# Diagnosis, Characteristics, and Outcome of Selective Anti-polysaccharide Antibody Deficiencies In A Retrospective Cohort of 55 Adult Patients.

Nicolas Perrard, Sarah Stabler, Sebastien Sanges, Louis Terriou, Catherine

Lamblin, Sacha Gaillard, Fanny Vuotto, Cecile Chenivesse, Geoffrey

Mortuaire, Frédéric Batteux, et al.

► To cite this version:

Nicolas Perrard, Sarah Stabler, Sebastien Sanges, Louis Terriou, Catherine Lamblin, et al. Diagnosis, Characteristics, and Outcome of Selective Anti-polysaccharide Antibody Deficiencies In A Retrospective Cohort of 55 Adult Patients. Journal of Clinical Immunology, 2025, Journal of Clinical Immunology, 45, pp.82. 10.1007/s10875-025-01874-2. hal-05026287

HAL Id: hal-05026287

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# Diagnosis, Characteristics, and Outcome of Selective Anti-polysaccharide Antibody Deficiencies In A Retrospective Cohort of 55 Adult Patients

Nicolas Perrard<sup>1,2,3,4</sup> · Sarah Stabler<sup>3,4,5,6</sup> · Sébastien Sanges<sup>1,2,4</sup> · Louis Terriou<sup>1,2,4</sup> · Catherine Lamblin<sup>7</sup> ·

Sacha Gaillard<sup>8</sup> · Fanny Vuotto<sup>4,5,6</sup> · Cécile Chenivesse<sup>4,6,9</sup> · Geoffrey Mortuaire<sup>4,10</sup> · Frédéric Batteux<sup>11,12</sup> ·

Floriane Mirgot<sup>3,4</sup> · Aurore Collet<sup>2,3,4</sup> · Benjamin Lopez<sup>13</sup> · Sylvain Dubucquoi<sup>2,3,4</sup> · Myriam Labalette<sup>2,3,4</sup> ·

Eric Hachulla<sup>1,2,4</sup> · David Launay<sup>1,2,4</sup> · Guillaume Lefèvre<sup>1,2,3,4</sup>

Received: 9 September 2024 / Accepted: 27 February 2025

© The Author(s) 2025

## Abstract

Selective anti-polysaccharide antibody deficiency (SPAD) predisposes to encapsulated bacterial infections. The diagnosis is challenging, and literature reports are scarce in adult patients, we therefore aim to describe the demographics, infectious complications, therapeutic strategies, and outcome of adult patients. We conducted a multicenter observational study involving 55 adult patients with SPAD. The median [interquartile range, IQR] age was 45 [36–60] years at diagnosis of SPAD, and 75% of patients were female. Twenty-one patients (38%) had a history of allergic and/or inflammatory disease, mainly asthma (n = 12), and rheumatic diseases (n = 6). Twelve patients (22%) were diagnosed after a single severe infection and 43 (78%) in a context of recurrent benign and/or severe infections. In the latter, the median time from first infections to diagnosis was 74.5 [33–167] months. Diagnostic delay was significantly higher in patients presenting with bronchiectasis than in those without (122 months [33–219.5] vs 24 months [14.5–74.5], p = 0.0042). In 22 patients (40%) receiving immunoglobulin replacement therapy (IgRT), 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) with a median follow-up period of 46 [27–73] months. Patients diagnosed after a single severe infection did not have any relapse during a median follow-up of 85 [80.5–104.5] months after diagnosis. Adult patients with SPAD have allergic or inflammatory disorders which could contribute to the diagnostic delay. IgRT is effective in preventing recurrent infections. Further studies are warranted to confirm if SPAD should be considered after a first unexplained severe bacterial infection.

**Keywords** Specific antibody deficiency · Selective anti-polysaccharide antibody deficiency · Primary immunodeficiency · Encapsulated bacterial infections · Preventive antibiotherapy · Immunoglobulin replacement therapy · Asthma

## Abbreviations

<table><tr><td>PID</td><td>Primary immunodeficiency</td></tr><tr><td>U/LRTI</td><td>Upper/lower respiratory tract infection</td></tr><tr><td>SPAD</td><td>Specific anti-polysaccharide antibody deficiency</td></tr><tr><td>PS</td><td>Polysaccharide</td></tr><tr><td>PnPS</td><td>Pneumococcal capsular polysaccharide</td></tr><tr><td>AAAAI</td><td>American Academy of Allergy, Asthma & Immunology</td></tr><tr><td>IgRT</td><td>Immunoglobulin replacement therapy</td></tr><tr><td>PPV23</td><td>23-Valent pneumococcal polysaccharide vaccine</td></tr></table>

<table><tr><td>PCV13</td><td>13-Valent pneumococcal conjugate vaccine</td></tr><tr><td>CVID</td><td>Common variable immunodeficiency</td></tr><tr><td>CRS</td><td>Chronic rhinosinusitis</td></tr><tr><td>RA</td><td>Rheumatoid arthritis</td></tr><tr><td>COPD</td><td>Chronic obstructive pulmonary disease</td></tr><tr><td>HibCV</td><td><i>Haemophilus influenzae</i> Serotype B conjugate vaccine</td></tr><tr><td>OVA</td><td>Overall anti-pneumococcal response assay</td></tr><tr><td>SSA</td><td>Single serotype assay</td></tr><tr><td>SITRAM</td><td>Systemic inflammatory trunk recurrent acute macular eruption</td></tr><tr><td>IQR</td><td>Interquartile range</td></tr></table>

Extended author information available on the last page of the article
# Introduction

