Incidence and prevalence of headache in influenza: A 2010-2021 surveillance-based study.

BACKGROUND AND PURPOSE: Influenza is a common cause of acute respiratory infection, with headache being one of the symptoms included in the European Commission case definition. The prevalence of headache as a symptom of influenza remains unknown. We aimed to describe the incidence and prevalence of headache in patients with influenza. METHODS: All consecutive patients who met the definition criteria of influenza-like illness during the influenza seasons 2010-2011 through 2021-2022 were included. The seasonal cumulative incidence of influenza per 1000 patients at risk and the prevalence of headache as an influenza symptom were calculated, including the 95% confidence intervals (CIs). Subgroup analyses were done based on patients' sex, age group, microbiological confirmation, vaccination status, and influenza type/subtype/lineage. RESULTS: During the study period, 8171 patients were eligible. The incidence of headache in the context of influenza varied between 0.24 cases per 1000 patients (season 2020-2021) and 21.69 cases per 1000 patients (season 2017-2018). The prevalence of headache was 66.1% (95% CI = 65.1%-67.1%), varying between 49.6% (season 2021-2022) and 80.1% (season 2010-2011). The prevalence of headache was higher in women (67.9% vs. 65.7%, p = 0.03) and higher in patients between 15 and 65 years old. Headache was more prevalent in patients infected with B subtypes than A subtypes (68.7% vs. 56.9%, p < 0.001). There were no notable differences regarding vaccination status or microbiological confirmation of the infection. CONCLUSIONS: Headache is a common symptom in patients with influenza, with a prevalence higher than that observed in other viral infections.

Factors associated to the presence of headache in patients with influenza infection and its consequences: a 2010-2020 surveillance-based study.

Headache is a common symptom of influenza infection; however, its causes and consequences remain uncertain. In this manuscript, we analyzed which demographic and clinical factors were associated with the presence of headache during the course of influenza infection and whether patients with headache had a different prognosis, evaluated by need of hospitalization, sick leave or school absenteeism. The influence study (NCT05704335) was an observational study that analyzed data routinely collected from the Health Sentinel Network between 2010 and 2020. During the study period, 7832 cases were considered, among which, 5275 (67.4%) reported headache. The presence of headache was independently associated with myalgia (2.753; 95%CI: 2.456-3.087, P < 0.001), asthenia (OR: 1.958; 95%CI: 1.732-2.214, P < 0.001), shivering (OR: 1.925; 95%CI: 1.718-2.156, P < 0.001), nasopharyngeal erythema (OR: 1.505; 95%CI: 1.293-1.753, P < 0.001), fever (OR: 1.469; 95%CI: 1.159-1.861; P = 0.001), sudden onset of symptoms (OR: 1.380; 95%CI: 1.120-1.702, p = 0.004), female sex (OR: 1.134; 95%CI: 1.023-1.257, P = 0.018), and gastrointestinal symptoms (OR: 1.169; 95%CI: 1.039-1.315; P = 0.01). Patients with headache had a sex and age adjusted lower odds of being referred to the hospital (OR: 0.463; 95%CI: 0.264-0.812, P = 0.007) and a higher odd of having a sick leave and/or school absenteeism (absenteeism (OR: 1.342; 95%CI: 1.190-1.514, P < 0.001). In conclusion, the presence of headache seems associated with symptoms caused by the innate immune response. These findings support a headache pathophysiology linked with the innate immune response. Due to the potential negative consequences and its treatable nature, clinicians should systematically evaluate it and, whenever necessary, treat it too.

Possible Mpox Protection from Smallpox Vaccine-Generated Antibodies among Older Adults.

Smallpox vaccination may confer cross-protection to mpox. We evaluated vaccinia virus antibodies in 162 persons ≥50 years of age in Spain; 68.5% had detectable antibodies. Highest coverage (78%) was among persons 71-80 years of age. Low antibody levels in 31.5% of this population indicates that addressing their vaccination should be a priority.

