Specific antibody deficiency (SAD, also SPAD; ICD-10 D80.6) is a predominantly-antibody inborn error of immunity recognised by the IUIS, and it is defined by what a patient cannot do rather than by what they lack. Total IgG, IgA, IgM and the IgG subclasses are all normal, and the response to protein antigens is intact; what fails is the antibody response to unconjugated polysaccharide antigen, measured as titres after the 23-valent pneumococcal polysaccharide vaccine. Clinically the result is recurrent sinopulmonary infection with encapsulated bacteria - otitis media, sinusitis, pneumonia - in someone whose routine immunoglobulin panel is reassuringly normal. The mechanism is an immature-for-age failure of the T-independent type 2 response. Unconjugated capsular polysaccharide has no peptide to present, so it cannot recruit T-cell help; it must activate B cells directly, and the cells able to do that mature late in childhood. The response is normally absent in healthy children under two and appears by about age two - which is why the diagnosis cannot be made before then. SAD is, in effect, that normal infant state persisting or recurring in an older child or adult. Two features set this disease apart from most inherited immune disorders. It has no known causal gene - the origin and molecular defect are unknown - so its mechanism is described functionally rather than from a locus. And its case definition is contested at the level of the assay: how many serotypes, what titre, what fold rise. Because the assay is the definition, moving a threshold does not reclassify patients within the disease, it changes who has it.
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name: Specific Antibody Deficiency
creation_date: "2026-08-31T09:40:00Z"
category: Complex
disease_term:
preferred_term: immunodeficiency due to selective anti-polysaccharide antibody deficiency
term:
id: MONDO:0019093
label: immunodeficiency due to selective anti-polysaccharide antibody deficiency
description: >
Specific antibody deficiency (SAD, also SPAD; ICD-10 D80.6) is a
predominantly-antibody inborn error of immunity recognised by the IUIS, and
it is defined by what a patient cannot do rather than by what they lack.
Total IgG, IgA, IgM and the IgG subclasses are all normal, and the response
to protein antigens is intact; what fails is the antibody response to
unconjugated polysaccharide antigen, measured as titres after the 23-valent
pneumococcal polysaccharide vaccine. Clinically the result is recurrent
sinopulmonary infection with encapsulated bacteria - otitis media,
sinusitis, pneumonia - in someone whose routine immunoglobulin panel is
reassuringly normal.
The mechanism is an immature-for-age failure of the T-independent type 2
response. Unconjugated capsular polysaccharide has no peptide to present, so
it cannot recruit T-cell help; it must activate B cells directly, and the
cells able to do that mature late in childhood. The response is normally
absent in healthy children under two and appears by about age two - which is
why the diagnosis cannot be made before then. SAD is, in effect, that normal
infant state persisting or recurring in an older child or adult.
Two features set this disease apart from most inherited immune disorders. It has no known
causal gene - the origin and molecular defect are unknown - so its mechanism
is described functionally rather than from a locus. And its case definition
is contested at the level of the assay: how many serotypes, what titre, what
fold rise. Because the assay is the definition, moving a threshold does not
reclassify patients within the disease, it changes who has it.
synonyms:
- specific antibody deficiency
- SAD
- SPAD
- selective antibody deficiency with normal immunoglobulins
- impaired polysaccharide responsiveness
- partial antibody deficiency
- selective anti-polysaccharide antibody deficiency
parents:
- Predominantly antibody deficiency
- Inborn error of immunity
notes: >
No gene, and the absence is curated rather than pending. There is no
`genetic:` section because there is no causal gene to put in one: the
defining review states the origin and molecular defect are unknown, and that
statement is carried as a `NO_EVIDENCE` evidence item on the mechanism node
so the gap is legible to a query and not only to a reader. It follows that
`category` is `Complex` rather than `Mendelian` and that there is no
`inheritance:` block.
No `animal_models:` either, and that is a judgement rather than an oversight.
The nearest system is a TACI A144E transgenic mouse on a TACI-null
background with impaired anti-TNP-Ficoll responses, which does model
T-independent type 2 failure - but TACI deficiency is a CVID-associated
genotype, and importing it here would quietly supply the monogenic basis
this disease does not have. The TI-2 model in this entry is therefore
supported by human observation and by the developmental argument, not by an
animal model, and it should be read that way.
No `loinc_term` on the reference range below. LOINC is not configured in
`conf/oak_config.yaml` and has no term cache, so a code could not be
validated here; rather than write an unverifiable identifier into a slot
that looks authoritative, it is left empty.
The case definition is the disease's largest uncertainty, and it is
methodological rather than biological. Diagnosis rests on titres after
PPSV23, and there is no consensus on the magnitude of response or the number
of serotypes that counts as adequate; responses are age-dependent and
probably serotype-dependent. Prevalence estimates in referral series
consequently range from about 6% to 24% of children investigated for
recurrent infection, which is a range about the criteria at least as much as
about the populations. Every prevalence and severity statement in this entry
is therefore tied to its stated criterion.
A conjugate-vaccine trap worth knowing. Because PCV13 generates a
T-dependent response, protective titres to serotypes contained in a
conjugate vaccine the patient has already received do not exclude SAD.
Testing has to use serotypes present in PPSV23 only - at least six of them
by the US practice-parameter recommendation. A "normal" pneumococcal panel
in a conjugate-vaccinated patient is one of the commonest ways this
diagnosis is missed.
Secondary and syndromic phenocopies. The SAD phenotype occurs inside other
established immunodeficiencies - Wiskott-Aldrich syndrome, partial DiGeorge
syndrome, NEMO deficiency - so a polysaccharide-response failure is a
finding that needs a differential, not a diagnosis on its own. This entry
covers the isolated entity.
Treatment evidence is thin and the entry does not inflate it. Antibiotic
prophylaxis is the mainstay by consensus, with no standardised regimen and
no efficacy studies in SAD specifically; immunoglobulin therapy is
recommended by expert guidelines on the strength of retrospective
observation. Both treatments carry `directness: INDIRECT` for exactly that
reason.
prevalence:
- population: Children investigated for recurrent infection (referral series)
measure_type: POINT_PREVALENCE
prevalence_class: COMMON
rate_per_100000: 10000.0
rate_low: 6000.0
rate_high: 14000.0
notes: >-
6-14% across three paediatric series of 100, 45 and 100 children evaluated
for recurrent infection. This is a prevalence within a referred and
already-symptomatic population, not a population prevalence, and it moves
with the serological criterion used. A separate chart review of 91 referred
children reported 23.1%.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In three studies evaluating children for recurrent infection (n = 100, 45, and 100, respectively), SAD was found to occur in 6-14% of individuals"
explanation: >-
The paediatric referral-series estimate with its three denominators
given explicitly.
- population: Adults with chronic rhinosinusitis (referral series)
measure_type: POINT_PREVALENCE
prevalence_class: COMMON
rate_per_100000: 17800.0
rate_low: 11600.0
rate_high: 24000.0
notes: >-
11.6% in one retrospective series of 129 adults and 23-24% in two larger
series (n = 239 and n = 595). The near-twofold spread between studies of
the same clinical population is the clearest available measure of how much
the diagnostic criterion matters.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "in 1 retrospective study of 129 adults with chronic rhinosinusitis, 11.6% were diagnosed with SAD"
explanation: >-
The lower of the two adult rhinosinusitis estimates, with its
denominator.
- population: Adults with SPAD, multicenter observational cohort
measure_type: CASES_IN_LITERATURE
prevalence_class: UNKNOWN
notes: >-
Not an occurrence rate. Recorded because it is the only cohort that
describes who adult patients actually are: 55 patients, median age 45 at
diagnosis, 75% female, 38% with a coexisting allergic or inflammatory
disorder. That sex ratio and comorbidity profile are what a clinician
should have in mind when deciding whom to test.
evidence:
- reference: PMID:40097777
reference_title: "Diagnosis, Characteristics, and Outcome of Selective Anti-polysaccharide Antibody Deficiencies In A Retrospective Cohort of 55 Adult Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We conducted a multicenter observational study involving 55 adult patients with SPAD."
explanation: >-
The largest adult cohort. The demographics quoted in `notes` above -
median age 45, 75% female, 38% with allergic or inflammatory
comorbidity - are in the same sentence and the ones following it; the
snippet stops before the first bracketed interquartile range, because
the reference validator strips square-bracketed spans before matching.