Primary immunodeficiencies (PIDs) encompass rare disorders predisposing individuals to various infections, autoimmune diseases, and neoplasia [1]. Antibody deficiencies typically manifest through bacterial upper and/or lower respiratory tract infections (U/LRTIs), with pathogens such as *Streptococcus pneumoniae*, *Streptococcus pyogenes*, and *Haemophilus influenzae* [2, 3]. Among antibody deficiencies, the first fully characterized case of specific anti-polysaccharide antibody deficiency (SPAD) was reported in 1987: Ambrosino and colleagues described an adult patient with a history of recurrent U/LRTIs, demonstrating impaired antibody responses to polysaccharide (PS) antigens but normal responses to protein antigens [4]. SPAD is now characterized by an impaired response to PS antigens, despite normal response to protein antigens, and normal levels of immunoglobulin (Ig), IgG subclasses, T cells, and B cells [5, 6]. This assessment of anti-PS response is made by evaluating antibodies against pneumococcal capsular polysaccharides (PnPS), using a standardized, serotype-by-serotype approach before and 4 to 8 weeks after immunization with the non-conjugate 23-valent polysaccharide pneumococcal vaccine (PPV23, PNEUMOVAX®) [7].

In a recent multicenter prospective study, we demonstrated that SPAD may represent a common etiology for recurrent benign and/or severe bacterial infections when local or systemic predisposing conditions are excluded [8]. However, several considerations remain unknown in the diagnosis and management of SPAD in adult patients. First, clinical practice shows that some SPAD patients could have common chronic respiratory diseases, tobacco use, or inflammatory disorders, even if these could be considered factors predisposing to infections [9]. Second, the benefit of anti-PS response assessment in patients who have had a single unexplained severe infection needs to be confirmed [8]. Third, the long-term benefit of SPAD diagnosis and the efficacy of IgRT require further evaluation.

In this study, we aimed to describe the demographics, diagnosis, infectious complications, immunological characteristics, therapeutic strategies, and outcome of adult patients with SPAD.

# Methods

## Patients

SPAD diagnosis was made if a patient had unexplained recurrent bacterial infections or at least one severe infection with encapsulated bacteria, normal levels of Ig and

IgG subclasses, normal B cell counts, and an impaired anti-polysaccharide response 4 to 8 weeks after vaccination with PPV23. The absence of vaccination with PPV23 at least two years prior to testing was also required to avoid the hypo-responsiveness phenomenon. Interpretation of anti-PnPS response and SPAD diagnosis were defined in accordance with the recommendations of the American Academy of Allergy, Asthma & Immunology (AAAAI) [2, 7], and assessing pre- and postimmunization anti-PnPS antibody titers using the third-generation World Health Organization enzyme-linked immunosorbent serotype-specific assay (SSA) [2, 7, 10]. An insufficient response for a given serotype was considered to correspond to post-immunization antibody titers below 1.3 mg/L or failing to show a fourfold increase. A twofold increase was deemed acceptable if the initial value was already greater than 1.3 mg/L. A poor response to PnPSs was defined as an insufficient response to at least 70% of the tested serotypes (7 to 13), and patients were therefore diagnosed with SPAD. The diagnosis of SPAD was also established if the anti-PnPS antibodies remained below 110 mg/L using the overall anti-pneumococcal response assay (OVA), with a positive predictive value of 100% according to a previous work published by our team [11].

The degree of vaccine response impairment in selective antibody deficiency was defined according to the SSA, as follows: a mild phenotype when patients had either multiple vaccine-containing serotypes to which they did not generate protective titers ≥ 1.3 mg/mL or an inability to increase titers two-fold for ≥ 70% of serotypes, assuming the prevaccination titers are below the threshold levels described earlier; a moderate phenotype when patients had fewer than the expected number of protective titers for 70% of serotypes but demonstrated protective titers ≥ 1.3 mg/mL for three or more serotypes; and a severe phenotype when patients had protective titers for no more than two serotypes, with any titers present tending to be < 1.3 mg/mL [7].

CD27+IgD-IgM- switched memory B cells were considered low if their count was below 6.5% of CD19+B cells, and CD27+IgD+IgM+ marginal zone-like B cells were considered low if below 7.4% of total CD19+B cell [12].

# Data Collection

Details of patients' demographic characteristics and personal medical histories, encompassing autoimmune or inflammatory disorders, practitioner reports of asthma or allergies, neoplasia, and the presence of bronchiectasis, were documented from medical records. Biological parameters, including T-cell, B-cell (with naive/memory subsets), and NK-cell counts, and levels of IgG, IgA, and IgM, were

<figure><img src="image_2.png" /></figure>
recorded at the time of diagnosis and throughout follow-up when available.

Bacterial infections evocative of SPAD corresponded to documented infections with encapsulated bacteria, or, in the absence of documentation, to infections involving sites commonly affected by encapsulated bacteria, i.e., the pharynx and ENT region (URTI), the bronchi, and lungs (LRTI). There were defined as benign if treated in an outpatient setting, severe if necessitating hospitalization and/or intravenous antibiotics and recurrent if occurring at least twice per year for a minimum of two years). Patients where then classified in 3 infectious phenotypes Antibody responses to 13-valent conjugate polysaccharide vaccines (PCV13, PREVENAR 13®), and conjugate anti-*Haemophilus influenzae* serotype B HibCV, ACT-HIB®) were collected if at least one assessment was available within six months following immunization. Additional data were gathered on patients undergoing IgRT, including the frequency of infections and courses of antibiotics per year before and after IgRT initiation (at the latest follow-up visit). PCV13 was administered at least 1 year after the pneumococcal polysaccharide vaccine administered for diagnostic to avoid the hyporesponsiveness phenomenon.

## Statistical Analysis

Continuous variables are expressed as median (interquartile range [IQR]) and categorical variables are expressed as number (percentage).

Inter-group comparisons with regard to clinical and biological characteristics were performed using Student's t test for continuous variables, and the chi-squared test or Fisher's exact test for categorical variables, as appropriate.

