Improved smell function with increased nasal mucus sonic hedgehog in hyposmic patients after treatment with oral theophylline

Am J Otolaryngol. Mar-Apr 2017;38(2):143-147. doi: 10.1016/j.amjoto.2016.11.010. Epub 2016 Nov 23.


Purpose: We previously demonstrated the presence of sonic hedgehog (Shh) in nasal mucus in normal subjects and in patients with smell loss (hyposmia). Nasal mucus Shh levels were found significantly diminished in untreated hyposmic patients of multiple etiologies. Since treatment with oral theophylline has been previously associated with improvement in smell function we wished to study if such treatment increased nasal mucus Shh as well as improved smell function in patients with hyposmia.

Methods: Forty-four patients with hyposmia of several etiologies were evaluated for changes in hyposmia by subjective measurements of smell, taste and flavor perception and by olfactometry. Measurements of nasal mucus Shh were made in relationship to each set of sensory measurements. Patients were treated with oral theophylline at doses of 200-800mg for periods of 2-10months with sensory function, nasal mucus Shh and serum theophylline levels evaluated at these time intervals. Nasal mucus Shh measurements were made with a sensitive spectrophotometric ELISA assay and theophylline with a fluorometric assay.

Results: There was consistent, significant improvement in subjective responses in smell, taste and flavor perception and in olfactometry associated with increased nasal mucus Shh and serum theophylline after theophylline treatment.

Conclusions: Improvement in smell function and in nasal mucus Shh was positively correlated in a dose-response relationship after treatment with oral theophylline. Results are consistent with a successful role for theophylline in improvement of smell function in hyposmic patients of multiple etiologies associated with increased nasal mucus Shh which can act as a biochemical marker for smell function.

Keywords: Hyposmia; Nasal mucus; Olfaction; Phosphodiesterase inhibitors; Smell; Sonic hedgehog; Theophylline.

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Child
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Hedgehog Proteins / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Mucus / metabolism*
  • Olfaction Disorders / drug therapy*
  • Phosphodiesterase Inhibitors / administration & dosage
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Smell / drug effects*
  • Theophylline / administration & dosage
  • Theophylline / therapeutic use*
  • Treatment Outcome


  • Hedgehog Proteins
  • Phosphodiesterase Inhibitors
  • SHH protein, human
  • Theophylline