The Bittersweet Symphony of COVID-19: Associations between TAS1Rs and TAS2R38 Genetic Variations and COVID-19 Symptoms.

The innate immune system is crucial in fighting SARS-CoV-2 infection, which is responsible for coronavirus disease 2019 (COVID-19). Therefore, deepening our understanding of the underlying immune response mechanisms is fundamental for the development of novel therapeutic strategies. The role of extra-oral bitter (TAS2Rs) and sweet (TAS1Rs) taste receptors in immune response regulation has yet to be fully understood. However, a few studies have investigated the association between taste receptor genes and COVID-19 symptom severity, with controversial results. Therefore, this study aims to deepen the relationship between COVID-19 symptom presence/severity and TAS1R and TAS2R38 (TAS2Rs member) genetic variations in a cohort of 196 COVID-19 patients. Statistical analyses detected significant associations between rs307355 of the TAS1R3 gene and the following COVID-19-related symptoms: chest pain and shortness of breath. Specifically, homozygous C/C patients are exposed to an increased risk of manifesting severe forms of chest pain (OR 8.11, 95% CI 2.26-51.99) and shortness of breath (OR 4.83, 95% CI 1.71-17.32) in comparison with T/C carriers. Finally, no significant associations between the TAS2R38 haplotype and the presence/severity of COVID-19 symptoms were detected. This study, taking advantage of a clinically and genetically characterised cohort of COVID-19 patients, revealed TAS1R3 gene involvement in determining COVID-19 symptom severity independently of TAS2R38 activity, thus providing novel insights into the role of TAS1Rs in regulating the immune response to viral infections.

Effects on hearing after long-term use of iron chelators in beta-thalassemia: Over twenty years of longitudinal follow-up.

OBJECTIVE: The role of iron chelation in causing hearing loss (HL) is still unclear. The present study assessed the prevalence of HL among transfusion-dependent thalassemia (TDT) patients who underwent audiological follow-up over a 20-year period. METHODS: We retrospectively analyzed clinical records and audiological tests from January 1990 (T0) to December 2022 (T22) of a group of TDT patients who received iron chelation therapy with deferoxamine (DFO), deferiprone (DFP) or deferasirox (DFX), in monotherapy or as part of combination therapy. RESULTS: A total of 42 adult TDT patients (18 male, 24 female; age range: 41-55 years; mean age: 49.2 ± 3.7 years) were included in the study. At the T22 assessment, the overall prevalence of sensorineural HL was 23.8 % (10/42). When patients were stratified into two groups, with and without ototoxicity, no differences were observed for sex, age, BMI, creatinine level, pre-transfusional hemoglobin, start of transfusions, cardiac or hepatic T2 MRI; only ferritin serum values and duration of chelation were significantly higher (p = 0.02 and p = 0.01, respectively) in patients with hearing impairment in comparison to those with normal hearing. CONCLUSION: This study with long-term follow-up suggests that iron chelation therapy might induce ototoxicity; therefore, a long and accurate audiological follow-up should be performed in TDT patients.

Sudden hearing loss and early hyperbaric oxygen therapy: A preliminary study.

Purpose: Sudden sensorineural hearing loss (SSNHL) is a time-sensitive urgent condition. The aim of this study was to evaluate the frequency of hearing improvement in patients with idiopathic SSNHL who only received hyperbaric oxygen (HBO2) therapy within three days of symptom onset, instead of conventional corticosteroid treatment. Methods: The medical charts of patients who experienced SSNHL between January 1, 2012, and December 31, 2021, were reviewed. The present study included all adult patients who were diagnosed with idiopathic SSNHL and started HBO2 therapy within 72 hours of symptom onset. These subjects did not take corticosteroids due to contraindications or because they were concerned about possible side effects. The HBO2 therapy protocol consisted of at least 10 sessions of 85 minutes each with pure oxygen inhalation at 2.5 atmospheres absolute pressure. Results: Overall, 49 subjects (26 males and 23 females) met the inclusion criteria, with a mean age of 47 (± 20.4) years. The mean initial hearing threshold was 69.8 dB (±18.0). After HBO2 therapy, complete hearing recovery was observed in 35 patients (71.4%), and the mean hearing threshold improved significantly (p≺0.001) to 31.4 dB (±24.5). In patients with complete hearing recovery, no significant differences were found between males and females (p=0.79), right and left ears (p=0.72) or initial grades of hearing loss (p=0.90). Conclusion: This study suggests that, in the absence of the confounding effect of concurrent steroid therapy, starting HBO2 therapy within three days of symptom onset could have a positive impact on patients with idiopathic SSNHL.

