopharyngeal colonization and acute
otitis media [20]. This may be due to poor memory B-cell
and T-helper cell generation associated with reduced levels
of pneumococcal-specic IgG in the serum after the infection [21].
Comparing acute to convalescent antibody titers after
AOM, otitis-prone children had no signicant change in total
IgG responses to three Hi proteins (protein D, P6, and
OMP26), whereas non-otitis-prone children had signicant
increases in protein D.Anti-protein D, P6, and OMP26 antibody levels measured longitudinally during Hi colonization
between the ages of 6 and 24months demonstrated subtle
anti-protein D IgG increases over time in otitis-prone children compared to more than fourfold increases in non-otitisprone children [22]. The raise in the antibody’s levels in
non-otitis-prone children probably prevents them from having recurrent otitis.
Cellular Immunity
T lymphocytes consist of two functionally distinct populations: helper T cells or CD4+ cells and cytotoxic T lymphocytes (CTLs) or CD8+ cells. The functions of helper T cells
are mainly mediated by secreted cytokines, whereas CTLs
produce molecules that directly kill other cells. CD4+ T cells
comprise functionally distinct populations characterized by
specic transcription factors and cytokine proles; T helper
1 (Th1), Th2, and Th17 [1].
Antigen-specic CD4+ T cells have been shown to reduce
Streptococcus pneumoniae nasopharyngeal colonization. An
effective pathogen-specic T-cell response in adults has been
associated with protection from invasive Streptococcus
pneumoniae disease (invasive pneumococcal disease, IPD)
and chronic obstructive pulmonary disease (COPD) caused
by Streptococcus pneumoniae and NTHi, respectively. More
recently, Th17 cells have been described to mediate antibodyindependent protection in a mouse model of pneumococcal
infection. Moreover, CD4+ T cells in samples collected from
the adenoids and tonsils of traditionally dened otitis-prone
children showed no proliferation in response to NTHi protein P6, which led the authors to conclude that otitis-prone
children lack pathogen-specic T cells. [23] Other authors
have shown that adenoids have a reduced capacity to produce
interferon-gamma (IFN-γ) and speculate that this alteration
could cause susceptibility to recurrent acute otitis media
[24].
For several decades, Pichichero etal. studied the underlying pathogenesis of AOM in children and also why the risk of
AOM decreases over time. They observed that this susceptibility is not only due to a Eustachian tube dysfunction but
also due to immune factors [13]. Peripheral blood mononuclear cells (PBMCs) from otitis-prone children between the
ages of 6 and 12 months display a general skewing away
from Th1 and Th17 immunity and toward Th2 and regulatory
T cell (Treg) dominance [25]. This abnormality was largely
outgrown by 3 years of age, coinciding with the epidemio-
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S. Concha and R. Hoyos-Bachiloglu
logical observation of diminishing AOM at that age [13].
They also showed that otitis-prone children are more frequently diagnosed with viral upper respiratory infections
possibly due to decient antiviral responses at the nasopharynx with decreased production of pro-inammatory cytokines and chemokines like IL-6, IL-10, and TNF-α [26].
Part II: TheEar Microbiota
The microbiota plays critical roles in the regulation and
development of the major components of the host’s immune
system, whereas the immune system orchestrates the maintenance of the key features of the host–microbe symbiosis
[27].
The human microbiota consists of ecological communities of commensal, symbiotic, and pathogenic microorganisms that colonize several body sites and play a critical
role in the regulation of many homeostatic processes,
including inammation and defense against pathogens, to
inhibit the colonization and growth of otopathogens [28].
Immediately after birth, the respiratory tract becomes colonized, and, in the rst week of life, there is a predominance of Staphylococcus spp., Corynebacterium,
Dolosigranulum, and Moraxella. This early bacterial colonization plays a pivotal role in the stability of microbial
communities: proles dominated by Moraxella and
Dolosigranulum/Corynebacterium are associated with a
stable microbiota and with lower rates of respiratory infections in later stages of life, whereas the less stable proles
are associated with a high abundance of Hi and
Streptococcus [29].
Several environmental factors can inuence the shaping
of the microbiota’s composition in the rst years of life.