- population: General population
measure_type: UNKNOWN
prevalence_class: UNKNOWN
notes: >-
Unknown. SAD has been estimated to be the eighth most commonly identified
inborn error of immunity globally, but registry figures rest on
inconsistent definitions across centres and the condition is not reported
in all regions, so that ranking cannot be converted into a rate.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The incidence of SAD in the general population is unclear"
explanation: >-
States directly that no population estimate exists, which is why this
record carries a class of UNKNOWN rather than a computed rate.
progression:
- phase: Childhood-onset, potentially transient
age_range: 2 years and above
notes: >-
In some patients, particularly children, SAD resolves over time - which
mirrors the fact that the polysaccharide response is normally acquired
around age two and can simply be late. This is the reason the diagnosis
should be re-tested rather than treated as permanent, and the reason
long-term immunoglobulin replacement in a child is a decision with a
horizon rather than a life sentence.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SAD may be a transient issue in some patients, especially children, and may resolve over time"
explanation: >
States the transient course directly, with the paediatric qualifier.
- phase: Progression to a broader humoral immunodeficiency
notes: >-
The other trajectory, and the one that complicates the differential. CVID
is not only the alternative diagnosis to exclude at presentation; it is a
destination SAD can reach. That makes the CVID differential in `diagnosis`
a statement about a moment in time rather than a permanent separation, and
it is an argument for continued immunoglobulin monitoring after the
diagnosis is made.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "it may evolve into more severe forms of humoral immunodeficiency such as CVID"
explanation: >
Records the progression to CVID, which is what makes the two entities a
sequence rather than only a pair of alternatives.
has_subtypes:
- name: Mild
display_name: Mild phenotype (multiple non-protective serotypes)
description: >
Multiple serotypes to which the patient did not generate protective titres
or could not raise titres twofold. The mildest of the four working-group
tiers and the commonest presentation.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients with a mild phenotype have multiple serotypes to which they did not generate protective titers or were unable to increase titers twofold."
explanation: >
The working-group definition of the mild tier, including the twofold-rise criterion this subtype states.
- name: Moderate
display_name: Moderate phenotype (protective titres to <50% or <70% of serotypes)
description: >
Protective titres to three or more serotypes, but to fewer than half of
serotypes tested in children under six, or fewer than 70% in those over
six. The age split matters: the same serological result means different
things at different ages.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients with a moderate phenotype produce protective titers to three or more serotypes but to <50% of serotypes for those under 6 years of age or <70% of serotypes for those over 6 years of age."
explanation: >
The working-group definition of the moderate tier, with both age-stratified thresholds.
- name: Severe
display_name: Severe phenotype (protective titres to two or fewer serotypes)
description: >
Protective titres against two or fewer serotypes, and the titres that are
generated tend to be low.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A severe phenotype is described as producing protective titers against two or fewer serotypes, and those protective titers generated tend to be low."
explanation: >
The working-group definition of the severe tier.
- name: Memory
display_name: Memory phenotype (adequate initial response, not sustained)
description: >
An initially adequate response to vaccination that is not sustained beyond
six months. Named by analogy rather than by mechanism - pure polysaccharide
vaccines do not generate a long-lived memory B-cell response in the first
place, so "memory phenotype" describes patients who lose their PPSV23
response faster than usual rather than patients with a demonstrated memory
defect. Detecting it requires a second titre at six months, so it is missed
by any protocol that measures only the four-week response.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients with a memory phenotype of deficient responses initially mount an adequate response to vaccination but do not sustain the response beyond 6 months."
explanation: >
The working-group definition of the memory tier, including the six-month
window this subtype states.
mechanistic_hypotheses:
- hypothesis_group_id: ti2_marginal_zone_maturation_failure
hypothesis_label: T-Independent Type 2 / Marginal-Zone Maturation Failure Model
status: EMERGING
description: >-
The proposal is that SAD is a persistent or relapsing failure of the
T-independent type 2 arm of humoral immunity - the pathway by which B
cells respond to repetitive capsular polysaccharide without T-cell help,
and which matures late, around the second year of life. The model explains
the entity's defining dissociation (normal protein responses, absent
polysaccharide responses), its age floor, and its infection pattern with
encapsulated organisms. Its status is EMERGING rather than CANONICAL
because no molecular lesion has been identified in this pathway in SAD
patients; the strongest cellular correlate is reduced switched memory B
cells, which is an association in a subset rather than a demonstrated
cause.
pathophysiology:
- name: Failure of T-Independent Type 2 B Cell Activation
biological_scale: CELLULAR
description: >
The core lesion, defined functionally because it cannot yet be defined
molecularly. Unconjugated capsular polysaccharide is a repetitive
carbohydrate with no peptide epitope, so it cannot be presented on MHC
class II and cannot recruit T-cell help; it must instead crosslink the B
cell receptor and activate B cells directly. In SAD that direct route
fails while the T-dependent route - protein antigens, conjugate vaccines -
works normally. The dissociation is the disease.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
- preferred_term: marginal zone B cell
term:
id: CL:0000845
label: marginal zone B cell of spleen
biological_processes:
- preferred_term: B cell activation
modifier: DECREASED
term:
id: GO:0042113
label: B cell activation
- preferred_term: immunoglobulin production
modifier: DECREASED
term:
id: GO:0002377
label: immunoglobulin production
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "is a pure polysaccharide vaccine, meaning that it induces a T-cell-independent response by stimulating B-cells in the absence of T-helper cells"
explanation: >
Establishes that the failing test antigen works through the
T-independent route, which is what makes this node the mechanism rather
than a restatement of the assay.
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SAD mimics the deficient immune response often seen in healthy young children and infants who are unable to mount a robust response to pure unconjugated polysaccharide antigens such as Streptococcus pneumoniae polysaccharide and Haemophilus influenzae type b capsular polysaccharide."
explanation: >
The developmental framing: the SAD state is the normal infant state
persisting. This is the observation that grounds the maturation model
and the age-two diagnostic floor.
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: NO_EVIDENCE
evidence_source: HUMAN_CLINICAL
snippet: "The origin and underlying molecular defects of SAD are not known"
explanation: >
Graded NO_EVIDENCE because it is precisely a statement that no evidence
identifies a molecular cause. It is curated here so that the absence of
a molecular node in this entry is visibly a finding rather than an
omission.
downstream:
- target: Reduced Switched Memory B Cell Compartment
description: >-
A reported cellular correlate in SAD patients, of uncertain causal
direction.
hypothesis_groups:
- ti2_marginal_zone_maturation_failure
- target: Absent Protective Anticapsular Antibody
description: >-
No opsonising antibody is generated against pneumococcal capsular
serotypes.
hypothesis_groups:
- ti2_marginal_zone_maturation_failure
- name: Reduced Switched Memory B Cell Compartment
biological_scale: CELLULAR
description: >
Decreased numbers of switched memory B cells have been reported in SAD
patients. This is the closest thing the disease has to a cellular marker,
and the entry is careful about what it supports: the observation is an
association reported in a subset, the direction of causation is untested,
and the cell type implicated is the one that carries T-dependent memory,
which is not obviously the compartment that should fail in a
T-independent-response disorder. It is curated because it is the only
cellular finding on record, not because it is established.
cell_types:
- preferred_term: class switched memory B cell
term:
id: CL:0000972
label: class switched memory B cell
biological_processes:
- preferred_term: isotype switching
modifier: DECREASED
term:
id: GO:0045190
label: isotype switching
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "decreased numbers of switched memory B-cells, which may play a key role in the protection against infection with polysaccharide-encapsulated bacteria, have been reported in patients with SAD"
explanation: >
The claim as originally stated. INDIRECT because the source hedges it
twice - "may play a key role", "have been reported" - and because it is
cited secondhand in this review rather than measured in it.
