Intranasal insulin for COVID-19-related smell loss.

BACKGROUND: Quantitative (hyposmia and anosmia) and qualitative (phantosmia and parosmia) olfactory disorders are common consequences of COVID-19 infection found in more than 38% of patients even months after resolution of acute disease. SARS-CoV-2 has tropism for angiotensin-converting enzyme 2 (ACE2) in the respiratory system, suggesting that it is the mechanism of damage to the olfactory neuroepithelium and of involvement at the central nervous system. The olfactory bulb is the organ with the highest insulin uptake in the central nervous system. Insulin increases the production of Growth Factors (GF); therefore, in this study, the administration of intranasal insulin is proposed as a viable treatment for olfactory disturbances. The aim of this study was to obtain improvement in olfaction after 4 weeks of intranasal insulin administration in a group of patients presenting chronic olfactory disturbances secondary to COVID-19 infection, quantified using the Threshold, Discrimination, and Identification (TDI) score based on the Sniffin Sticks®. METHODS: Experimental, longitudinal, prolective and prospective study of patients with a previous diagnosis of COVID-19 in the last 3-18 months and who persisted with anosmia or hyposmia. The sample size was calculated with "satulator". The intervention was performed from January to May 2022. Throughout four appointments, a baseline olfactory measurement was obtained using the TDI score based on the Sniffin Sticks® test. In the first three appointments, Gelfoam® cottonoids soaked in 40 IU of NPH insulin were placed on the nasal roof of each nostril for 15 min. Descriptive statistics, student's paired t test and a multiple linear regression were utilized to ascertain statistical significance of the outcome on the TDI score obtained on the fourth and final appointment. RESULTS: 27 patients were included in the study. Table 1 summarizes the sample characteristics. The results exhibit that 93% of the sample had an improvement. The initial mean TDI score was 67% (63-71) compared to the final mean of 83% (80-86, p < 0.01). TDI subsection analysis is shown in Table 2. There was no significant difference in pre-intervention and post-intervention glucose measurements after the intranasal insulin administration. CONCLUSIONS: The administration of intranasal insulin has promising results, pointing towards an alternative of treatment for chronic olfactory disturbances secondary to neuroepithelial damage caused by upper respiratory tract infections. Furthermore, this is the first study to use a three-point assessment of olfaction in post-COVID-19 patients, while using the Sniffin Sticks® TDI score adapted to Latin Spanish.

Design and Evaluation of a Potential Non-Invasive Neurostimulation Strategy for Treating Persistent Anosmia in Post-COVID-19 Patients.

A new pandemic was declared at the end of 2019 because of coronavirus disease 2019 (COVID-19). One of the effects of COVID-19 infection is anosmia (i.e., a loss of smell). Unfortunately, this olfactory dysfunction is persistent in around 5% of the world's population, and there is not an effective treatment for it yet. The aim of this paper is to describe a potential non-invasive neurostimulation strategy for treating persistent anosmia in post-COVID-19 patients. In order to design the neurostimulation strategy, 25 subjects who experienced anosmia due to COVID-19 infection underwent an olfactory assessment while their electroencephalographic (EEG) signals were recorded. These signals were used to investigate the activation of brain regions during the olfactory process and identify which regions would be suitable for neurostimulation. Afterwards, 15 subjects participated in the evaluation of the neurostimulation strategy, which was based on applying transcranial direct current stimulation (tDCS) in selected brain regions related to olfactory function. The results showed that subjects with lower scores in the olfactory assessment obtained greater improvement than the other subjects. Thus, tDCS could be a promising option for people who have not fully regained their sense of smell following COVID-19 infection.

Use of platelet-rich plasma for COVID-19-related olfactory loss: a randomized controlled trial.