Children born by vaginal delivery have predominance of
bacteria previously associated with microbiome stability and
respiratory health, but some authors suggest that this impact
disappears at 6 weeks of age. Breastfed infants develop a
bacterial prole enriched by Dolosigranulum and
Corynebacterium at 6 weeks of age in comparison with
formula- fed infants; however, this effect also disappears
around 6 months of age. In children with AOM, recent antibiotic therapy induces a reduction of benecial bacteria such
as Streptococcaceae and Corynebacteriaceae and an
increased abundance of Enterobacteriaceae and
Pasteurellaceae in the upper respiratory tract. The effect of
the conjugated pneumococcal vaccines in the microbiome is
controversial and it seems to vary by ethnicity; Swiss vaccinated children have an increase in benecial bacteria and in
bacterial diversity, whereas in children from Gambia, vaccination reduced the nasopharyngeal carriage of vaccine serotypes, but pneumococcal carriage remained high among
vaccinated infants, probably because of an immediate expansion of non-vaccine serotypes [30].
According to the pathogen reservoir hypothesis (PRH),
the adenoid pad serves as a source of pathogens that can grow
in this region and further spread to the respiratory system and
middle ear, leading to infections and diseases [31]. Owing to
the introduction of culture-independent techniques such as
gene analysis with a polymerase chain reaction (PCR) using
primers that target a segment of the 16SrRNA gene, microbiological investigations now allow the knowledge of entire bacterial communities. There are keystone species that maintain
the balance and function of the bacterial community such as
Dolosigranulum spp. and Corynebacterium spp. In children,
a diverse microbiota and a higher relative abundance of
Corynebacterium, Dolosigranulum, Propionibacterium,
Lactococcus, and Staphylococcus were associated with a
lower incidence of S. pneumoniae, H. inuenzae, and
Moraxella catarrhalis colonization, lower AOM, a shorter
course of AOM, and a better clinical outcome [30]. An unstable microbiota during an acute respiratory tract infection episode with the predominance of otopathogens is associated
with the occurrence of a symptomatic viral infection and with
a higher risk of transition to otitis, whereas children with
asymptomatic viral infections had no predominance of otopathogens [32]. There are several trials of probiotic administration for prevention of middle ear diseases in children, but
there is lack of evidence for their use [33].
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When toSuspect andHow toEvaluate
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Immune Deficiencies inOtitis Media
SaraConcha andRodrigoHoyos-Bachiloglu
9
Part I: General Features ofInborn Errors
ofImmunity (IEI)
Immunodeciencies are clinical situations where there is a
quantitative or functional deciency of the immune system.
They can be divided into two main groups based on their
ontogeny. Secondary immunodeciencies include conditions
such as surgical asplenia, prematurity, human immunodeciency virus (HIV) infection, malnutrition, hematological
diseases, autoimmune diseases, and metabolic diseases such
as diabetes and can result from various immunosuppressive
drugs. Inborn errors of immunity (IEI), also referred to as
primary immunodeciencies (PIDs), are caused by mutations affecting genes involved in the normal functioning of
the immune system. Although recurrent infections are the
main symptoms of such conditions, PIDs have a broad spectrum of clinical presentations even for the same genetic
defect (Table9.1). An underlying immunodeciency should
be considered not only in patients presenting with frequent
infections but also in those with infections lasting for a longer duration than usual, severe infections, infections with a
poor response to antibiotic treatment, complicated infections, and infections due to unusual, multiple, or opportunistic microorganisms (Table9.2). Noninfectious manifestations
of an underlying PID can be extremely broad and include
severe allergic diseases like eczema and food allergies, recurrent skin inammation, oral ulcers, autoimmunity (most frequently autoimmune cytopenias), and lymphoproliferative
diseases amongst others [1]. IEI are caused by monogenic
germline mutations that result in loss of expression and/or
loss of function or gain of function of the encoded protein.