Outcomes of viral coinfections in infants hospitalized for acute bronchiolitis.

BACKGROUND AND OBJECTIVE: The clinical relevance of the detection of multiple respiratory viruses in acute bronchiolitis (AB) has not been established. Our goal was to evaluate the effect of viral coinfections on the progression and severity of AB. METHODS: A retrospective observational study was conducted in a tertiary hospital in Spain from September 2012 to March 2020. Infants admitted for AB with at least one respiratory virus identified by molecular diagnostic techniques were included. A comparison was made between single-virus infections and viral coinfections. The evolution and severity of AB were determined based on the days of hospitalization and admission to the pediatric intensive care unit (PICU). RESULTS: Four hundred forty-five patients were included (58.4% male). The median weight was 5.2 kg (IQR 4.2-6.5), and the median age was 2.5 months (IQR 1.4-4.6). A total of 105 patients (23.6%) were admitted to the PICU. Respiratory syncytial virus (RSV) was the most frequent etiological agent (77.1%). A single virus was detected in 270 patients (60.7%), and viral coinfections were detected in 175 (39.3%), of which 126 (28.3%) had two viruses and 49 (11%) had three or more viruses. Hospital length of stay (LOS) increased in proportion to the number of viruses detected, with a median of 6 days (IQR 4-8) for single infections, 7 days (IQR 4-9) for coinfections with two viruses and 8 days (IQR 5-11) for coinfections with ≥ 3 viruses (p = 0.003). The adjusted Cox regression model showed that the detection of ≥ 3 viruses was an independent risk factor for a longer hospital LOS (HR 0.568, 95% CI 0.410-0.785). No significant association was observed between viral coinfections and the need for PICU admission (OR 1.151; 95% CI 0.737-1.797). CONCLUSIONS: Viral coinfections modified the natural history of AB, prolonging the hospital LOS in proportion to the number of viruses detected without increasing the need for admission to the PICU.

SIGNIFICANCE: What is KnownThe main etiological agent of acute bronchiolitis (AB) is respiratory syncytial virus (RSV); however, other viruses are frequently detected. All viruses may be the sole etiological cause or may occur in association, and a high prevalence of viral coinfection has been described.To date, there are conflicting results on the role of viral coinfections in the severity of bronchiolitis.What is NewViral coinfections influence the progression of AB. The simultaneous detection of 3 or more respiratory viruses is a risk factor for longer hospital stay.The presence of viral coinfections does not condition a greater need for admission to the PICU.

InfluenCEF study: Clinical phenotype and duration of headache attributed to influenza infection.

INTRODUCTION: Headache is a frequent symptom of infections. We aimed to characterize the clinical phenotype and duration of headache attributed to influenza infection. METHODS: Prospective cohort study done in 53 primary care centers between January and April 2023. Patients were included if they had a confirmed influenza diagnosis, were older than 15 years and had a new-onset headache. Patients' demographics, prior medical history, headache phenotype and duration, associated symptoms and patients' outcomes were assessed. The International Classification of Headache Disorders criteria for headache attributed to a systemic viral infection, migraine and tension-type headache were assessed. RESULTS: Of the 478 patients 75 fulfilled eligibility criteria. The mean age was 43, 56% were men, and 27% had a prior headache history. The headache phenotype was a bilateral headache (52%), with frontal topography (48%), pressing quality (61%), moderate intensity, rhinorrhea (79%), nasal congestion (76%), and photophobia (59%). All patients fulfilled headache attributed to acute systemic viral infection criteria, 43% fulfilled migraine criteria and 31% tension-type headache criteria. The median duration of the headache was four (Inter-quartile range: two-six) days. CONCLUSION: The clinical phenotype of headache attributed to influenza infection was similar to other infections, with more pronounced cranial autonomic symptoms. The headache was an early symptom and was self-limited within a few days.Trial Registration: The study protocol is registered in ClinicalTrial.gov (NCT05704335).