Comparisons of infection frequency after IgRT versus baseline were done using the Wilcoxon' signed rank test.

Data analyses and graphs were performed using the GraphPad Prism version 9.1.2 (GraphPad Software, La Jolla, CA).

All tests were two-tailed, and the threshold for statistical significance was set to *p* < 0.05.

## Ethics Statement

All patients were aged 18 or older, and non-opposition to data use was collected (“Protection des Données – GHT Lille Métropole Flandre intérieure”, Agreement No. DEC23-109). Data from the 36 patients included from the prospective multicenter study were collected after written consent from each patient, with the approval of our Institutional Review Board and by an independent ethics committee in accordance with French legislation (“Comité de Protection des Personnes Nord Ouest IV”, Agreement No. 2014–100739-38).

## Results

### Bacterial Infections and Immunological Characteristics

Fifty-five patients were included in the study (41 females [75%]), and the median (IQR) age at diagnosis was 45 years (36–60 years) (Table 1). Thirty-nine patients were diagnosed using a 7 serotype SSA and 10 using a 13 serotype SSA, the 6 remaining patients were diagnosed using the OVA [7, 11].

Infectious manifestations at diagnosis were previously reported in 47 patients [8, 11]. Three groups were identified according to the infectious phenotype: (i) 12 (22%) patients presented with a single severe infection (meningitis [$n$ = 8], acute respiratory distress syndrome due to pneumonia [$n$ = 2], pneumococcal endophthalmitis [$n$ = 1], pneumococcal spondylodiscitis [$n$ = 1]), (ii) 24 (44%) patients presented with recurrent benign infections, and (iii) 19 (34%) presented with recurrent infections with at least one severe infection requiring hospitalization ($n$ = 8) or recurrent severe infections ($n$ = 11) (Fig. 1a, Table 1). The degree of vaccine response impairment did not differ between the various groups identified based on infectious clinical presentation (Fig. 1b). Thirteen patients (23%) presented with bronchiectasis (diffuse [$n$ = 7], localized [$n$ = 6]). Patients with recurrent infections were diagnosed after a median delay of 74.5 (33–167) months. Diagnostic delay was significantly higher in patients presenting with bronchiectasis at diagnosis (24 months [14.5–74.5] versus 122 months [33–219.5], *p* = 0.0042) (Fig. 2). T-cell, B-cell, and NK-cell counts were available in 48 patients: T- and B-cell counts were normal in all patients, but a decreased NK-cell count (below 100/mm³) was present in 12 cases (25%). Naive/memory B-cell counts were available in 30 patients and 7 had decreased relative counts of (Table 1, see also Figure S11).

### Non-infectious Characteristics At Diagnosis

Allergic and/or inflammatory disorders were present in 21 patients (38%), comprising asthma ($n$ = 12), rheumatic diseases ($n$ = 6; including rheumatoid arthritis [RA] [$n$ = 2], ankylosing spondylitis [$n$ = 2], polymyalgia rheumatica, and unclassified chronic inflammatory rheumatism [$n$ = 1]), autoimmune thyroiditis ($n$ = 4), Sjögren's syndromes ($n$ = 2), cutaneous psoriasis ($n$ = 2), and a recently described auto-inflammatory disorder known as systemic inflammatory trunk recurrent acute macular eruption (SIT-RAME syndrome, $n$ = 1) [13]. These patients with allergic and/or inflammatory disorders were not undergoing
<table><caption>**Table 1** Patients' characteristics according to their clinical infectious phenotype</caption><thead><tr><th></th><th>SPAD Cohort<br>(n=55)</th><th>Single severe<br>infection<br>(n=12)</th><th>Recurrent benign<br>infections<br>(n=24)</th><th>Recurrent infections<br>with ≥ 1 severe infection<br>(n=19)</th><th>p</th></tr></thead><tbody><tr><td>Female gender, n (%)</td><td>41 (75)</td><td>8 (72)</td><td>18 (75)</td><td>15 (79)</td><td>0.463</td></tr><tr><td>Age (y) at diagnosis, median (IQR)</td><td>45 (36–60)</td><td>45.5 (36.5–67.5)</td><td>45.5 (40.5–52.5)</td><td>45 (35–61.5)</td><td>0.738</td></tr><tr><td>Infected phenotype</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Single severe infection, n (%)</td><td>12 (22)</td><td></td><td></td><td></td><td></td></tr><tr><td>Recurrent benign infections, n (%)</td><td>24 (44)</td><td></td><td></td><td></td><td></td></tr><tr><td>Recurrent infections with ≥ 1 severe infection,<br>n (%)</td><td>19 (34)</td><td></td><td></td><td></td><td></td></tr><tr><td>Vaccine response impairment according to SSA<sup>§</sup></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mild, n (%)</td><td>18 (33)</td><td>5 (42)</td><td>9 (37)</td><td>4 (21)</td><td>0.231</td></tr><tr><td>Moderate, n (%)</td><td>12 (22)</td><td>2 (16)</td><td>4 (16)</td><td>6 (32)</td><td>0.260</td></tr><tr><td>Severe, n (%)</td><td>23 (42)</td><td>5 (42)</td><td>9 (37)</td><td>9 (47)</td><td>0.526</td></tr><tr><td>Bacteriological documentation<sup>*</sup>, n (%)</td><td>24 (44)</td><td>12 (100)</td><td>3 (12)</td><td>9 (47)</td><td>&lt;0.001</td></tr><tr><td>Streptococcus pneumonia, n</td><td>12</td><td>6</td><td>-</td><td>5</td><td></td></tr><tr><td>Neisseria meningitidis, n</td><td>8</td><td>6</td><td>-</td><td>2</td><td></td></tr><tr><td>Haemophilus influenzae, n</td><td>7</td><td>-</td><td>3</td><td>4</td><td></td></tr><tr><td>Streptococcus pyogenes, n</td><td>2</td><td>-</td><td>1</td><td>-</td><td></td></tr><tr><td>No documentation, n</td><td>31</td><td>0</td><td>21</td><td>10</td><td></td></tr><tr><td>Bronchiectasis, n (%)</td><td>13 (24)</td><td>0 (0)</td><td>6 (25)</td><td>7 (37)</td><td>0.016</td></tr><tr><td>Allergic/Inflammatory diseases, n (%)</td><td>21 (38)</td><td>4 (33)</td><td>11 (58)</td><td>9 (47)</td><td>0.457</td></tr><tr><td>Asthma, n</td><td>12</td><td>1</td><td>7</td><td>4</td><td></td></tr><tr><td>Inflammatory rheumatism<sup>**</sup>, n</td><td>6</td><td>2</td><td>1</td><td>3</td><td></td></tr><tr><td>Autoimmune thyroiditis, n</td><td>4</td><td>0</td><td>2</td><td>2</td><td></td></tr><tr><td>Sjögren's syndrome, n</td><td>2</td><td>0</td><td>0</td><td>2</td><td></td></tr><tr><td>Psoriasis, n</td><td>2</td><td>1</td><td>0</td><td>1</td><td></td></tr><tr><td>Auto-inflammatory disease, n</td><td>1</td><td>0</td><td>1</td><td>0</td><td></td></tr><tr><td>Inflammatory bowel disease, n</td><td>1</td><td>0</td><td>1</td><td>0</td><td></td></tr><tr><td>Biological only autoimmunity<sup>***</sup>, n</td><td>4</td><td>0</td><td>1</td><td>3</td><td></td></tr><tr><td>Biological parameters (n=48)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Decreased NK cell, n (%)</td><td>12 (22)</td><td>3 (25)</td><td>5 (21)</td><td>4 (21)</td><td>0.806</td></tr><tr><td>Decreased switched memory B cells, n (%)</td><td>7 (13)</td><td>1 (8)</td><td>2 (8)</td><td>4 (21)</td><td>0.242</td></tr><tr><td>Decreased marginal zone-like B cells, n (%)</td><td>5 (9)</td><td>0 (0)</td><td>2 (8)</td><td>3 (16)</td><td>0.157</td></tr></tbody></table>