- reference: PMID:40097777
reference_title: "Diagnosis, Characteristics, and Outcome of Selective Anti-polysaccharide Antibody Deficiencies In A Retrospective Cohort of 55 Adult Patients."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Decreased switched memory B cells, n (%)7 (13)"
explanation: >
The measured result rather than the method: 7 of 55 patients, 13%. Real
but a minority, which is the honest size of this correlate.
- reference: PMID:40097777
reference_title: "Diagnosis, Characteristics, and Outcome of Selective Anti-polysaccharide Antibody Deficiencies In A Retrospective Cohort of 55 Adult Patients."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Decreased marginal zone-like B cells, n (%)5 (9)"
explanation: >
The marginal-zone measurement - 5 of 55, 9% - and the only direct human
measurement anywhere in this entry bearing on the marginal-zone limb of
its own hypothesis.
downstream:
- target: Absent Protective Anticapsular Antibody
description: >-
Fewer memory B cells available to produce or sustain anticapsular
antibody.
hypothesis_groups:
- ti2_marginal_zone_maturation_failure
- name: Absent Protective Anticapsular Antibody
biological_scale: ORGANISM
description: >
The measurable endpoint and the diagnostic criterion at once: serotype
-specific IgG against pneumococcal capsular polysaccharide fails to reach
or to sustain protective titres after PPSV23. Note that this node is
unusual in being simultaneously the mechanism's output and the assay that
defines the disease, which is why the entity's boundary moves whenever the
assay's cut-offs are renegotiated.
biological_processes:
- preferred_term: B cell mediated immunity
modifier: DECREASED
term:
id: GO:0019724
label: B cell mediated immunity
evidence:
- reference: PMID:32654695
reference_title: "Diagnosis and management of Specific Antibody Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "defined by recurrent respiratory infections with normal immunoglobulins, but diminished antibody responses to polysaccharide antigens after vaccination with the 23 valent pneumococcal polysaccharide vaccine"
explanation: >
The case definition, which is also the statement of this node.
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the definition of an adequate response to immunization remains controversial, including the magnitude of response and number of pneumococcal serotypes needed to determine a normal response"
explanation: >
Records that the threshold on this node is contested, which is the
caveat every downstream claim in the entry inherits.
downstream:
- target: Recurrent Encapsulated-Organism Sinopulmonary Infection
description: >-
Loss of opsonisation against encapsulated respiratory pathogens.
hypothesis_groups:
- ti2_marginal_zone_maturation_failure
- name: Recurrent Encapsulated-Organism Sinopulmonary Infection
biological_scale: ORGANISM
description: >
The clinical consequence: recurrent upper and lower respiratory tract
infection, otitis media and sinusitis, with encapsulated bacteria. SAD is
among the most commonly identified immune disorders in patients presenting
with recurrent sinopulmonary infection, which is the practical reason to
know about it - the presenting picture is common and the diagnosis is
invisible on a standard immunoglobulin panel.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients are highly susceptible to severe respiratory tract infections with encapsulated bacteria, and SAD is one of the most commonly identified immune disorders in patients presenting with recurrent sinopulmonary infections"
explanation: >
Links the antibody defect to its organism-specific clinical
consequence, and states the diagnostic yield in this presentation.
phenotypes:
- category: Immunologic
name: Impaired Antibody Response to Unconjugated Pneumococcal Polysaccharide
description: >
The defining laboratory phenotype. Measured as serotype-specific IgG four
weeks after PPSV23, and repeated at six months where a memory phenotype is
suspected. The HP term used here is the severe-end term; milder tiers are
captured by the `has_subtypes` entries.
phenotype_term:
preferred_term: Impaired specific antibody response
term:
id: HP:0012475
label: Impaired specific antibody response
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Specific antibody deficiency (SAD) is a primary immunodeficiency disease characterized by normal immunoglobulins (Igs), IgA, IgM, total IgG, and IgG subclass levels, but with recurrent infection and diminished antibody responses to polysaccharide antigens following vaccination."
explanation: >
The full case definition, including the normal immunoglobulin levels
that are as definitional as the failed response.
- category: Immunologic
name: Severely Absent Pneumococcal Polysaccharide Response
subtype: Severe
description: >
The severe tier: protective titres against two or fewer serotypes, and
those low. Recorded as a separate phenotype because HPO has a term at
exactly this granularity, which makes the severity tier machine-queryable
rather than only prose.
phenotype_term:
preferred_term: Complete or near-complete absence of specific antibody response to unconjugated pneumococcus polysaccharide
term:
id: HP:0410300
label: Complete or near-complete absence of specific antibody response to unconjugated pneumococcus polysaccharide
severity: SEVERE
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A severe phenotype is described as producing protective titers against two or fewer serotypes, and those protective titers generated tend to be low."
explanation: >
Defines the severe tier in the working-group classification this
entry's subtypes follow.
- category: Infectious
name: Recurrent Sinopulmonary Infections
phenotype_term:
preferred_term: Recurrent sinopulmonary infections
term:
id: HP:0005425
label: Recurrent sinopulmonary infections
temporality: RECURRENT
description: >
The presenting complaint in almost every case, and the reason the
diagnosis is worth chasing in an otherwise normal immunological workup.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "patients typically present with recurrent upper and lower respiratory tract infections, otitis media, and sinusitis"
explanation: >
The presenting infection pattern, upper and lower tract together.
- category: Infectious
name: Recurrent Otitis Media
phenotype_term:
preferred_term: Recurrent otitis media
term:
id: HP:0000403
label: Recurrent otitis media
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "patients typically present with recurrent upper and lower respiratory tract infections, otitis media, and sinusitis"
explanation: >
Records otitis media specifically, which is the commonest paediatric
presentation.
- category: Infectious
name: Chronic Rhinosinusitis
phenotype_term:
preferred_term: Sinusitis
term:
id: HP:0000246
label: Sinusitis
temporality: CHRONIC
description: >
The characteristic adult presentation. Between 11.6% and 24% of adults
referred with chronic rhinosinusitis in retrospective series were
diagnosed with SAD, which makes this the single highest-yield clinical
setting in which to test for it.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "in 1 retrospective study of 129 adults with chronic rhinosinusitis, 11.6% were diagnosed with SAD"
explanation: >
Quantifies the yield of testing in the adult chronic-rhinosinusitis
population.
- category: Infectious
name: Recurrent Pneumonia
phenotype_term:
preferred_term: Recurrent pneumonia
term:
id: HP:0006532
label: Recurrent pneumonia
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The prevalence of SAD in adults with recurrent pneumonia has been reported to be approximately 8%"
explanation: >
Establishes recurrent pneumonia as a presenting phenotype and
quantifies the diagnostic yield in that group.
- category: Respiratory
name: Bronchiectasis
description: >
The complication that makes delayed diagnosis costly rather than merely
untidy. In the adult cohort, patients who had developed bronchiectasis had
been symptomatic for a median of 122 months before diagnosis against 24
months for those who had not - a fivefold difference, and the strongest
argument in this entry for testing earlier rather than after another
winter of antibiotics.
phenotype_term:
preferred_term: Bronchiectasis
term:
id: HP:0002110
label: Bronchiectasis
evidence:
- reference: PMID:40097777
reference_title: "Diagnosis, Characteristics, and Outcome of Selective Anti-polysaccharide Antibody Deficiencies In A Retrospective Cohort of 55 Adult Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Diagnostic delay was significantly higher in patients presenting with bronchiectasis than in those without"
explanation: >
Establishes that diagnostic delay is significantly longer in patients
who have developed bronchiectasis. The medians and p value are in the
same sentence but not in the snippet: the reference validator strips
square-bracketed spans, and the interquartile ranges sit inside them.
The figures are given in this phenotype's description instead.
- category: Immunologic
name: Allergic Rhinitis
description: >
Not an incidental comorbidity. In 74 children investigated for recurrent
infection, allergic rhinitis was significantly associated with having SAD
at a relative risk of 3.77. It matters clinically in the wrong direction:
an atopic explanation for recurrent sinopulmonary symptoms is exactly what
delays the immunological workup, and in the adult cohort 38% had an
allergic or inflammatory disorder that the authors suggest contributes to
diagnostic delay.
phenotype_term:
preferred_term: Allergic rhinitis
term:
id: HP:0003193
label: Allergic rhinitis
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "allergic rhinitis was significantly associated with the presence of SAD"
explanation: >
The association itself, in a paediatric cohort investigated for recurrent
infection.
