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Empty Nose Syndrome

Complex MONDO:1060148 Nasal disorder Iatrogenic condition

Empty Nose Syndrome (ENS) is a debilitating iatrogenic condition that develops following surgical reduction or resection of the nasal turbinates, most commonly the inferior turbinates. Despite having objectively patent nasal airways, patients experience paradoxical nasal obstruction, dyspnea, nasal dryness, and crusting. The loss of turbinate tissue disrupts normal nasal airflow patterns, mucociliary clearance, and sensory feedback, resulting in a subjective sensation of suffocation. The condition is frequently associated with significant psychological morbidity including depression, anxiety, and sleep disturbance.

0
Mappings
0
Definitions
0
Inheritance
6
Pathophysiology
3
Histopathology
11
Phenotypes
0
Genes
3
Treatments
0
Subtypes
3
Differentials
3
Datasets
0
Trials
⚙

Pathophysiology

6
Turbinate tissue loss from surgical resection
Surgical reduction or total resection of the nasal turbinates, most commonly the inferior turbinates and sometimes the middle turbinates, removes the mucosal and bony tissue that normally modulates nasal airflow. This can result from turbinectomy, aggressive turbinoplasty, or submucosal resection performed for chronic nasal obstruction or rhinitis.
Nasal cavity respiratory epithelium epithelial cell link
Inferior nasal concha link Nasal cavity mucosa link
Show evidence (2 references)
PMID:25430954 SUPPORT Human Clinical
"Empty nose syndrome (ENS) is a rare, late complication of turbinate surgery."
Confirms ENS develops as a complication of turbinate surgery, establishing the iatrogenic surgical origin.
PMID:40461852 SUPPORT Human Clinical
"Empty nose syndrome (ENS) is a complex iatrogenic condition resulting from excessive inferior turbinate resection, leading to paradoxical nasal obstruction despite an objectively patent airway."
Confirms ENS as an iatrogenic condition specifically resulting from excessive inferior turbinate resection.
Disrupted nasal airflow dynamics
The turbinates normally create resistance and direct laminar airflow through the nasal cavity. Their removal results in abnormally wide nasal passages with turbulent airflow patterns and paradoxical redistribution of airflow away from the inferior meatus toward the middle meatus, reducing mucosal wall shear stress and sensory stimulation.
Nasal cavity link
Show evidence (2 references)
DOI:10.1002/alr.22350 PARTIAL Computational
"symptomatic ENS patients have paradoxical significantly less airflow in the inferior meatus"
CFD analysis demonstrates paradoxical redistribution of airflow away from the inferior meatus in ENS patients despite surgical enlargement of the nasal passages.
PMID:34630863 SUPPORT Human Clinical
"ENS pathogenesis is multifactorial and includes changes in laminar physiological airflow, disruption of mucosa functions and deficient neural sensation."
Confirms that altered laminar airflow is a key component of ENS pathogenesis alongside mucosal and neural factors.
Impaired mucociliary clearance
Turbinate mucosa is rich in goblet cells that produce the mucus blanket essential for mucociliary clearance. Surgical removal of turbinate tissue reduces goblet cell density and disrupts the mucociliary escalator, impairing particle trapping and pathogen removal. Histopathology shows goblet cell metaplasia, indicating mucosal remodeling that alters normal secretory function and mucociliary transport.
Nasal mucosa goblet cell link
Mucociliary clearance link ↓ DECREASED
Nasal cavity mucosa link
Show evidence (1 reference)
PMID:32125703 SUPPORT Human Clinical
"Additionally, a unique histological change called goblet cell metaplasia was found in the ENS group."
Identifies goblet cell metaplasia as a distinct histological feature of ENS, reflecting mucosal remodeling that disrupts normal goblet cell secretory function and mucociliary clearance.
Impaired nasal air conditioning
The nasal turbinates play a critical role in warming, humidifying, and filtering inspired air through their rich vascular supply and seromucinous glands. Surgical resection of turbinate tissue reduces the mucosal surface area and submucosal gland density available for conditioning inspired air, leading to mucosal dryness, crusting, and nasal discomfort. Histopathology demonstrates squamous metaplasia, submucosal fibrosis, and reduced submucosal gland number.
Nasal serous secreting cell link
Mucus secretion link ↓ DECREASED
Nasal cavity mucosa link
Show evidence (1 reference)
PMID:32125703 SUPPORT Human Clinical
"Patients with ENS presented significantly more squamous metaplasia, a higher rate of submucosal fibrosis, and a lower submucosal gland number grading."
Histopathological evidence directly demonstrating reduced submucosal glands and mucosal remodeling that impairs the capacity to warm and humidify inspired air.
Trigeminal neurosensory dysfunction
Loss of nasal airflow sensory feedback due to damage or downregulation of trigeminal cool thermoreceptors, particularly TRPM8 channels, in the remaining nasal mucosa. ENS patients demonstrate impaired menthol lateralization detection thresholds and significantly lower TRPM8 immunoexpression compared to controls, indicating peripheral neurosensory dysfunction that contributes to paradoxical obstruction.
Trigeminal sensory neuron link
Sensory perception of temperature stimulus link ↓ DECREASED
Trigeminal ganglion link Nasal cavity mucosa link
Show evidence (5 references)
PMID:32125703 SUPPORT Human Clinical
"The ENS group had a significantly lower expression level of TRPM8."
Direct immunohistochemical evidence of TRPM8 downregulation in ENS nasal mucosa, confirming peripheral neurosensory dysfunction.
DOI:10.1002/alr.22350 SUPPORT Computational
"a combination of distorted nasal aerodynamics and loss of mucosal sensory function may potentially lead to ENS symptomology."
Supports combined aerodynamic and sensory mechanisms as a plausible contributor, but wording in the source remains tentative.
PMID:31116142 PARTIAL Human Clinical
"new data suggest that impaired trigeminal nerve function may also play a role in the pathophysiology of the disease."
Review notes impaired trigeminal function as a possible mechanism, providing partial support.
+ 2 more references
Paradoxical nasal obstruction and dyspnea
The central clinical paradox of ENS: patients with wide-open nasal passages experience subjective nasal obstruction and air hunger. This results from the convergence of disrupted airflow dynamics and trigeminal neurosensory dysfunction, where inadequate mucosal cooling and mechanosensory stimulation are interpreted by the brain as inadequate ventilation. The sensation of suffocation causes significant distress and psychological morbidity.
Nasal cavity link
Show evidence (3 references)
PMID:34630863 SUPPORT Human Clinical
"The main feature of ENS is paradoxical nasal obstruction feeling despite objectively wide nasal airway."
Directly describes the paradoxical nature of ENS where patients experience obstruction despite patent airways.
PMID:25430954 SUPPORT Human Clinical
"The most common clinical symptoms are paradoxical nasal obstruction, nasal dryness and crusting, and a persistent feeling of dyspnea."
Review confirming paradoxical nasal obstruction and dyspnea as the most common clinical symptoms of ENS.
PMID:19328896 SUPPORT Human Clinical
"The problem with empty nose syndrome is probably not that it does not exist, it is that we cannot adequately explain its existence by what we currently understand about the nose."
Editorial acknowledging the reality of ENS as a clinical entity while highlighting the difficulty of explaining the paradoxical symptoms.
✶