Audiological and vestibular symptoms following SARS-CoV-2 infection and COVID-19 vaccination in children aged 5-11 years.

PURPOSE: The present study assessed the prevalence of audio-vestibular symptoms following SARS-COV-2 infection or COVID-19 vaccination among children, comparing the two groups. A further aim was to evaluate whether children with pre-existing unilateral hearing loss were more prone to adverse events. MATERIALS AND METHODS: This retrospective study included children aged 5-11 years with normal hearing or a proven history of unilateral hearing loss who contracted SARS-CoV-2 or received two doses of COVID-19 vaccine. Tinnitus, hyperacusis, aural fullness, otalgia, otorrhea, new-onset hearing loss, vertigo and dizziness were investigated as possible complications of SARS-CoV-2 infection or the COVID-19 vaccine. RESULTS: This study included 272 children (143 boys, 129 girls), with a mean age of 7.8 ± 2.3 years. Among these, 120 were affected by pre-existing unilateral hearing loss. The most common audio-vestibular symptoms reported by children following SARS-CoV-2 infection and COVID-19 vaccination were aural fullness (33/132, 25 %) and dizziness (5/140, 3.6 %), respectively. All symptoms following COVID-19 vaccination resolved within 24 h. Compared to children who received the COVID-19 vaccine, those infected with SARS-CoV-2 had a higher prevalence of tinnitus (p = 0.009), hyperacusis (p = 0.003), aural fullness (p < 0.001), otalgia (p < 0.001), otorrhea (p < 0.001), and vertigo (p = 0.006). Two girls also experienced new-onset unilateral sensorineural hearing loss following SARS-CoV-2 infection. Children with a known history of unilateral hearing loss did not have a higher prevalence of audio-vestibular symptoms than children with normal hearing. CONCLUSIONS: Our results suggest that the COVID-19 vaccine is safe and can be recommended for children with unilateral hearing loss without fear of possible audio-vestibular sequelae.

Hearing outcomes in children with congenital cytomegalovirus infection: From management controversies to lack of parents' knowledge.

