Long COVID exhibits clinically distinct phenotypes at 3-6 months post-SARS-CoV-2 infection: results from the P4O2 consortium.

BACKGROUND: Four months after SARS-CoV-2 infection, 22%-50% of COVID-19 patients still experience complaints. Long COVID is a heterogeneous disease and finding subtypes could aid in optimising and developing treatment for the individual patient. METHODS: Data were collected from 95 patients in the P4O2 COVID-19 cohort at 3-6 months after infection. Unsupervised hierarchical clustering was performed on patient characteristics, characteristics from acute SARS-CoV-2 infection, long COVID symptom data, lung function and questionnaires describing the impact and severity of long COVID. To assess robustness, partitioning around medoids was used as alternative clustering. RESULTS: Three distinct clusters of patients with long COVID were revealed. Cluster 1 (44%) represented predominantly female patients (93%) with pre-existing asthma and suffered from a median of four symptom categories, including fatigue and respiratory and neurological symptoms. They showed a milder SARS-CoV-2 infection. Cluster 2 (38%) consisted of predominantly male patients (83%) with cardiovascular disease (CVD) and suffered from a median of three symptom categories, most commonly respiratory and neurological symptoms. This cluster also showed a significantly lower forced expiratory volume within 1 s and diffusion capacity of the lung for carbon monoxide. Cluster 3 (18%) was predominantly male (88%) with pre-existing CVD and diabetes. This cluster showed the mildest long COVID, and suffered from symptoms in a median of one symptom category. CONCLUSIONS: Long COVID patients can be clustered into three distinct phenotypes based on their clinical presentation and easily obtainable information. These clusters show distinction in patient characteristics, lung function, long COVID severity and acute SARS-CoV-2 infection severity. This clustering can help in selecting the most beneficial monitoring and/or treatment strategies for patients suffering from long COVID. Follow-up research is needed to reveal the underlying molecular mechanisms implicated in the different phenotypes and determine the efficacy of treatment.

Effects of a pulmonary rehabilitation program on pulmonary function, exercise performance, and quality of life in patients with severe COVID-19.

BACKGROUND: Severe coronavirus 2019 disease (COVID-19) causes acute hypoxemic respiratory failure requiring invasive mechanical ventilation (IMV). Once these symptoms are resolved, patients can present systemic deterioration. OBJECTIVE: The two objectives of this study were as follows: to describe the results of a pulmonary rehabilitation program (PRP), which is divided into three groups with different numbers of sessions (12, 24, and 36), and to associate the variables of pulmonary function, exercise performance, and functionality with the number of sessions and functional improvement. DESIGN: Prospective, observational study. METHODS: PRP consisted of aerobic + strength + flexibility exercises under the supervision and individualized into 12, 24, or 36 sessions (12s, 24s, and 36s), depending on the evolution of each patient. At the beginning of the study and immediately after the intervention, forced vital capacity (FVC), maximal inspiratory pressure, 6-minute walk test (6MWT), sit-to-stand test (STS), maximal handgrip strength (HGS), Fatigue Assessment Scale, Post-COVID-19 Functional Status (PCFS), and health-related quality of life (HRQoL) were measured. RESULTS: The proposed PRP demonstrated a positive effect on pulmonary function, exercise performance, and HRQoL, regardless of the number of sessions. A higher score on the PCFS and more days on IMV were associated with the increased likelihood of needing more sessions, whereas more meters on the 6MWT in the initial evaluation was associated with a reduced likelihood of needing more sessions. Finally, more repetitions on the STS and less distance covered on the initial 6MWT were associated with a greater improvement in exercise performance evaluated with the 6MWT. CONCLUSION: Supervised and individualized PRP for patients with severe post-COVID-19 improves pulmonary function, exercise performance, functionality, and quality of life. Functionality, distance covered on the 6MWT, and the days on IMV are central to the scheduling of the number of sessions for these patients.