INTRODUCTION: The current study evaluated the use of platelet-rich plasma (PRP), an autologous blood product with supraphysiologic concentrations of growth factors, in the treatment of prolonged coronavirus disease 2019 (COVID-19)-related smell loss. METHODS: This multi-institutional, randomized controlled trial recruited patients with COVID-19 who had objectively measured smell loss (University of Pennsylvania Smell Identification Test [UPSIT] ≤ 33) between 6 and 12 months. Patients were randomized to three intranasal injections of either PRP or sterile saline into their olfactory clefts. The primary outcome measure was change in Sniffin' Sticks score (threshold, discrimination, and identification [TDI]) from baseline. The secondary end point measures included responder rate (achievement of a clinically significant improvement, ≥5.5 points TDI), change in individual TDI olfaction scores, and change in subjective olfaction via a visual analog scale. RESULTS: A total of 35 patients were recruited and 26 completed the study. PRP treatment resulted in a 3.67-point (95% CI: 0.05-7.29, p = 0.047) greater improvement in olfaction compared with the placebo group at 3 months and a higher response rate (57.1% vs 8.3%, odds ratio 12.5 [95% exact bootstrap confidence interval, 2.2-116.7]). There was a greater improvement in smell discrimination following PRP treatment compared with placebo but no difference in smell identification or threshold. There was no difference in subjective scores between PRP and placebo. No adverse effects were reported. CONCLUSION: Olfactory function following COVID-19 can improve spontaneously after 6 months and can improve to a greater extent with PRP injection. These data build on the promise of PRP to be a safe potential treatment option for patients with COVID-19-related smell loss, and larger-powered studies will help further assess its efficacy.

Corticosteroid nasal irrigation as early treatment of olfactory dysfunction in COVID-19: A prospective randomised controlled trial.

OBJECTIVE: This study aimed to evaluate the efficacy of corticosteroid irrigation compared to saline to no nasal irrigation in COVID-19 patients with olfactory loss. DESIGN AND SETTING: A randomised controlled study was conducted at the Otolaryngology-Head & Neck Surgery Department, Ramathibodi Hospital, Faculty of Medicine, Mahidol University. PARTICIPANTS: Two hundred thirty-seven COVID-19 participants with a new-onset smell loss were recruited into the study. Two hundred twenty-two participants met the inclusion criteria and were randomised into three groups: corticosteroid irrigation, saline irrigation and no treatment. MAIN OUTCOME MEASURES: The primary outcome was the mean difference in the smell sensation score among the groups after treatment at 1, 2 and 6 weeks. The secondary outcomes measurements included (1) a self-rating quality of life (QOL)-related smell dysfunction score, (2) the change over time in smell sensation score and self-rating QOL-related smell dysfunction score and (3) the median time to complete recovery of smell loss. RESULTS: The mean differences in smell sensation scores among the three groups were not statistically significant at any follow-up period. The mean score of self-rating QOL-related smell dysfunction in the corticosteroid group was significantly better than the other groups at 1 week. The change of outcome scores showed significant improvement over time, regardless of the treatments. The median time to complete smell recovery was similar: 3 weeks. CONCLUSION: This study emphasised that corticosteroid nasal irrigation is not superior to saline or no nasal irrigation in restoring the sense of smell in COVID-19-associated olfactory loss.

Effects of classical olfactory training in patients with COVID-19-related persistent loss of smell.

PURPOSE: The management of post-COVID-19 persistent olfactory dysfunction (OD) is uncertain. Currently, olfactory training is the only evidence-based therapy for post-viral OD. In this study, we evaluated the effectiveness of classical olfactory training (COT) in the treatment of post-COVID-19 persistent OD. MATERIALS AND METHODS: Patients with persistent OD after COVID-19 were assessed using the Sniffin' Sticks test. Fifty-one patients were then divided into two groups based on personal preference: the COT group (n = 31) included subjects who performed COT over 12 weeks, and the control group (n = 20) included subjects who did not receive any treatment. After the exclusion of eight patients, the olfactory performances of 43 patients were re-evaluated and compared to the baseline values. RESULTS: A significantly higher proportion of patients in the COT group improved their olfactory scores above the clinically important difference compared to the control group (40% versus 6%) (p = 0.014). The subjective smell improvement by COT was independent of age, gender, OD duration, presence of parosmia, or the initial olfactory score (all p > 0.05). CONCLUSION: Twelve weeks of COT appears to increase the olfactory sensitivity in patients with persistent OD following COVID-19.