This results in aberrant immunity due to the critical roles that
these proteins play in the development, maintenance, and
function of cells of the immune system or cells other than
S. Concha (*) · R. Hoyos-Bachiloglu
Department of Pediatric Immunology and Infectious Diseases,
Ponticia Universidad Católica de Chile, Santiago, Chile
e-mail: sconcha1@uc.cl; rhoyos@med.puc.cl
leukocytes that contribute to immunity, during homeostasis
and in response to external (e.g., infectious agents or environmental antigens) and internal (e.g., cytokines, selfantigens, and cancer cells) stimuli [2]. For a long time, IEI
were consider rare diseases, but with the technological
advances in genetics leading to improved diagnostic capabilities, the number of IEI has increased in more than 200
new conditions over the past 10years and their incidence is
now estimated to be around 1:1000 to 1:5000in newborns
[3]. In the last International Union of Immunological
Societies (IUIS) classication of 2019, 404 phenotypes with
430 known genetic defects were included and they were separated into 10 groups (Table9.1) [2].
In the last few years, there has been great advances in the
development of new methods to expedite the identication of
defects of the immune system and the cellular, molecular,
and genetic aberrations underlying these conditions.
Sequencing in general and next-generation sequencing
(NGS) techniques are becoming technically more accurate,
fast, and affordable and are therefore widely available to
researchers and physicians [1]. A new insight into the pathogenesis of IEI has introduced targeted treatments next to substitution and symptomatic therapy (immunoglobulin
replacement, antimicrobial and anti-inammatory or immunosuppressive treatments), on one side, and replacement of
the awed immune system by hematopoietic stem cell trans-
Table 9.1 Inborn errors of immunity: International Union of
Immunological Societies (IUIS) classication of 2019
1. Immunodeciencies affecting cellular and humoral immunity
2. Combined immunodeciencies with associated or syndromic
features
3. Predominantly antibody deciencies
4. Diseases of immune dysregulation
5. Congenital defects of phagocyte number or function
6. Defects in intrinsic and innate immunity
7. Autoinammatory disorders
8. Complement deciencies
9. Bone marrow failure
10. Phenocopies of inborn errors of immunity
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
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plantation (HSCT) or gene therapy, on the other [4]. This has
improved not only the survival rate but also the quality of life
of these patients.
Part II: When toSuspect IEI inPatients
withRecurrent Otitis Media
Otitis media is one of the most common diseases in young
children. The decrease in the occurrence of otitis with age is
explained by the transitioning of the Eustachian tube’s anatomy by 3–5years of age to a more “adult-like” structure and
also by the maturation of the immune system [5]. In most
children, otitis will not reveal a decient immune system
beyond physiological immaturity; however, it can be the rst
sign of a congenital disorder and unrecognized immunodeciencies can lead to severe and potentially fatal infections.
Recurrent otitis, with more than 4 episodes in a year, has
been established as the rst of the 10 warning signs of EIE in
children by the Jeffrey Modell Foundation and the American
Red Cross (Table9.2). In adults, the European Society for
Immunodeciencies (ESID) advise suspecting IEI in case of
four or more infections treated with antibiotics in 1year (otitis, bronchitis, sinusitis, pneumonia) and recurrent infections
needing prolonged therapy with antibiotics [6]. Although the
number of infections is an important warning sign, the most
important red ag is a family history of IEI.This feature has
proven to be the key warning sign suggesting the presence of
IEI and, as such, should be actively investigated when evaluating a patient with recurrent infections, including patients
with recurrent otitis media [7]. Bardou etal. have proposed
four warning signs for underlying IEI in otitis media: progressing infections leading to mastoiditis, associated
abscesses or systemic infections, lack of responsiveness to
adequate antibiotic treatment, and occurrence of unusual,
severe, or frequently relapsing infections in other sites [6]
(Table9.3).
Table 9.2 Warning signs of primary immunodeciency
1. Four or more new ear infections within 1year
2. Two or more serious sinus infections within 1year
3. Two or more months on antibiotics with little effect
4. Two or more pneumonias within 1year
5. Failure of an infant to gain weight or grow normally
6. Recurrent, deep skin or organ abscesses
7. Persistent thrush in the mouth or fungal infection on the skin
8. Need for intravenous antibiotics to clear infections
9. Two or more deep-seated infections, including septicemia
10. A family history of primary immunodeciency
Table 9.3
otitis
1. Otitis media evolving with mastoiditis, abscesses or systemic
2. No response to appropriate antibiotic therapy
3. Otitis media associated with other infections
4. Recurrent otitis, leading to failure to thrive and general
5. Family history of primary immunodeciency and/or consanguinity
Warning signs to investigate inborn errors of immunity in
infections
developmental delay
Part III: IEI Presenting withOtitis Media
Otitis media and pneumonia are the main infectious manifestations of IEI, with up to 57% of patients reporting having
otitis media [8]. We will detail those IEI most frequently
associated with otitis media.