Lower airway microbiota compositions differ between influenza, COVID-19 and bacteria-related acute respiratory distress syndromes.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is responsible for 400,000 deaths annually worldwide. Few improvements have been made despite five decades of research, partially because ARDS is a highly heterogeneous syndrome including various types of aetiologies. Lower airway microbiota is involved in chronic inflammatory diseases and recent data suggest that it could also play a role in ARDS. Nevertheless, whether the lower airway microbiota composition varies between the aetiologies of ARDS remain unknown. The aim of this study is to compare lower airway microbiota composition between ARDS aetiologies, i.e. pulmonary ARDS due to influenza, SARS-CoV-2 or bacterial infection. METHODS: Consecutive ARDS patients according to Berlin's classification requiring invasive ventilation with PCR-confirmed influenza or SARS-CoV-2 infections and bacterial infections (> 105 CFU/mL on endotracheal aspirate) were included. Endotracheal aspirate was collected at admission, V3-V4 and ITS2 regions amplified by PCR, deep-sequencing performed on MiSeq sequencer (Illumina®) and data analysed using DADA2 pipeline. RESULTS: Fifty-three patients were included, 24 COVID-19, 18 influenza, and 11 bacterial CAP-related ARDS. The lower airway bacteriobiota and mycobiota compositions (ß-diversity) were dissimilar between the three groups (p = 0.05 and p = 0.01, respectively). The bacterial α-diversity was significantly lower in the bacterial CAP-related ARDS group compared to the COVID-19 ARDS group (p = 0.04). In contrast, influenza-related ARDS patients had higher lung mycobiota α-diversity than the COVID-19-related ARDS (p = 0 < 01). CONCLUSION: Composition of lower airway microbiota (both microbiota and mycobiota) differs between influenza, COVID-19 and bacterial CAP-related ARDS. Future studies investigating the role of lung microbiota in ARDS pathophysiology should take aetiology into account.

Autonomic cardiac function in children and adolescents with long COVID: a case-controlled study.

Although the mechanisms underlying the pathophysiology of long COVID condition are still debated, there is growing evidence that autonomic dysfunction may play a role in the long-term complications or persisting symptoms observed in a significant proportion of patients after SARS-CoV-2 infection. However, studies focused on autonomic dysfunction have primarily been conducted in adults, while autonomic function has not yet been investigated in pediatric subjects. In this study, for the first time, we assessed whether pediatric patients with long COVID present abnormalities in autonomic cardiac function. Fifty-six long COVID pediatric patients (mean age 10.3 ± 3.8 y) and 27 age-, sex-, and body surface area-matched healthy controls (mean age 10.4 ± 4.5y) underwent a standard 12-lead electrocardiography (ECG) and 24-h ECG Holter monitoring. Autonomic cardiac function was assessed by time-domain and frequency-domain heart rate variability parameters. A comprehensive echocardiographic study was also obtained by two-dimensional echocardiography and tissue Doppler imaging. Data analysis showed that pediatric patients with long COVID had significant changes in HRV variables compared to healthy controls: significantly lower r-MSSD (root mean square of successive RR interval differences, 47.4 ± 16.9 versus 60.4 ± 29.1, p = 0.02), significant higher values VLF (very low frequency, 2077.8 ± 1023.3 versus 494.3 ± 1015.5 ms, p = 0.000), LF (low frequency, 1340.3 ± 635.6 versus 354.6 ± 816.8 ms, p = 0.000), and HF (high frequency, 895.7 ± 575.8 versus 278.9 ± 616.7 ms, p = 0.000). No significant differences were observed between the two groups both in systolic and diastolic parameters by echocardiography.  Conclusion: These findings suggest that pediatric patients with long COVID have an imbalance of cardiac autonomic function toward a relative predominance of parasympathetic tone, as already reported in adult patients with long COVID. Further studies are needed to clarify the clinical significance of this autonomic dysfunction and demonstrate its role as a pathophysiological mechanism of long COVID, paving the way for effective therapeutic and preventive strategies. What is Known: • Long Covid in children has been described globally, but studies have mostly focused on collecting the temporal evolution of persisting symptoms. What is New: • Cardiac autonomic imbalance toward a relative predominance of parasympathetic tone is a mechanism underlying Long Covid in children, as also described in adults.

Longitudinal strain and myocardial work in symptomatic patients having recovered from COVID-19 and possible associations with the severity of the disease.

COVID-19 may have residual consequences in multiple organs, including the cardiovascular system. The purpose of the present investigation is to quantify myocardial function in symptomatic individuals with long COVID and investigate the association between illness severity and myocardial function. A retrospective cross-sectional study was conducted in which symptomatic individuals with previous COVID-19 underwent echocardiographic analysis of left ventricle global longitudinal strain (LVGLS) and myocardial work (MW). Individuals also performed cardiopulmonary testing (CPX) to assess peak oxygen uptake (VO2peak). Differences between illness severity subgroups were analyzed by the Mann-Whitney test. Correlations were calculated using the Spearman correlation test. Multilinear regressions were performed to evaluate the influences of COVID-19 severity, body mass index, age, and sex on MW. Fifty-six individuals were included (critical subgroup: 17; moderate/severe subgroup: 39), 59% females; median age: 56 years (IQR: 43-63). CPX revealed a substantial reduction in VO2peak (median of 53% of predicted values). LVGLS were not statistically different between subgroups. Global wasted work (GWW) was higher in the critical subgroup [146 (104-212) versus 121 (74-163) mmHg%, p = 0.01], and global work efficiency (GWE) was lower in this subgroup [93 (91-95) versus 94 (93-96), p = 0.03]. Illness severity was the only independent predictor of GWW and GWE (GWW: r2 = 0.167; p = 0.009; GWE: r2 = 0.172; p = 0.005) in multilinear regressions. In our study with long COVID-19 individuals, despite having a similar LVGLS, patients had subclinical LV dysfunction, demonstrated only by an increase in GWW and a decrease in GWE.