- reference: PMID:40097777
reference_title: "Diagnosis, Characteristics, and Outcome of Selective Anti-polysaccharide Antibody Deficiencies In A Retrospective Cohort of 55 Adult Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Adult patients with SPAD have allergic or inflammatory disorders which could contribute to the diagnostic delay."
explanation: >
The adult counterpart, and the reason this phenotype is curated rather
than left as background: the authors name it as a contributor to delayed
diagnosis.
- category: Respiratory
name: Asthma
description: >
Reported commonly in children with SAD, alongside rhinitis. Worth
recording as a comorbid feature rather than a complication: it is a
frequent reason such children are already under specialist care, and
recurrent "asthma exacerbations" in this group may be recurrent infection.
phenotype_term:
preferred_term: Asthma
term:
id: HP:0002099
label: Asthma
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Asthma and rhinitis are also commonly reported in children with SAD"
explanation: >
Records the reported association with asthma and rhinitis in the
paediatric population.
biochemical:
- name: Serotype-specific anti-pneumococcal capsular polysaccharide IgG
notes: >
The measurement that defines the disease, and therefore the one place its
numbers should be recorded rather than only argued about. Two thresholds
operate at once and they are independent of each other: a per-serotype
protective concentration, and a proportion of tested serotypes that must
reach it, which is itself age-stratified. A patient can fail on either.
The interpretation bands below are the working-group severity tiers
expressed against the serotype-proportion axis for a child under six.
They are not laboratory reference intervals in the usual sense - they are
a consensus classification with, as the knowledge gap on this entry
records, no demonstrated relationship to outcome.
reference_ranges:
- lower_bound: 1.3
unit: ug/mL
population: Per serotype, protective concentration after polysaccharide vaccination
notes: >-
No `loinc_term` is set: LOINC is not configured in `conf/oak_config.yaml`
and has no term cache in this repository, so a code could not be
validated. No `interpretation_bands` here either - the working-group
severity tiers are defined on serotype counts and proportions, not on
concentration, so they belong on the ranges below and not on this axis.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "has been considered protective with respect to invasive disease following polysaccharide immunization"
explanation: >
The per-serotype protective concentration of 1.3 ug/mL. The snippet
starts after the number because the cached sentence writes the unit
with a Greek mu, which does not survive a clean substring match.
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "other studies have shown that levels of 0.35"
explanation: >
A second, lower protective concentration - 0.35 ug/mL - applying after
*conjugate* vaccination. Curated because it is the sharpest available
illustration of this entry's thesis: the threshold that defines the
disease depends on which vaccine was given.
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "these studies are based on small cohorts and protective levels in response to pneumococcal vaccination and should be interpreted with caution"
explanation: >
The source's own caution about both concentration thresholds, and a
reminder that these are not laboratory reference intervals in the
ordinary sense.
- lower_bound: 50.0
unit: percent of serotypes tested
population: Children under 6 years
notes: >-
The proportion axis, which is independent of the concentration axis
above: a patient can fail on either.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "report on diagnostic vaccination in PIDD recommend that a normal response to pneumococcal vaccines is a response to \u226550% of serotypes for patients under 6 years of age and a response to \u226570% of serotypes for patients over 6 years of age"
explanation: >
The age-stratified proportion thresholds, covering this range and the
one below it.
interpretation_bands:
- name: Deficient response, under 6 years
upper_bound: 50.0
unit: percent of serotypes tested
abnormal_flag: LOW
interpretation: >-
Below the age-appropriate proportion. The moderate/severe split inside
this band is an absolute serotype count - three or more versus two or
fewer - and is therefore not expressible on a proportion axis; it is
carried on the count range below.
- name: Normal response, under 6 years
lower_bound: 50.0
unit: percent of serotypes tested
abnormal_flag: NORMAL
interpretation: >-
Protective titres to at least half of the serotypes tested.
- lower_bound: 70.0
unit: percent of serotypes tested
population: Patients 6 years and over
notes: >-
The same axis with the older-age threshold. The age split is why an
identical serological result means different things in a four-year-old
and a ten-year-old.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a response to \u226570% of serotypes for patients over 6 years of age"
explanation: >
The over-six proportion threshold.
interpretation_bands:
- name: Deficient response, 6 years and over
upper_bound: 70.0
unit: percent of serotypes tested
abnormal_flag: LOW
interpretation: >-
Below the age-appropriate proportion.
- name: Normal response, 6 years and over
lower_bound: 70.0
unit: percent of serotypes tested
abnormal_flag: NORMAL
interpretation: >-
Protective titres to at least 70% of the serotypes tested.
- unit: serotypes with protective titre
population: Severity tier, absolute serotype count
notes: >-
The third axis, and the honest home for the severe tier: it is defined
by a count, not a proportion. Separating it is what stops "two or fewer
serotypes" being written as a percentage it is not.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A severe phenotype is described as producing protective titers against two or fewer serotypes, and those protective titers generated tend to be low."
explanation: >
Defines the severe tier on the count axis, which is the reason this
range exists separately from the proportion ranges above.
interpretation_bands:
- name: Severe phenotype
upper_bound: 3.0
unit: serotypes with protective titre
abnormal_flag: LOW
severity: SEVERE
interpretation: >-
Protective titres against two or fewer serotypes, and those titres
typically low.
- name: Moderate phenotype or better
lower_bound: 3.0
unit: serotypes with protective titre
abnormal_flag: LOW
severity: MODERATE
interpretation: >-
Three or more serotypes with protective titres. Whether this is
moderate or normal is then decided on the age-stratified proportion
axis above, not on this one.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "report on diagnostic vaccination in PIDD recommend that a normal response to pneumococcal vaccines is a response to \u226550% of serotypes for patients under 6 years of age and a response to \u226570% of serotypes for patients over 6 years of age"
explanation: >
The age-stratified proportion threshold, which is the second and
independent axis of the case definition.
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Recent attention has been focused upon other studies that report an adequate response as \u22651.3"
explanation: >
Records that a combined criterion - a concentration threshold applied
across a proportion of serotypes - is a more recent and competing
formulation, which is part of why the definition is contested.
discussions:
- discussion_id: spad_case_definition_instability
kind: KNOWLEDGE_GAP
attaches_to:
- pathophysiology#Absent Protective Anticapsular Antibody
- prevalence#
prompt: >-
What serological threshold - how many serotypes, what absolute titre, what
fold rise, at what age - actually separates people who benefit from
treatment for specific antibody deficiency from people who do not?
rationale: >
Every other uncertainty in this entry is downstream of this one. The
prevalence range in adults with chronic rhinosinusitis, 11.6% to 24%
across three retrospective series of the same clinical population, is
largely a range about the criterion rather than about the populations. The
four severity tiers are defined by the same contested numbers. And because
the assay is the case definition, changing the cut-off does not
reclassify patients within the disease - it changes who has the disease.
Two things make this resolvable in principle rather than merely
lamentable. Antibody responses are age-dependent and probably
serotype-dependent, so a criterion that conditioned on both would be
better founded than the current flat thresholds. And the outcome that
matters - infection burden, and response to prophylaxis or immunoglobulin
- is measurable, so a criterion could in principle be validated against
it rather than set by consensus.
The first has not been done. The second has been attempted, and the early
answer is unfavourable: in the 55-patient adult cohort, at least a quarter
of patients with recurrent severe infections, bronchiectasis, or a
requirement for immunoglobulin replacement fell into the so-called mild
tier, and the authors saw no clear association between the level of
anti-polysaccharide response and prognosis. That is this experiment's
`refuting_outcome` partially realised in an observational setting, and it
is the strongest single reason to treat the severity tiers as
serological descriptions rather than as a graded prediction.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Confounding these issues, anti-polysaccharide antibody responses are age- and probably serotype dependent."
explanation: >
Names the two variables a validated criterion would have to condition
on, and does so with the hedge ("probably") that shows the second is not
yet established.
- reference: PMID:32654695
reference_title: "Diagnosis and management of Specific Antibody Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinical immunologists struggle with diagnosis and treatment, because the definition of an adequate response to immunization remains controversial."
explanation: >
An independent statement, three years later, that the definitional
problem is unresolved and that it is the reason management is difficult.