OBJECTIVES: Congenital cytomegalovirus (cCMV) is the leading nongenetic cause of sensorineural hearing loss (HL). However, there are no universally accepted approaches to diagnosis, follow-up and treatment. The aim of this study was to evaluate the main characteristics of cCMV-infected children, focusing on their management and long-term hearing outcomes. METHODS: This retrospective study included all children with cCMV infection who were referred to a third-level referral audiologic center for a 6-year hearing follow-up. The main information collected from the medical records included gestational age, birth weight, trimester of maternal seroconversion, hearing status at birth and after 6 years, hearing fluctuations, treatment with oral valganciclovir (within the first month of life and for 6 months), use of hearing devices, presence of speech-language delay, motor delay, cognitive delay and balance disorders, awareness of cCMV among parents, and parents' engagement in behaviors that could increase the risk of CMV infection during pregnancy. RESULTS: A total of 141 children with cCMV infection (72 males and 69 females; mean gestational age: 37+3 weeks; mean birth weight: 2893 g) were assessed. Overall, 48 children (34.0%) had a diagnosis of speech-language delay, 32 (22.7%) of sensorineural HL (59.4% bilaterally; 50% of profound degree), 18 (12.8%) of motor delay, 16 (11.3%) of balance disorders, and 6 (4.3%) of cognitive delay. Among children with HL, 8 (25.0%) were fitted with hearing aids (5 unilaterally and 3 bilaterally), and 5 (15.6%) had undergone cochlear implantation (1 unilaterally and 4 bilaterally), while a bimodal hearing solution was adopted for 2 (6.3%) patients. Compared to children with asymptomatic cCMV infection, symptomatic children had a higher prevalence of neurological and auditory sequelae (P < 0.01) and bilateral (P = 0.003) and severe-to-profound HL (P = 0.004). Overall, 23 children (16.3%) received oral valganciclovir, and only one of them experienced hearing deterioration. Only 14.9% of mothers and 5% of fathers were aware that cCMV could cause progressive or late-onset HL, and 87.9% of parents (248/282) had engaged in behaviors that increased the risk of CMV infection during pregnancy. CONCLUSION: This study confirmed the importance of performing a long audiological follow-up in children diagnosed with cCMV infection due to the possible late-onset, progressive and fluctuating nature of HL. Moreover, the study highlighted many current controversies in preventive (poor prenatal education), diagnostic (routine maternal serological screening) and therapeutic (valganciclovir administered to asymptomatic children) approaches to cCMV infection. More efforts should be made to improve prevention strategies and raise awareness of cCMV infection risks among the population.

Chronic Rhinosinusitis: T2r38 Genotyping and Nasal Cytology in Primary Ciliary Dyskinesia.

OBJECTIVES: Chronic rhinosinusitis (CRS) is a major hallmark of primary ciliary dyskinesia (PCD). We investigated the possible correlation between some severity markers of CRS and several clinical features of the disease. We further studied the bitter taste receptor TAS2R38 polymorphisms to identify the genotypes associated with more severe disease. METHODS: We included 39 adult PCD patients with (CRSwNP) and without nasal polyposis (CRSsNP); a sample for nasal cytology was obtained and clinical cytological grading (CCG) was determined. The SNOT-22 and Lund-Mackay scores were recorded. A sample of DNA was extracted from peripheral blood to investigate TAS2R38 polymorphisms. RESULTS: CRSwNP patients had features of more severe disease: indeed, they had statistically significantly higher frequency of previous sinus surgery, higher SNOT-22, LM scores, and CCG than CRSsNP patients. Upon genotyping of TAS2R38 polymorphisms, we observed that the AVI-AVI genotype, associated to homozygous nonfunctional bitter TAS2R38 receptor, was more prevalent among CRSwNP (100%) than in CRSsNP patients (0%); furthermore, AVI-AVI subjects showed statistically significantly worse SNOT-22 and CCG scores than PAV-PAV and PAV-AVI subjects. The group of AVI-AVI patients also had more frequent respiratory exacerbations, Gram-negative infections, and Pseudomonas aeruginosa colonization than PAV-PAV and PAV-AVI patients. CONCLUSION: Our findings indicate for the first time that PCD patients with CRSwNP display a more severe disease than those with CRSsNP. Genotyping of TAS2R38 polymorphisms demonstrated that in PCD patients, the AVI-AVI genotype is strikingly more prevalent among CRSwNP than in CRSsNP, while the PAV-PAV genotype might be protective against Gram-negative infections and respiratory exacerbations. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:248-254, 2023.

Hearing outcomes in preterm infants with confirmed hearing loss.