Histopathology

3
Squamous metaplasia VERY_FREQUENT
Replacement of normal pseudostratified ciliated respiratory epithelium by stratified squamous epithelium in remnant turbinate tissue. This is significantly more prevalent in ENS patients than controls and reflects chronic airway remodeling from the altered nasal environment.
Show evidence (1 reference)
PMID:32125703 SUPPORT Human Clinical
"Patients with ENS presented significantly more squamous metaplasia, a higher rate of submucosal fibrosis, and a lower submucosal gland number grading."
Prospective case-control study demonstrating significantly increased squamous metaplasia in ENS nasal mucosa compared to controls.
Submucosal fibrosis VERY_FREQUENT
Fibrotic changes in the submucosa of remnant turbinate tissue with replacement of normal submucosal glands by fibrous tissue. ENS patients show a higher rate of submucosal fibrosis and reduced submucosal gland number compared to controls.
Show evidence (1 reference)
PMID:32125703 SUPPORT Human Clinical
"Patients with ENS presented significantly more squamous metaplasia, a higher rate of submucosal fibrosis, and a lower submucosal gland number grading."
Histopathological evidence of increased submucosal fibrosis and reduced submucosal gland density in ENS tissue.
Goblet cell metaplasia FREQUENT
A unique histological change found in ENS where goblet cells undergo metaplastic transformation. This finding is distinct to ENS and is not observed in control nasal tissue. The respiratory epithelium is mostly intact with preservation of ciliated cells and goblet cells, but the goblet cells show metaplastic changes.
Show evidence (2 references)
PMID:32125703 SUPPORT Human Clinical
"Additionally, a unique histological change called goblet cell metaplasia was found in the ENS group."
Identifies goblet cell metaplasia as a distinct and unique histological finding in ENS, potentially useful as a diagnostic marker.
PMID:32125703 SUPPORT Human Clinical
"The respiratory epitheliums of ENS were mostly intact with preservation of ciliated cells and goblet cells."
Characterizes the unique histological pattern where respiratory epithelium is preserved despite the goblet cell metaplasia and other remodeling changes.
⬡

Causal Graph

graph LR
    Impaired_mucociliary_clearance["Impaired mucociliary clearance"]
    Paradoxical_nasal_obstruction_and_dyspnea["Paradoxical nasal obstruction and dyspnea"]
    Turbinate_tissue_loss_from_surgical_resection["Turbinate tissue loss from surgical resection"]
    Impaired_nasal_air_conditioning["Impaired nasal air conditioning"]
    Trigeminal_neurosensory_dysfunction["Trigeminal neurosensory dysfunction"]
    Disrupted_nasal_airflow_dynamics["Disrupted nasal airflow dynamics"]

    Turbinate_tissue_loss_from_surgical_resection --> Disrupted_nasal_airflow_dynamics
    Turbinate_tissue_loss_from_surgical_resection --> Impaired_mucociliary_clearance
    Turbinate_tissue_loss_from_surgical_resection --> Impaired_nasal_air_conditioning
    Turbinate_tissue_loss_from_surgical_resection --> Trigeminal_neurosensory_dysfunction
    Disrupted_nasal_airflow_dynamics --> Paradoxical_nasal_obstruction_and_dyspnea
    Trigeminal_neurosensory_dysfunction --> Paradoxical_nasal_obstruction_and_dyspnea

    style Impaired_mucociliary_clearance fill:#dbeafe
    style Paradoxical_nasal_obstruction_and_dyspnea fill:#dbeafe
    style Turbinate_tissue_loss_from_surgical_resection fill:#dbeafe
    style Impaired_nasal_air_conditioning fill:#dbeafe
    style Trigeminal_neurosensory_dysfunction fill:#dbeafe
    style Disrupted_nasal_airflow_dynamics fill:#dbeafe
●

Phenotypes

11
Head and Neck(4) Nervous System(5) Respiratory(2)
Head and Neck 4
Paradoxical nasal obstruction VERY_FREQUENT Nasal congestion (HP:0001742)
The hallmark symptom of ENS. Patients report subjective nasal obstruction and inability to sense airflow despite objectively patent nasal passages on endoscopy and imaging.
Show evidence (2 references)
PMID:34630863 SUPPORT Human Clinical
"The main feature of ENS is paradoxical nasal obstruction feeling despite objectively wide nasal airway."
Directly describes paradoxical nasal obstruction as the main feature of ENS.
PMID:34665687 PARTIAL Human Clinical
"ENS patients demonstrated high symptom severity."
Supports high overall symptom burden, but does not specifically quantify paradoxical obstruction.
Nasal dryness VERY_FREQUENT Nasal dryness (HP:0033521)
Show evidence (2 references)
PMID:25430954 SUPPORT Human Clinical
"The most common clinical symptoms are paradoxical nasal obstruction, nasal dryness and crusting, and a persistent feeling of dyspnea."
Review identifying nasal dryness and crusting as among the most common clinical symptoms of ENS.
PMID:34630863 SUPPORT Human Clinical
"This leads to the development of ENS symptomatology such as dyspnea, nasal dryness, nasal burning, nasal obstruction, feeling of suffocation and even comorbid psychiatric disorders that significantly impairs life quality."
Confirms nasal dryness as a core ENS symptom arising from the multifactorial pathogenesis.
Abnormal nasal mucosa morphology VERY_FREQUENT Abnormal nasal mucosa morphology (HP:0000433)
Histopathological changes include squamous metaplasia, submucosal fibrosis, goblet cell metaplasia, reduced submucosal gland density, and reduced TRPM8 expression, while respiratory epithelium with ciliated cells is partially preserved.
Show evidence (3 references)
PMID:32125703 SUPPORT Human Clinical
"The nasal mucosa of ENS experienced some airway remodeling and thermoreceptors downregulation, which contribute to clinical symptoms."
Demonstrates distinct histopathological changes in ENS nasal mucosa including airway remodeling.
PMID:32125703 SUPPORT Human Clinical
"The respiratory epitheliums of ENS were mostly intact with preservation of ciliated cells and goblet cells."
Characterizes the unique histological pattern where respiratory epithelium is partially preserved despite other mucosal remodeling.
PMID:34665687 SUPPORT Human Clinical
"Turbinate histopathology in ENS showed a tissue-remodeling pattern."
Systematic review confirming tissue remodeling as a pathophysiologic theme in ENS.
Hyposmia OCCASIONAL Hyposmia (HP:0004409)
Subjective olfactory impairment is reported by ENS patients, though quantitative measures are often similar to non-ENS controls.
Show evidence (1 reference)
PMID:34665687 PARTIAL Human Clinical
"Subjective impairment was reported in ENS, but quantitative measures were similar to non-ENS patients."
Systematic review finding that subjective olfactory impairment is reported but objective quantitative measures show no significant difference from controls.
Nervous System 5
Headache FREQUENT Headache (HP:0002315)
Facial pain/pressure is a recognized symptom correlating with inferior turbinate volume loss, particularly anterior ITV reduction.
Show evidence (1 reference)
PMID:26692010 SUPPORT Human Clinical
"Facial pain was significantly correlated with smaller anterior ITV (P = 0.011)."
SNOT-25 data showing facial pain/pressure significantly correlates with reduced anterior inferior turbinate volume in ENS patients.
Depression VERY_FREQUENT Depression (HP:0000716)
Depression is very common in ENS patients, with meta-analysis showing a prevalence of 76.6% among ENS patients and significantly increased risk compared to chronic rhinosinusitis patients.
Show evidence (3 references)
PMID:40617870 SUPPORT Human Clinical
"Depression and anxiety are common among patients with ENS, with a possible increased prevalence of depression in patients with ENS compared to those with CRS."
Meta-analysis confirming high prevalence of depression in ENS patients, with prevalence significantly exceeding that in chronic rhinosinusitis.
PMID:34665687 SUPPORT Human Clinical
"Anxiety and depression including hyperventilation were reported in >50% of ENS patients and correlated with ENS symptom severity."
Systematic review confirming depression in over 50% of ENS patients with correlation to symptom severity.
PMID:35155779 PARTIAL Human Clinical
"Suicidal thoughts are frequently identified in patients with ENS."
Supports severe psychological burden in ENS, but only indirectly supports depression prevalence.
Anxiety VERY_FREQUENT Anxiety (HP:0000739)
Anxiety prevalence of 77.0% reported in meta-analysis, frequently accompanied by hyperventilation phenomena.
Show evidence (2 references)
PMID:40617870 SUPPORT Human Clinical
"Depression and anxiety are common among patients with ENS, with a possible increased prevalence of depression in patients with ENS compared to those with CRS."
Meta-analysis confirming high prevalence of anxiety in ENS patients.
PMID:34665687 PARTIAL Human Clinical
"There is evidence of high comorbid mental health disorders in ENS patients."
Supports psychiatric comorbidity broadly, but only partially supports anxiety specifically.
Sleep disturbance FREQUENT Sleep disturbance (HP:0002360)
Show evidence (2 references)
PMID:36306524 SUPPORT Human Clinical
"Patients with ENS experienced significantly impaired sleep quality and sleepiness."
Prospective study demonstrating significantly impaired sleep quality and daytime sleepiness in ENS patients compared to controls.
PMID:36306524 SUPPORT Human Clinical
"The severity of sleep dysfunction is associated with the severity of ENS symptoms."
Demonstrates that sleep dysfunction severity correlates with overall ENS symptom severity.
Suicidal ideation FREQUENT Suicidal ideation (HP:0031589)
Suicidal thoughts were identified in 23 of 62 (37%) ENS patients preoperatively in one prospective study, reducing to 4 postoperatively after nasal reconstruction.
Show evidence (2 references)
PMID:35155779 SUPPORT Human Clinical
"Suicidal thoughts were identified in 23 ENS patients preoperatively and in four patients postoperatively."
Prospective study demonstrating high prevalence of suicidal thoughts in ENS patients, with improvement after surgical reconstruction.
PMID:35155779 SUPPORT Human Clinical
"ENS patients with suicidal thoughts experienced significantly more severe symptoms, impaired quality of life, and psychological burden than those without suicidal thoughts."
Suicidal ideation correlates with more severe ENS symptoms and greater psychological burden.
Respiratory 2
Dyspnea VERY_FREQUENT Dyspnea (HP:0002094)
Patients describe a sensation of suffocation or air hunger despite adequate nasal patency. This is driven by loss of sensory feedback from destroyed nasal thermoreceptors.
Show evidence (2 references)
PMID:25430954 SUPPORT Human Clinical
"The most common clinical symptoms are paradoxical nasal obstruction, nasal dryness and crusting, and a persistent feeling of dyspnea."
Identifies persistent dyspnea as one of the most common clinical symptoms of ENS.
PMID:34630863 SUPPORT Human Clinical
"This leads to the development of ENS symptomatology such as dyspnea, nasal dryness, nasal burning, nasal obstruction, feeling of suffocation and even comorbid psychiatric disorders that significantly impairs life quality."
Lists dyspnea and suffocation among the core ENS symptoms.
Hyperventilation FREQUENT Hyperventilation (HP:0002883)
Hyperventilation phenomena reported in association with anxiety and depression in ENS patients, likely driven by the sensation of air hunger from impaired nasal thermoreceptor feedback.
Show evidence (1 reference)
PMID:34665687 SUPPORT Human Clinical
"Anxiety and depression including hyperventilation were reported in >50% of ENS patients and correlated with ENS symptom severity."
Identifies hyperventilation as occurring in association with anxiety and depression in ENS patients.
💊