Antibody Deciencies
Antibodies are antigen-specic proteins produced by B cells
and are synthesized and secreted by plasma cells, which
arise from terminally differentiated B cells. They neutralize
toxins and viruses, prevent colonization by pathogenic
organisms, opsonize bacteria and fungi, activate the complement cascade, which enhances opsonization, and may
directly lyse Gram-negative bacteria. Most patients with primary antibody deciencies present with recurrent, severe, or
persistent bacterial infections of the sinopulmonary tract,
including recurrent otitis media, sinusitis, and pneumonia
most commonly secondary to Streptococcus pneumoniae,
Hemophilus inuenzae, Staphylococcus, and Pseudomonas.
Diarrhea affects up to 25% of these patients, often caused by
Giardia lamblia infection [9]. Of the nine IEI categories,
predominantly, antibody deciency has the highest prevalence (1:25,000), but, despite advances in genomics, utilizing the current gold standard of whole exome sequencing for
diagnosis, pathogenic gene variants are only identied in
less than 20% of patients, especially in nonconsanguineous
populations [10].
They are classied into four groups:
1. Severe reduction in all serum immunoglobulin isotypes
with profoundly decreased or absent B cells,
agammaglobulinemia
Agammaglobulinemia is dened by the complete or
near absence of B cells (less than 1%) and severe reduction of all major serum immunoglobulin isotypes (immunoglobulin (Ig)G, IgM, IgA). Clinical onset is typically
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within the rst year(s) of life and is characterized by
recurrent infections, mainly by encapsulated bacteria,
which may affect the respiratory and gastrointestinal
tracts, the skin, the joints, and the central nervous system
[11]. The most common IEI in this group is X-linked
agammaglobulinemia (XLA) due to Bruton’s tyrosine
kinase (BTK) deciency, which plays a critical role in
precursor B-cell development in the bone marrow [12].
The incidence of XLA is around 1:100,000 to 1:200,000
depending on ethnicity [11]. Clinical symptoms in
affected patients initiate between the age of 6 and
12months, when the maternal IgGs are catabolized; however, some patients may remain asymptomatic in the rst
years of life. Recurrent bacterial respiratory and/or gastrointestinal infections are the hallmarks of this disorder.
The most frequent type of upper respiratory tract infection in large cohorts of XLA patients is otitis media
(70%), followed by sinusitis (almost 60%). Recurrent
otitis media may be the only infectious manifestation
prior to diagnosis in XLA patients and should therefore
always be considered as an alarm sign for immune deciency during routine clinical practice [13]. Other frequent infections are pneumonia and gastrointestinal
infections due to Giardia lamblia, the mycoplasma species, and enteroviruses. They also present with autoimmunity and up to 20% may develop arthritis. In a limited
number of cases, gross deletions encompassing BTK and
TIMM8A (translocase of inner mitochondrial membrane
8A) have been associated with sensorineural hearing loss
in the rst year of life, even though the underlying pathogenic mechanisms are not known [14]. Immunoglobulin
replacement therapy is fundamental in XLA as in all
humoral immunodeciencies. Maintaining pre-infusion
IgG levels >500mg/dL assures a notable reduction in the
number of infections. Using a dose of 400mg/kg/dose
every 3–4weeks (in the case of intravenous immunoglobulin (IVIG)) or 100mg/kg/dose every week (in the case
of subcutaneous immunoglobulin) is usually sufcient to
maintain such levels [15]. Frequently, antibiotic prophylaxis is necessary in order to control the number of infections even when IVIG therapy is adequate [11].
