Could Substance P Explain Why Children Rarely Get Severe COVID-19?

This is a hypothesis paper drawing on the authors' neuropathological experience at the Lino Rossi Research Center in Milan, which studies unexpected infant death and SIDS. They combine observations about brainstem neuropeptide development with published COVID-19 epidemiological and clinical data to construct their theory about Substance P's role in age-dependent disease severity.

This hypothesis connects two well-established observations — children's resistance to severe COVID-19 and age-dependent changes in neuropeptide signaling — through the lens of Substance P biology. If correct, it points to an already-available drug class (NK-1R antagonists like aprepitant) as a potential treatment. The paper also highlights the broader role of neuropeptides in respiratory inflammation, relevant far beyond COVID-19.

Substance P is increasingly recognized as a major player in inflammatory diseases beyond its classic role in pain signaling. This hypothesis extends that understanding to COVID-19 and raises the broader question of whether neuropeptide-targeted therapies could modulate inflammatory responses in respiratory infections. The concept of repurposing NK-1R antagonists has generated interest across multiple inflammatory conditions.

This is a hypothesis paper — no experimental data is presented. The authors did not directly measure Substance P levels in children versus elderly patients with COVID-19. Many other factors contribute to age-dependent COVID-19 severity (immune maturation, ACE2 expression, comorbidities), and the SP hypothesis is one of several competing explanations. The causal chain from brainstem SP production to respiratory inflammation severity in COVID-19 involves multiple unverified steps.