SARS-CoV-2 sneezing explained.

Viral protein prods nerve cells, may be treatment target.

The role of free vitamin D and vitamin D binding protein in SARS-Cov-2 infection in children.

BACKGROUND: Many studies have discussed the effects of serum vitamin D deficiency in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients. This study aimed to investigate the relationship between SARS-CoV-2 infection severity and free vitamin D (FVD) and bioavailable vitamin D (BAVD) levels in children. METHODS: A prospective case-control study design was used. Participants were divided into three groups based on the World Health Organization COVID-19 Clinical Progression Scale. Serum 25-hydroxyvitamin D (ng/mL), albumin (g/L), and vitamin D binding protein (ng/mL) levels were evaluated to investigate the relationship between disease severity and FVD and BAVD levels. RESULTS: In total, 82 participants were included in the study. Of those, 24.4% were uninfected (n = 20), 50% had a mild case of SARS-CoV-2 (n = 41), and 25.6% had a moderate case (n = 21). There was a statistically significant difference in FVD and BAVD levels between the groups (p = 0.026). Median FVD (p = 0.007, Cohen's d = 0.84) and BAVD (p = 0.007, Cohen's d = 0.86) levels were significantly higher in the mild group compared to the moderate group. FVD and BAVD metabolites were moderately positively correlated with lymphocyte counts (FVD: r = 0.437, p < 0.001; BAVD: r = 0.439, p < 0.001). CONCLUSIONS: This is the first study to demonstrate a relationship between SARS-CoV-2 symptom severity and FVD and BAVD levels. The relationship between FVD and BAVD levels and lymphocyte counts could play an important role in symptom severity and should be evaluated in further studies.

Assessment of thermal and temporal stability of SARS-CoV-2 samples using real-time qRT-PCR.

BACKGROUND: As per the guidelines of the Indian Council of Medical Research, nasopharyngeal and oropharyngeal swabs in viral transport medium (VTM) are to be stored at 4 °C for less than 5 days and for more than 5 days at -70 °C. Samples are not transported or stored as per prescribed conditions because of the limitations, resulting in an apprehensive diagnosis. The aim of the study was to test the stability of the SARS-CoV-2 sample stored in VTM at different temperatures. METHODS: In this study, the stability of 21 positive and 9 negative samples for SARS-CoV-2 was evaluated in commercial VTM at different temperatures (-80 °C, -20 °C, 4 °C, and 25 to 30 °C). Stability was checked for up to 50 days in the above storage conditions at different intervals. PathoDetect™ and Hi-PCR® kits were used for the detection of the four genes of SARS-CoV-2. The Cycle Threshold (Ct) value for determining the positivity of samples for PathoDetect™ was < 40 and for Hi-PCR® was < 38. RESULTS: The SARS-CoV-2 confirmatory genes (RdRp and E genes) and the internal housekeeping gene remained detectable even on the 50th day of the study. The Ct of the RdRp and E genes were found to increase with storage duration, but all positive samples remained positive till the end of the study, or the Ct value remained below the cut-off level. The negative samples gave consistent results until the end of the study. When the differences in Ct values were compared between the days in a set of experiments, they were not significantly different except in a few samples. CONCLUSION: The SARS-CoV-2 genetic materials in commercial VTM were stable at room temperature to -80 °C for 50 days.

A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection.

Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic1-4. Although most global efforts have focused on severe illness in COVID-19, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01-peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.

New Alzheimer Disease Drugs, Long COVID and the Central Nervous System, and a Nasal Spray for Migraines-Highlights From the 2023 American Academy of Neurology Conference.

This Medical News article discusses research presented at the recent American Academy of Neurology Conference.

Mucosal immunity in health care workers' respiratory tracts in the post-COVID-19 period.