2. Severe reduction in at least two serum immunoglobulin
isotypes with a normal or low number of B cells, common
variable immunodeciency (CVID) phenotype
CVID is a heterogeneous condition in which there is
reduction of serum IgG by two or more standard deviations (SDs) below the mean age, along with a reduction of
at least one of the other two isotypes (IgA or IgM) and
with poor-to-absent specic antibody responses to an
infection or vaccination [11]. Bonilla and coworkers, in
an international consensus document in 2016, proposed
that the main diagnostic criteria should also include the
onset of immune deciency after 2years of age and that
Table 9.4 Diagnostic criteria for probable common variable immunodeciency (CVID)
European Society for
International consensus
document CVID
Male or female patient who has
a marked decrease of IgG (at
least 2 SD below the mean
age), a marked decrease in
either IgM or IgA, and fullls
all of the following criteria:
1. Onset of immune deciency
at greater than 2years of age
2. Absent isohemagglutinins
and/or poor response to
vaccines
3. Dened causes of
hypogammaglobulinemia
have been excluded
Immunodeciencies (ESID)
criteria for CVID
Male or female patient older than
4years with at least one of the
following: increased susceptibility
to infection, autoimmunity,
granulomatous disease,
unexplained polyclonal
lymphoproliferation, and/or
affected family member with
antibody deciency
AND marked decrease of IgG and
marked decrease of IgA with or
without low IgM levels (measured
at least twice; <2 SD of the normal
levels for their age)
AND at least one of the following:
poor antibody response to vaccines
(and/or absent isohemagglutinins),
i.e., the absence of protective levels
despite vaccination where dened
and/or low switched memory B
cells (<70% of the age-related
normal value)
AND secondary causes of
hypogammaglobulinemia have
been excluded
AND no evidence of profound
T-cell deciency, based on T cell
and naive T cell numbers and T
cell proliferative capacity
the dened causes of hypogammaglobulinemia must be
excluded to establish a diagnosis of CVID [16]. In 2019,
the European Society for Immunodeciencies (ESID)
added that there should be no evidence of profound T-cell
deciency, based on T cell and naive T cell numbers and
T cell proliferative capacity in children older than 4years
[17] (Table9.4). The prevalence of CVID is estimated at
1:25,000in Europeans, but there are regional differences,
with CVID being less commonly diagnosed in Asians and
Afro-Americans [18]. The percentage of patients with
monogenic defects associated with CVID is only about
20–25%. Although the rst genes to be identied were
autosomal recessive mutations, increasing numbers of
autosomal dominant defects, with variable penetrance,
have been discovered and now constitute the majority of
genetic defects identied in CVID patients [19]. The
onset of symptoms may be at any age but is generally
between the ages of 15 and 40 years. The history of severe
or recurrent bacterial infections of the upper and/or lower
respiratory tract is commonly the reason an immune
defect is rst suspected. Pneumonia, usually due to
Streptococcus pneumoniae, H. inuenzae, or mycoplasma
species is found in up to 70% of patients. Almost 50% of
patients present noninfectious complications such as
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autoimmunity (most frequently autoimmune cytopenias),
allergy, chronic pulmonary disease, granulomatous disease, and lymphoproliferation. The treatment goal for
patients with CVID is to prevent infections and control
additional secondary complications when present and
clinically relevant and mainly consists of immunoglobulin replacement therapy and antibiotics [11].
3. Severe reduction in serum IgG and IgA with normal/ele-
vated IgM and normal numbers of B cells, hyper-IgM
The presence of elevated or normal serum IgM levels
and low or null serum levels of the switched isotypes
(IgG, IgA, and IgE) is called hyper-IgM syndrome.
Defective production of IgG, IgA, and IgE and normal
IgM production result from abnormal class switch recombination, a process that is essential for antibody maturation [20]. Although IgM antibodies have been shown to
be protective against bacteria (such as non-typable
Haemophilus inuenzae), the production of switched iso-
types is required for a fully efcient humoral response
[21]. The estimated frequency of hyper-IgM syndrome is
around 1 in 500,000 births. These patients suffer from
recurrent bacterial infections that predominantly affect
the respiratory tract and lead to severe sinusitis and bronchiectasis if left untreated. The clinical features and treatment depend on the precise nature of the molecular defect
[11].
