**1. Introduction**

Primary antibody deficiencies (PADs) consist of a varied group of conditions with different genetic etiologies characterized by an impairment of B cell development, differentiation or class switch recombination leading to hypogammaglobulinemia, and/or defective antibody production [1]. They represent the most common form of inborn errors of immunity (IEIs), counting for more than 60% of them [2]. PADs show a wide clinical spectrum, ranging from asymptomatic to severe forms. Common variable immunodeficiency disorder (CVID) represents the most frequent PAD, with a heterogeneous clinical phenotype, ranging from recurrent bacterial infections, mostly of the respiratory and gastrointestinal tracts to autoimmune disorders, allergy, lymphoproliferation, hyperinflammation, and/or malignancies [3]. Several other forms of milder PADs exist such as IgG deficiency, IgG

**Citation:** Sgrulletti, M.; Costagliola, G.; Giardino, G.; Graziani, S.; Del Duca, E.; Di Cesare, S.; Di Matteo, G.; Consolini, R.; Pignata, C.; Moschese, V. The Evolutionary Scenario of Pediatric Unclassified Primary Antibody Deficiency to Adulthood. *J. Clin. Med.* **2023**, *12*, 4206. https://doi.org/10.3390/ jcm12134206

Academic Editor: David S. Fedson

Received: 17 May 2023 Revised: 17 June 2023 Accepted: 19 June 2023 Published: 22 June 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

subclass deficiency, selective IgA or IgM deficiency, and specific antibody defects. Some are in combination with each other [4–7]. In this context, a recent entity named "unclassified primary antibody deficiency" (unPAD) has been recognized and entered the European Society for Immunodeficiencies (ESID) definitions for clinical diagnosis. UnPAD patients match the following criteria: marked decrease in at least one of total IgG, IgG1, IgG2, IgG3, IgA, or IgM levels and/or failure of IgG antibody response(s) to vaccines, plus at least one of the following conditions: (I) recurrent or severe bacterial infections, (II) autoimmune phenomena (especially cytopenias), (III) polyclonal lymphoproliferation, (IV) affected family member. Secondary causes of hypogammaglobulinemia and clinical signs of T-cell-related diseases need to be excluded. UnPAD patients show a highly variable clinical spectrum as well [4–6]. Some children with unPAD may normalize their immunoglobulin levels within 4 years of age, framing the condition of transient hypogammaglobulinemia of infancy (THI); conversely, others may develop persistent or severe forms of PID. Although Ig levels might be less compromised in unPAD than in CVID, they may long remain unrecognized and undiagnosed. Moreover, they may suffer an underestimated risk of organ damage with a severe pulmonary involvement and a negative outcome. In fact, Janssen et al. reported that bronchial wall thickening, bronchiectasis, and atelectasis could be detected in 44%, 21%, and 19% of unPAD patients, respectively, similarly to CVID patients [7]. Immunoglobulin replacement therapy (IRT) is scarcely used in these patients, despite its efficacy being reported [1,8–11]. Recently, Karaman et al. found no significant difference in B-lymphocyte subset distribution of unPAD patients receiving Ig replacement therapy vs CVID patients [12]. In this study we provide a clinical, immunological, and genetic characterization of children with an early diagnosis of unPAD monitored for a mean time of 14 years (range 3–32 years, median 16 years) to outline their natural history and identify potential predictive and/or prognostic markers of final diagnosis.