Coronavirus disease (COVID-19) has generated interest in the assessment of systemic immune status, but existing knowledge about mucosal immunity is clearly insufficient to understand the full pathogenetic mechanisms of the disease. The aim of this study was to evaluate the long-term effects of novel coronavirus infection on mucosal immunity in the postinfection period among health care workers (HCWs). A total of 180 health care workers with and without a history of COVID-19 who ranged in age from 18 to 65 years were enrolled in this one-stage, cross-sectional study. The study subjects completed the 36-Item Short Form (36) Health Survey (SF-36) and the Fatigue Assessment Scale. Secretory immunoglobulin A (sIgA) and total immunoglobulin G (IgG) levels were quantified in saliva samples, induced sputum samples, and nasopharyngeal and oropharyngeal scrapings by an enzyme-linked immunosorbent assay. Specific anti-SARS-CoV-2 IgG antibodies were quantified in serum samples by chemiluminescence immunoassay. Analysis of the questionnaire data showed that all HCWs with a history of COVID-19 reported health problems that limited their daily activities and negative changes in their emotional health three months after the disease, regardless of its severity. The following shifts were detected in the adaptive arm of the immune response in different mucosal compartments. Among subjects who had severe or moderate-to-severe COVID-19, salivary sIgA levels were significantly higher than those in the control group (p < 0.05 and p < 0.005, respectively). Compared to the subjects in the control group, all subjects with prior COVID-19 had significantly higher levels of total IgG in induced sputum. In the group of patients who had had severe infection, total IgG in saliva was also higher (p < 0.05). A direct statistically significant correlation was also detected between the levels of total IgG in all studied samples and the levels of specific IgG antibodies against SARS-CoV-2 in the serum. A significant correlation was observed between total IgG levels and the parameters of physical and social activities, mental health, and fatigue levels. Our study demonstrated long-term changes in the humoral mucosal immune response, which were most pronounced in health care workers with a history of severe or moderate-to-severe COVID-19, and an association of these changes with certain clinical signs of post-COVID-19 syndrome.

SARS-CoV-2 Infection of Human Neurons Is TMPRSS2 Independent, Requires Endosomal Cell Entry, and Can Be Blocked by Inhibitors of Host Phosphoinositol-5 Kinase.

2019 coronavirus disease (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to respiratory illness, COVID-19 patients exhibit neurological symptoms lasting from weeks to months (long COVID). It is unclear whether these neurological manifestations are due to an infection of brain cells. We found that a small fraction of human induced pluripotent stem cell (iPSC)-derived neurons, but not astrocytes, were naturally susceptible to SARS-CoV-2. Based on the inhibitory effect of blocking antibodies, the infection seemed to depend on the receptor angiotensin-converting enzyme 2 (ACE2), despite very low levels of its expression in neurons. The presence of double-stranded RNA in the cytoplasm (the hallmark of viral replication), abundant synthesis of viral late genes localized throughout infected cells, and an increase in the level of viral RNA in the culture medium (viral release) within the first 48 h of infection suggested that the infection was productive. Productive entry of SARS-CoV-2 requires the fusion of the viral and cellular membranes, which results in the delivery of the viral genome into the cytoplasm of the target cell. The fusion is triggered by proteolytic cleavage of the viral surface spike protein, which can occur at the plasma membrane or from endosomes or lysosomes. We found that SARS-CoV-2 infection of human neurons was insensitive to nafamostat and camostat, which inhibit cellular serine proteases, including transmembrane serine protease 2 (TMPRSS2). Inhibition of cathepsin L also did not significantly block infection. In contrast, the neuronal infection was blocked by apilimod, an inhibitor of phosphatidyl-inositol 5 kinase (PIK5K), which regulates early to late endosome maturation. IMPORTANCE COVID-19 is a disease caused by the coronavirus SARS-CoV-2. Millions of patients display neurological symptoms, including headache, impairment of memory, seizures, and encephalopathy, as well as anatomical abnormalities, such as changes in brain morphology. SARS-CoV-2 infection of the human brain has been documented, but it is unclear whether the observed neurological symptoms are linked to direct brain infection. The mechanism of virus entry into neurons has also not been characterized. Here, we investigated SARS-CoV-2 infection by using a human iPSC-derived neural cell model and found that a small fraction of cortical-like neurons was naturally susceptible to infection. The productive infection was ACE2 dependent and TMPRSS2 independent. We also found that the virus used the late endosomal and lysosomal pathway for cell entry and that the infection could be blocked by apilimod, an inhibitor of cellular PIK5K.

Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology. Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II. Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022. Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo. Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension. Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo. Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

Heat shock protein 90 facilitates SARS-CoV-2 structural protein-mediated virion assembly and promotes virus-induced pyroptosis.

Inhibition of heat shock protein 90 (Hsp90), a prominent molecular chaperone, effectively limits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but little is known about any interaction between Hsp90 and SARS-CoV-2 proteins. Here, we systematically analyzed the effects of the chaperone isoforms Hsp90α and Hsp90ß on individual SARS-CoV-2 viral proteins. Five SARS-CoV-2 proteins, namely nucleocapsid (N), membrane (M), and accessory proteins Orf3, Orf7a, and Orf7b were found to be novel clients of Hsp90ß in particular. Pharmacological inhibition of Hsp90 with 17-DMAG results in N protein proteasome-dependent degradation. Hsp90 depletion-induced N protein degradation is independent of CHIP, a ubiquitin E3 ligase previously identified for Hsp90 client proteins, but alleviated by FBXO10, an E3 ligase identified by subsequent siRNA screening. We also provide evidence that Hsp90 depletion may suppress SARS-CoV-2 assembly partially through induced M or N degradation. Additionally, we found that GSDMD-mediated pyroptotic cell death triggered by SARS-CoV-2 was mitigated by inhibition of Hsp90. These findings collectively highlight a beneficial role for targeting of Hsp90 during SARS-CoV-2 infection, directly inhibiting virion production and reducing inflammatory injury by preventing the pyroptosis that contributes to severe SARS-CoV-2 disease.

Headache as a COVID-19 onset symptom or Post-COVID symptom according to the SARS-CoV-2 Variant.

INTRODUCTION: COVID19 associated headaches are highly common and there is currently an unmet need to better understand their association with SARSCoV2 variants. Headaches are a prevalent symptom in the acute phase of COVID19 and are associated with a better prognosis and better immune response. They are also a relevant post-COVID symptom. AREAS COVERED: This article analyses the differences in the prevalence of headache as an onset symptom and in post-COVID headache among the different SARS-CoV-2 variants: the historical strain, Alpha, Delta and Omicron. The different pathophysiological mechanisms by which SARS-CoV-2 infection may cause headache are also discussed. EXPERT OPINION: The presence of headache at the acute phase is a risk factor for post-COVID headache, whereas a history of primary headache does not appear to be associated with post-COVID headache. The prevalence of headache as an onset symptom appears to be variable for the different SARS-CoV-2 variants, but current data are inconclusive. However, the current evidence also suggests that headache represents a prevalent symptom in the acute and post-infection COVID-19 phase, regardless of SARS-CoV-2 variant.

Prevalence of olfactory dysfunction in D614G, alpha, delta and omicron waves: a psychophysical case-control study.

BACKGROUND: The purpose of this study was to compare the prevalence of olfactory dysfunction (OD) at different stages of the COVID-19 pandemic by evaluating subjects diagnosed with SARS-CoV-2 infection during the Omicron wave with psychophysical tests and comparing the results with those obtained from patients infected during the D614G, Alpha and Delta waves and with those of a control group. METHODOLOGY: The study included adult patients diagnosed with SARS-CoV-2 infection. Depending on the time of diagnosis, the subjects were divided into four study groups: D614G; Alpha, Delta and Omicron variant groups. A group of uninfected individuals was used as control. All subjects underwent psychophysical evaluation of the olfactory function with the Connecticut Chemosensory Clinical Research Center olfactory test (D614G and Alpha groups) or the extended version of the Sniffin'Sticks test (Delta, Omicron and control groups). RESULTS: 372 cases (134 D614G group, 118 Alpha group, 32 in Delta group and 88 Omicron group) were recruited and evaluated within 10 days of infection, alongside 80 controls. Patients self-reported olfactory loss in 72.4% of cases in the D614G group, in 75.4% of cases in the Alpha group, in 65.6% of cases in the Delta group and in 18.1% in the Omicron group. Psychophysical evaluation revealed a prevalence of OD: 80.6%, 83.0%, 65.6% and 36.3% in the D614G, Alpha, Delta and Omicron group respectively. The differences between the D614G, Alpha and Delta groups were not statistically significant. The Omicron group demonstrated a significantly lower prevalence of OD than the other variants but still significantly higher than the controls. CONCLUSIONS: During the Omicron wave OD was less prevalent than during the D614G, Alpha and Delta periods. One-third of patients have reduced olfactory function on psychophysical evaluation during the Omicron wave. Our results should be considered with caution as the VOC has not been determined with certainty.