Treatments

3
Turbinate implant surgery MAXO:0000004
Surgical implantation of biocompatible materials (such as Medpor, AlloDerm, or costal cartilage grafts) into the submucosal space of the lateral nasal wall to restore turbinate volume, redirect nasal airflow, and stimulate mucosal sensory receptors. This is the primary surgical treatment for refractory ENS.
Show evidence (4 references)
PMID:40461852 SUPPORT Human Clinical
"While surgical interventions demonstrate sustained improvements in patient quality of life, substantial heterogeneity across meta-analyses and overlapping primary data highlight the need for standardized protocols"
Meta-analysis of meta-analyses covering over 1500 cases confirms sustained quality of life improvements from surgical interventions, though evidence heterogeneity is noted.
PMID:37750541 SUPPORT Human Clinical
"These data and analysis suggest that performing inferior turbinate/meatus augmentation on ENS patients may improve not only nasal symptom scores but also accompanying psychological problems such as anxiety and depression."
Meta-analysis showing that turbinate augmentation improves both nasal symptoms and psychological comorbidities.
PMID:25430954 SUPPORT Human Clinical
"Surgical therapy should be reserved for refractory cases and may involve turbinate reconstruction, most commonly using implantable biomaterials."
Review recommending surgical reconstruction with implantable biomaterials for refractory ENS cases.
+ 1 more reference
Nasal moisturization and saline irrigation MAXO:0000950
Conservative first-line management with regular nasal saline irrigations, nasal moisturizing gels or sprays, and humidification to alleviate dryness and crusting.
Show evidence (2 references)
PMID:31116142 SUPPORT Human Clinical
"Nasal humidification, patient education, and treatment of possible concomitant medical conditions (e.g., depression) constitute first lines of treatment."
Identifies nasal humidification as a first-line treatment along with patient education and management of psychological comorbidities.
PMID:25430954 NO_EVIDENCE Human Clinical
"Medical therapies include mucosal humidification, irrigations, and emollients."
Review listing mucosal humidification, irrigations, and emollients as medical therapy options for ENS.
Platelet-rich plasma injection MAXO:0000004
Submucosal injection of platelet-rich plasma (PRP) into the nasal mucosa to promote tissue regeneration and restore mucosal function. This is an emerging treatment approach with case report-level evidence.
Show evidence (1 reference)
PMID:36630732 SUPPORT Human Clinical
"We present two cases of ENS treated by injection of PRP as a simple and less invasive method, and describe its efficacy with nasal endoscopy and subjective questionnaires."
Case report demonstrating PRP injection as a less invasive treatment option for ENS with documented symptomatic improvement.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Empty Nose Syndrome:

Atrophic rhinitis Not Yet Curated MONDO:0005659
Overlapping Features Primary atrophic rhinitis shares features of nasal dryness, crusting, and widened nasal cavity but occurs without a history of turbinate surgery. ENS is sometimes termed iatrogenic atrophic rhinitis, though the pathophysiology may differ.
Show evidence (2 references)
PMID:19328896 SUPPORT Human Clinical
"The result of empty nose syndrome or iatrogenic atrophic rhinitis as a consequence of turbinectomy remains a controversial topic that deserves further scrutiny."
Editorial discussing the relationship between ENS and iatrogenic atrophic rhinitis, noting the overlap and controversy.
PMID:32125703 SUPPORT Human Clinical
"The distinct histology of ENS included preserved respiratory epithelium and goblet cell metaplasia, accompanying with characteristics similar to atrophic rhinitis."
Histopathological study showing ENS has features similar to atrophic rhinitis but with distinct characteristics like preserved respiratory epithelium.
Chronic rhinosinusitis Not Yet Curated MONDO:0006031
Overlapping Features Chronic rhinosinusitis presents with nasal obstruction and may have psychological comorbidities, but is distinguished by mucosal inflammation, nasal polyps, or purulent discharge rather than absent turbinate tissue.
Show evidence (1 reference)
PMID:40617870 NO_EVIDENCE Human Clinical
"As patients with ENS often have mental health comorbidities, further research should investigate whether anxiety and depression are true sequelae of ENS or factors contributing to its development."
Snippet addresses psychiatric comorbidity uncertainty and does not directly support chronic rhinosinusitis differential features.
Allergic rhinitis Not Yet Curated MONDO:0011786
Overlapping Features Allergic rhinitis causes nasal obstruction and congestion but is characterized by allergic inflammation, eosinophilic infiltration, and response to antihistamines, without the paradoxical obstruction or turbinate tissue loss seen in ENS. Depression prevalence is significantly lower in allergic rhinitis compared to ENS.
Show evidence (1 reference)
PMID:31272211 PARTIAL Human Clinical
"The degree and severity of depression in patients with ENS was higher than in patients with CRS or AR."
Provides partial support by distinguishing ENS from allergic rhinitis via psychological burden, but not full differential pathophysiology.
📊