4. Isotype, light chain, or functional deciencies with gener-
ally normal numbers of B cells
Patients with recurrent respiratory infections may have
defects in the amount or function of immunoglobulins.
Those with a defect in the quantity can have reduced IgG
in the context of normal IgA and IgM, and are dened as
hypogammaglobulinemia, can have low quantity of IgG
subclasses, or y can have low quantity of IgA or IgM.The
most common functional defect is specic antibody deciency (SAD) with a normal Ig level and normal B cells.
Quantity Defects
• Hypogammaglobulinemia: The age of the patient rst
needs to be considered as transient hypogammaglobulinemia of infancy presents in children, usually under the
age of 3years. Secondary causes, such as drug-induced
hypogammaglobulinemia (steroids, immunosuppressants, certain biologicals and small molecules, selected
anticonvulsants, and others), protein loss due to renal,
gastrointestinal disease or potentially less well-dened
third space, and lymphoma, must be considered. Patients
with hypogammaglobulinemia of unknown signicance
and origin need to be referred for regular follow-up and
further diagnostic testing [11].
• IgA deciency: This is frequently asymptomatic, but
affected patients can have a minor risk of allergy, autoim-
munity, and bacterial infections. The genetic defect is
commonly unknown. There is no specic treatment, but
prophylactic antibiotics can be used in case of recurrent
infections.
• IgG subclasses deciency: This is dened as a level of
IgG subclasses less than 2 SDs below the mean age with
normal total IgG levels [22]. Up to 20% of the population
has a subnormal IgG subclass level for one or more subclasses. Most IgG subclass-decient subjects are asymptomatic, particularly those with an IgG4 deciency. Thus,
IgG subclass deciency does not dene a disease; instead,
it denes a clinical laboratory nding [11]. A clinically
signicant IgG subclass deciency occurs when the IgG
subclass deciency is associated with recurrent infections, a signicant defect in functional antibody response,
or is part of another IEI.
Functional Defects: Specic Antibody Deciency
Polysaccharide antigens are repetitive molecular structures
present in the outer capsule of bacteria, against which B cells
can mount a T cell-independent immune response. The difference with a T cell-dependent response is that without the
help of activated T cells, B cells do not experience a germinal
center reaction, leading to the production of high-afnity
antibodies and memory cells and immunoglobulin class
switching [20]. The immunological responsiveness to polysaccharide antigens matures during the rst years of life so
that children below 2years of age can have decient antibody responses to those types of antigens. The consequence
of this immaturity is an increased susceptibility to infections
with encapsulated bacteria such as pneumococcus [23].
In order to bypass the poor immunological responses to
polysaccharide antigens during the rst 2 years of life and
elicit protective humoral responses using vaccines, these
antigens must be conjugated to a protein. These conjugated
antigens can generate a T cell-dependent anti-polysaccharide
response with a T cell–B cell interaction, resulting in adequate protection against disease [24]. The Centers for
Disease Control and Prevention recommends four doses of a
13-valent pneumococcal conjugate vaccine for children
under 2years of age and a 23-valent pneumococcal polysaccharide vaccine for all adults 65years or older. Vaccine indications and timings depend on age, previous vaccinations,
and the presence of high-risk conditions, including congenital immunodeciency [25].
Specic antibody deciency (SAD) is dened as the
inability to mount an antibody response to Streptococcus
pneumoniae capsular polysaccharide antigens in the presence of normal immunoglobulin concentrations and normal
antibody responses to protein antigens [26]. Patients with
SAD generally present with recurrent, chronic, or/and severe
rhinosinusitis, otitis and bronchopulmonary infections due to
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capsulated bacteria such as Streptococcus pneumoniae,
Haemophilus inuenzae, and Moraxella catarrhalis; how-
ever, they can also be asymptomatic [11].
The estimated incidence of SAD is unclear, and studies
reporting prevalence should be evaluated with caution as
they are based on reports from different centers, use different
denitions, and normal values can differ between referral
populations. Nevertheless, SAD is estimated to one of the
most common IEI [27], with a reported prevalence of 6–14%
in children with recurrent respiratory infections, 11–24% in
adults with chronic rhinosinusitis, and 8% in adults with
recurrent pneumonia.
