Natural trajectory of recovery of COVID-19 associated olfactory loss.

IMPORTANCE: Prevalence of post-viral olfactory loss has increased dramatically due to the frequency and severity of olfactory dysfunction associated with infection by the SARS-CoV-2 virus. OBJECTIVE: To determine the trajectory of COVID-19 olfactory loss over a six-month period. A key secondary objective is to assess predictive factors associated with the recovery of olfaction. DESIGN: Longitudinal repeated-measures study that enrolled from May 5, 2020 to February 2, 2021, with the last date of data collection on June 15, 2021. SETTING: Barnes-Jewish HealthCare/Washington University School of Medicine facilities (Saint Louis, Missouri, USA). PARTICIPANTS: Individuals who tested positive for SARS-CoV-2 by real-time polymerase chain reaction on nasopharyngeal swab and indicated olfactory loss on COVID-19 screening questionnaire. Individuals were excluded if they had previously diagnosed history of olfactory loss, neurodegenerative disorders, <18 years of age, admitted to hospital service, unable to read, write, and understand English, or lacked computer or internet access. INTERVENTIONS/EXPOSURES: Watch and wait for spontaneous recovery. MAIN OUTCOME(S) AND MEASURE(S): Participants completed olfactory assessments every 30 days for six months. Each assessment consisted of the University of Pennsylvania Smell Identification Test (UPSIT), an objective "scratch-and-sniff" test, and Clinical Global Impressions (CGI), a subjective Likert rating scale. RESULTS: The mean age was 41 years old (SD = 16). 39 (80 %) were female and 42 (86 %) white. At baseline assessment of objective olfaction, 18 (36 %) participants had anosmia or severe hyposmia. Subjective, complete recovery at six months was 81 % (95 % CI 74 % to 88 %). Likelihood of recovery was associated with age <50 years (aHR = 8.1 (95 % CI 1.1 to 64.1)) and mild olfactory loss at baseline (UPSIT = 30-33 for males and 31-34 for females) (aHR 6.2 (95 % CI 1.2 to 33.0)). CONCLUSIONS AND RELEVANCE: The trajectory of olfactory recovery among adults with COVID-19 olfactory loss illustrated rapid recovery within 2-3 weeks of infection, and by six months 81 % had recovered based on self-report. Age <50 years old and mild severity of olfactory loss at baseline were associated with increased likelihood of recovery of olfaction. These findings can be used to inform shared decision-making with patients.

Smell Changes and Efficacy of Nasal Theophylline (SCENT) irrigation: A randomized controlled trial for treatment of post-viral olfactory dysfunction.

OBJECTIVE: To evaluate the efficacy and safety of intranasal theophylline saline irrigation on olfactory recovery in patients with post-viral olfactory dysfunction (PVOD). METHODS: Between May 2019 and April 2020, we conducted a double-blinded, placebo-controlled randomized clinical trial of adults with 6-36 months of PVOD. Patients were randomized to nasal theophylline saline irrigation or placebo saline irrigation twice a day for 6 weeks. The primary outcome was the Global Rating of Smell Change. Secondary outcomes were changes in the University of Pennsylvania Smell Identification Test (UPSIT) and Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS). RESULTS: Twenty-two patients (n = 12, theophylline; n = 10, placebo) completed the study. Slightly more patients in the theophylline group (33%) reported improved smell compared to the placebo group (30%, difference 3.3%, 95% CI -35.6% to 42.3%). The median differences in pre- and post-treatment UPSIT and QOD-NS change between the two groups were 1 (95% CI -3 to 5) and -10 (95% CI -15 to -4), respectively in favor of theophylline. Three patients receiving theophylline and 2 receiving placebo had clinically meaningful improvements on the UPSIT (difference 5%, 95% CI -30% to 40%). There were no adverse events, and serum theophylline levels were undetectable in 10/10 patients. CONCLUSIONS: While safe, there were no clinically meaningful differences in olfactory change between the two groups except for olfaction-related quality of life, which was better with theophylline. The imprecise estimates suggest future trials will need substantially larger sample sizes or treatment modifications, such as increasing the theophylline dose, to observe larger treatment effects.

Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia.

DESCRIPTION: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. METHODS: The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. RECOMMENDATIONS: The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

Trends in the risk and burden of second primary malignancy among survivors of smoking-related cancers in the United States.