Altered Surface Expression of Insulin-Degrading Enzyme on Monocytes and Lymphocytes from COVID-19 Patients Both at Diagnosis and after Hospital Discharge.

Although the COVID-19 disease has developed into a worldwide pandemic, its pathophysiology remains to be fully understood. Insulin-degrading enzyme (IDE), a zinc-metalloprotease with a high affinity for insulin, has been found in the interactomes of multiple SARS-CoV-2 proteins. However, the relevance of IDE in the innate and adaptative immune responses elicited by circulating peripheral blood mononuclear cells is unknown. Here, we show that IDE is highly expressed on the surface of circulating monocytes, T-cells (both CD4+ and CD4-), and, to a lower extent, in B-cells from healthy controls. Notably, IDE's surface expression was upregulated on monocytes from COVID-19 patients at diagnosis, and it was increased in more severe patients. However, IDE's surface expression was downregulated (relative to healthy controls) 3 months after hospital discharge in all the studied immune subsets, with this effect being more pronounced in males than in females, and thus it was sex-dependent. Additionally, IDE levels in monocytes, CD4+ T-cells, and CD4- T-cells were inversely correlated with circulating insulin levels in COVID-19 patients (both at diagnosis and after hospital discharge). Of note, high glucose and insulin levels downregulated IDE surface expression by ~30% in the monocytes isolated from healthy donors, without affecting its expression in CD4+ T-cells and CD4- T-cells. In conclusion, our studies reveal the sex- and metabolism-dependent regulation of IDE in monocytes, suggesting that its regulation might be important for the recruitment of immune cells to the site of infection, as well as for glucometabolic control, in COVID-19 patients.

Association of viral loads of influenza A (H3N2) with age and care setting on presentation-a prospective study during the 2022-2023 influenza season in Spain.

OBJECTIVES: The aim of this study was to analyze the viral load (VL) using cycle threshold (Ct) in patients infected with influenza A (H3N2). METHODS: This prospective study was conducted during the 2022-2023 influenza season in sentinel, non-sentinel, and hospitalized patients of Castilla y León (Spain). Respiratory samples were obtained from nasopharyngeal swabs and analyzed by quantitative reverse transcription-polymerase chain reaction specific for influenza A (H3N2) to obtain the Ct value. RESULTS: A total of 1047 individuals were enrolled (174 [16.6%] sentinel, 200 [19.1%] non-sentinel, 673 [64.3%] hospitalized). The mean Ct value was lower in infants, young children, and in the elderly, with a sharp increase in the last from 65 years until 90 years. In addition, the lower Ct values were observed in non-sentinel patients and then in hospitalized patients, probably because non-sentinel are outpatients in the acute phase of the influenza infection. CONCLUSIONS: A higher VL (lower Ct value) is related to the extreme ages of life: children and the elderly. Furthermore, a higher VL is related with the care setting, being probably higher in outpatients because they are in the acute phase of the disease and slightly lower in hospitalized patients because they are attended during the post-acute phase.

Impact on the time elapsed since SARS-CoV-2 infection, vaccination history, and number of doses, on protection against reinfection.

