Immunomodulatory activity of pidotimod administered with standard antibiotic therapy in children hospitalized for community-acquired pneumonia

Abstract

Background: Several attempts to improve immune function in young children have been made and encouraging results have been collected with pidotimod (PDT), a synthetic dipeptide molecule that seems to have immunomodulatory activity on both innate and adaptive responses. Until now, the effects of PDT on the immune system have only been studied in vivo after long-term administration to evaluate whether its immunomodulatory activity might prevent the development of infections. This study was planned to evaluate the immunomodulatory activity of PDT administered together with standard antibiotic therapy in children hospitalized for community-acquired pneumonia (CAP).

Methods: A total of 20 children hospitalized for community-acquired pneumonia (CAP) were randomized at a 1:1 ratio to receive either standard antibiotics plus pidotimod (PDT) or standard antibiotics alone to evaluate the immunomodulatory activity of PDT. Blood samples for the evaluation of immunological parameters were drawn at the time of recruitment (T0) (i.e., before therapy administration), at T3 and T5 (i.e., 3 and 5 days after the initiation of therapy) as well as at T21 (i.e., 7 days after the therapy ended).

Results: Following pneumococcal polysaccharide stimulation, the percentage of dendritic cells (DCs) expressing activation and costimulatory molecules was significantly higher in children receiving PDT plus antibiotics than in the controls. A significant increase in tumor necrosis factor-α and/or interleukin-12 secretion and expression of toll like receptor 2 was observed in PDT-treated children compared with controls; this was followed by an increased release of proinflammatory cytokines by monocytes. In the PDT-treated group, mRNA expression of antimicrobial peptides and genes involved in the inflammatory response were also augmented in comparison with the controls.

Conclusions: These results demonstrate, for the first time, that PDT administered together with standard antibiotics is associated with a favorable persistent immunomodulatory effect in children with CAP.

Fig. 1

Percentages of pneumococcal-stimulated positive dendritic cells (CD11c⁺) expressing HLA-DRII (a), CD86 (b) and CD80 (c) molecules are shown at baseline and in response to therapy in children with community-acquired pneumonia (CAP) treated with antibiotics plus pidotimod and in controls treated with antibiotics only. For each analysis, 30,000 events were acquired and gated on CD11c expression and side scatter properties. Mean values + SD and statistically significant differences are indicated

Fig. 2

Percentages of pneumococcal-stimulated dendritic cells (CD11c⁺) secreting TNF-α (a) and IL-12 (b) are shown at baseline and in response to therapy in children with community-acquired pneumonia (CAP) treated with antibiotics plus pidotimod and in controls treated with antibiotics only. The percentage of TNF-α/IL-12 secreting CD11c⁺ cells was higher in the therapy group than in the controls, although significant differences were observed only at T5 and T21 (c). For each analysis, 30,000 events were acquired and gated on CD11c expression and side scatter properties. Mean values + SD and statistically significant differences are indicated

Fig. 3

TLR2 expression on monocytes (CD14⁺) (a) and percentages of CD14 + cells expressing TNF-α (b), IL-12 (c) or TNF-α/IL-12 (d) are shown at baseline and in response to therapy in children with community-acquired pneumonia (CAP) treated with antibiotics plus pidotimod and in controls treated with antibiotics only. For each analysis, 30,000 events were acquired and gated on CD11c expression and side scatter properties. Mean values + SD and statistically significant differences are indicated

Fig. 4

Antibacterial response signaling pathway: antimicrobial peptides (a) and genes involved in the inflammatory response (b) at baseline as well as at days 3, 5 and 21 in children with community-acquired pneumonia (CAP) treated with antibiotics plus pidotimod and in controls treated with antibiotics only