While there are a growing number of cancer survivors, this population is at increased risk of developing second primary malignancies (SPMs). We described the incidence, most common tumor sites, and trends in burden of SPM among survivors of the most commonly diagnosed smoking-related cancers. The current study was a population-based study of patients diagnosed with a primary malignancy from the top 10 smoking-related cancer sites between 2000 and 2014 from Surveillance, Epidemiology, and End Results data. SPM risks were quantified using standardized incidence ratios (SIRs) and excess absolute risks (EARs) per 10,000 person-years at risk (PYR). Trends in the burden of SPM were assessed using Joinpoint regression models. A cohort of 1,608,607 patients was identified, 119,980 (7.5%) of whom developed SPM (76% of the SPMs were smoking-related). The overall SIR of developing second primary malignancies was 1.51 (95% CI, 1.50-1.52) and the EAR was 73.3 cases per 10,000 PYR compared to the general population. Survivors of head and neck cancer had the highest risk of developing a SPM (SIR = 2.06) and urinary bladder cancer had the highest excess burden (EAR = 151.4 per 10,000 PYR). The excess burden of SPM for all smoking-related cancers decreased between 2000 and 2003 (annual percentage change [APC] = -13.7%; p = 0.007) but increased slightly between 2003 and 2014 (APC = 1.6%, p = 0.032). We show that 1-in-12 survivors of smoking-related cancers developed an SPM. With the significant increase in the burden of SPM from smoking-related cancers in the last decade, clinicians should be cognizant of long-term smoking-related cancer risks among these patients as part of their survivorship care plans.

Prevalence of Inappropriate Antibiotic Prescriptions Among US Ambulatory Care Visits, 2010-2011.

IMPORTANCE: The National Action Plan for Combating Antibiotic-Resistant Bacteria set a goal of reducing inappropriate outpatient antibiotic use by 50% by 2020, but the extent of inappropriate outpatient antibiotic use is unknown. OBJECTIVE: To estimate the rates of outpatient oral antibiotic prescribing by age and diagnosis, and the estimated portions of antibiotic use that may be inappropriate in adults and children in the United States. DESIGN, SETTING, AND PARTICIPANTS: Using the 2010-2011 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, annual numbers and population-adjusted rates with 95% confidence intervals of ambulatory visits with oral antibiotic prescriptions by age, region, and diagnosis in the United States were estimated. EXPOSURES: Ambulatory care visits. MAIN OUTCOMES AND MEASURES: Based on national guidelines and regional variation in prescribing, diagnosis-specific prevalence and rates of total and appropriate antibiotic prescriptions were determined. These rates were combined to calculate an estimate of the appropriate annual rate of antibiotic prescriptions per 1000 population. RESULTS: Of the 184,032 sampled visits, 12.6% of visits (95% CI, 12.0%-13.3%) resulted in antibiotic prescriptions. Sinusitis was the single diagnosis associated with the most antibiotic prescriptions per 1000 population (56 antibiotic prescriptions [95% CI, 48-64]), followed by suppurative otitis media (47 antibiotic prescriptions [95% CI, 41-54]), and pharyngitis (43 antibiotic prescriptions [95% CI, 38-49]). Collectively, acute respiratory conditions per 1000 population led to 221 antibiotic prescriptions (95% CI, 198-245) annually, but only 111 antibiotic prescriptions were estimated to be appropriate for these conditions. Per 1000 population, among all conditions and ages combined in 2010-2011, an estimated 506 antibiotic prescriptions (95% CI, 458-554) were written annually, and, of these, 353 antibiotic prescriptions were estimated to be appropriate antibiotic prescriptions. CONCLUSIONS AND RELEVANCE: In the United States in 2010-2011, there was an estimated annual antibiotic prescription rate per 1000 population of 506, but only an estimated 353 antibiotic prescriptions were likely appropriate, supporting the need for establishing a goal for outpatient antibiotic stewardship.

The role of postoperative chemoradiation for oropharynx carcinoma: a critical appraisal of the published literature and National Comprehensive Cancer Network guidelines.

The National Comprehensive Cancer Network (NCCN) describes the presence of extracapsular spread and/or positive margins in oropharynx cancer (OPC) as an indication for the addition of chemotherapy to postoperative radiation. The guideline's category 1 consensus is based on what they term high-level evidence. For this study, the authors performed a critical appraisal of the research upon which the NCCN guideline is based and assessed its relevance in the era of human papillomavirus (HPV)/p16-positive OPC. Multiple shortcomings were identified, including patient exclusion after randomization and the use of unplanned subgroup analyses without multivariate adjustment, which undermined internal validity. Indeterminate HPV/p16 status limited external validity. Given the unique biology of HPV/p16-positive tumors and the problems of internal and external validity, the authors concluded that the literature upon which the recommendation for the addition of chemotherapy to adjuvant radiation was based does not generate high-level evidence, and its relevance for the postoperative management of patients with HPV/p16-positive OPC remains unknown.

Cognitive impairment after chemotherapy related to atypical network architecture for executive control.