Related Datasets

3
Cell function and identity revealed by comparative scRNA-seq analysis in human nasal, bronchial and epididymis epithelia. [scRNA-Seq] geo:GSE191041
Single-cell RNA-seq characterization of human nasal epithelial cell populations including basal, secretory, goblet, and ciliated cells. Provides a reference atlas of the cell types present in normal nasal epithelium, relevant to understanding the cellular composition lost following turbinate resection in ENS.
human SINGLE CELL RNA SEQ n=7
nasal epithelial cell link
Conditions: normal human nasal epithelium normal human bronchial epithelium
PMID:35597096
No ENS-specific omics datasets exist. This reference atlas of normal human nasal epithelial cell types is relevant for understanding the cellular populations disrupted by turbinate surgery.
Single-cell RNA-seq reveals novel cell differentiation dynamics during human airway epithelium regeneration geo:GSE121600
Single-cell transcriptomic characterization of multiciliated, goblet, secretory, and basal cells during human airway epithelium regeneration. Includes nasal brushing and turbinate samples, with cross-species validation. Relevant to understanding mucociliary differentiation dynamics disrupted in ENS.
human SINGLE CELL RNA SEQ n=22
nasal mucosa goblet cell link
Conditions: human airway epithelium regeneration fresh nasal brushing
PMID:31558434
Characterizes goblet cell and multiciliated cell differentiation trajectories relevant to the mucociliary dysfunction seen in ENS.
Isolation of novel multipotent neural crest-derived stem cells from adult human inferior turbinate geo:GSE30596
Expression profiling of neural crest-derived stem cells isolated from adult human inferior turbinate respiratory epithelium. These stem cells express neural crest markers and demonstrate multipotent differentiation capacity. Relevant to ENS as it characterizes progenitor cells present in the turbinate tissue that is resected.
human MICROARRAY n=12 Illumina HumanHT-12 v4
inferior turbinate tissue
Conditions: inferior turbinate stem cells control
PMID:22128806
Characterizes stem cell populations in the human inferior turbinate, the tissue most commonly resected in surgeries that lead to ENS.
{ }