- reference: PMID:40097777
reference_title: "Diagnosis, Characteristics, and Outcome of Selective Anti-polysaccharide Antibody Deficiencies In A Retrospective Cohort of 55 Adult Patients."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "we do not see any clear association between the level of anti-PS response and the prognosis, since at least 25% of patients with recurrent severe infections, bronchiectasis or IgRT initiation, can have a so-called 'mild' phenotype. This raises questions about the relevance of phenotype responsiveness"
explanation: >
The strongest evidence for this gap, and the item that most changes what
the entry claims: an observational test of whether the severity tiers
predict outcome, finding that they do not. DIRECT because it measures
exactly the relationship the gap is about.
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "there has never been a study evaluating the correlation between degree of responsiveness and infection susceptibility"
explanation: >
States the absence of a formal validation study, which is what the
cohort observation above is a partial and unfavourable substitute for.
proposed_experiments:
- experiment_id: spad_criterion_outcome_validation
name: Prospective validation of PPSV23 response criteria against infection outcome
description: >-
Follow a prospectively enrolled cohort presenting with recurrent
sinopulmonary infection and normal immunoglobulins, measure
serotype-specific titres at four weeks and six months using serotypes
absent from any conjugate vaccine received, and test each candidate
criterion for how well it predicts subsequent infection burden and
response to prophylaxis - rather than how well it agrees with expert
opinion.
would_support:
- pathophysiology#Absent Protective Anticapsular Antibody
supporting_outcome:
- >-
One criterion separates patients by subsequent infection burden and by
benefit from prophylaxis, giving the entity an outcome-anchored boundary
and turning the four severity tiers into a graded prediction rather than
a serological description.
would_refute:
- pathophysiology#Absent Protective Anticapsular Antibody
refuting_outcome:
- >-
No threshold predicts infection burden or treatment benefit, which would
mean the polysaccharide response measures something real but not the
thing that makes these patients ill, and that SAD as currently defined is
a laboratory finding rather than a disease entity.
treatments:
- name: Pneumococcal Conjugate Vaccination
description: >
Given first, and given for two reasons. Therapeutically, a conjugate
vaccine drives a T-dependent response and so can generate protective
titres by the route that is intact in SAD - including in patients
vaccinated in early childhood, where repeating it may produce titres later
in life. Diagnostically, it is why testing must use PPSV23-only serotypes.
therapeutic_modality: VACCINE
treatment_term:
preferred_term: Vaccination
term:
id: NCIT:C15346
label: Vaccination
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "If patients have not received the conjugate pneumococcal vaccine, immunization with the conjugate vaccine with the largest number of serotypes available is recommended in all patients with recurrent infections."
explanation: >
The recommendation itself. INDIRECT because the source states in the
same passage that conjugate-vaccine titre generation has not been
studied in a SAD population, so the benefit is inferred from the
preserved T-dependent pathway rather than demonstrated.
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "pneumococcal conjugate vaccines were developed, which generate a T-cell-dependent antibody response and are effective in children under 2 years"
explanation: >
States the mechanistic rationale - conjugation converts the antigen to
the T-dependent route, which is the arm SAD leaves intact.
- reference: PMID:34290713
reference_title: "The 13-Valent Pneumococcal Conjugate Vaccine Elicits Serological Response and Lasting Protection in Selected Patients With Primary Humoral Immunodeficiency."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "71.4%, 66.7% and 56.0% of the patients were protected at one, six and twelve months respectively"
explanation: >
Quantifies both the benefit and its limit: protection is real but wanes
to roughly half of patients by twelve months, which bears on revaccination
intervals. INDIRECT and important to read carefully - the 29 patients
were common variable immunodeficiency or IgG subclass deficiency, not
SPAD, so this is class-level evidence borrowed across a related
population.
- name: Antibiotic Prophylaxis
description: >
The mainstay of management by consensus, and the entry is explicit that
consensus is all it is. There is no standardised regimen, no efficacy
study in SAD, and current practice is extrapolated from immunocompetent
patients with recurrent otitis media, chronic rhinosinusitis and cystic
fibrosis.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Antibiotic Prophylaxis
term:
id: NCIT:C51993
label: Antibiotic Prophylaxis
therapeutic_agent:
- preferred_term: azithromycin
term:
id: CHEBI:2955
label: azithromycin
- preferred_term: trimethoprim
term:
id: CHEBI:45924
label: trimethoprim
- preferred_term: sulfamethoxazole
term:
id: CHEBI:9332
label: sulfamethoxazole
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "practice parameter recommends regimens including azithromycin (500 mg weekly or 250 mg every other day in adults; 10 mg/kg weekly or 5 mg/kg every other day in children) and TMP-SMX (160 mg daily or twice daily in adults; 5 mg/kg daily or twice daily in children)"
explanation: >
Names the agents and their doses, which is what makes the regimen
unstandardised rather than unspecified - two different claims. INDIRECT
because it is a practice-parameter recommendation rather than an
efficacy result in this disease.
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "The mainstay of therapy for patients with SAD is antibiotic prophylaxis. However, there is no consensus regarding the frequency and severity of infections warranting antibiotic prophylaxis and no standardized regimens and no studies of efficacy."
explanation: >
Records the treatment and, in the same sentence, that its evidence base
in this disease is absent. INDIRECT for exactly that reason.
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Most cases of SAD present with a relatively mild clinical phenotype, and the consensus is that these should be initially treated with antibiotic prophylaxis."
explanation: >
Places prophylaxis as first-line for the majority phenotype, which is
the practical treatment-sequencing claim.
- name: Immunoglobulin Replacement Therapy
description: >
Reserved for patients who fail prophylaxis or have a severe phenotype.
Recommended by published expert guidelines and supported by retrospective
observation; the source states that definitive data are lacking, and this
entry does not imply otherwise.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: Immunoglobulin Therapy
term:
id: NCIT:C62710
label: Immunoglobulin Therapy
evidence:
- reference: PMID:40097777
reference_title: "Diagnosis, Characteristics, and Outcome of Selective Anti-polysaccharide Antibody Deficiencies In A Retrospective Cohort of 55 Adult Patients."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "the mean (min-max) frequency of antibiotic courses decreased from 7.9 (2-18) to 0.7 (0-2) courses per year (p < 0.001)"
explanation: >
The only quantified treatment effect in this disease: an eleven-fold
fall in antibiotic courses in 22 SPAD patients over a median 46 months.
DIRECT because the cohort is SPAD patients and the outcome is measured,
not inferred - though it is observational and uncontrolled, so it
establishes the size of an association rather than an effect.
- reference: PMID:40097777
reference_title: "Diagnosis, Characteristics, and Outcome of Selective Anti-polysaccharide Antibody Deficiencies In A Retrospective Cohort of 55 Adult Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "IgRT is effective in preventing recurrent infections."
explanation: >
The authors' own conclusion, recorded alongside the number it rests on
so a reader can weigh the claim against its design.
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Published expert guidelines and opinions have recommended IgG therapy, which are supported by observations from retrospective studies, although definitive data are lacking."
explanation: >
The earlier, weaker evidence position. Kept rather than replaced,
because the 2025 cohort does not turn retrospective observation into a
trial and the guideline framing is still what practice rests on.
- reference: PMID:32654695
reference_title: "Diagnosis and management of Specific Antibody Deficiency."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Specific antibody deficiency is managed clinically with close follow-up and prompt treatment of infections, antibiotic prophylaxis, or immune globulin therapy."
explanation: >
Independent confirmation of the management ladder, from a review three
years later. INDIRECT: it restates practice rather than reporting
outcome data.
diagnosis:
- name: Pneumococcal polysaccharide vaccine challenge with serotype-specific titres
description: >
The diagnostic test is a deliberate immunisation followed by titres:
PPSV23, serotype-specific IgG at about four weeks, and - where an initial
response is adequate but infections recur - a repeat at six months to
catch the memory phenotype. Three constraints make this harder than it
looks. The diagnosis cannot be made before age two, because failure to
respond is normal below it. Serotypes present in any conjugate vaccine the
patient has received must be excluded, and at least six PPSV23-only
serotypes tested. And normal immunoglobulins, including IgG subclasses,
are required - a low IgG points to common variable immunodeficiency
instead.
evidence:
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "for patients who have previously received at least one dose of conjugate vaccine, normal antibody levels against serotypes in the conjugate vaccine do not exclude the diagnosis of SAD; thus, at least six serotypes should be tested that are present in PPSV23 only"
explanation: >
The conjugate-vaccine confound and the specific testing rule that
handles it - the commonest way this diagnosis is missed.