OBJECTIVES: Premature infants are at high risk for hearing loss (HL). The aim of the present study is to assess the frequency of preterm infants affected by HL who experience hearing improvement over months and evaluate possible factors associated with hearing changes. METHODS: This retrospective study was conducted in a third-level referral audiologic center. Preterm infants with a confirmed diagnosis of sensorineural HL within the first 3 months of life were reassessed at 18 months corrected age using the click-evoked auditory brainstem response between January 1, 2012, and June 30, 2020. The frequency of hearing improvement and associations between possible risk factors and hearing changes were evaluated. RESULTS: A total of 138 preterm infants (71 male and 67 female; mean gestational age: 30+2 weeks) were assessed. The percentages of hearing improvement and hearing threshold normalization were 58.7% (81/138) and 35.5% (49/138), respectively. We observed a higher frequency of hearing improvement among preterm infants who had received exclusive breastfeeding or mixed feeding compared with those who had received exclusive infant formula (80% versus 29.3%, P < 0.001). CONCLUSION: This study confirms the importance of performing a long audiological follow-up and postponing the indication for cochlear implantation in children with a history of preterm birth. Because of the expression of mesenchymal stem cells and high total antioxidant capacity, breast milk might play a protective role in the auditory system of preterm infants. These findings could have important implications for clinical practice, positively impacting the long-term hearing outcomes of preterm infants.

A novel genetic variant in DNAI2 detected by custom gene panel in a newborn with Primary Ciliary Dyskinesia: case report.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a highly heterogeneous genetic disorder caused by defects in motile cilia. The hallmark features of PCD are the chronic infections of the respiratory tract, moreover, clinical manifestations include also laterality defects and risk of male infertility. Clinical phenotypes of PCD are the result of mutations in genes encoding components of axonema or factors involved in axonemal assembly. Recent studies have identified over 45 PCD-associated genes, therefore, molecular analysis represents a powerful diagnostic tool to confirm and uncover new genetic causes of this rare disease. CASE PRESENTATION: Here, we describe a female infant of Moroccan origin with normal pressure hydrocephalus (NPH) in addition to most common PCD symptoms. Transmission Electron Microscopy (TEM) and molecular tests, such as a Next generation Sequencing panel and a custom array CGH, were performed for diagnosis of PCD. TEM revealed outer dynein arm (ODA) defects, whilst molecular analyses detected a novel 6,9 kb microdeletion in DNAI2 gene. CONCLUSIONS: Since DNAI2 mutations are very rare, this case report contributes to better delineate the important role of DNAI2 as causative of PCD phenotype, suggesting, furthermore, that the variations in DNAI2 may be as a new genetic risk factor for NPH. Indeed, although the association of hydrocephalus with PCD has been well documented, however, only a small number of human patients show this defect. Furthermore, this study highlights the importance of high-throughput technologies in advancing our understanding of heterogeneous genetic disorders.

Primary Ciliary Dyskinesia: The Impact of Taste Receptor (TAS2R38) Gene Polymorphisms on Disease Outcome and Severity.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare genetic disease leading to recurrent respiratory infections of upper and lower airways. Chronic rhinosinusitis (CRS) and bronchiectasis are very common in PCD patients. Recently, it has been shown the presence of taste receptors in respiratory tract and the possible involvement of bitter taste receptor TAS2R38 gene in susceptibility to respiratory infections and rhinosinusitis. OBJECTIVE: Aim of this study was to evaluate the frequency of TAS2R38 polymorphisms in PCD patients and their possible correlations with clinical outcomes of the disease. METHODS: Genetic and phenotypic data of 35 PCD patients were collected. Clinical evaluation included neonatal respiratory distress (NRD) at birth, presence of situs inversus, CRS, and bronchiectasis. We also measured the number of respiratory infections per year and the relevant pathogens, Lund-Mackay score, FEV1, and modified Bhalla score. With regard to genetics data, 3 polymorphisms (rs1726866, rs713598, and rs10246939) within TAS2R38 gene were analyzed and the patients were classified as PAV/PAV, PAV/AVI, and AVI/AVI. RESULTS: A significant difference in the distribution of TAS2R38 haplotype between patients with and without NRD emerged (p value = 0.01). A lower percentage of PAV/PAV individuals showed frequent respiratory exacerbations (≥2/year) (p value = 0.04) compared to those with AVI/AVI and AVI/PAV haplotypes. Moreover, no patients homozygous for PAV/PAV haplotype presented chronic colonization by Pseudomonas aeruginosa, thus supporting the possible role of TAS2R38 gene in susceptibility to respiratory infections. CONCLUSIONS: Here, we report, for the first time, a possible association of TAS2R38 polymorphisms with PCD phenotype.