Resultados terapêuticos da homeopatia em pacientes suspeitos ou confirmados de COVID-19: um estudo longitudinal prospectivo / Therapeutic results of homeopathy in suspected or confirmed COVID-19 patients: a longitudinal study

A infecção humana causada pelo vírus SARS-CoV-2 (COVID-19), diagnosticada como pneumonia de causa desconhecida originalmente na cidade de Wuhan (China), foi considerada como pandemia pela Organização Mundial da Saúde. Com a inexistência inicial de uma vacina para proteção dos sadios, foi adotada a estratégia de isolamento social e tratamento com medidas de suporte geral e/ou avançado. Neste contexto, coube investigar a contribuição da terapêutica homeopática no enfrentamento da doença, notadamente no alívio dos sintomas desconfortáveis por ela provocados em sua fase inicial, com acompanhamento e registro dos resultados obtidos pelos médicos homeopatas. MÉTODO: Este estudo coletou, durante o período de maio a setembro de 2020 (após aprovação pelo CEP), informações de pacientes diagnosticados com a doença, tratados por médicos homeopatas com medicamentos homeopáticos escolhidos de acordo com a sintomatologia apresentada pelo paciente. Foram avaliados os efeitos no estado de saúde do paciente, por meio de escores e escalas clínicas, bem como aspectos relacionados à segurança do medicamento, variação na duração da doença e medicamentos mais associados a eventuais sucessos terapêuticos. Questionário padronizado e específico para a COVID-19 foi elaborado e e aplicado para preenchimento dos médicos colaboradores do estudo durante o acompanhamento dos pacientes. Os dados foram armazenados em planilhas eletrônicas e analisados com técnicas estatísticas descritivas e inferenciais. Os pacientes selecionados eram colaboradores do Hospital Santo Antônio - Obras Sociais Irmã Dulce (OSID) e foram submetidos a uma avaliação preliminar presencial no ambulatório de Otorrinolaringologia deste hospital. As consultas homeopáticas foram realizadas por plataforma de Telemedicina para seguimento e acompanhamento do caso. Foram avaliados 116 colaboradores, com faixa etária que variou entre 21 e 66 anos, sendo a média de idade 38 anos; destes, 84 (72%) eram do gênero feminino e 32 (16%) gênero masculino; 53 pacientes (70% dos colaboradores atendidos) eram profissionais da saúde (médicos, enfermeiros e técnicos de enfermagem); 63 (30%) eram colaboradores de áreas administrativas ou técnicas; 50 pacientes tinham critérios para inclusão no grupo de risco (43%). Quanto ao resultado do RT-PCR: 58 pacientes (50%) tiveram RT-PCR detectado (confirmados); 58 pacientes (50%) tiveram RT-PCR não-detectado - destes, 18 pacientes (31%) apresentaram anosmia em sua evolução. Dos 116 pacientes do critério de inclusão, 77 estavam incluídos na síndrome clássica da COVID19. Destes 77 colaboradores, 3 não usaram o medicamento homeopático (N=74). Os medicamentos homeopáticos mais indicados foram: Arsenicum album (42%); Bryonia (24%), Phosphorus (15%); Gelsemium (15%); Pulsatilla (2%); outros (4%). O Score médio de sintomas antes do tratamento foi 12,27 e após o tratamento foi 0,52 (p < xxxxx). Dos 57 pacientes que tiveram anosmia, houve recuperação total em 43 (75%) dos casos no momento da reavaliação. O tempo médio decorrido entre o uso da medicação homeopática e a recuperação dos sintomas foi de 9 dias. Apenas 3 pacientes (3,9%) necessitaram de internamento hospitalar sem necessidade de intubação, sendo 2 deles pertencentes ao grupo de risco. apesar destes resultados serem parciais (pois ainda existem sujeitos da pesquisa ainda em fase de avaliação), os resultados sugerem que o tratamento homeopático promoveu o restabelecimento do quadro infeccioso sem necessidade de internamento em 97% dos pacientes. A anosmia teve recuperação completa em 75% dos pacientes. Arsenicum album, Bryonia e Phosphorus foram os medicamentos predominantemente eleitos para o tratamento, o que corrobora com outros estudos homeopáticos.