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "As a result, the diagnosis should not be conferred until after 2 years of age"
explanation: >
The age floor, which follows from the normal developmental immaturity of
the polysaccharide response.
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "patients with CVID exhibit low IgG and usually IgA levels, and potentially low IgM levels, whereas patients with SAD exhibit normal IgG, IgA and IgM, and IgG subclass levels"
explanation: >
The differential against common variable immunodeficiency, stated in
terms of the laboratory finding that separates them.
- reference: PMID:28588580
reference_title: "Specific Antibody Deficiency: Controversies in Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "If the response is adequate, titers should be measured again 6 months after the vaccination in consideration of a possible"
explanation: >
The six-month repeat titre, which is the only way the memory phenotype
is detected.
references:
- reference: PMID:35748970
title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
findings: []
Disease: Specific Antibody Deficiency (also Specific Polysaccharide Antibody Deficiency, SPAD) Category as framed by request: "Mendelian" — but see Summary; the disease is best classified as a functional, largely idiopathic primary (predominantly) antibody deficiency, not a single-gene Mendelian disorder. Parent classification: IUIS-2022 Group III — Predominantly Antibody Deficiencies (PAD) Suggested MONDO/ontology anchors: MONDO "specific antibody deficiency"; ICD-10 D80.8/D80.9 (other/unspecified immunodeficiency with predominantly antibody defects); MeSH concepts under Primary Immunodeficiency Diseases / Immunologic Deficiency Syndromes.
Specific Antibody Deficiency (SAD), also termed Specific/Selective Polysaccharide Antibody Deficiency (SPAD), is a primary immunodeficiency recognized by the International Union of Immunological Societies and defined by an impaired IgG antibody response to polysaccharide antigens after 23-valent pneumococcal polysaccharide vaccine (PPSV23) challenge, in the setting of otherwise normal total IgG, IgA, IgM, and IgG subclass concentrations and normal responses to protein antigens (PMID: 32654695; PMID: 28588580). The core lesion is a functional failure of the thymus-independent type-2 (TI-2) antibody response to bacterial capsular polysaccharides — a response that normally matures only after ~2 years of age, forms no immunologic memory, and uses a restricted IgM/IgG2 isotype repertoire (PMID: 8167745). Because anti-capsular antibody is deficient, encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae type b) are poorly opsonized, producing the hallmark phenotype of recurrent sinopulmonary infection that can progress to bronchiectasis when diagnosis is delayed.
Despite the "Mendelian" label of the research template, SAD is not a single-gene disorder. It is a functionally defined, heterogeneous, and largely idiopathic condition — effectively a diagnosis of exclusion (PMID: 8167745; PMID: 28588580). The same laboratory picture (impaired polysaccharide IgG with normal total IgG and normal protein-antigen responses) can arise secondarily within other defined immunodeficiencies (IgG subclass deficiency, selective IgA deficiency, Wiskott–Aldrich syndrome, DiGeorge anomaly) and acquired states (post-splenectomy, HIV, lymphoid malignancy), and rare monogenic inborn errors of immunity (IEI) can phenocopy SAD (PMID: 38933494). A mechanistic anchor is provided by the TACI (TNFRSF13B)–NF-κB pathway: a mouse model carrying the murine equivalent of the human CVID-associated TNFRSF13B A181E mutation shows selectively impaired TI-2 (TNP-Ficoll) antibody responses (PMID: 19605846).
Prognosis is generally good. In children the deficiency may resolve over time (PMID: 26454312). Management is tiered: prompt treatment of infections, pneumococcal conjugate vaccination (which bypasses the defect by presenting polysaccharide as a T-dependent conjugate), antibiotic prophylaxis, and — in refractory or severe cases — immunoglobulin replacement therapy (IgRT), which in an adult SPAD cohort reduced antibiotic courses from a mean of 7.9 to 0.7 per year (p < 0.001) (PMID: 40097777; PMID: 32654695).
Overview. SAD/SPAD is an IUIS-recognized primary immunodeficiency in which patients experience recurrent respiratory infections with normal immunoglobulins but diminished antibody responses to polysaccharide antigens after PPSV23 (PMID: 32654695). The defining laboratory phenotype is normal IgA, IgM, total IgG and IgG subclass levels combined with impaired anti-polysaccharide responses (PMID: 28588580). Diagnosis requires age ≥ 2 years (because the polysaccharide response is physiologically immature before then) and otherwise intact immunity.
"Specific antibody deficiency is a primary immunodeficiency disease recognized by the International Union of Immunology Societies and defined by recurrent respiratory infections with normal immunoglobulins, but diminished antibody responses to polysaccharide antigens after vaccination with the 23 valent pneumococcal polysaccharide vaccine" (PMID: 32654695).
Key identifiers. - ICD-10: D80.8 / D80.9 (immunodeficiency with predominantly antibody defects, other/unspecified). - MeSH: indexed under Primary Immunodeficiency Diseases / Immunologic Deficiency Syndromes (no unique legacy MeSH term for SPAD specifically). - IUIS-2022: Group III, predominantly antibody deficiencies. - OMIM / Orphanet / MONDO: No single OMIM phenotype number applies because the disorder is functionally (not molecularly) defined. Where a knowledge base requires a MONDO node, use the MONDO term for "specific antibody deficiency."
Synonyms / alternative names. Specific Antibody Deficiency (SAD); Specific/Selective Polysaccharide Antibody Deficiency (SPAD); Selective Anti-Polysaccharide Antibody Deficiency; Impaired Polysaccharide Responsiveness; Partial antibody deficiency with normal immunoglobulins.
Data source type. The evidence base is aggregated disease-level (case series, cohort studies, registry data, and expert reviews) rather than derived from a single EHR dataset; there is a recognized lack of consensus on case definition (PMID: 28588580).
Primary causal mechanism. SAD is a functional defect of the antibody response to capsular (TI-2) polysaccharide antigens (PMID: 8167745). It is largely idiopathic and comprises multiple immunologic phenotypes with no single established causal gene (PMID: 28588580).
Genetic risk factors. No single Mendelian gene defines primary SAD. However: - The TACI (TNFRSF13B)–NF-κB axis is mechanistically implicated: TNFRSF13B is mutated in ~10% of CVID patients, and the murine A144E equivalent of human A181E selectively impairs TI-2 responses (PMID: 19605846). - Defined monogenic IEI can phenocopy SAD, presenting with impaired polysaccharide IgG but normal total IgG and normal protein/conjugate responses (PMID: 38933494).
Environmental / host risk factors. Age (immature < 2 years), and a strong association with atopic/allergic disease (asthma, allergic rhinitis) — see Section 3. Adult SPAD shows female predominance (~75%) (PMID: 40097777). Secondary causes that must be excluded include splenectomy, HIV/AIDS, and lymphoid malignancy (PMID: 8167745).
Protective factors. No germline protective variant is established. The strongest acquired protective intervention is pneumococcal conjugate vaccination, which converts the polysaccharide into a T-dependent antigen and restores protection (Section 12).
Gene–environment interactions. Not formally characterized. The clinical picture is best understood as a functional threshold phenomenon in which an intrinsically restricted TI-2 response, host age, and a co-existing allergic diathesis converge to produce recurrent encapsulated-bacterial infection.