OBJECTIVES: A common complaint of cancer patients is the experience of cognitive difficulty during and after chemotherapy. We hypothesized that cognitive impairment may result from dysfunction in large-scale brain networks, particularly those involved in attentional control. METHODS: Using a case-control design, this study includes women with a history of invasive ductal or lobular triple-negative breast cancer who completed standard adjuvant chemotherapy within 2 years of study entry. Women who reported cognitive impairment by the Global Rating of Cognition question were considered to be cases (n = 15). Women who reported no cognitive impairment were considered to be controls (n = 13). All enrolled participants were eligible for MRI investigation and underwent resting-state functional connectivity MRI. RESULTS: Women who self-reported cognitive impairment were found to have disrupted resting-state functional connectivity, as measured by MRI, when compared to women who did not self-report cognitive impairment. These findings suggest that some women may be more sensitive to the standard treatments for breast cancer and that this increased sensitivity may result in functional connectivity alterations in the brain networks supporting attention and executive function. CONCLUSIONS: Neuroimaging analyses confirmed self-reported cognitive deficits in women with breast cancer treated with chemotherapy.

Assessment of comorbidities in surgical oncology outcomes.

The impact of comorbidities on treatment, postoperative complications, survival, prognosis, and quality of life, makes comorbidities' assessment essential in surgically managed cancer patients. Multiple indices exist to measure the presence and severity of comorbidities, of which the Charlson Comorbidity Index and the Adult Comorbidity Evaluation-27 are the most widely employed. Incorporation of comorbidity data in cancer registries facilitates surgical oncology research conduct with an objective to improve cancer care through better-informed patient counseling and treatment planning.

Validation of Minimal Clinically Important Difference (MCID) for University of Pennsylvania Smell Identification Test (UPSIT).

BACKGROUND: The University of Pennsylvania Smell Identification Test is widely used to measure change in olfactory function, but a minimal clinically important difference (MCID) has not been well-established. A study published in 1997 regarding patients with head trauma reported an MCID of 4 but did not detail the methods used in the calculation. OBJECTIVE: To validate the MCID for UPSIT in patients with postviral, sinusitis, and procedure-associated olfactory loss. METHODS: This was a secondary analysis of prospectively collected data from 5 clinical research studies related to olfactory function. Three studies included subjects with COVID-19-related olfactory dysfunction, one with chronic sinusitis subjects, and one with subjects undergoing transsphenoidal surgery. All subjects had completed a baseline and follow-up UPSIT, baseline and follow-up Clinical Global Impression-Severity (CGI-Severity), and a follow-up CGI-Improvement. Both distribution- and anchor-based methods were used to determine the MCID of UPSIT. Distribution-based method calculated MCID using half standard deviation of baseline UPSIT and delta UPSIT scores. Clinical-anchor method determined MCID by comparing delta UPSIT scores between consecutive CGI-I clinical categories ranging from very much better to very much worse. RESULTS: The study population comprised 295 subjects. Subjects had a mean (SD) baseline UPSIT score of 27 (7.5), and follow-up score of 28 (7.9), and a mean UPSIT change of 0.6 (5.8). Half the baseline UPSIT SD was 3.75 and half the delta UPSIT SD was 2.9. With the anchor-based approach, an MCID of 4 was defined as clinically meaningful by exploring the relationship between delta UPSIT and CGI-Improvement. Using a more conservative approach based on the MCID values identified from both methods, we determined that a change of 4 or greater is the appropriate MCID for UPSIT. CONCLUSION: Investigators in the future should use 4 as MCID for UPSIT and report the percentage of study subjects who achieve a clinically meaningful difference. LEVEL OF EVIDENCE: III.

Clinical studies in COVID-related olfactory disorders: Review of an institutional experience.

Objective: To share a single institutional experience with clinical research on COVID-related olfactory dysfunction (OD). Data Source/Method: Narrative review of published original data and ongoing clinical trials on COVID-related OD at Washington University from 2020 to 2023. Results: There were three new diagnostic-/patient-reported outcome measures developed and tested. We report five clinical trials of interventions for COVID-related olfactory disorders: combined Visual-Olfactory Training (VOLT) with patient-preferred scents versus standard olfactory training (VOLT trial), oral gabapentin versus placebo (Gabapentin for the Relief of Acquired Chemosensory Experience trial), nasal theophylline irrigations versus placebo (Smell Changes and Efficacy of Nasal Theophylline trial), stellate ganglion block (single-arm), and mindfulness-based stress reduction (MBSR) versus lifestyle intervention (MBSR trial). Conclusions: Initial intervention trials for COVID-related OD have shown potential for improving subjective and objective olfactory outcomes. However, there remains no gold standard treatment that definitively outperforms placebo in controlled trials. Therefore, continued investigation of novel therapeutic strategies for COVID-related OD is necessary to maximize olfactory outcomes for affected patients.