Source YAML

click to show 
name: Empty Nose Syndrome
creation_date: '2026-02-13T17:09:37Z'
updated_date: '2026-02-17T21:53:14Z'
synonyms:
- ENS
- Empty nose syndrome
- Iatrogenic turbinate atrophy syndrome
category: Complex
description: >-
  Empty Nose Syndrome (ENS) is a debilitating iatrogenic condition that develops
  following surgical reduction or resection of the nasal turbinates, most commonly
  the inferior turbinates. Despite having objectively patent nasal airways, patients
  experience paradoxical nasal obstruction, dyspnea, nasal dryness, and crusting.
  The loss of turbinate tissue disrupts normal nasal airflow patterns, mucociliary
  clearance, and sensory feedback, resulting in a subjective sensation of
  suffocation. The condition is frequently associated with significant psychological
  morbidity including depression, anxiety, and sleep disturbance.
disease_term:
  term:
    id: MONDO:1060148
    label: empty nose syndrome
  preferred_term: Empty Nose Syndrome
parents:
- Nasal disorder
- Iatrogenic condition
pathophysiology:
- name: Turbinate tissue loss from surgical resection
  description: >-
    Surgical reduction or total resection of the nasal turbinates, most commonly
    the inferior turbinates and sometimes the middle turbinates, removes the
    mucosal and bony tissue that normally modulates nasal airflow. This can
    result from turbinectomy, aggressive turbinoplasty, or submucosal
    resection performed for chronic nasal obstruction or rhinitis.
  cell_types:
  - preferred_term: Nasal cavity respiratory epithelium epithelial cell
    term:
      id: CL:2000094
      label: nasal cavity respiratory epithelium epithelial cell of
        viscerocranial mucosa
  locations:
  - preferred_term: Inferior nasal concha
    term:
      id: UBERON:0005922
      label: inferior nasal concha
  - preferred_term: Nasal cavity mucosa
    term:
      id: UBERON:0001826
      label: nasal cavity mucosa
  evidence:
  - reference: PMID:25430954
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Empty nose syndrome (ENS) is a rare, late complication of turbinate surgery.
    explanation: >-
      Confirms ENS develops as a complication of turbinate surgery, establishing
      the iatrogenic surgical origin.
  - reference: PMID:40461852
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Empty nose syndrome (ENS) is a complex iatrogenic condition resulting from
      excessive inferior turbinate resection, leading to paradoxical nasal
      obstruction despite an objectively patent airway.
    explanation: >-
      Confirms ENS as an iatrogenic condition specifically resulting from
      excessive inferior turbinate resection.
  downstream:
  - target: Disrupted nasal airflow dynamics
    description: >-
      Loss of turbinate tissue eliminates the structures that direct and
      regulate laminar airflow through the nasal cavity.
  - target: Impaired mucociliary clearance
    description: >-
      Removal of turbinate mucosa reduces goblet cell density and disrupts
      the mucus blanket essential for mucociliary transport.
  - target: Impaired nasal air conditioning
    description: >-
      Loss of seromucinous glands and mucosal surface area reduces the
      ability to warm, humidify, and filter inspired air.
  - target: Trigeminal neurosensory dysfunction
    description: >-
      Surgical resection destroys or damages trigeminal sensory nerve fibers
      and TRPM8-expressing cool thermoreceptors in the turbinate mucosa.
- name: Disrupted nasal airflow dynamics
  description: >-
    The turbinates normally create resistance and direct laminar airflow through
    the nasal cavity. Their removal results in abnormally wide nasal passages
    with turbulent airflow patterns and paradoxical redistribution of airflow
    away from the inferior meatus toward the middle meatus, reducing mucosal
    wall shear stress and sensory stimulation.
  locations:
  - preferred_term: Nasal cavity
    term:
      id: UBERON:0001707
      label: nasal cavity
  evidence:
  - reference: DOI:10.1002/alr.22350
    supports: PARTIAL
    evidence_source: COMPUTATIONAL
    snippet: >-
      symptomatic ENS patients have paradoxical significantly less airflow in the
      inferior meatus
    explanation: >-
      CFD analysis demonstrates paradoxical redistribution of airflow away from
      the inferior meatus in ENS patients despite surgical enlargement of the
      nasal passages.
  - reference: PMID:34630863
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ENS pathogenesis is multifactorial and includes changes in laminar
      physiological airflow, disruption of mucosa functions and deficient
      neural sensation.
    explanation: >-
      Confirms that altered laminar airflow is a key component of ENS
      pathogenesis alongside mucosal and neural factors.
  downstream:
  - target: Paradoxical nasal obstruction and dyspnea
    description: >-
      Inadequate sensory feedback from nasal airflow receptors generates a
      perception of obstruction and suffocation despite patent airways.
- name: Impaired mucociliary clearance
  description: >-
    Turbinate mucosa is rich in goblet cells that produce the mucus blanket
    essential for mucociliary clearance. Surgical removal of turbinate tissue
    reduces goblet cell density and disrupts the mucociliary escalator,
    impairing particle trapping and pathogen removal. Histopathology shows
    goblet cell metaplasia, indicating mucosal remodeling that alters normal
    secretory function and mucociliary transport.
  cell_types:
  - preferred_term: Nasal mucosa goblet cell
    term:
      id: CL:0002480
      label: nasal mucosa goblet cell
  biological_processes:
  - preferred_term: Mucociliary clearance
    modifier: DECREASED
    term:
      id: GO:0120197
      label: mucociliary clearance
  locations:
  - preferred_term: Nasal cavity mucosa
    term:
      id: UBERON:0001826
      label: nasal cavity mucosa
  evidence:
  - reference: PMID:32125703
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, a unique histological change called goblet cell metaplasia
      was found in the ENS group.
    explanation: >-
      Identifies goblet cell metaplasia as a distinct histological feature
      of ENS, reflecting mucosal remodeling that disrupts normal goblet cell
      secretory function and mucociliary clearance.
- name: Impaired nasal air conditioning
  description: >-
    The nasal turbinates play a critical role in warming, humidifying, and
    filtering inspired air through their rich vascular supply and seromucinous
    glands. Surgical resection of turbinate tissue reduces the mucosal surface
    area and submucosal gland density available for conditioning inspired air,
    leading to mucosal dryness, crusting, and nasal discomfort. Histopathology
    demonstrates squamous metaplasia, submucosal fibrosis, and reduced
    submucosal gland number.
  cell_types:
  - preferred_term: Nasal serous secreting cell
    term:
      id: CL:4042016
      label: nasal serous secreting cell
  biological_processes:
  - preferred_term: Mucus secretion
    modifier: DECREASED
    term:
      id: GO:0070254
      label: mucus secretion
  locations:
  - preferred_term: Nasal cavity mucosa
    term:
      id: UBERON:0001826
      label: nasal cavity mucosa
  evidence:
  - reference: PMID:32125703
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with ENS presented significantly more squamous metaplasia, a
      higher rate of submucosal fibrosis, and a lower submucosal gland number
      grading.
    explanation: >-
      Histopathological evidence directly demonstrating reduced submucosal
      glands and mucosal remodeling that impairs the capacity to warm and
      humidify inspired air.
- name: Trigeminal neurosensory dysfunction
  description: >-
    Loss of nasal airflow sensory feedback due to damage or downregulation
    of trigeminal cool thermoreceptors, particularly TRPM8 channels, in the
    remaining nasal mucosa. ENS patients demonstrate impaired menthol
    lateralization detection thresholds and significantly lower TRPM8
    immunoexpression compared to controls, indicating peripheral neurosensory
    dysfunction that contributes to paradoxical obstruction.
  cell_types:
  - preferred_term: Trigeminal sensory neuron
    term:
      id: CL:4023170
      label: trigeminal sensory neuron
  biological_processes:
  - preferred_term: Sensory perception of temperature stimulus
    modifier: DECREASED
    term:
      id: GO:0050951
      label: sensory perception of temperature stimulus
  locations:
  - preferred_term: Trigeminal ganglion
    term:
      id: UBERON:0001675
      label: trigeminal ganglion
  - preferred_term: Nasal cavity mucosa
    term:
      id: UBERON:0001826
      label: nasal cavity mucosa
  evidence:
  - reference: PMID:32125703
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ENS group had a significantly lower expression level of TRPM8.
    explanation: >-
      Direct immunohistochemical evidence of TRPM8 downregulation in ENS
      nasal mucosa, confirming peripheral neurosensory dysfunction.
  - reference: DOI:10.1002/alr.22350
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      a combination of distorted nasal aerodynamics and loss of mucosal sensory
      function may potentially lead to ENS symptomology.
    explanation: >-
      Supports combined aerodynamic and sensory mechanisms as a plausible contributor,
      but wording in the source remains tentative.
  - reference: PMID:31116142
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      new data suggest that impaired trigeminal nerve function may also play
      a role in the pathophysiology of the disease.
    explanation: >-
      Review notes impaired trigeminal function as a possible mechanism, providing
      partial support.
  - reference: PMID:24978195
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aberrations in neurosensory systems from improper healing may play a
      major role in the abnormal sensations ENS patients experience.
    explanation: >-
      Hypothesis-level review statement provides partial support for neurosensory
      contribution.
  - reference: PMID:34665687
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An abnormal trigeminal-thermoreceptor response may be present in some
      patients.
    explanation: >-
      Systematic review indicates abnormal trigeminal-thermoreceptor response in some
      patients, partially supporting this claim.
  downstream:
  - target: Paradoxical nasal obstruction and dyspnea
    description: >-
      Reduced TRPM8-mediated cool sensing leads the brain to misinterpret
      adequate airflow as insufficient ventilation.
- name: Paradoxical nasal obstruction and dyspnea
  description: >-
    The central clinical paradox of ENS: patients with wide-open nasal passages
    experience subjective nasal obstruction and air hunger. This results from
