Therapeutic diminution of Interleukin-10 with intranasal theophylline administration in hyposmic patients.

OBJECTIVE: To determine changes in nasal mucus Interleukin-10 (IL-10) before and after intranasal theophylline treatment in hyposmic patients, and the relationship of these changes to orally administered theophylline treatment. DESIGN: IL-10 was measured in nasal mucus samples of 17 normal subjects and 39 patients with hyposmia of multiple etiologies by use of a sensitive spectrophotometric ELISA assay. Hyposmia is defined clinically by standardized evaluation of impaired olfactometry, as well as subjectively self reported by the patient. RESULTS: Prior to treatment, IL-10 levels in nasal mucus were increased in hyposmic patients compared to controls. Following intranasal theophylline administration, over half of treated patients experienced a decrease of nasal mucus IL-10 toward control levels, correlated with a significant improvement in taste and smell function. Patients who increased with intranasal administration, similar to previously reported oral administration, showed no significant improvement in taste or smell function. CONCLUSIONS: Nasal mucus IL-10 decreased in patients treated with intranasal theophylline. Mechanisms of action include phosphodiesterase and nuclear factor kappa-B inhibition, correlated with an improvement in both olfaction and gustation. IL-10 is induced by therapeutic and systemic administration of theophylline as with oral dosage, but reduced by lower and localized treatment.

Theophylline increases saliva sonic hedgehog and improves taste dysfunction.

OBJECTIVE: To determine changes in saliva sonic hedgehog (Shh) and in taste dysfunction before and after oral theophylline treatment. DESIGN: Shh was measured in parotid saliva of both normal subjects and patients with taste dysfunction of multiple etiologies by use of a sensitive spectrophotometric ELISA assay. Taste dysfunction was defined clinically by both subjective inhibition of taste function (including acuity loss) and impaired gustometry. RESULTS: Theophylline treatment increased patient saliva Shh and improved taste dysfunction both subjectively and by gustometry. CONCLUSIONS: By use of these systematic clinical measurements theophylline can be demonstrated to increase saliva Shh and improve taste dysfunction. These results are consistent with saliva Shh acting as a taste bud growth factor which stimulates stem cells of taste buds to initiate development and perpetuation of taste bud receptors. Measurements of saliva Shh provide an important marker for the presence of taste dysfunction and in the improvement by theophylline treatment.

Sonic hedgehog is present in parotid saliva and is decreased in patients with taste dysfunction.

PURPOSE: To demonstrate that sonic hedgehog (Shh) is present in human parotid saliva and is decreased in human taste dysfunction. METHODS: Shh was measured in parotid saliva of 27 normal subjects and 81 patients with taste dysfunction of multiple etiologies using a sensitive spectrophotometric ELISA assay. Taste dysfunction was defined clinically both by subjective decreases of taste acuity and flavor perception and by impaired gustometry. RESULTS: Shh was found in parotid saliva of both normal subjects and patients with taste dysfunction. Levels were significantly lower in patients than in normal subjects. Both subjective loss of taste acuity and flavor perception and impaired gustometry was measured in untreated patients. CONCLUSIONS: This is the first demonstration of Shh in human saliva. As Shh has been related to taste bud growth and development, its presence in saliva is consistent with its role as a cell signaling moiety involved with stimulation of taste bud stem cells to generate taste receptors. Decreased saliva Shh secretion can be considered a marker of taste dysfunction in patients with multiple pathologies for their dysfunction.

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

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.

A genetic marker of the ACKR1 gene is present in patients with Type II congenital smell loss who have type I hyposmia and hypogeusia.

PURPOSE: Our previous study of Type II congenital smell loss patients revealed a statistically significant lower prevalence of an FY (ACKR1, formerly DARC) haplotype compared to controls. The present study correlates this genetic feature with subgroups of patients defined by specific smell and taste functions. METHODS: Smell and taste function measurements were performed by use of olfactometry and gustometry to define degree of abnormality of smell and taste function. Smell loss was classified as anosmia or hyposmia (types I, II or III). Taste loss was similarly classified as ageusia or hypogeusia (types I, II or III). Based upon these results patient erythrocyte antigen expression frequencies were categorized by smell and taste loss with results compared between patients within the Type II group and published controls. RESULTS: Comparison of antigen expression frequencies revealed a statistically significant decrease in incidence of an Fyb haplotype only among patients with type I hyposmia and any form of taste loss (hypogeusia). In all other patient groups erythrocyte antigens were expressed at normal frequencies. CONCLUSIONS: Data suggest that Type II congenital smell loss patients who exhibit both type I hyposmia and hypogeusia are genetically distinct from all other patients with Type II congenital smell loss. This distinction is based on decreased Fyb expression which correlated with abnormalities in two sensory modalities (hyposmia type I and hypogeusia). Only patients with these two specific sensory abnormalities expressed the Fyb antigen (encoded by the ACKR1 gene on the long arm of chromosome 1) at frequencies different from controls.