SARS-CoV-2 reinfections have been frequent, even among those vaccinated. The aim of this study is to know if hybrid immunity (infection + vaccination) is affected by the moment of vaccination and number of doses received. We conducted a retrospective study in 746 patients with a history of COVID-19 reinfection and recovered the dates of infection and reinfection and vaccination status (date and number of doses). To assess differences in the time to reinfection(tRI) between unvaccinated, vaccinated before 6 months, and later; and comparing one, two or three doses (incomplete, complete and booster regime) we performed the log-rank test of the cumulative incidence calculated as 1 minus the Kaplan-Meier estimator. Also, an adjusted Cox-regression was performed to evaluate the risk of reinfection in all groups. The tRI was significantly higher in those vaccinated vs. non-vaccinated (p < 0.001). However, an early incomplete regime protects similar time than not receiving a vaccine. Vaccination before 6 months after infection showed a lower tRI compared to those vaccinated later with the same regime (adj-p < 0.001). Actually, early vaccination with complete and booster regimes provided lower length of protection compared to vaccinating later with incomplete and complete regime, respectively. Vaccination with complete and booster regimes significantly increases the tRI (adj-p < 0.001). Vaccination increases the time it takes for a person to become reinfected with SARS-CoV-2. Increasing the time from infection to vaccination increases the time in which a person could be reinfected and reduces the risk of reinfection, especially in complete and booster regimes. Those results emphasize the role of vaccines and boosters during the pandemic and can guide strategies on future vaccination policy.

RSV Risk Profile in Hospitalized Adults and Comparison with Influenza and COVID-19 Controls in Valladolid, Spain, 2010-2022.

INTRODUCTION: We aimed to describe the risk profile of respiratory syncytial virus (RSV) infections among adults ≥ 60 years in Valladolid from January 2010 to August 2022, and to compare them with influenza and COVID-19 controls. METHODS: This was a retrospective cohort study of all laboratory-confirmed RSV infections identified in centralized microbiology database during a 12-year period. We analyzed risk factors for RSV hospitalization and severity (length of stay, intensive care unit admission, in-hospital death or readmission < 30 days) and compared severity between RSV patients vs. influenza and COVID-19 controls using multivariable logistic regression models. RESULTS: We included 706 RSV patients (635 inpatients and 71 outpatients), and 598 influenza and 60 COVID-19 hospitalized controls with comparable sociodemographic profile. Among RSV patients, 96 (15%) had a subtype identified: 56% A, 42% B, and 2% A + B. Eighty-one percent of RSV patients had cardiovascular conditions, 65% endocrine/metabolic, 46% chronic lung, and 43% immunocompromising conditions. Thirty-six percent were coinfected (vs. 21% influenza and 20% COVID-19; p = < .0001 and 0.01). Ninety-two percent had signs of lower respiratory infection (vs. 85% influenza and 72% COVID-19, p = < .0001) and 27% cardiovascular signs (vs. 20% influenza and 8% COVID-19, p = 0.0031 and 0.0009). Laboratory parameters of anemia, inflammation, and hypoxemia were highest in RSV. Among RSV, being a previous smoker (adjusted OR 2.81 [95% CI 1.01, 7.82]), coinfection (4.34 [2.02, 9.34]), and having cardiovascular (3.79 [2.17, 6.62]), neurologic (2.20 [1.09, 4.46]), or chronic lung (1.93 [1.11, 3.38]) diseases were risks for hospitalization. Being resident in care institutions (1.68 [1.09, 2.61]) or having a coinfection (1.91[1.36, 2.69]) were risks for higher severity, while RSV subtype was not associated with severity. Whereas RSV and influenza patients did not show differences in severity, RSV patients had 68% (38-84%) lower odds of experiencing any severe outcome compared to COVID-19. CONCLUSIONS: RSV especially affects those with comorbidities, coinfections, and living in care institutions. RSV vaccination could have an important public health impact in this population.

Long-term influenza antibodies profiles in previously vaccinated and non-vaccinated adults.

The aim of this work is to describe the dynamics of influenza antibodies after vaccination in adults. We conducted a case-cohort serological study in the automobile manufacturing plants of the Renault España S.A. group in Valladolid and Palencia (Spain), including 550 workers (66.9%) previously vaccinated against influenza (group V), and 272 (33.1%) never vaccinated (group NV). A pre-vaccination serum sample was collected, another after 30-40 days and another after 6 months. The dynamics of antibodies were analyzed. A lower seroprotection of NV before vaccination was observed, but an antibody response between 2 and 4 times higher than in V was assessed. After 6 months, antibodies declined in both groups until equalize. Antibodies titers decrease with age, and no differences were found among underlying pathologies. Adults never vaccinated against influenza had lower seroprotection than those previously vaccinated, but influenza vaccination produces a more intense serological response in them, acquiring significantly higher antibody titers than those previously vaccinated. The antibodies, although in lower titers, persist and equalize among both groups at least 6 months after vaccination, which allows the individual to be protected during the entire circulation of the influenza virus in the same season.

