Table 2:
Adjunctive and Preventive Immunomodulatory Therapies Evaluated in LOS
| Intervention | Mechanism | Meta-analyses/RCTs | Overall Results | Recommendation |
|---|---|---|---|---|
| Adjunctive Therapies | ||||
| Pentoxifylline | Non-specific phosphodiesterase inhibitor with immunomodulatory and anti-inflammatory properties. | (79) | Pentoxifylline used as adjunct to antibiotics decreased mortality without adverse effects - however, overall quality low. | No recommendation for routine use. Future studies needed. |
| Immunoglobulins (IVIG) | Low levels of immunoglobulins (Ig) in preterm infants and reduced Ig levels in severe sepsis. | (74, 78) | No effect on in-hospital mortality and death/major disability at 2y age in preterm infants with suspected/proven LOS | Routine administration not recommended. |
| Granulocyte Transfusion | Quantitative and qualitative deficits in neonatal granulocyte function have been described. | (75) | No significant difference in all-cause mortality. Pulmonary complications. | Not recommended due to inconclusive evidence of safety and efficacy. |
| Granulocyte / Granulocyte-Macrophage Colony Stimulating Factors (G-CSF / GM-CSF) | Reversion of sepsis-induced neutropenia to promote phagocytosis and granulocyte-driven mechanisms of resolution of inflammation. | (71) | No survival advantage at 14 days of G-CSF / GM-CSF treatment. One study: prophylactic GM-CSF may protect against infection in infants with neutropenia/high risk of neutropenia. |
Insufficient evidence both for prophylactic administration and treatment. |
| Antioxidants (Selenium, Vitamin A, Melatonin) | Reduced blood levels of antioxidants in preterm infants and increased risk of oxidative stress. Melatonin has additional anti-inflammatory and anti-apoptotic properties. |
(72, 77, 80, 86) | Routine selenium supplementation reduced number of sepsis episodes. No effect on overall mortality or major neonatal morbidities. Adjunctive Melatonin improved condition. No effect of routine Vitamin A. |
Not yet recommended. |
| Recombinant Activated Human Protein C (rhAPC) | Role of rhAPC in modulating coagulation and inflammation. | (76) | Increased risk of bleeding and higher mortality in trials in adults and children. Withdrawn from the market. |
Neonates should NOT be treated with rhAPC. |
| Antibiotics with Anti-inflammatory Activity (Azithromycin) | Anti-inflammatory and immunomodulatory properties of macrolide antibiotics by inhibition of IL-1 p response. | (88) | Promising results in adult sepsis. No existing trial in neonatal sepsis. Ongoing study on the effect of early IV azithromycin as anti-inflammatory therapy on survival without BPD. |
Research ongoing. |
| Preventive Strategies | ||||
| Human Milk | Contains antimicrobial proteins and peptides and other beneficial components (lyzozymes, secretory IgA, lactoferrin, growth factors, antioxidants, microbiota) protecting against infection and contibuting to healthy microbiome. | (73, 84) | Many benefits of human milk. Formula feeding might be associated with NEC|. However, existing studies provide inconclusive evidence that human milk fe eding p revents infection and mortality. |
Human milk feeding, esp. breast feeding, highly recommended for many reasons. |
| Probiotics & Prebiotics | Dysbiosis of skin and gut microbiome has been associated with increased risk of infection. | (83) | Beneficial effect of probiotic supplementation on LOS risk. However, optimal composition remains to be determined. No evidence of efficacy of prebiotics. |
AAP does not recommend routine and universal use in preterm infants (conflicting data on safety, efficacy and potential harm) |
| Lactoferrin | Iron-binding protein, present in high concentrations in human milk. Wide range of antimicrobial/ immuno- modulatory/anti-inflammatory properties. | (85, 87) | Low quality/no evidence that routine routine enteral lactoferrin reduces the incidence of infection. No effect on mortality or morbidity in preterm infants. | Not recommended. Future studies needed. |
| Glutamine | Insufficiently synthesized in conditions of metabolic sress. | (82) | No effect of preventive supplementation on mortality or major neonatal morbidities. | No evid ence for supplementation apart from clinical trials. |
| Zinc | Vital trace element for growth, cell differentiation and immune function (oxidative stress↓ and pro-inflammatory↓) Low zinc stores in preterm infants. | (89) | Enteral zinc moderately decreased mortality, while no effect on LOS incidence and common morbidities in preterm infants. | No recommendation for use. Future studies needed. |
| Future Therapies? | ||||
| Inflammasome Inhibitors (e.g., Anakinra, MCC950) | Specific blocking of pro-inflammatory IL-1 cytokine cascades initiated by multiprotein complexes of the innate immune system acknowledged as the “inflammasome”. | (70) | Evidence from animal models. Promising results in adult inflammatory diseases. | Research is ongoing. |
| Antimicrobial Proteins & Peptides (α-/β defensins, cathelicidins, bactericidal/permeability-i increasing protein (BPI)) | Antimcrobial peptides and proteins released by innate immune cells and mucosal surfaces contribute to mucosal immunity. Low levels in early life. |
(81) | Evidence of potential benefits in pediatric sepsis. | Research is ongoing. |