The dominant clinical phenotype is recurrent sinopulmonary infection with a striking co-association with allergic disease.
| Phenotype | Type | Frequency | Suggested HPO |
|---|---|---|---|
| Recurrent pneumonia | Clinical sign / infection | 91.7% in a pediatric SAD cohort (11/12) | HP:0006532 (Recurrent pneumonia) |
| Recurrent respiratory / sinopulmonary infection | Clinical sign | Defining feature | HP:0002205; HP:0011108 (Recurrent respiratory infections) |
| Recurrent otitis media | Clinical sign | Common | HP:0000403 |
| Chronic/recurrent rhinosinusitis | Clinical sign | Common | HP:0011109 (Chronic sinusitis) |
| Asthma | Comorbid allergic disease | 100% (12/12) in pediatric SAD cohort | HP:0002099 |
| Allergic rhinitis | Comorbid allergic disease | 11/12 pediatric SAD | HP:0003193 |
| Bronchiectasis | Complication (delayed dx) | Associated with long diagnostic delay | HP:0002110 |
| Impaired polysaccharide vaccine response | Laboratory abnormality | Defining | HP:0005425 (Abnormal antibody level) / functional |
In a pediatric cohort of 12 children (mean age 6 y), recurrent pneumonia predominated (91.7%), and all patients had asthma with 11/12 having allergic rhinitis (PMID: 27614984):
"recurrent pneumonia predominated (91.7%) as well as other respiratory and invasive infections. All patients with SAD had associated asthma, 11 had allergic rhinitis" (PMID: 27614984).
Onset / severity / progression. Onset is typically childhood (but adult diagnosis is common, median age 45 years in an adult SPAD cohort). Severity is variable, ranging from mild recurrent infection to severe/invasive disease. Course is episodic (recurrent infections) and can be progressive toward bronchiectasis if untreated.
Impaired-persistence phenotype. Some children respond normally to PPSV23 acutely but lose protective titers over one year — an "impaired persistence" (memory) phenotype: at one year, 8/20 children showed deficient responses (PMID: 25498324).
Quality of life. Primary antibody deficiencies impose substantial physical, psychological, and socioeconomic burden beyond infections and significantly reduce HRQOL (PMID: 42447994). In pediatric PID, lower child QoL correlates strongly with higher maternal caregiving burden (r = −0.710, p < 0.001) (PMID: 42119234). Validated instruments: SF-36, PedsQL, PROMIS, and disease-specific PADQOL and CVID-QOL (PMID: 42447994).
Causal genes. None established for primary SAD. The disorder is defined functionally and lacks a robust molecular case definition (PMID: 28588580).
Mechanistically implicated gene. TNFRSF13B (TACI) — HGNC:18153; encodes Transmembrane Activator and CAML Interactor. A CVID-associated mutation (A181E; murine equivalent A144E) impairs constitutive and ligand-induced NF-κB signaling and selectively degrades TI-2 antibody responses (PMID: 19605846). Variant type: missense; functional consequence: impaired signaling (hypomorphic / dominant-negative depending on allele). TNFRSF13B is mutated in ~10% of CVID patients.
Monogenic phenocopies. A 2024 review catalogs genetically defined IEI that initially present with impaired polysaccharide IgG, normal/near-normal IgG, and normal protein/conjugate responses — a picture indistinguishable from primary SAD (PMID: 38933494):
"genetically defined IEI, that may initially present with an impaired IgG response to polysaccharide antigens, but normal or only slightly decreased IgG levels and normal responses to protein or conjugate vaccine antigens" (PMID: 38933494).
Modifier genes / epigenetics / chromosomal abnormalities. Not established for isolated SAD. Anti-polysaccharide deficiency does occur in chromosomal/syndromic disorders (e.g., DiGeorge/22q11) as a secondary phenomenon (PMID: 8167745). Allele frequency, somatic-vs-germline, and gnomAD data are not applicable to a functionally defined disease.
"In infants and young children up to the age of 2 years the antibody response to capsular polysaccharides is inadequate resulting in an increased incidence of diseases such as pneumonia, meningitis, otitis" (PMID: 8167745).
Branch (therapeutic bypass): Presenting the polysaccharide as a protein-conjugate vaccine converts the antigen to a T-dependent stimulus → germinal-center help → memory + higher-affinity IgG → restores protection, bypassing the TI-2 defect (PMID: 34290713; PMID: 27614984).
[TI-2 / TACI–NF-κB defect]
│ leads to
▼
[Deficient anti-capsular IgG2/IgM] ── bypassed by ──► [Conjugate vaccine → T-dependent response → protection]
│ results in
▼
[Impaired opsonization of S. pneumoniae / Hib]
│ results in
▼
[Recurrent sinopulmonary + invasive infection]
│ (if diagnosis delayed) leads to
▼
[Bronchiectasis / chronic lung damage]
Epidemiology. Precise SAD-specific incidence/prevalence is not well established because diagnosis depends on vaccine-challenge testing and case definitions vary; SAD is frequently under-recognized. Its parent category — predominantly antibody deficiencies — is consistently the largest IEI group across registries: 41.3% (38/92) in a Colombian tertiary cohort (PMID: 39836844) and 46.3% of 24,879 patients across 30 J-Project countries (PMID: 36605210). Among adults with unexplained recurrent/severe encapsulated-bacterial infection, PID was found in 39.8% (95% CI 30.4–48.8), and SPAD was the most frequent diagnosis (37/47 = 78.7%) (PMID: 36285530):
"SPAD was the most frequent diagnosis by far (n = 37/47, 78.7%)" (PMID: 36285530).
Inheritance. No Mendelian inheritance pattern for primary SAD (functional, largely idiopathic). Phenocopying monogenic IEI follow their own (AD/AR/X-linked) patterns (PMID: 38933494). Penetrance, expressivity, anticipation, founder effects, and carrier frequency are not applicable to a non-Mendelian functional diagnosis.
Demographics. - Sex ratio: adult SPAD is female-predominant (~75% female; ~3:1 F:M) (PMID: 40097777). - Age: bimodal recognition — childhood onset and adult diagnosis (median 45 y in adults). - Geographic/ethnic distribution: no specific predilection documented; recognition depends on access to vaccine-challenge testing.
Core diagnostic test — PPSV23 vaccine challenge. Measure serotype-specific IgG before and 4–6 weeks after PPSV23 in patients ≥ 2 years with recurrent infection and otherwise intact immunity. An adequate response to an individual serotype is conventionally post-immunization titer ≥ 1.3 µg/mL or a ≥ 4-fold rise over baseline (PMID: 9723664):
"An adequate IgG antibody response to an individual serotype was arbitrarily defined as a postimmunization antibody titer of 1.3 microg/ml or greater or at least four times the baseline value." (PMID: 9723664)
Age-adjusted proportion-of-serotypes criteria (pediatric). A response above 1.3 µg/mL for > 50% of serotypes is normal for ages 2–5 years, and for > 70% of serotypes in children older than 5 years (PMID: 25498324). Responses rise sharply in adults versus all pediatric age groups (7 months–16 years) (PMID: 9723664).
Diagnostics in the conjugate-vaccine (PCV) era. Widespread PCV13/15/20 reduces the number of unique PPSV23 serotypes available for interpretation (11 unique after PCV13; only 4 after PCV20), yet PPSV23 challenge retains 81–84% diagnostic accuracy in patients aged 2–65 (PMID: 39681261). A validated 18-plex electrochemiluminescence (ECL) assay benchmarked against WHO ELISA in 164 sera showed sensitivity 95%, specificity 84%, PPV 84%, NPV 95% for SPAD (PMID: 40637813):
"the 18-plex ECL assay for SPAD diagnosis showed a sensitivity of 95% and specificity of 84%, positive and negative predictive values of 84% and 95%, respectively" (PMID: 40637813).
Supporting labs. Normal total IgG, IgA, IgM and IgG subclasses (definitional); consider IgM/IgA anti-pneumococcal assays as adjuncts (do not replace serotype-specific IgG) (PMID: 33877708). Genetic testing (WES/panels) is warranted when a monogenic IEI phenocopy is suspected — anti-polysaccharide IgG testing is recommended in the initial IEI work-up (PMID: 38933494).
Clinical criteria / differential. No universally accepted quantitative threshold; definition of an "adequate" response (magnitude, number of serotypes) remains controversial (PMID: 28588580; PMID: 32654695). Differential diagnosis: CVID, IgG subclass deficiency, selective IgA deficiency, XLA, Wiskott–Aldrich, DiGeorge, and secondary causes (splenectomy, HIV, malignancy) — all must be excluded (PMID: 8167745).
