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 [16,17,18]. 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 [20,21,22].

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 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 single severe infection, none experienced a recurrence of bacterial 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 studies 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 preferences. This management typically includes administration of conjugate vaccines, patient education regarding the risks of bacterial infections, and, in cases of persistent recurrent 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 [16,17,18, 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 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, as the infectious complications may better define the severity of SPAD and its management.