    the convergence of disrupted airflow dynamics and trigeminal neurosensory
    dysfunction, where inadequate mucosal cooling and mechanosensory
    stimulation are interpreted by the brain as inadequate ventilation.
    The sensation of suffocation causes significant distress and
    psychological morbidity.
  locations:
  - preferred_term: Nasal cavity
    term:
      id: UBERON:0001707
      label: nasal cavity
  evidence:
  - reference: PMID:34630863
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main feature of ENS is paradoxical nasal obstruction feeling despite
      objectively wide nasal airway.
    explanation: >-
      Directly describes the paradoxical nature of ENS where patients
      experience obstruction despite patent airways.
  - reference: PMID:25430954
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common clinical symptoms are paradoxical nasal obstruction, nasal
      dryness and crusting, and a persistent feeling of dyspnea.
    explanation: >-
      Review confirming paradoxical nasal obstruction and dyspnea as the
      most common clinical symptoms of ENS.
  - reference: PMID:19328896
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The problem with empty nose syndrome is probably not that it does not
      exist, it is that we cannot adequately explain its existence by what we
      currently understand about the nose.
    explanation: >-
      Editorial acknowledging the reality of ENS as a clinical entity while
      highlighting the difficulty of explaining the paradoxical symptoms.
phenotypes:
- name: Paradoxical nasal obstruction
  category: Otolaryngologic
  frequency: VERY_FREQUENT
  notes: >-
    The hallmark symptom of ENS. Patients report subjective nasal obstruction
    and inability to sense airflow despite objectively patent nasal passages
    on endoscopy and imaging.
  phenotype_term:
    preferred_term: Nasal congestion
    term:
      id: HP:0001742
      label: Nasal congestion
    located_in:
      preferred_term: Nasal cavity
      term:
        id: UBERON:0001707
        label: nasal cavity
  evidence:
  - reference: PMID:34630863
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main feature of ENS is paradoxical nasal obstruction feeling despite
      objectively wide nasal airway.
    explanation: >-
      Directly describes paradoxical nasal obstruction as the main feature
      of ENS.
  - reference: PMID:34665687
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ENS patients demonstrated high symptom severity.
    explanation: >-
      Supports high overall symptom burden, but does not specifically quantify paradoxical
      obstruction.
- name: Nasal dryness
  category: Otolaryngologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Nasal dryness
    term:
      id: HP:0033521
      label: Nasal dryness
  evidence:
  - reference: PMID:25430954
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common clinical symptoms are paradoxical nasal obstruction, nasal
      dryness and crusting, and a persistent feeling of dyspnea.
    explanation: >-
      Review identifying nasal dryness and crusting as among the most common
      clinical symptoms of ENS.
  - reference: PMID:34630863
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This leads to the development of ENS symptomatology such as dyspnea,
      nasal dryness, nasal burning, nasal obstruction, feeling of suffocation
      and even comorbid psychiatric disorders that significantly impairs life
      quality.
    explanation: >-
      Confirms nasal dryness as a core ENS symptom arising from the
      multifactorial pathogenesis.
- name: Dyspnea
  category: Respiratory
  frequency: VERY_FREQUENT
  notes: >-
    Patients describe a sensation of suffocation or air hunger despite
    adequate nasal patency. This is driven by loss of sensory feedback
    from destroyed nasal thermoreceptors.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:25430954
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common clinical symptoms are paradoxical nasal obstruction, nasal
      dryness and crusting, and a persistent feeling of dyspnea.
    explanation: >-
      Identifies persistent dyspnea as one of the most common clinical
      symptoms of ENS.
  - reference: PMID:34630863
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This leads to the development of ENS symptomatology such as dyspnea,
      nasal dryness, nasal burning, nasal obstruction, feeling of suffocation
      and even comorbid psychiatric disorders that significantly impairs life
      quality.
    explanation: >-
      Lists dyspnea and suffocation among the core ENS symptoms.
- name: Abnormal nasal mucosa morphology
  category: Otolaryngologic
  frequency: VERY_FREQUENT
  notes: >-
    Histopathological changes include squamous metaplasia, submucosal fibrosis,
    goblet cell metaplasia, reduced submucosal gland density, and reduced
    TRPM8 expression, while respiratory epithelium with ciliated cells is
    partially preserved.
  phenotype_term:
    preferred_term: Abnormal nasal mucosa morphology
    term:
      id: HP:0000433
      label: Abnormal nasal mucosa morphology
    located_in:
      preferred_term: Nasal cavity mucosa
      term:
        id: UBERON:0001826
        label: nasal cavity mucosa
  evidence:
  - reference: PMID:32125703
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The nasal mucosa of ENS experienced some airway remodeling and
      thermoreceptors downregulation, which contribute to clinical symptoms.
    explanation: >-
      Demonstrates distinct histopathological changes in ENS nasal mucosa
      including airway remodeling.
  - reference: PMID:32125703
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The respiratory epitheliums of ENS were mostly intact with preservation
      of ciliated cells and goblet cells.
    explanation: >-
      Characterizes the unique histological pattern where respiratory
      epithelium is partially preserved despite other mucosal remodeling.
  - reference: PMID:34665687
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Turbinate histopathology in ENS showed a tissue-remodeling pattern.
    explanation: >-
      Systematic review confirming tissue remodeling as a pathophysiologic
      theme in ENS.
- name: Headache
  category: Neurologic
  frequency: FREQUENT
  notes: >-
    Facial pain/pressure is a recognized symptom correlating with inferior
    turbinate volume loss, particularly anterior ITV reduction.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:26692010
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial pain was significantly correlated with smaller anterior ITV
      (P = 0.011).
    explanation: >-
      SNOT-25 data showing facial pain/pressure significantly correlates with
      reduced anterior inferior turbinate volume in ENS patients.
- name: Hyposmia
  category: Otolaryngologic
  frequency: OCCASIONAL
  notes: >-
    Subjective olfactory impairment is reported by ENS patients, though
    quantitative measures are often similar to non-ENS controls.
  phenotype_term:
    preferred_term: Hyposmia
    term:
      id: HP:0004409
      label: Hyposmia
    located_in:
      preferred_term: Nasal cavity
      term:
        id: UBERON:0001707
        label: nasal cavity
  evidence:
  - reference: PMID:34665687
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subjective impairment was reported in ENS, but quantitative measures
      were similar to non-ENS patients.
    explanation: >-
      Systematic review finding that subjective olfactory impairment is
      reported but objective quantitative measures show no significant
      difference from controls.
- name: Depression
  category: Psychiatric
  frequency: VERY_FREQUENT
  notes: >-
    Depression is very common in ENS patients, with meta-analysis showing
    a prevalence of 76.6% among ENS patients and significantly increased
    risk compared to chronic rhinosinusitis patients.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:40617870
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Depression and anxiety are common among patients with ENS, with a
      possible increased prevalence of depression in patients with ENS
      compared to those with CRS.
    explanation: >-
      Meta-analysis confirming high prevalence of depression in ENS patients,
      with prevalence significantly exceeding that in chronic rhinosinusitis.
  - reference: PMID:34665687
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anxiety and depression including hyperventilation were reported in >50%
      of ENS patients and correlated with ENS symptom severity.
    explanation: >-
      Systematic review confirming depression in over 50% of ENS patients
      with correlation to symptom severity.
  - reference: PMID:35155779
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Suicidal thoughts are frequently identified in patients with ENS.
    explanation: >-
      Supports severe psychological burden in ENS, but only indirectly supports depression
      prevalence.
- name: Anxiety
  category: Psychiatric
  frequency: VERY_FREQUENT
  notes: >-
    Anxiety prevalence of 77.0% reported in meta-analysis, frequently
    accompanied by hyperventilation phenomena.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:40617870
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Depression and anxiety are common among patients with ENS, with a
      possible increased prevalence of depression in patients with ENS
      compared to those with CRS.
    explanation: >-
      Meta-analysis confirming high prevalence of anxiety in ENS patients.
  - reference: PMID:34665687
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is evidence of high comorbid mental health disorders in ENS
      patients.
    explanation: >-
      Supports psychiatric comorbidity broadly, but only partially supports anxiety
      specifically.
- name: Hyperventilation
  category: Respiratory
  frequency: FREQUENT
  notes: >-
    Hyperventilation phenomena reported in association with anxiety and
    depression in ENS patients, likely driven by the sensation of air
    hunger from impaired nasal thermoreceptor feedback.
  phenotype_term:
    preferred_term: Hyperventilation
    term:
      id: HP:0002883
      label: Hyperventilation
  evidence:
  - reference: PMID:34665687
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anxiety and depression including hyperventilation were reported in >50%
      of ENS patients and correlated with ENS symptom severity.
    explanation: >-
      Identifies hyperventilation as occurring in association with anxiety
      and depression in ENS patients.
- name: Sleep disturbance
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:36306524
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with ENS experienced significantly impaired sleep quality
      and sleepiness.