treatment with systemic steroids or immunosuppressants at the time of anti-PS response assessment, but 9 patients would have required oral steroids and/or immunosuppressants for conditions such as rheumatic diseases, cutaneous psoriasis, and connective tissue diseases. In the two cases of RA, the use of steroids and immunosuppressants was contraindicated due to recurrent benign and/or severe infections, resulting in progressive joints destruction and a decline in quality of life prior to the diagnosis of SPAD (Table 1). No history of lymphadenopathy, splenomegaly, or neoplasia was documented in our cohort.

## Follow-up

The median duration of follow-up was 67.8 months (48–84 months). No deaths occurred during the study period.

All patients were educated about warning signs necessitating prompt consultation with their general practitioner. All patients received conjugate vaccines against *Streptococcus pneumoniae* (PCV13) and *Haemophilus influenzae* type b (HibCV), and against *Neisseria meningitidis* in case of previous meningococcal infection. Pre- and post-vaccination

<figure><img src="image_3.png" /></figure>

<footnote>§ Two missing data</footnote>

<footnote>* Some patients were documented for multiple bacteria</footnote>

<footnote>** Rheumatoid arthritis (n=2), ankylosing spondylitis (n=2), polymyalgia rheumatica (n=1), chronic inflammatory rheumatism (n=1)</footnote>

<footnote>*** Type III cryoglobulinemia (n=2), positive rheumatoid factor (n=1), positive antinuclear antibodies > 1/1280 (n=1)</footnote>
<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>**Fig. 1** Infectious phenotypes of SPAD and patient management. a Distribution of SPAD phenotype among 3 patient groups: (i) a single severe infection, (ii) recurrent benign infections only and (iii) recurrent infections with at least 1 severe infection requiring hospitalization, with therapeutic management (b) Repartition of biologic phenotypes vaccine response impairment among the 3 infectious groups, defined as mild (green), moderate (orange) or severe (red) vaccine response impairment (according to [7]) * 2 missing data</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>**Fig. 2** Diagnostic delay according to presence or absence of bronchiectasis</figcaption></figure>

paired serological assessments were only available for 5 patients receiving PCV13 and 5 patients receiving HibCV: low response were observed in 4 and 2 cases, respectively (Figure SI2). Some patients kept low serum antibody levels despite repeated conjugate vaccines (data not shown).

Seventeen patients underwent treatment with low-dose azithromycin as “bronchial anti-inflammatory therapy” (250 or 500 mg three times a week). The efficacy of this treatment was deemed in 7 out of 15 evaluated (47%, with 5 partial and 2 complete improvements; 2 losses to follow-up prior to evaluation). After azithromycin failure or partial improvement, 11 patients subsequently received IgRT, including one patient whose bronchiectasis progressed despite azithromycin (Fig. 1a).

Overall, 22 patients were treated with IgRT at an initial dose of 0.1 g/kg/week (subcutaneous route) or 0.4 g/kg/month (intravenous route). This choice was made by the referent specialist in case of recurrent infections, with 3 additional criteria: a history of severe infection (n=7; e.g. requiring ICU hospitalizations – Figure SI3), the presence of bronchiectasis (n=8) and/or highly frequent RTIs (n=8 patients without severe infections or bronchiectasis, were prescribed between 6 to 12 antibiotics per year).