Cilia and Ear.

OBJECTIVE: To investigate the prevalence of otological complications derived from primary ciliary dyskinesia (PCD) in adulthood. METHODS: Twenty-three patients with diagnosed PCD underwent medical history aimed at recording the presence of ear, nose, and throat manifestations (ENT) and any surgical treatments. The ENT objectivity was annotated, and then patients were subjected to audiometric test, tympanometry, registration of otoacoustic emission, and vestibular evaluation. RESULTS: Otitis media with chronic middle ear effusion (OME) during childhood was reported in 52% of the subjects, no patient had undergone ear surgery, and only 2 patients had an episode of otitis in the last year. Eleven of 23 patients showed normal hearing, 11 had a conductive hearing impairment, and 1 showed a severe sensorineural hearing loss unrelated to the syndrome. The bilateral stapedial reflex was only found in all cases of normoacusia and type A tympanogram, distortion product otoacoustic emissions (DPOAE) were present in 8 patients, and no patient had vestibular alterations. CONCLUSION: Our study confirms a very frequent prevalence of OME in PCD during childhood. Careful monitoring of otological complications of the syndrome is always desirable, also given the high presence in adults of other manifestations in the upper airways, such as chronic rhinosinusitis and nasal polyposis.

Pulmonary dysfunction in thalassaemia major: is there any relationship with body iron stores?

Although pulmonary function abnormalities in thalassaemia major (TM) were described in 1980, the pathogenetic mechanism is not clear and data are contradictory, probably because of study heterogeneity and the multifactorial nature of the pathogenesis. We retrospectively analysed 73 adult TM patients to evaluate the prevalence of pulmonary dysfunction in adult TM and investigate relationships with iron load. All patients underwent body plethysmography and carbon monoxide diffusion (DLCO) was assessed in 63, in addition to blood tests, echocardiogram and T2* myocardial and liver magnetic resonance imaging. Restrictive lung disease was present in 26 (35·6%) patients. Serum ferritin levels were higher in patients with restrictive pattern (1526 µg/l vs. 975 µg/l, P = 0·05). Restrictive lung disease did not correlate with cardiac or liver iron overload. However, considering only patients with serum ferritin >2500 µg/l, those with restrictive pattern also had heart (T2* 14·28 ± 9·99 ms vs. 31·59 ± 7·43 ms) and liver iron overload (LIC 16·02 ± 8·44 mg vs. 5·02 ± 2·69 mg Fe/g dry weight) compared to those without restrictive pattern. Twenty-five patients (39·7%) had decreased DLCO. No correlation was observed with iron parameters. In our data restrictive pattern was predominant; we observed a relationship with serum ferritin levels suggesting that iron, particularly its chronic effect, could play a role in the pathogenesis of pulmonary disease.

Body plethysmographic study of specific airway resistance in a sample of healthy adults.

BACKGROUND AND OBJECTIVE: sRaw (specific airway resistance) is a corrected index (Raw multiplied by thoracic gas volume) that describes airway behaviour regardless of lung volume. Normal values of sRaw in adult subjects have never been formally defined. To establish sRaw interpretation criteria and to define a range of reference values, we evaluated variability, reproducibility and reliability of sRaw measurements in a group of healthy adults. METHODS: We analysed 517 subjects of both genders, aged 18-65 (group A), and to assess the reproducibility of the measurements, we investigated intra-individual variation and potential daily and weekly sRaw rhythms in a subgroup of 18 co-operative healthy subjects (group B). RESULTS: In group A, there was no pattern of association between any of the considered anthropometric parameters; mean sRaw was higher in men (6.24 vs.5.95 cmH2O s in females; P = 0.0128), but when the data were stratified by age, gender-related differences were only found in the group aged 46-60 (males 6.45 cmH2O s, females 6.01 cmH2O s; P = 0.0219). In group B, there was no statistically significant, time-dependent variation during the single tests, nor any circadian or weekly rhythm. CONCLUSIONS: sRaw is a reliable parameter; therefore, we propose that the lower and upper 95% confidence limits should be considered as reference values for adults of both genders, regardless of age. The availability of reference values may be useful in clinical practice and research.