Screening. Immunoglobulin and vaccine-response testing should be part of the work-up of patients with recurrent sinopulmonary infection, chronic rhinosinusitis, or bronchiectasis of unclear cause; SAD/SPAD is under-diagnosed in these groups (PMID: 36285530).
"Most patients have a good prognosis. The deficiency may resolve over time, especially in children." (PMID: 26454312)
Tiered management ladder: (1) prompt treatment of infections → (2) pneumococcal conjugate vaccination → (3) antibiotic prophylaxis → (4) immunoglobulin replacement (IVIG/SCIG) in refractory/severe cases (PMID: 32654695; PMID: 40097777).
"Specific antibody deficiency is managed clinically with close follow-up and prompt treatment of infections, antibiotic prophylaxis, or immune globulin therapy." (PMID: 32654695)
Pneumococcal conjugate vaccine (PCV). Because conjugate vaccines present polysaccharide as a T-dependent protein-linked antigen, they bypass the TI-2 defect. In primary humoral immunodeficiency (n = 29) given PCV13, protection was 71.4%, 66.7%, and 56.0% at 1, 6, and 12 months; IgG subclass deficiency, Ig replacement, and higher IgG2 at diagnosis predicted long-term protection (PMID: 34290713). Conjugate vaccination was favorable in 11/12 pediatric SAD patients (PMID: 27614984). Suggested NCIT: Pneumococcal Conjugate Vaccine.
"71.4%, 66.7% and 56.0% of the patients were protected at one, six and twelve months respectively" (PMID: 34290713).
Immunoglobulin replacement therapy (IgRT). In adult SPAD, 40% received IgRT with a fall in mean antibiotic courses from 7.9 to 0.7 per year (p < 0.001) (PMID: 40097777). Route (IVIG vs SCIG) did not significantly affect pediatric QoL (PMID: 42119234). Suggested NCIT: Intravenous Immunoglobulin Therapy, Subcutaneous Immunoglobulin.
Antibiotic prophylaxis. Mainstay for reducing recurrent infection (PMID: 32654695).
Personalized strategy. Individualized because of the absence of a robust case definition and lack of controlled trials (PMID: 28588580). Gene/cell/RNA-based therapies are not applicable to primary SAD (relevant only to specific monogenic phenocopies).
| Treatment tier | Intervention | Evidence / effect | NCIT-type term |
|---|---|---|---|
| 1 | Prompt antibiotic treatment of acute infection | Standard of care | Antibiotic Therapy |
| 2 | Pneumococcal conjugate vaccine (PCV13/15/20) | Bypasses TI-2 defect; 56–71% protected over 12 mo (PID) | Pneumococcal Conjugate Vaccine |
| 3 | Antibiotic prophylaxis | Reduces recurrent infection | Antibiotic Prophylaxis |
| 4 | IgRT (IVIG/SCIG) | Antibiotic courses 7.9 → 0.7/yr (p<0.001) | Immunoglobulin Replacement Therapy |
"Transgenic mice expressing the A144E mutant on TACI(-/-) background had low serum IgA levels and significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll." (PMID: 19605846)
SAD/SPAD is best understood as a functional failure at one node of the humoral immune system — the thymus-independent type-2 response to bacterial capsular polysaccharides. This response is intrinsically fragile: it matures late (inadequate < 2 years), forms no memory, and uses a narrow IgM/IgG2 repertoire (PMID: 8167745). When it fails, anti-capsular antibody is insufficient to opsonize S. pneumoniae and Hib, producing recurrent sinopulmonary infection. The two therapeutic levers both make sense in this framework: (1) conjugate vaccines re-route the antigen through T-dependent germinal-center help, restoring durable IgG (PMID: 34290713); and (2) IgRT supplies the missing antibody directly (PMID: 40097777).
The disease's "Mendelian" framing is misleading. Primary SAD has no single causal gene and is a diagnosis of exclusion (PMID: 28588580; PMID: 8167745). The genetic dimension enters in two ways: as mechanistic insight (TACI–NF-κB governs TI-2 responses; PMID: 19605846) and as differential diagnosis (monogenic IEI can phenocopy SAD and should be sought when clinically indicated; PMID: 38933494).
| PMID | Title (abbrev.) | Role |
|---|---|---|
| 32654695 | Diagnosis and management of Specific Antibody Deficiency | Definition + management ladder |
| 28588580 | SAD: Controversies in Diagnosis and Management | Normal Ig phenotype; lack of consensus |
| 8167745 | Anti-capsular polysaccharide antibody deficiency states | TI-2 immunobiology; secondary causes |
| 9723664 | Influence of age on S. pneumoniae vaccine response | 1.3 µg/mL / 4-fold thresholds; age dependence |
| 25498324 | SAD with normal Ig in children | Age-adjusted pediatric criteria; impaired persistence |
| 27614984 | SAD: PID associated to respiratory allergy | Recurrent pneumonia 91.7%; asthma/rhinitis; PCV benefit |
| 36285530 | High frequency of SPAD in adults | SPAD = 78.7% of PIDs; PID freq 39.8% |
| 26454312 | Specific Antibody Deficiencies | Good prognosis; may resolve |
| 38933494 | Monogenic IEI with impaired polysaccharide IgG | Phenocopies; test anti-PS IgG |
| 19605846 | Murine A181E TACI mutation | Mouse model; TACI–NF-κB; TNP-Ficoll |
| 34290713 | PCV13 in primary humoral immunodeficiency | Conjugate-vaccine protection over 12 mo |
| 40097777 | 55 adult SPAD patients | Female 75%; delay/bronchiectasis; IgRT efficacy |
| 39681261 | Functional testing in the Prevnar 20 era | PPSV23 accuracy 81–84% in PCV era |
| 40637813 | Multiplex ECL assay for SPAD | Sens 95% / Spec 84% vs WHO ELISA |
| 39836844 | Colombian IEI service | PAD = largest IEI group (41.3%) |
| 36605210 | J Project 30 countries | PAD = 46.3% of 24,879 patients |
| 42447994 | Shared decision-making / HRQOL in IEI | QoL burden; PADQOL/CVID-QOL |
| 42119234 | QoL and care burden SCIG/IVIG | r = −0.710 child QoL vs caregiver burden |
| 42565624 | Neutrophils and PCV responses | Neutrophil–Treg regulation of conjugate response |
| 33877708 | IgM/IgA anti-PnPS assays | Serotype-specific IgG remains the standard |
Report compiled from 15 confirmed findings across 5 investigation iterations and 72 reviewed papers. Evidence types: predominantly human clinical (cohorts, case series, registries) plus one mouse mechanistic model (PMID: 19605846) and mouse/human conjugate-vaccine immunobiology (PMID: 42565624).
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 20 |
| Resolved | 20 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 11 |
| Quoted claims found in source | 11 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 20 |
| On topic | 15 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 27 |
| Resolved | 25 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 1 |
| Unverifiable | 1 |
| Terms whose name was checked | 13 |
| Terms named correctly | 5 |
| Terms named as a different term | 7 |
| Terms whose name is worth a second look | 1 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
HP:0000403 (1 mention) - the report calls it "Common"; HP calls it Recurrent otitis mediaHP:0002099 (1 mention) - the report calls it "100% (12/12) in pediatric SAD cohort"; HP calls it AsthmaHP:0003193 (1 mention) - the report calls it "11/12 pediatric SAD"; HP calls it Allergic rhinitisHP:0002110 (1 mention) - the report calls it "Associated with long diagnostic delay"; HP calls it BronchiectasisHP:0005425 (1 mention) - the report calls it "Abnormal antibody level"; HP calls it Recurrent sinopulmonary infectionsGO:0002374 (1 mention) - the report calls it "immunoglobulin production"; GO calls it GO_0002374UBERON:0002106 (1 mention) - the report calls it "Immune tissue: spleen"; UBERON calls it spleen**These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
GO:0002374 (GO_0002374) (1 mention) - replaced by GO:0002367The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
GO:0007249 (1 mention) - the report calls it "canonical NF-κB signal transduction"; GO calls it canonical NF-kappaB signal transduction