Response to pneumococcal vaccines is usually determined by assessing the levels of serotype-specic IgG by
multiplex bead immunoassays or enzyme-linked immunosorbent assays [23]. In order to stablish the diagnosis,
serotype- specic IgG levels must be measured before and
4–8 weeks after receiving a pneumococcal polysaccharide
vaccine in children older than 2 years of age. In patients
exclusively vaccinated with pneumococcal conjugate vaccines, serotype-specic antibody levels ≥0.35 μg/mL are
considered protective. In patients who have received the
polysaccharide vaccine, a normal response is dened as
serotype-specic antibody levels ≥1.3 μg/mL and/or
increases in antibody levels between two and four times
postimmunization with the polysaccharide vaccine with
respect to basal levels in at least 50% of the serotypes tested
in patients aged 2–5years and in at least 70% in patients
aged 6years and over.
Treatment recommendations by the American Academy
and the American College of Allergy, Asthma and
Immunology are dened according to the severity of the disease. Most patients with mild-to-moderate disease might
benet from the use of prophylactic antibiotics, whereas
unresponsive patients might benet from a period of IgG
replacement [3].
Defects in different proteins of the complement system
present with susceptibility to different kinds of microbes,
depending on the biological function of the affected component. Patients with C3 deciencies have an increased susceptibility to encapsulated bacteria for which opsonization is the
primary host defense. Patients with deciencies of C1, C4, or
C2 have a lower prevalence of infection compared to
C3-decient patients because their alternative pathway is
intact and therefore are able to activate C3. The terminal
components, C5–C9, form a membrane attack complex
required for the bactericidal/bacteriolytic functions of the
complement system. Patients with C5–C9 deciencies are
susceptible to Neisserial infections [11].
During the initial evaluation of patients with a suspected
defect in the complement system, it is recommended to functionally evaluate the classic pathway using a test known as
CH50. The CH50 evaluates the time in which 50% of sensitized sheep erythrocytes are lysed in the presence of functional C1–C9 proteins. A similar test exists for the alternative
pathway, namely, the AH50. Almost all complement deciencies are associated with either a CH50 or AH50 near
zero. Moderately low CH50, C3, or C4 levels are a common
nding and are most frequently due to inadequate sample
handling.
Treatment of patients with recurrent capsulated bacteria
due to complement deciency is mostly with prophylactic
antibiotics.
Phagocytic Defects
Defects of the phagocytes most frequently associated with
recurrent otitis media can be classied into those due to a
numerical defect, such as congenital neutropenia, and those
due to functional defects, like chronic granulomatous disease
(CGD).
Inborn Errors oftheComplement System
The complement system is composed of serum and cell surface proteins that play a major role in host defense, inammation, immune complex clearance, induction of a normal
humoral immune response and clearance of apoptotic cells.
This system can be activated by IgM or IgG antibodies bound
to a pathogen (classical pathway) or by the spontaneous
hydrolysis of C3 and its attachment to a cell surface (alternative pathway). Each activation pathway requires a subgroup
of complement proteins, but both use the same terminal components. As a group, defects of the complement system are
infrequent, but, in specic groups of patients, such as those
with systemic infections with encapsulated organisms, their
frequency can be up to 11% [28].
Congenital Neutropenia
Neutropenia is dened as an absolute neutrophil count of
less than 1500 cells/μL in individuals over 1 year of age and
less than 2000 cells/μL during the rst year of life. Severe
neutropenia is dened as a neutrophil count less than 500
cells/μL; these patients are usually symptomatic and present
with severe bacterial infections. The temporal course of neutropenia may vary and can be classied as persistent, intermittent, or cyclic. Persistent neutropenia, also referred to as
chronic neutropenia, is dened as a low neutrophil count
lasting at least 3months. Cyclic neutropenia is characterized
by uctuating neutrophil counts, with a decreased number of
neutrophils every 2–3weeks and normal counts between episodes [11].
The risk of infections in neutropenia patients correlates
with the severity and duration of neutropenia. Patients with
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