The human infection caused by the SARS-CoV-2 virus (COVID-19), originally diagnosed as pneumonia of unknown cause in the city of Wuhan (China), was considered a pandemic by the World Health Organization. With the initial lack of a vaccine to protect healthy people, the strategy relating to social isolation and treatment with general and/or advanced support measures was adopted. In this context, it was necessary to investigate the contribution of homeopathic therapy in coping with the disease, particularly in terms of relieving the uncomfortable symptoms caused by it in its initial phase, with monitoring and recording of the results obtained by homeopathic physicians. METHOD: This study collected information from patients diagnosed with the disease, treated by homeopathic physicians with homeopathic medications chosen according to the symptoms manifested by the patient, from May to September 2020 (after approval by the REC). The effects on the health conditions of patients were assessed using clinical scores and scales, as well as aspects related to the safety of the medication, variations in the duration of the disease and the medications most associated with any therapeutic successes. A standardized questionnaire specific to COVID-19 was drawn up and filled in by the physicians who collaborated in the study during patient monitoring. The data was stored in electronic spreadsheets and analyzed using descriptive and inferential statistical techniques. The selected patients were employees of Hospital Santo Antônio - Obras Sociais Irmã Dulce (OSID) and underwent a preliminary in-person assessment at the otolaryngology outpatient clinic of this hospital. The homeopathic consultations were carried out via a telemedicine platform to follow-up and monitor the case. A total of 116 employees were assessed, ranging in age from 21 to 66, with the average age being 38; of these, 84 (72%) were females and 32 (16%) males; 53 patients (70% of the employees cared for) were health care professionals (physicians, nurses and nursing technicians); 63 (30%) were employees from administrative or technical areas; 50 patients met the criteria for inclusion in the risk group (43%). As for the RT-PCR result: 58 patients (50%) had RT-PCR detected (confirmed); 58 patients (50%) had RT-PCR not detected - of these, 18 patients (31%) had anosmia during their evolution. Of the 116 patients who met the inclusion criteria, 77 were included in the classic COVID-19 syndrome. Of these 77 collaborators, 3 did not use homeopathic medication (N=74). The most indicated homeopathic medications were: Arsenicum album (42%); Bryonia (24%), Phosphorus (15%); Gelsemium (15%); Pulsatilla (2%); others (4%). The average symptom score before treatment was 12.27 and after treatment was 0.52 (p < xxxxx). Of the 57 patients who had anosmia, there was full recovery in 43 (75%) of the cases at the time of reassessment. The average time elapsed between the use of homeopathic medication and the recovery of symptoms was 9 days. Only 3 patients (3.9%) required hospitalization without the need for intubation, 2 of whom belonged to the risk group. Although these results are partial (as there are still research subjects in the evaluation phase), the results suggest that homeopathic treatment promoted the re-establishment of the infectious condition without the need for hospitalization in 97% of the patients. Anosmia recovered completely in 75% of the patients. Arsenicum album, Bryonia and Phosphorus were the drugs predominantly chosen for treatment, which corroborates other homeopathic studies.

Olfactory training for olfactory dysfunction in COVID-19: A promising mitigation amidst looming neurocognitive sequelae of the pandemic.

Olfactory dysfunction (OD) is a recognized symptom of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is independently associated with neurodegenerative disorders. Moreover, the central nervous system manifestations in patients infected with the coronavirus-2019 (COVID-19) have demonstrated cognitive decline and neuropsychiatric manifestations. Hence, OD in COVID-19 necessitates perusal of its mechanism and available treatment options to avert possible development of neurocognitive sequelae of the pandemic. The article presents a literature review organized from the published information about olfactory training (OT) for OD during COVID-19. The methodology comprised retrieval of available literature from database searches and subsequent scrutinization of relevant information. Inferentially, injury to the sustentacular cells, possessing angiotensin-converting enzyme 2 (ACE-2) receptors, is an important mechanism causing OD in COVID-19. Olfactory dysfunction may be prolonged in severe cases of anosmia predisposing to neurodegenerative and cognitive impairment in COVID-19 infection. Olfactory training demonstrates an effective treatment for OD based on human and animal-derived evidence through recent studies. It curtails the progression of OD, besides inducing neural rearrangement and changes in functional connectivity in patients receiving OT. Additionally, contemporary reports support that the administration of OT for COVID-induced anosmia is effective and encompasses no significant adverse effects. The present review highlights the prominence of olfactory training as a recommended intervention for OD in COVID-19. This review can guide the clinicians in curbing neurological repercussions of COVID besides enhancing cognitive rehabilitation through olfactory training.