Initiation of smell function in patients with congenital hyposmia.

BACKGROUND: Patients with congenital smell loss (hyposmia) are born without a sense of smell. They comprise two types. Type I patients have genetic abnormalities manifested by brain, gonadal and other somatic abnormalities. Type II patients have neither a family history of smell loss nor any somatic abnormalities. No systematic attempts to initiate smell function in Type II patients have been reported. METHODS: Smell function was measured in 19 Type II congenital smell loss patients by both subjective responses and by olfactometry using measurements of detection and recognition thresholds, magnitude estimation and hedonics in response to four odors (pyridine, nitrobenzene, thiophene and amyl acetate) before and after treatment with oral theophylline, 200-800mg daily for periods of 2-36months with evaluation of smell function and serum theophylline measured at intervals of 2-6months. RESULTS: In 12 of the 19 Type II patients (63%) smell function was initiated for the first time and was quantitated by both subjective responses and by olfactometry. Initiation of smell function occurred after treatment with 200-800mg of oral theophylline for periods of 2-19months. INTERPRETATION: This is the first systematic demonstration of initiation of smell in patients who were born without smell function. Oral theophylline presumably acts to increase both olfactory receptor growth, development and perpetuation and brain plasticity which enables them to recognize olfactory signals with initiation of olfactory function.

On the mechanism of smell loss in patients with Type II congenital hyposmia.

BACKGROUND: Smell function has been initiated with theophylline treatment in 63% of patients with Type II congenital smell loss. Based upon a systematic evaluation of the protein components of nasal mucus we have demonstrated that interactions among four chemical moieties in nasal mucus may play significant roles in this initiation. Prior to treatment three of these moieties, cAMP, cGMP and sonic hedgehog (Shh), were significantly decreased in concentration whereas one of these moieties, TNFalpha, was increased in concentration. The mechanism(s) responsible for initiation of smell function in these patients, not immediately apparent, may depend upon understanding interactions among these moieties. METHODS: Measurements of cAMP, cGMP, Shh and TNFalpha in nasal mucus by specific spectrophotometric immunoassays before and after treatment with theophylline. RESULTS: Before theophylline treatment cAMP, cGMP and Shh in nasal mucus, which act as growth factors to support olfactory receptor function, were significantly decreased below normal levels whereas TNFalpha which acts as a "death factor" to inhibit olfactory receptor function was significantly increased above normal. After theophylline treatment cAMP, cGMP and Shh increased significantly whereas TNFalpha decreased significantly. CONCLUSIONS: These results indicate that there are specific biochemical changes associated with smell loss in patients with Type II congenital smell loss and that correction of these biochemical changes are associated with initiation of smell function in these patients. Understanding these relationships play an important role in understanding receptor action in smell function.

Erythrocyte membrane antigen frequencies in patients with Type II congenital smell loss.

OBJECTIVE: The objective of this study was to determine whether there are genetic factors associated with Type II congenital smell loss. STUDY DESIGN: The expression frequencies of 16 erythrocyte antigens among patients with Type II congenital smell loss were determined and compared to those of a large control group. METHODS: Blood samples were obtained from 99 patients with Type II congenital smell loss. Presence of the erythrocyte surface antigens A, B, M, N, S, s, Fy(a), Fy(b), D, C, c, E, e, K, Jk(a), and Jk(b) was analyzed by blood group serology. Comparisons of expression frequencies of these antigens were made between the patients and a large control group. RESULTS: Patients tested for the Duffy b antigen (Fy(b) haplotype) exhibited a statistically significant 11% decrease in expression frequency compared to the controls. There were no significant differences between patients and controls in the expression frequencies for all other erythrocyte antigens (A, B, M, N, S, s, Fy(a), D, C, c, E, e, K, Jk(a), or Jk(b)). CONCLUSIONS: These findings describe the presence of a previously unrevealed genetic tendency among patients with Type II congenital smell loss related to erythrocyte surface antigen expression. The deviation in expression rate of Duffy b suggests a target gene and chromosome region in which future research into this form of congenital smell loss may reveal a more specific genetic basis for Type II congenital smell loss.

Effects of smell loss (hyposmia) on salt usage.