    explanation: >-
      Prospective study demonstrating significantly impaired sleep quality
      and daytime sleepiness in ENS patients compared to controls.
  - reference: PMID:36306524
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The severity of sleep dysfunction is associated with the severity of
      ENS symptoms.
    explanation: >-
      Demonstrates that sleep dysfunction severity correlates with overall
      ENS symptom severity.
- name: Suicidal ideation
  category: Psychiatric
  frequency: FREQUENT
  notes: >-
    Suicidal thoughts were identified in 23 of 62 (37%) ENS patients
    preoperatively in one prospective study, reducing to 4 postoperatively
    after nasal reconstruction.
  phenotype_term:
    preferred_term: Suicidal ideation
    term:
      id: HP:0031589
      label: Suicidal ideation
  evidence:
  - reference: PMID:35155779
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Suicidal thoughts were identified in 23 ENS patients preoperatively and
      in four patients postoperatively.
    explanation: >-
      Prospective study demonstrating high prevalence of suicidal thoughts
      in ENS patients, with improvement after surgical reconstruction.
  - reference: PMID:35155779
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ENS patients with suicidal thoughts experienced significantly more
      severe symptoms, impaired quality of life, and psychological burden
      than those without suicidal thoughts.
    explanation: >-
      Suicidal ideation correlates with more severe ENS symptoms and
      greater psychological burden.
treatments:
- name: Turbinate implant surgery
  description: >-
    Surgical implantation of biocompatible materials (such as Medpor,
    AlloDerm, or costal cartilage grafts) into the submucosal space of the
    lateral nasal wall to restore turbinate volume, redirect nasal airflow,
    and stimulate mucosal sensory receptors. This is the primary surgical
    treatment for refractory ENS.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:40461852
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While surgical interventions demonstrate sustained improvements in
      patient quality of life, substantial heterogeneity across meta-analyses
      and overlapping primary data highlight the need for standardized
      protocols
    explanation: >-
      Meta-analysis of meta-analyses covering over 1500 cases confirms
      sustained quality of life improvements from surgical interventions,
      though evidence heterogeneity is noted.
  - reference: PMID:37750541
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data and analysis suggest that performing inferior turbinate/meatus
      augmentation on ENS patients may improve not only nasal symptom scores
      but also accompanying psychological problems such as anxiety and
      depression.
    explanation: >-
      Meta-analysis showing that turbinate augmentation improves both nasal
      symptoms and psychological comorbidities.
  - reference: PMID:25430954
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical therapy should be reserved for refractory cases and may involve
      turbinate reconstruction, most commonly using implantable biomaterials.
    explanation: >-
      Review recommending surgical reconstruction with implantable
      biomaterials for refractory ENS cases.
  - reference: PMID:31116142
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there has been a marked increase in surgical treatment strategies to
      reconstitute turbinate volume with various implant materials.
    explanation: >-
      Documents increased use of implant strategies, but does not directly establish
      treatment efficacy.
- name: Nasal moisturization and saline irrigation
  description: >-
    Conservative first-line management with regular nasal saline irrigations,
    nasal moisturizing gels or sprays, and humidification to alleviate dryness
    and crusting.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:31116142
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nasal humidification, patient education, and treatment of possible
      concomitant medical conditions (e.g., depression) constitute first lines
      of treatment.
    explanation: >-
      Identifies nasal humidification as a first-line treatment along with
      patient education and management of psychological comorbidities.
  - reference: PMID:25430954
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Medical therapies include mucosal humidification, irrigations, and
      emollients.
    explanation: >-
      Review listing mucosal humidification, irrigations, and emollients
      as medical therapy options for ENS.
- name: Platelet-rich plasma injection
  description: >-
    Submucosal injection of platelet-rich plasma (PRP) into the nasal mucosa
    to promote tissue regeneration and restore mucosal function. This is an
    emerging treatment approach with case report-level evidence.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:36630732
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present two cases of ENS treated by injection of PRP as a simple and
      less invasive method, and describe its efficacy with nasal endoscopy and
      subjective questionnaires.
    explanation: >-
      Case report demonstrating PRP injection as a less invasive treatment
      option for ENS with documented symptomatic improvement.
diagnosis:
- name: Cotton test
  description: >-
    Placement of a moistened cotton pledget on the lateral nasal wall at the
    site of the absent inferior or middle turbinate. Improvement in subjective
    nasal breathing with the cotton in place supports the diagnosis of ENS.
    This is a key diagnostic maneuver specific to ENS.
  diagnosis_term:
    preferred_term: physical examination
    term:
      id: MAXO:0000527
      label: physical examination
  evidence:
  - reference: PMID:31116142
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The newly validated empty nose syndrome 6 item questionnaires and Cotton
      test are steps forward to standardize the diagnosis of ENS.
    explanation: >-
      Identifies the Cotton test as a newly validated diagnostic tool that
      helps standardize ENS diagnosis.
  - reference: PMID:34665687
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cotton placement in the airway improved ENS symptoms.
    explanation: >-
      Systematic review confirming that cotton placement in the airway
      improves ENS symptoms, supporting its diagnostic utility.
- name: Empty Nose Syndrome 6-Item Questionnaire (ENS6Q)
  description: >-
    A validated patient-reported outcome measure specifically designed for
    ENS diagnosis and symptom monitoring. A score of 11 or higher on the
    ENS6Q supports the diagnosis of ENS.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  evidence:
  - reference: PMID:31116142
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The newly validated empty nose syndrome 6 item questionnaires and Cotton
      test are steps forward to standardize the diagnosis of ENS.
    explanation: >-
      Identifies the ENS6Q as a validated diagnostic questionnaire for
      standardizing ENS diagnosis.
  - reference: PMID:37750541
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By reference to the minimal clinically important difference of the
      ENS6Q (6.25), inferior turbinate/meatus augmentation relieved the nasal
      symptoms of ENS in the long term.
    explanation: >-
      Demonstrates the ENS6Q's utility in measuring treatment response,
      with a defined minimal clinically important difference.
- name: Nasal endoscopy
  description: >-
    Direct visualization of the nasal cavity demonstrating absent or severely
    reduced turbinate tissue with widened nasal passages, mucosal dryness,
    and crusting despite patient complaints of obstruction.
  diagnosis_term:
    preferred_term: nasal endoscopy
    term:
      id: MAXO:0035089
      label: nasal endoscopy
  evidence:
  - reference: PMID:25430954
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Little is known about the pathogenesis of ENS, though it is speculated
      that anatomical changes leading to alterations in local environment,
      disruption of mucosal cooling, and disruption of neurosensory mechanisms
      are strongly implicated.
    explanation: >-
      Snippet discusses pathogenesis generally and does not directly support nasal
      endoscopy as a diagnostic method.
- name: Computed tomography of the sinuses
  description: >-
    CT imaging demonstrating reduced or absent turbinate tissue with widely
    patent nasal passages, confirming the post-surgical anatomical changes.
    CT-based computational fluid dynamics can further characterize abnormal
    airflow patterns.
  diagnosis_term:
    preferred_term: computed tomography procedure
    term:
      id: MAXO:0000571
      label: computed tomography procedure
  evidence:
  - reference: PMID:38520707
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ITV was obtained from finely cut (1-mm-thick slices) sino-nasal
      computed tomography scan images and analyzed using ImageJ.
    explanation: >-
      Demonstrates the use of fine-cut CT imaging to quantify remnant inferior
      turbinate volume and morphology in ENS patients, establishing CT as a
      key objective assessment tool.
  - reference: PMID:26692010
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ENS group presented with a significantly smaller inferior turbinate
      volume than the control group (P < 0.001).
    explanation: >-
      CT volumetric analysis demonstrating significantly reduced inferior
      turbinate volume in ENS patients compared to controls, confirming the
      diagnostic utility of CT imaging.
- name: Menthol lateralization detection test
  description: >-
    Assessment of trigeminal chemosensory function by testing the patient's
    ability to lateralize a menthol stimulus applied to one nostril. ENS
    patients demonstrate impaired menthol detection thresholds compared to
    controls, reflecting damage to TRPM8-expressing nasal thermoreceptors.
  diagnosis_term:
    preferred_term: diagnostic procedure of respiratory system
    term:
      id: MAXO:0001408
      label: diagnostic procedure of respiratory system
  evidence:
  - reference: PMID:34665687
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The menthol detection test was impaired in ENS, and cotton placement in
      the airway improved ENS symptoms.
    explanation: >-
      Systematic review identifying impaired menthol detection as a
      diagnostic finding in ENS, reflecting trigeminal-thermoreceptor
      dysfunction.
- name: Inferior turbinate biopsy with TRPM8 immunohistochemistry
  description: >-
    Biopsy of remnant inferior turbinate tissue with immunohistochemical
    staining for TRPM8 (transient receptor potential melastatin 8). ENS