Síndrome Pos-COVID y Síndrome de Fatiga Crónica: ¿Dos caras de la misma moneda? / POST-COVID SYNDROME AND CHRONIC FATIGUE SYNDROME: TWO SIDES OF THE SAME COIN

El síndrome de fatiga crónica es una enfermedad caracterizada, principalmente, por la manifestación de la fatiga, el dolor muscular difuso, y alteraciones en el sueño, en un periodo de no menos de 6 meses y que no son explicables por alguna causa. Es llamativo que, luego de un periodo de tiempo de padecer la COVID-19, los pacientes presenten síntomas similares a los hallados en el síndrome de fatiga crónica. A esta afección se la denomino síndrome pos-COVID. Los virus son los principales sospechosos en la aparición de ambos síndromes, estos podrían ocasionar la generación de daño mitocondrial, una neuroinflamación, alteración en el sistema glinfático o la disfunción en el eje hipotálamo-pituitario-adrenal entre otros. Dichos mecanismos serían los implicados en la aparición de los síntomas que padecen los pacientes con estos síndromes. El objetivo de esta revisión literaria es analizar y describir los posibles mecanismos que explicarían la manifestación de los síntomas del síndrome de fatiga crónica en los pacientes que hayan sufrido la COVID-19. Hasta el momento no existen tratamientos totalmente efectivos para erradicar los síntomas en ambos síndromes. Dado el abanico de síntomas que padecen estos pacientes, el enfoque terapéutico debe ser interdisciplinario para tratar de mejorar su calidad de vida.

Olfactory Training and Visual Stimulation Assisted by a Web Application for Patients With Persistent Olfactory Dysfunction After SARS-CoV-2 Infection: Observational Study.

BACKGROUND: Persistent olfactory dysfunction is a significant complication of SARS-CoV-2 infection. Olfactory training involving aromatic oils has been recommended to improve olfactory recovery, but quantitative data are missing. OBJECTIVE: We aimed to quantify the benefit of olfactory training and visual stimulation assisted by a dedicated web application for patients who experienced olfactory dysfunction for ≥1 month. METHODS: We performed an observational, real-life, data-based study on a cohort of patients who experienced at least 1 month of persistent olfactory dysfunction between January 30 and March 26, 2021. An analysis was performed after a mean olfactory training time of 4 weeks, and at least 500 patients were assessable for primary outcome assessment. Participants exposed themselves twice daily to odors from 4 high-concentration oils and visual stimulation assisted by a dedicated web application. Improvement was defined as a 2-point increase on a 10-point, self-assessed olfactory visual analogue scale. RESULTS: In total, 548 patients were assessable for primary outcome assessment. The mean baseline, self-assessed olfactory score was 1.9 (SD 1.7), and this increased to 4.6 (SD 2.8) after a mean olfactory training time of 27.7 days (SD 17.2). Olfactory training was associated with at least a 2-point increase in 64.2% (352/548) of patients. The rate of patients' olfactory improvement was higher for patients who trained for more than 28 days than that rate for patients who trained for less than 28 days (73.3% vs 59%; P=.002). The time to olfactory improvement was 8 days faster for patients with hyposmia compared to the time to improvement for patients with anosmia (P<.001). This benefit was observed regardless of the duration of the olfactory dysfunction. CONCLUSIONS: Olfactory training and visual stimulation assisted by a dedicated web application was associated with significant improvement in olfaction, especially after 28 days of olfactory training.

Anosmia in the first coronavirus disease 2019 outbreak in Europe: functional recovery after eight months.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 is a formidable virus, responsible for coronavirus disease 2019 and endowed with marked neurotropism. The damage it causes to the nervous system is manifold. The main neurological manifestation is anosmia. Olfactory damage is often transient, but there are no data reflecting an observational period of several months. OBJECTIVE: This study evaluated the trend of anosmia in patients affected by coronavirus disease 2019 in the eight months following diagnosis. METHODS: Fifty-five subjects who presented with symptoms suggestive of coronavirus disease 2019 and who developed anosmia, between the end of February and the beginning of March 2020, were investigated. The patients were interviewed after eight months to determine functional recovery and assess the degree of recovery. RESULTS: Ninety-one per cent of the population reported olfactory recovery and, of these, 53 per cent had total recovery after eight months. Females and younger age groups seem slightly advantaged in functional recovery. The elderly population appears to have excellent prospects for full functional recovery. CONCLUSION: Anosmia represents a frequent neurological manifestation during coronavirus disease 2019. Fortunately, it is transient in most cases, and only a small percentage of patients affected by it report long-term functional deficits.