OBJECTIVE: Smell loss (hyposmia) inhibits flavor perception and influences food intake. To compensate for flavor loss, some patients with hyposmia appear to increase salt usage. The purpose of this study was to compare self-reported salt usage in patients with hyposmia with that in normal volunteers. METHODS: Salt usage was compared in 56 patients with hyposmia but with normal taste function with that in 27 normal volunteers. Salt usage was formulated with respect to 1) a standard quantitative salt intake scale, 2) salt addition related to food intake, 3) intake of foods and beverages with high salt content, and 4) salt intake related to presence or absence of hypertension. RESULTS: Eighteen (32%) of the 56 patients self-reported increased salt usage; they were labeled "increased users." The other 38 hyposmic patients (68%) did not report increased salt usage; they were labeled "non-changers." Increased users estimated their salt usage rose an average 2.8 times that experienced before their hyposmia onset. They also reported adding salt to their food before tasting it and ate more highly salted foods than did the non-changers. Salt usage was not increased further among increased users with hypertension but was increased further among non-changers with hypertension. CONCLUSIONS: Salt usage is increased among some patients with hyposmia presumably to enhance flavor perception to compensate for diminished flavor perception related to loss of smell.

Anatomic olfactory structural abnormalities in congenital smell loss: magnetic resonance imaging evaluation of olfactory bulb, groove, sulcal, and hippocampal morphology.

BACKGROUND AND PURPOSE: There are 2 groups of patients with congenital smell loss: group 1 (12% of the total), in which patients exhibit a familial smell loss in conjunction with severe anatomical, somatic, neurological, and metabolic abnormalities such as hypogonadotropic hypogonadism; and a larger group, group 2 (88% of the total), in which patients possess a similar degree of smell loss but without somatic, neurological, or anatomical abnormalities or hypogonadism. Both groups are characterized by similar olfactory dysfunction, and both have been reported to have absent or decreased olfactory bulbs and grooves, which indicates some overlap in olfactory pathophysiology and anatomy. The purpose of this study was to evaluate patients with congenital smell loss, primarily among group 2 patients, comparing brain magnetic resonance imaging (MRI) results in patients with types of hyposmia. METHODS: Forty group 2 patients were studied by measurements of taste (gustometry) and smell (olfactometry) function and by use of MRI in which measurements of olfactory bulbs, olfactory sulcus depth, olfactory grooves, and hippocampal anatomy were performed. Anatomical results were compared with similar studies in group 1 patients and in 22 control subjects with normal sensory function. RESULTS: Olfactometry was abnormal in all patients with no patient reporting ever having normal olfaction. No patient had a familial history of smell loss. On MRI, all exhibited at least 1 abnormality in olfactory system anatomy, including absence or decreased size of at least 1 olfactory bulb, decreased depth of an olfactory sulcus, and abnormalities involving hippocampal anatomy with hippocampal malrotations. One patient had bilateral bulb duplication. Normal subjects with normal smell and taste function exhibited some but very few or significant neuroanatomical changes on MRI. CONCLUSIONS: Although both groups have similar abnormalities of smell function, group 2 patients demonstrate anatomical anomalies in olfactory structures that are neither as common nor as severe as in group 1 patients. Group 2 patients can have a wide range of olfactory anatomical abnormalities.

Interleukin 6 in hyposmia.

IMPORTANCE: Olfaction is a complex sensory process that has not been fully studied. Elevated plasma levels of interleukin 6 (IL-6) have been found in patients with several acute and chronic diseases but have not been reported in patients with smell loss (hyposmia). OBJECTIVE: To determine IL-6 levels in patients with hyposmia. DESIGN: Retrospective study. All measurements were made without reference to the origin of any collected sample. SETTING An ambulatory private practice at The Taste and Smell Clinic in Washington, DC. PARTICIPANTS: Fifty-nine consecutive patients who presented to the clinic between 2005 and 2008 for evaluation and treatment of various degrees of hyposmia were studied. Nine volunteers with normal sensory function served as controls. MAIN OUTCOMES AND MEASURES: Levels of IL-6 were measured in samples of plasma, urine, saliva, and nasal mucus. RESULTS: All biological fluid samples studied contained IL-6. Mean (SEM) levels in plasma, saliva, and nasal mucus in patients were significantly higher than in controls (0.95 [0.10] vs 0.12 [0.03] pg/mL, 0.57 [0.05] vs 0.30 [0.01] pg/mL, and 29.7 [3.8] vs 11.6 [0.5] pg/mL, respectively; all P < .001). The concentration of IL-6 in nasal mucus in patients was significantly higher than in controls and was more than 30 times higher than in any other biological fluid. Mean (SEM) levels in urine were not significantly different: 0.92 (0.17) pg/mL for patients and 1.26 (0.41) pg/mL for controls (P > .50). CONCLUSIONS AND RELEVANCE: Compared with controls, IL-6 in patients was significantly elevated in plasma, saliva, and nasal mucus. Because IL-6 is a proinflammatory cytokine, these changes can relate to local or systemic inflammatory processes, which can be a cause or a result of pathological processes associated with hyposmia. These results support the concept that hyposmia has a biochemical basis and IL-6 may play a role in biochemical pathological processes underlying hyposmia and its treatment.

Taste and smell function in chronic disease: a review of clinical and biochemical evaluations of taste and smell dysfunction in over 5000 patients at The Taste and Smell Clinic in Washington, DC.