The mean frequency of antibiotic courses decreased significantly from 7.9 (2–18) courses per year to 0.7 (0–2) course per year following IgRT (p < 0.001), with a median follow-up period of 46 months (27–73.3 months) (Fig. 3). Mild vaccine response impairment was present in groups

<figure><img src="image_7.png" /><figcaption>**Fig. 3** Change in the number of antibiotic courses per year before and after introducing IgRT (n=22)</figcaption></figure>

of patients with and without bronchiectasis, with and without IgRT (respectively 25% and 36%; 25% and 39%—Figure SI4). One patient with severe chronic obstructive pulmonary disease (COPD) and bronchiectasis, requiring supplemental oxygen therapy and non-invasive ventilation, had a poor response to both PCV13 and PPV23. He received azithromycin and IgRT was then added: bacterial infections decreased from 1–2 per month prior to diagnosis to 3–4 per year, and lung transplantation, which was contraindicated, was reconsidered.

Among the 12 patients who presented exclusively with a single severe infection, no recurrence of a relevant bacterial infection was observed during a median follow-up of 85 months (80.5–104.5 months) after diagnosis, despite absence of any prophylaxis excepted conjugate vaccines.

One patient with Sjögren's syndrome later developed systemic lupus erythematosus and thrombotic thrombocytopenic purpura. Despite various immunosuppressant therapies (including corticoids and rituximab), no infections occurred while IgRT was maintained. Patients with RA who received IgRT for their specific anti-polysaccharide antibody deficiency were also optimally managed for their inflammatory disorder with agents such as rituximab, abatacept, tocilizumab, and certolizumab, without experiencing new infections (Figure SI5).

No significant decrease was observed in IgA and IgM levels 47 patients with available follow-up data, no significant decrease in IgG levels was observed in 26 patients not receiving IgRT. IgRT was discontinued by 4 patients; however, infections recurred in all cases, and IgRT was started again. In 2 pregnant women who previously experienced a

<figure><img src="image_8.png" /></figure>
dose reduction of IgRT, new bacterial infections occurred, and the dose was subsequently increased, with a recovered efficacy in preventing infections (Fig. 4).

Discussion

We present a cohort of 55 adult patients with SPAD, detailing their characteristics at diagnosis and their outcomes after a median follow-up period exceeding 5 years.

We observed a notable prevalence of allergic and inflammatory diseases among patients with SPAD. Twenty-two percent (n = 12/55) were diagnosed with asthma, occasionally accompanied by severe and recurrent asthma exacerbations linked to bacterial infections, with 10 patients experiencing recurrent bacterial sinusitis. In a large cohort of asthmatic patients, Lee et al. reported a prevalence of antibody deficiencies in 5% of patients [14]. This is of importance as U/LRTIs can precipitate asthma exacerbations [14, 15]. The frequency of antibody deficiency in severe chronic rhinosinusitis (CRS) patients, with or without asthma, is also high, with up to 40% of SPAD [16–18]. We also report on a severe COPD patient with monthly bacterial infections despite smoking cessation. In a case series of 42 COPD patients with very frequent exacerbations of infectious origin, 29 were diagnosed with PID (8 common

variable immunodeficiency [CVID], 20 SPAD, and 1 IgA deficiency), and 22 patients benefited from IgRT (less exacerbations, reduction of steroids and antibiotics use) [19]. As the diagnosis of SPAD may represent a significant turning point in their management, assessing the anti-PS response can be crucial in patients with severe asthma, CRS and COPD, and recurrent RTIs [20–22].

Thirteen patients in our cohort were presented with autoimmune and/or inflammatory disorders. Only few studies have been conducted on vaccine response to polysaccharides, mostly in RA patients, and using only the OVA [23, 24]. Our case series suggest that SPAD diagnosis must be considered in these patients in case of recurrent bacterial infections. Indeed, 9 of our patients would have required oral steroids and/or immunosuppressants for their autoimmune/allergic conditions. However, these patients received suboptimal treatment due to their recurrent infections. Following the diagnosis of SPAD, IgRT prevented recurrent severe RTI and facilitated the introduction of appropriate immunosuppressants.

The criteria defining a good or poor anti-PS response were established based on an expert consensus in 2012 and grounded in various pediatric and adult studies [2, 7] using a complex and non-automated SSA [10]. We also proposed that, notwithstanding its limitations, the OVA could be utilized when a post-vaccination antibody titer below 110 mg/L was recorded, as this consistently correlated with

<figure><img src="image_9.png" /><figcaption>**Fig. 4** Infectious events in 6 patients with reduction or discontinuation of IgRT. ICU, intensive care unit; IgRT, immunoglobulin replacement therapy; IV, intravenous</figcaption></figure>
a poor PPV23 response using the SSA [11]. Six patients in our cohort were diagnosed using this method, and five of them received IgRT, which effectively prevented recurrent infections. It is important to note that a defective response may be observed in healthy individuals, depending on the choice of specific antibody levels, of pre/post immunization fold-increases, of the number of tested serotypes, and of the methodology employed [17, 25]. This is why it is important to consider this hypothesis in adult patients with unexplained bacterial infections [8]. In the present cohort, we identified 3 infectious phenotypes: (i) a single unexplained severe infection, (ii) recurrent benign infections, and (iii) recurrent benign and ≥ 1 severe infection.

Of the 12 patients in our study who presented with a sin-
gle severe infection, none experienced a recurrence of bac-
terial infections during a median follow-up of 85 months
(80.5–104.5 months) after diagnosis. This raises questions
regarding the utility of investigating SPAD after a single
severe infection, particularly considering the prevalence of

low anti-PS responses in healthy individuals [17]. Pre/post
conjugate vaccine immunization assessments (PCV13 and
HibCV) were available in only five patients. Despite the lack
of standardization, it seems that conjugate vaccines induce a
poor immune response in some SPAD patients. Further stud-
ies are needed to determine the response to conjugate vaccines
according to the SSA and their clinical benefit in preventing
recurrent RTIs and severe infections in these patients.