Chlamydophila pneumoniae induces a sustained airway hyperresponsiveness and inflammation in mice.

BACKGROUND: It has been reported that Chlamydophila (C.) pneumoniae is involved in the initiation and promotion of asthma and chronic obstructive pulmonary diseases (COPD). Surprisingly, the effect of C. pneumoniae on airway function has never been investigated. METHODS: In this study, mice were inoculated intranasally with C. pneumoniae (strain AR39) on day 0 and experiments were performed on day 2, 7, 14 and 21. RESULTS: We found that from day 7, C. pneumoniae infection causes both a sustained airway hyperresponsiveness and an inflammation. Interferon-gamma (IFN-gamma) and macrophage inflammatory chemokine-2 (MIP-2) levels in bronchoalveolar lavage (BAL)-fluid were increased on all experimental days with exception of day 7 where MIP-2 concentrations dropped to control levels. In contrast, tumor necrosis factor-alpha (TNF-alpha) levels were only increased on day 7. From day 7 to 21 epithelial damage and secretory cell hypertrophy was observed. It is suggested that, the inflammatory cells/mediators, the epithelial damage and secretory cell hypertrophy contribute to initiation of airway hyperresponsiveness. CONCLUSION: Our study demonstrates for the first time that C. pneumoniae infection can modify bronchial responsiveness. This has clinical implications, since additional changes in airway responsiveness and inflammation-status induced by this bacterium may worsen and/or provoke breathlessness in asthma and COPD.

Effects of long-term nasal continuous positive airway pressure therapy on morphology, function, and mucociliary clearance of nasal epithelium in patients with obstructive sleep apnea syndrome.

OBJECTIVES/HYPOTHESIS: The objective was to investigate the possible modification of nasal mucosa function and mucociliary clearance in a group of patients with severe obstructive sleep apnea syndrome receiving mechanical ventilation with long-term nasal continuous positive airway pressure (n-CPAP), without nasal diseases. STUDY DESIGN: The study design was experimental. Eight (six male and two female) nonsmoker patients were selected on the basis of two sleep questionnaires, were identified as needing n-CPAP therapy, and showed normal values of mucociliary transport time, ciliary beat frequency, and anterior rhinomanometry. METHODS: After a full polysomnographic examination, the authors recorded respiratory disturbance index (RDI), apnea/hypopnea index, nadir arterial oxygen saturation, and sleep stage. Every patient underwent pulmonary function test; arterial blood gas analysis; chest radiography; electrocardiography; ear, nose, and throat evaluation with rhinoscopy; anterior rhinomanometry; a saccharine test to measure the mucociliary transport time; and a brushing of nasal epithelium for study of ciliary beat frequency. All patients underwent polysomnographic examination in basal condition with overnight n-CPAP (without humidifier) and repeated this examination after 1 and 6 months with Auto CPAP (Autoset Res Care, Sidney, Australia) to titrate n-CPAP pressure and measure the new respiratory disturbance index. RESULTS: The mean basal respiratory disturbance index (number of respiratory events during sleep per hour of recording time) was 53.7 +/- 21.5 events/h; after 6 months of n-CPAP therapy (mean value, 7.5 +/- 0.7 cm H2O) the respiratory disturbance index was 5.7 +/- 3.76 events/h. Values for nasal resistance, mucociliary transport time, and ciliary beat frequency were normal before and after the ventilatory treatment. CONCLUSION: In the study group of patients with severe obstructive sleep apnea syndrome, the nocturnal use of n-CPAP without humidifier did not modify the function and mucociliary clearance of nasal epithelium.