**4. Clinical presentations**

Patients with PID present highly heterogeneous clinical symptoms with increased susceptibility to infections and other immune complications [12, 13]. Recurrent infection is the hallmark of the PIDs although a variety of other clinical manifestations may appear before the infection [13, 14]. In fact, noninfectious manifestations, such as gastrointestinal disorders, hematological diseases, autoimmune/autoinflammatory conditions, atopy or malignancy, can be the predominant clinical presentations in some patients with underlying immunodeficiency [3, 15]. Furthermore, patients with PID also demonstrate overlapping symptoms and share similarities with many "routine" diseases.

#### **4.1 Infections**

Majority of patients with PID suffer mild to severe or life-threatening infections. The unique clinical characteristics of infections in PIDs are recurring, chronic, and can appear in multiple anatomic sites. Recurrent infections in both the sinuses and the respiratory tract, such as sinusitis, bronchitis, otitis, and pneumonia, are the most frequent symptoms observed in patients with PID [16], while recurrent systemic infections (e.g., meningitis and bacteremia) are also not rare [17, 18]. Patients with SCID may suffer from unusual or opportunistic infections leading to unexpected complications or death [19].

#### **4.2 Autoimmune and autoinflammatory disorders**

Autoimmune and autoinflammatory disorders are more frequently seen in some categories of the PIDs than in other diseases [20]. The associated conditions in PID individuals may present in a single tissue or organ, such as autoimmune hemolytic anemia, thrombocytopenia, and autoimmune thyroiditis, or affect multiple organs, exemplified by an related vasculitis, or resemble rheumatic symptoms such as (e.g., dermatomyositis, rheumatoid arthritis, and systemic lupus erythematosus) [3, 20, 21]. To note, family members that carry the same gene mutation may present different types of autoimmune/autoinflammatory symptoms, or without such disorders [22]. In comparison with other types of defects, the autoimmune presentations are relatively common in PIDs with antibody deficiencies (e.g., CVID, selective IgA deficiency), and absence of initial components (C1–C4) of the classical complement system [23, 24].