PURPOSE: To describe systematic methods developed over 40 years among over 5000 patients at The Taste and Smell Clinic in Washington, DC to evaluate taste and smell dysfunction. MATERIALS AND METHODS: A tripartite methodology was developed. First, methods to determine clinical pathology underlying the multiple disease processes responsible for taste and smell dysfunction were developed. Second, methods to determine biochemical parameters responsible for these pathologies were developed. Third, methods to implement these techniques were developed to form a unified basis upon which treatment strategies can be developed to treat these patients. RESULTS: Studies were performed in 5183 patients. Taste loss was present in 62% of patients, smell loss in 87%. Most patients with taste loss (52%) exhibited Type II hypogeusia; most patients with smell loss (56%) exhibited Type II hyposmia. Sensory distortions were present in 60%. Four common diagnostic entities were found: post influenza-type hyposmia and hypogeusia (27% of patients), idiopathic causes (16%), allergic rhinitis (15%) and post head injury (14%). Regardless of clinical diagnosis the major biochemical abnormality found in most patients (~70%) was diminished parotid salivary and nasal mucus secretion of cAMP and cGMP. CONCLUSIONS: Taste and smell dysfunctions are common clinical problems associated with chronic disease processes. These symptoms require a systematic, integrated approach to understand their multiple and complex components. The approach presented here can and has led to effective treatment.

Olfactory Hallucinations without Clinical Motor Activity: A Comparison of Unirhinal with Birhinal Phantosmia.

Olfactory hallucinations without subsequent myoclonic activity have not been well characterized or understood. Herein we describe, in a retrospective study, two major forms of olfactory hallucinations labeled phantosmias: one, unirhinal, the other, birhinal. To describe these disorders we performed several procedures to elucidate similarities and differences between these processes. From 1272, patients evaluated for taste and smell dysfunction at The Taste and Smell Clinic, Washington, DC with clinical history, neurological and otolaryngological examinations, evaluations of taste and smell function, EEG and neuroradiological studies 40 exhibited cyclic unirhinal phantosmia (CUP) usually without hyposmia whereas 88 exhibited non-cyclic birhinal phantosmia with associated symptomology (BPAS) with hyposmia. Patients with CUP developed phantosmia spontaneously or after laughing, coughing or shouting initially with spontaneous inhibition and subsequently with Valsalva maneuvers, sleep or nasal water inhalation; they had frequent EEG changes usually ipsilateral sharp waves. Patients with BPAS developed phantosmia secondary to several clinical events usually after hyposmia onset with few EEG changes; their phantosmia could not be initiated or inhibited by any physiological maneuver. CUP is uncommonly encountered and represents a newly defined clinical syndrome. BPAS is commonly encountered, has been observed previously but has not been clearly defined. Mechanisms responsible for phantosmia in each group were related to decreased gamma-aminobutyric acid (GABA) activity in specific brain regions. Treatment which activated brain GABA inhibited phantosmia in both groups.

Intranasal theophylline treatment of hyposmia and hypogeusia: a pilot study.

OBJECTIVE: To determine whether intranasal theophylline methylpropyl paraben can correct hyposmia and hypogeusia. DESIGN: We performed an open-label pilot study in patients with hyposmia and hypogeusia under the following 3 conditions: (1) before treatment, (2) after oral theophylline anhydrous treatment, and (3) after intranasal theophylline treatment. Under each condition, we performed subjective evaluations of taste and smell functions, quantitative measurements of taste (gustometry) and smell (olfactometry), and measurements of serum theophylline level and body weight. SETTING: The Taste and Smell Clinic in Washington, DC. PATIENTS: Ten patients with hyposmia and hypogeusia clinically related to the effects of viral illness, allergic rhinitis, traumatic brain injury, congenital hyposmia, and other chronic disease processes were selected. INTERVENTIONS: Oral theophylline anhydrous, 200 to 800 mg/d for 2 to 12 months, was administered to each patient. This treatment was discontinued for 3 weeks to 4 months when intranasal theophylline methylpropyl paraben, 20 µg/d in each naris, was administered for 4 weeks. MAIN OUTCOME MEASURES: At termination of each condition, taste and smell function was determined subjectively, by means of gustometry and olfactometry, with measurement of serum theophylline levels and body weight. RESULTS: Oral theophylline treatment improved taste and smell acuity in 6 patients after 2 to 12 months of treatment. Intranasal theophylline treatment improved taste and smell acuity in 8 patients after 4 weeks, with improvement greater than after oral administration. No adverse effects accompanied intranasal drug use. Body weight increased with each treatment but was greater after intranasal than after oral administration. CONCLUSIONS: Intranasal theophylline treatment is safer and more effective in improving hyposmia and hypogeusia than oral theophylline anhydrous treatment.