    patients show significantly lower TRPM8 expression compared to controls,
    providing an objective tissue-level marker. Biopsy also reveals distinct
    histopathological changes including squamous metaplasia, goblet cell
    metaplasia, and submucosal fibrosis.
  diagnosis_term:
    preferred_term: biopsy of head
    term:
      id: MAXO:0000326
      label: biopsy of head
  evidence:
  - reference: PMID:32125703
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ENS group had a significantly lower expression level of TRPM8.
    explanation: >-
      Immunohistochemical evidence showing TRPM8 downregulation in ENS
      nasal mucosa, supporting its use as a diagnostic tissue marker.
  - reference: PMID:32125703
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biopsy of the inferior turbinate may help diagnose ENS.
    explanation: >-
      The study authors explicitly recommend turbinate biopsy as a
      diagnostic adjunct for ENS based on the distinct histological
      and immunohistochemical findings.
histopathology:
- name: Squamous metaplasia
  description: >-
    Replacement of normal pseudostratified ciliated respiratory epithelium
    by stratified squamous epithelium in remnant turbinate tissue. This
    is significantly more prevalent in ENS patients than controls and
    reflects chronic airway remodeling from the altered nasal environment.
  finding_term:
    preferred_term: Squamous metaplasia
    term:
      id: NCIT:C3237
      label: Squamous Metaplasia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32125703
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with ENS presented significantly more squamous metaplasia, a
      higher rate of submucosal fibrosis, and a lower submucosal gland number
      grading.
    explanation: >-
      Prospective case-control study demonstrating significantly increased
      squamous metaplasia in ENS nasal mucosa compared to controls.
- name: Submucosal fibrosis
  description: >-
    Fibrotic changes in the submucosa of remnant turbinate tissue with
    replacement of normal submucosal glands by fibrous tissue. ENS patients
    show a higher rate of submucosal fibrosis and reduced submucosal gland
    number compared to controls.
  finding_term:
    preferred_term: Fibrosis
    term:
      id: NCIT:C3044
      label: Fibrosis
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32125703
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with ENS presented significantly more squamous metaplasia, a
      higher rate of submucosal fibrosis, and a lower submucosal gland number
      grading.
    explanation: >-
      Histopathological evidence of increased submucosal fibrosis and
      reduced submucosal gland density in ENS tissue.
- name: Goblet cell metaplasia
  description: >-
    A unique histological change found in ENS where goblet cells undergo
    metaplastic transformation. This finding is distinct to ENS and is not
    observed in control nasal tissue. The respiratory epithelium is mostly
    intact with preservation of ciliated cells and goblet cells, but the
    goblet cells show metaplastic changes.
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:32125703
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, a unique histological change called goblet cell metaplasia
      was found in the ENS group.
    explanation: >-
      Identifies goblet cell metaplasia as a distinct and unique
      histological finding in ENS, potentially useful as a diagnostic
      marker.
  - reference: PMID:32125703
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The respiratory epitheliums of ENS were mostly intact with preservation
      of ciliated cells and goblet cells.
    explanation: >-
      Characterizes the unique histological pattern where respiratory
      epithelium is preserved despite the goblet cell metaplasia and other
      remodeling changes.
differential_diagnoses:
- name: Atrophic rhinitis
  description: >-
    Primary atrophic rhinitis shares features of nasal dryness, crusting,
    and widened nasal cavity but occurs without a history of turbinate surgery.
    ENS is sometimes termed iatrogenic atrophic rhinitis, though the
    pathophysiology may differ.
  disease_term:
    term:
      id: MONDO:0005659
      label: atrophic rhinitis
    preferred_term: Atrophic rhinitis
  evidence:
  - reference: PMID:19328896
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The result of empty nose syndrome or iatrogenic atrophic rhinitis as a
      consequence of turbinectomy remains a controversial topic that deserves
      further scrutiny.
    explanation: >-
      Editorial discussing the relationship between ENS and iatrogenic
      atrophic rhinitis, noting the overlap and controversy.
  - reference: PMID:32125703
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The distinct histology of ENS included preserved respiratory epithelium
      and goblet cell metaplasia, accompanying with characteristics similar
      to atrophic rhinitis.
    explanation: >-
      Histopathological study showing ENS has features similar to atrophic
      rhinitis but with distinct characteristics like preserved respiratory
      epithelium.
- name: Chronic rhinosinusitis
  description: >-
    Chronic rhinosinusitis presents with nasal obstruction and may have
    psychological comorbidities, but is distinguished by mucosal inflammation,
    nasal polyps, or purulent discharge rather than absent turbinate tissue.
  disease_term:
    term:
      id: MONDO:0006031
      label: chronic rhinosinusitis
    preferred_term: Chronic rhinosinusitis
  evidence:
  - reference: PMID:40617870
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As patients with ENS often have mental health comorbidities, further
      research should investigate whether anxiety and depression are true
      sequelae of ENS or factors contributing to its development.
    explanation: >-
      Snippet addresses psychiatric comorbidity uncertainty and does not directly
      support chronic rhinosinusitis differential features.
- name: Allergic rhinitis
  description: >-
    Allergic rhinitis causes nasal obstruction and congestion but is
    characterized by allergic inflammation, eosinophilic infiltration, and
    response to antihistamines, without the paradoxical obstruction or
    turbinate tissue loss seen in ENS. Depression prevalence is significantly
    lower in allergic rhinitis compared to ENS.
  disease_term:
    term:
      id: MONDO:0011786
      label: allergic rhinitis
    preferred_term: Allergic rhinitis
  evidence:
  - reference: PMID:31272211
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The degree and severity of depression in patients with ENS was higher
      than in patients with CRS or AR.
    explanation: >-
      Provides partial support by distinguishing ENS from allergic rhinitis via psychological
      burden, but not full differential pathophysiology.
datasets:
- accession: geo:GSE191041
  title: >-
    Cell function and identity revealed by comparative scRNA-seq analysis
    in human nasal, bronchial and epididymis epithelia. [scRNA-Seq]
  description: >-
    Single-cell RNA-seq characterization of human nasal epithelial cell
    populations including basal, secretory, goblet, and ciliated cells.
    Provides a reference atlas of the cell types present in normal nasal
    epithelium, relevant to understanding the cellular composition lost
    following turbinate resection in ENS.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: nasal epithelial cell
    cell_type_term:
      preferred_term: nasal cavity respiratory epithelium epithelial cell
      term:
        id: CL:2000094
        label: nasal cavity respiratory epithelium epithelial cell of
          viscerocranial mucosa
  sample_count: 7
  conditions:
  - normal human nasal epithelium
  - normal human bronchial epithelium
  publication: PMID:35597096
  notes: >-
    No ENS-specific omics datasets exist. This reference atlas of normal
    human nasal epithelial cell types is relevant for understanding the
    cellular populations disrupted by turbinate surgery.
- accession: geo:GSE121600
  title: >-
    Single-cell RNA-seq reveals novel cell differentiation dynamics during
    human airway epithelium regeneration
  description: >-
    Single-cell transcriptomic characterization of multiciliated, goblet,
    secretory, and basal cells during human airway epithelium regeneration.
    Includes nasal brushing and turbinate samples, with cross-species
    validation. Relevant to understanding mucociliary differentiation
    dynamics disrupted in ENS.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: nasal mucosa goblet cell
    cell_type_term:
      preferred_term: nasal mucosa goblet cell
      term:
        id: CL:0002480
        label: nasal mucosa goblet cell
  sample_count: 22
  conditions:
  - human airway epithelium regeneration
  - fresh nasal brushing
  publication: PMID:31558434
  notes: >-
    Characterizes goblet cell and multiciliated cell differentiation
    trajectories relevant to the mucociliary dysfunction seen in ENS.
- accession: geo:GSE30596
  title: >-
    Isolation of novel multipotent neural crest-derived stem cells from
    adult human inferior turbinate
  description: >-
    Expression profiling of neural crest-derived stem cells isolated from
    adult human inferior turbinate respiratory epithelium. These stem cells
    express neural crest markers and demonstrate multipotent differentiation
    capacity. Relevant to ENS as it characterizes progenitor cells present
    in the turbinate tissue that is resected.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: inferior turbinate tissue
    tissue_term:
      preferred_term: inferior nasal concha
      term:
        id: UBERON:0005922
        label: inferior nasal concha
  sample_count: 12
  conditions:
  - inferior turbinate stem cells
  - control
  platform: Illumina HumanHT-12 v4
  publication: PMID:22128806
  notes: >-
    Characterizes stem cell populations in the human inferior turbinate,
    the tissue most commonly resected in surgeries that lead to ENS.
references:
- reference: DOI:10.1002/lary.26530
  title: Computational fluid dynamics and trigeminal sensory examinations of
    empty nose syndrome patients
  findings: []
- reference: DOI:10.1002/lary.28586
  title: Distinct Histopathology Characteristics in Empty Nose Syndrome
  findings: []
- reference: DOI:10.1016/j.fsc.2019.07.005
  title: Management of Postsurgical Empty Nose Syndrome
  findings: []
- reference: DOI:10.1097/moo.0000000000000544
  title: 'Update on empty nose syndrome: disease mechanisms, diagnostic tools, and
    treatment strategies'
  findings: []
- reference: DOI:10.54905/disssi.v29i156.e26ms3504
  title: 'Empty Nose Syndrome: A review of pathogenic mechanisms, diagnostic strategies,
    and patient-centered treatments'
  findings: []