Patients with antibody deficiency experiencing recurrent infections often face delayed diagnosis and may develop bronchiectasis. In a study conducted by Van Kessel and colleagues in 2005, 26 patients with bronchiectasis of unknown etiology were examined, revealing that 15 of them were non-responders to PPV23 [26]. Early diagnosis is crucial for averting life-threatening infections and lung disease, and the high incidence of bronchiectasis in our cohort of SPAD patients underscores the consequences of delayed diagnosis.

Therapeutic management remains non-standardized and
largely relies on expert recommendations and clinician

<figure><img src="image_10.png" /><figcaption>**Fig. 5** SPAD diagnosis and management according to the infectious complications. \*Relevant bacterial infections are RTIs and/or invasive infection with encapsulated bacteria, when the patient's history or investigations do not explain the frequency or the severity of the infections. \*\*Complement explorations and search of Howell-Jolly bodies are indicated in invasive infection with encapsulated bacteria. \*\*\* SSA must be used if locally available, OVA can be used in other</figcaption></figure>

cases, but SSA will be mandatory in many cases (see Lopez et al.
[11]). IgRT: immunoglobulin replacement therapy; IFE, immunofixa-
tion electrophoresis; OVA, overall anti-pneumococcal response assay;
RTIs: respiratory tract infections; SPAD: specific antibody antibody
deficiency; SPEP: serum protein electrophoresis; SSA: single-sero-
type assay
preferences. This management typically includes adminis-
tration of conjugate vaccines, patient education regarding the
risks of bacterial infections, and, in cases of persistent recur-
rent infections, initiation of preventive antibiotic therapy or
IgRT [27, 28]. In our cohort, all patients received conjugate
vaccines and were educated on symptoms and situations
warranting prompt medical attention and early initiation of
antibiotic therapy. A letter was also sent to their primary care
physicians for the same purpose.

Azithromycin was found to be effective in reducing the incidence of infections, decreasing the risk of hospitalization, and enhancing quality of life in patients with CVID and X-linked agammaglobulinemia [29] Among the 17 SPAD patients initially treated with azithromycin in our cohort, 11 eventually required a switch to IgRT due to poor effectiveness of azithromycin. The decision to initiate IgRT was based on the severity and the frequency of infections, and on the presence of bronchiectasis. IgRT demonstrated efficacy in 100% of cases, whether employed as first- or second-line therapy. This observed efficacy surpassed that reported in previous case series [16–18, 30, 31]. This difference can be attributed to the systematic exclusion of all potential differential diagnoses prior to SPAD diagnosis in our cohort, as well as the higher frequency of infections, and the bacterial infections requiring antibiotics (and not mild infections, or likely viral infections) [30]. This efficacy was also highlighted by the recurrence of bacterial infections, sometimes severe, in patients who discontinued IgRT or reduced the dose. Monitoring of immunoglobulin levels in our adult patients receiving IgRT did not indicate a progression to a quantitative deficit such as CVID, as it can encountered in children [32].

Finally, we also wondered if the phenotype of anti-PS
responsiveness was associated with prognosis [7, 25, 33]. This
classification suggested by experts has never been compared
to the clinical phenotype of patients. If we consider the ‘mild’,
‘moderate’ or ‘severe’ phenotypes, we do not see any clear
association between the level of anti-PS response and the prog-
nosis, since at least 25% of patients with recurrent severe infec-
tions, bronchiectasis or IgRT initiation, can have a so-called
“mild” phenotype. This raises questions about the relevance
of phenotype responsiveness, as the infectious complications
may better define the severity of SPAD and its management.

Conclusion

In summary, our study addresses the diagnostic challenges and
management strategies associated with SPAD in a cohort of
55 adult patients. This diagnosis should also be considered
in patients exhibiting autoimmune manifestations alongside
such infectious complications, or in those with severe chronic

lung disease experiencing difficult-to-treat exacerbations and/
or unexplained bronchiectasis. Patients who had a single unex-
plained bacterial infection and did not have any other infections
after diagnosis should be tested for other immunodeficiencies
and receive conjugate vaccines but may not be tested for SPAD
(Fig. 5). In patients with recurrent bacterial RTIs, SPAD diag-
nosis must be considered in absence of any other immuno-
deficiency. IgRT must be considered as a first-line treatment,
or after low dose azithromycin or prophylactic antibiotics, in
case of frequent recurrent RTIs, history of severe infections or
bronchiectasis, (Fig. 5). Prospective studies are warranted to
confirm the benefit of this therapeutic strategy.

**Supplementary Information** The online version contains supplementary material available at https://doi.org/10.1007/s10875-025-01874-2.

**Acknowledgements** We acknowledge Mr. Nick Barton for his valuable and thorough professional advice about the writing of this manuscript.

**Authors Contribution** NP, SSt, GL, AC: Project development, data collection, writing, statistical analysis, review, and revision CL, SG, FM, SSa, LT, FV, CC, GM, AC, SD, ML, EH, DL: Data collection, review, and revision BL: Statistical analysis, review, and revision.

**Funding** Open access funding provided by Centre Hospitalier Universitaire de Lille. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

**Data Availability** No datasets were generated or analysed during the current study.

Declarations

**Conflicts of Interest** G. Lefèvre received consulting fees for advisory boards from Grifols, Biotest, and Takeda; personal fees for meetings from LFB, Octapharma, and Grifols; and research funding from LFB, CSL Behring, Octapharma, Takeda, Vitalaire, and Biotest. C. Chenivesse declares research grants from AstraZeneca, GlaxoSmith-Kline, Santelys, and Novartis; personal fees from ALK-Abello, AstraZeneca, Boehringer-Ingelheim, Chiesi, Sanofi, and GlaxoSmithKline; and congress support from AstraZeneca, Boehringer Ingelheim, Chiesi, and Novartis, outside the submitted work. F. Vuotto received consulting fees for advisory boards from Takeda and AstraZeneka; and congress support from Gilead and Grifols, outside the submitted work. The rest of the authors declare they have no relevant conflicts of interest.

