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

The takeaway

Researchers hypothesize that age-dependent Substance P levels in the brainstem explain why elderly patients get severe COVID-19 while children are largely spared, and propose NK-1R antagonists as potential treatment.

Already FDA-approved drugs available
NK-1R antagonists that block Substance P's receptor are already approved for other uses — if this hypothesis is correct, they could be rapidly repurposed for severe respiratory inflammation

What the researchers found

The authors hypothesize that age-dependent differences in Substance P (SP) levels explain why children rarely develop severe COVID-19 while elderly patients suffer the worst outcomes. Substance P is a neuropeptide produced in the brainstem's spinal trigeminal nucleus that drives inflammation in the airways. The authors propose that higher SP activity in elderly patients amplifies the inflammatory cascade in COVID-19, worsening respiratory illness.

Their central recommendation: NK-1R antagonists — drugs that block the Substance P receptor — should be urgently investigated as COVID-19 treatments. These drugs are already FDA-approved for other uses (notably as anti-nausea medications), making rapid repurposing feasible.

Why it matters

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.

The numbers in context

Substance P from spinal trigeminal nucleus · Age-dependent expression hypothesis · NK-1R antagonist proposed as intervention · Based on neuropathological observations from SIDS research

How the study worked

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.

Who was studied

Theoretical discussion of age-dependent COVID-19 severity (no direct patient enrollment)

What this study cannot tell us

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.

How to read the evidence

This is a hypothesis paper that presents a theoretical framework without new experimental data. While grounded in established neuropathological observations, the proposed mechanism involves multiple unverified steps. The evidence grade reflects the speculative nature of the work.

When this study was published

Published in early 2021 during the COVID-19 pandemic. While the immediate urgency has diminished, the underlying biology of Substance P in respiratory inflammation and the broader question of neuropeptide involvement in viral disease severity remain scientifically relevant.

The bigger picture

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.

Questions still open

Has anyone directly measured Substance P levels in COVID-19 patients stratified by age and disease severity?
Have NK-1R antagonists been tested in clinical trials for severe respiratory inflammation from COVID-19 or other infections?
Could age-related changes in Substance P also explain vulnerability to other respiratory viral infections beyond SARS-CoV-2?

Common questions

What is Substance P and how might it worsen COVID-19?

Substance P is a neuropeptide — a signaling molecule made by nerve cells — that triggers inflammation, particularly in the airways. The authors propose that elderly people produce more Substance P from their brainstem, which amplifies the inflammatory response when infected with COVID-19. In children, lower Substance P activity may explain their milder disease. This is a hypothesis — it hasn't been experimentally proven yet.

Could existing drugs block Substance P to treat severe respiratory infections?

Potentially. NK-1R antagonists are drugs that block the receptor Substance P uses to trigger inflammation. Some are already FDA-approved for preventing nausea (like aprepitant). If Substance P truly drives severe respiratory inflammation, these drugs could theoretically be repurposed. But clinical trials would be needed to confirm this works in practice.

Read the original research

Neuropathological explanation of minimal COVID-19 infection rate in newborns, infants and children - a mystery so far. New insight into the role of Substance P.

Journal of the neurological sciences, 420, 117276

View on PubMed ↗Publisher’s paper ↗

Citation

Mehboob, Riffat; Lavezzi, Anna Maria. (2021). Neuropathological explanation of minimal COVID-19 infection rate in newborns, infants and children - a mystery so far. New insight into the role of Substance P.. Journal of the neurological sciences, 420, 117276. https://doi.org/10.1016/j.jns.2020.117276