Olfactory and taste dysfunctions in COVID-19.

PURPOSE OF REVIEW: Olfactory dysfunction (OD) can be a single and early prominent symptom of severe acute respiratory syndrome (SARS)-COV-2 infection unlike middle east respiratory syndrome (MERS) and SARS. OD data are very informative but many are not peer-reviewed, often inconclusive and may reveal variable and sometimes contradictory results. This is often due to incongruent data of subjective and objective OD testing. Mechanistic pathways of OD and taste dysfunction (TD) are slowly unveiling, not infrequently extrapolated from historical models of SARS and MERS and are still partly unclear. RECENT FINDINGS: We reviewed the literature on OD and TD during the COVID-19 pandemic analyzing current data on pathogenesis and clinical correlates including prevalence, recovery rates, risk factors, and predictive power. Also, we evaluated various methods of subjective and objective olfactory testing and discussed challenges in management of patients with OD and rhinitis during the pandemic. SUMMARY: Subjective evaluation of smell disturbances during COVID-19 pandemic likely underestimates true prevalence, severity, and recovery rates of OD when compared to objective testing. OD is predictive of COVID-19 infection, more so when associated with TD. Recognizing inherent limitations of both subjective and objective OD and TD testing enables us better to manage chemosensory dysfunction in COVID-19 patients. Besides, current mechanistic data suggest neurotropism of COVID-19 for olfactory neuro-epithelium and a potential role of transient receptor potential (TRP) channels. Future studies are needed to explore further the neurogenic inflammation in COVID-19.

COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice.

The ongoing coronavirus disease 2019 (COVID-19) pandemic is associated with substantial morbidity and mortality. Although much has been learned in the first few months of the pandemic, many features of COVID-19 pathogenesis remain to be determined. For example, anosmia is a common presentation, and many patients with anosmia show no or only minor respiratory symptoms1. Studies in animals infected experimentally with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of COVID-19, provide opportunities to study aspects of the disease that are not easily investigated in human patients. Although the severity of COVID-19 ranges from asymptomatic to lethal2, most experimental infections provide insights into mild disease3. Here, using K18-hACE2 transgenic mice that were originally developed for SARS studies4, we show that infection with SARS-CoV-2 causes severe disease in the lung and, in some mice, the brain. Evidence of thrombosis and vasculitis was detected in mice with severe pneumonia. Furthermore, we show that infusion of convalescent plasma from a recovered patient with COVID-19 protected against lethal disease. Mice developed anosmia at early time points after infection. Notably, although pre-treatment with convalescent plasma prevented most signs of clinical disease, it did not prevent anosmia. Thus, K18-hACE2 mice provide a useful model for studying the pathological basis of both mild and lethal COVID-19 and for assessing therapeutic interventions.

Remission of anosmia in a patient receiving chiropractic care: A case report.

OBJECTIVE: To chronicle the remission of anosmia in a 79-year-old female receiving chiropractic care using the Activator Methods Chiropractic Technique (AMCT) protocol. CLINICAL FEATURES: A 79-year-old white female with a 4-year history of medically diagnosed anosmia. Postural alterations, reduction in cervical ranges of motion (ROM), and absent cranial nerve I function were found in conjunction with vertebral subluxation throughout the spine and mild to severe degenerative changes throughout the spine present on radiographic studies. INTERVENTION & OUTCOMES: Chiropractic care using AMCT was provided for the assessment and correction of vertebral subluxations. The patient reported subjective improvement in olfaction, physical functioning and life enjoyment, and demonstrated objective improvement in posture, cervical ROM, cranial nerve I function. CONCLUSION: A course of chiropractic care, following the AMCT protocol, was associated with remission of anosmia.