**Open Access** This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
## References

1. Seidel MG, Kindle G, Gathmann B, et al. The European Society for Immunodeficiencies (ESID) registry working definitions for the clinical diagnosis of inborn errors of immunity. J Allerg Clin Immunol In Pract. 2019;7:1763-70. https://doi.org/10.1016/j.jaip.2019.02.004.

2. Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allerg Clin Immunol. 2015;136:1186-1205.e78. https://doi.org/10.1016/j.jaci.2015.04.049.

3. Oksenhendler E, Gérard L, Fieschi C, et al. Infections in 252 patients with common variable immunodeficiency. Clin Infect Dis. 2008;46:1547-54. https://doi.org/10.1086/587669.

4. Ambrosino DM, Siber GR, Chilmonczyk BA, et al. An immunodeficiency characterized by impaired antibody responses to polysaccharides. N Engl J Med. 1987;316:790-3. https://doi.org/10.1056/NEJM198703263161306.

5. Perez E, Bonilla FA, Orange JS, Ballow M. Specific antibody deficiency: controversies in diagnosis and management. Front Immunol. 2017;8:586. https://doi.org/10.3389/fimmu.2017.00586.

6. Perez EE, Ballow M. Diagnosis and management of specific antibody deficiency. Immunol Allergy Clin North Am. 2020;40:499-510. https://doi.org/10.1016/j.iac.2020.03.005.

7. Orange JS, Ballow M, Stiehm ER, et al. Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the basic and clinical immunology interest section of the american academy of allergy, asthma & immunology. J Allerg Clin Immunol. 2012;130:S1-24. https://doi.org/10.1016/j.jaci.2012.07.002.

8. Stabler S, Lamblin C, Gaillard S, et al (2022) High Frequency of Specific Polysaccharide Antibody Deficiency (SPAD) in adults with unexplained, recurrent and/or severe infections with encapsulated bacteria. Clin Infect Dis ciac842. https://doi.org/10.1093/cid/ciac842

9. Berger M, Geng B, Cameron DW, et al. Primary immune deficiency diseases as unrecognized causes of chronic respiratory disease. Respir Med. 2017;132:181-8. https://doi.org/10.1016/j.rmed.2017.10.016.

10. Wernette CM, Frasch CE, Madore D, et al. Enzyme-linked immunosorbent assay for quantitation of human antibodies to pneumococcal polysaccharides. Clin Vaccine Immunol. 2003;10:514-9. https://doi.org/10.1128/CDLI.10.4.514-519.2003.

11. Lopez B, Bahauad M, Fieschi C, et al. Value of the overall pneumococcal polysaccharide response in the diagnosis of primary humoral immunodeficiencies. Front Immunol. 2017;8:1862. https://doi.org/10.3389/fimmu.2017.01862.

12. Warnatz K, Schlesier M. Flowcytometric phenotyping of common variable immunodeficiency. Cytometry Part B Clinical. 2008;74B:261-71. https://doi.org/10.1002/cyto.b.20432.

13. Soria A, Amsler E, Garel B, et al. Systemic inflammatory trunk recurrent acute macular eruption (SITRAME): A new autoinflammatory syndrome in adult? J Eur Acad Dermatol Venereol. 2023;37:e538-42. https://doi.org/10.1111/jdv.18771.

14. Lee S-H, Ban G-Y, Kim S-C, et al. Association between primary immunodeficiency and asthma exacerbation in adult asthmatics. Korean J Intern Med. 2020;35:449-56. https://doi.org/10.3904/kjim.2018.413.

15. Guilbert TW, Denlinger LC. Role of infection in the development and exacerbation of asthma. Expert Rev Respir Med. 2010;4:71-83. https://doi.org/10.1586/ers.09.60.

16. Carr TF, Koterba AP, Chandra R, et al. Characterization of specific antibody deficiency in adults with medically refractory chronic rhinosinusitis. Am J Rhinol Allergy. 2011;25:241-4. https://doi.org/10.2500/ajra.2011.25.3653.

17. Keswani A, Dunn NM, Manzur A, et al. The Clinical Significance of Specific Antibody Deficiency (SAD) Severity in Chronic Rhinosinusitis (CRS). J Allerg Clin Immunol In Pract. 2017;5:1105-11. https://doi.org/10.1016/j.jaip.2016.11.033.

18. Kashani S, Carr TF, Grammer LC, et al. Clinical characteristics of adults with chronic rhinosinusitis and specific antibody deficiency.

J Allerg Clin Immunol In Pract. 2015;3:236-42. https://doi.org/10.1016/j.jaip.2014.09.022.

19. McCullagh BN, Comellas AP, Ballas ZK, et al. Antibody deficiency in patients with frequent exacerbations of Chronic Obstructive Pulmonary Disease (COPD). PLoS ONE. 2017;12:e0172437. https://doi.org/10.1371/journal.pone.0172437.

20. Darveaux JI, Lemanske RF. Infection-related asthma. J Allergy Clin Immunol Pract. 2014;2:658-63. https://doi.org/10.1016/j.jaip.2014.09.011.

21. Tiotiu A, Salvator H, Jaussaud R, et al. Efficacy of immunoglobulin replacement therapy and azithromycin in severe asthma with antibody deficiency. Allergol Int. 2020;69:215-22. https://doi.org/10.1016/j.alit.2019.10.011.

22. Vivarelli E, Matucci A, Parronchi P, et al. Primary antibody deficiencies represent an underestimated comorbidity in asthma patients: efficacy of immunoglobulin replacement therapy in asthma control. J Asthma. 2023;60:1227-36. https://doi.org/10.1080/02770903.2022.2140435.

23. Snowden N, Moran A, Booth J, et al. Defective antibody production in patients with rheumatoid arthritis and bronchiectasis. Clin Rheumatol. 1999;18:132-5. https://doi.org/10.1007/s100670050070.

24. Broyde A, Arad U, Madar-Balakirski N, et al. longterm efficacy of an antipneumococcal polysaccharide vaccine among patients with autoimmune inflammatory rheumatic diseases. J Rheumatol. 2016;43:267-72. https://doi.org/10.3899/jrheum.150397.

25. Sorensen RU, Leiva LE, Javier FC, et al. Influence of age on the response to Streptococcus pneumoniae vaccine in patients with recurrent infections and normal immunoglobulin concentrations. J Allerg Clin Immunol. 1998;102:215-21. https://doi.org/10.1016/S0091-6749(98)70089-2.

26. van Kessel DA. Impaired pneumococcal antibody response in bronchiectasis of unknown aetiology. Eur Respir J. 2005;25:482-9. https://doi.org/10.1183/09031936.05.00073204.

27. United Kingdom Primary Immunodeficiency Network (UKPIN) Immunoglobulin Decision to Treat Study Group, Edgar JDM, Richter AG, et al. Prescribing Immunoglobulin replacement therapy for patients with non-classical and secondary antibody deficiency: an analysis of the practice of clinical immunologists in the UK and Republic of Ireland. J Clin Immunol. 2018;38:204-13. https://doi.org/10.1007/s10875-017-0469-4.

28. Hajjar J, Nguyen AL, Constantine G, et al. Prophylactic antibiotics versus immunoglobulin replacement in specific antibody deficiency. J Clin Immunol. 2020;40:158-64. https://doi.org/10.1007/s10875-019-00716-2.

29. Milito C, Pulvirenti F, Cinetto F, et al. Double-blind, placebo-controlled, randomized trial on low-dose azithromycin prophylaxis in patients with primary antibody deficiencies. J Allergy Clin Immunol. 2019;144:584-593.e7. https://doi.org/10.1016/j.jaci.2019.01.051.

30. Smits BM, Kleine Budde I, de Vries E, et al. Immunoglobulin replacement therapy versus antibiotic prophylaxis as treatment for incomplete primary antibody deficiency. J Clin Immunol. 2021;41:382-92. https://doi.org/10.1007/s10875-020-00841-3.

31. Cheng YK, Decker PA, O'Byrne MM, Weiler CR. Clinical and laboratory characteristics of 75 patients with specific polysaccharide antibody deficiency syndrome. Ann Allergy Asthma Immunol. 2006;97:306-11. https://doi.org/10.1016/S1081-1206(10)60794-6.

32. Wall LA, Dimitriades VR, Sorensen RU. Specific antibody deficiencies. Immunol Allergy Clin North Am. 2015;35:659-70. https://doi.org/10.1016/j.iac.2015.07.003.

33. Sorensen RU. A critical view of specific antibody deficiencies. Front Immunol. 2019;10:986. https://doi.org/10.3389/fimmu.2019.00986.

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## Authors and Affiliations

Nicolas Perrard<sup>1,2,3,4</sup> · Sarah Stabler<sup>3,4,5,6</sup> · Sébastien Sanges<sup>1,2,4</sup> · Louis Terriou<sup>1,2,4</sup> · Catherine Lamblin<sup>7</sup> ·

Sacha Gaillard<sup>8</sup> · Fanny Vuotto<sup>4,5,6</sup> · Cécile Chenivesse<sup>4,6,9</sup> · Geoffrey Mortuaire<sup>4,10</sup> · Frédéric Batteux<sup>11,12</sup> ·

Floriane Mirgot<sup>3,4</sup> · Aurore Collet<sup>2,3,4</sup> · Benjamin Lopez<sup>13</sup> · Sylvain Dubucquoi<sup>2,3,4</sup> · Myriam Labalette<sup>2,3,4</sup> ·

Eric Hachulla<sup>1,2,4</sup> · David Launay<sup>1,2,4</sup> · Guillaume Lefèvre<sup>1,2,3,4</sup>

<figure><img src="image_11.png" /></figure>

Nicolas Perrard
Nicolas.perrard@chu-lille.fr

<footnote n="1">1 Department of Internal Medicine and Clinical Immunology, CHU Lille, F-59000 Lille, France</footnote>

<footnote n="2">2 University of Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France</footnote>

<footnote n="3">3 Institute of Immunology, CHU Lille, F-59000 Lille, France</footnote>

<footnote n="4">4 Regional Center for Primary Immune Deficiency, CEREDIH Lille, CHU Lille, F-59000 Lille, France</footnote>

<footnote n="5">5 Department of Infectious and Tropical Diseases, CHU Lille, F-59000 Lille, France</footnote>

<footnote n="6">6 U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, F-59000 Lille, France</footnote>

<footnote n="7">7 Department of Pneumology, Private Hospital La Louvière, F-59000 Lille, France</footnote>

<footnote n="8">8 Department of Pneumology, Clinique Tessier, F-59300 Valenciennes, France</footnote>

<footnote n="9">9 Department of Pneumology, CHU Lille, F-59000 Lille, France</footnote>

<footnote n="10">10 Department of Oto-Rhino-Laryngology, CHU Lille, F-59000 Lille, France</footnote>

<footnote n="11">11 Department of Biological Immunology, Cochin Hospital, F-75014 Paris, France</footnote>

<footnote n="12">12 Cochin Institute, INSERM U1016, University of Paris, F-75014 Paris, France</footnote>

<footnote n="13">13 CH Dunkerque, Medical Laboratory Department, F-59240, Dunkirk, France</footnote>