Evolution of antibody profiles against SARS-CoV-2 in experienced and naïve vaccinated elderly people.

Introduction: The third dose of the COVID-19 vaccine is especially necessary in people over 65 years of age due to their lower immune response. Methods: We designed a multicentre, prospective observational study including 98 people ≤65 years old who lived in two nursing homes in Valladolid, Spain. One of the groups had previous experience with SARS-CoV-2 (n=68;69.4%) and the other was naïve (n=30;30.6%). We evaluated the response to the three doses of the Comirnaty vaccine and the dynamics of antibodies during 5 consecutive serum samplings: 2 after the first two doses of vaccination, one three months after the first dose, another at 6 months and the last one month after the third dose. IgG antibodies against SARS-CoV-2 S1, RBD and N antigens were analysed. Results: Both groups increased the level of Abs against S1 and RBD, but the experienced group showed a 130-fold higher humoral response due to hybrid immunisation (infection+vaccination). The response to vaccination with Comirnaty against COVID-19 was higher in those ≤65 years with previous experience than those who were naïve. However, the amount of antibodies against S1 and RBD equalised at 6 months. After the third dose, both groups raised the amount of antibodies to a similar level. The reinfections suggested by the analysis of antibodies against N were frequent in both groups. Discussion: The third dose showed a clear benefit for elderly people, with the reinforcement of the antibody levels after the decline suffered after six months of the first two doses.

Whole blood DNA methylation analysis reveals respiratory environmental traits involved in COVID-19 severity following SARS-CoV-2 infection.

SARS-CoV-2 infection can cause an inflammatory syndrome (COVID-19) leading, in many cases, to bilateral pneumonia, severe dyspnea, and in ~5% of these, death. DNA methylation is known to play an important role in the regulation of the immune processes behind COVID-19 progression, however it has not been studied in depth. In this study, we aim to evaluate the implication of DNA methylation in COVID-19 progression by means of a genome-wide DNA methylation analysis combined with DNA genotyping. The results reveal the existence of epigenomic regulation of functional pathways associated with COVID-19 progression and mediated by genetic loci. We find an environmental trait-related signature that discriminates mild from severe cases and regulates, among other cytokines, IL-6 expression via the transcription factor CEBP. The analyses suggest that an interaction between environmental contribution, genetics, and epigenetics might be playing a role in triggering the cytokine storm described in the most severe cases.

PCR-based diagnosis of respiratory virus in postsurgical septic patients: A preliminary study before SARS-CoV-2 pandemic.

Respiratory viruses are part of the normal microbiota of the respiratory tract, which sometimes cause infection with/without respiratory insufficiency and the need for hospital or ICU admission. The aim of this study is to determine the prevalence of respiratory viruses in nontransplanted postoperative septic patients as well as lymphocyte count influence in their presence and its relationship to mortality. 223 nontransplanted postsurgical septic patients were recruited on the Intensive Care Unit (ICU) at Hospital Clínico Universitario de Valladolid prior to the SARS-COV-2 pandemic. Patients were split into 2 groups according to the presence/absence of respiratory viruses. Multivariate logistic regression analysis was used to identify independent factors related to positive respiratory virus PCR test. Respiratory viruses were isolated in 28.7% of patients. 28-day mortality was not significantly different between virus-positive and virus-negative groups. Logistic regression analysis revealed that lymphocyte count ≤ 928/µl is independently associated with a positive PCR result [OR 3.76, 95% CI (1.71-8.26), P = .001] adjusted by platelet count over 128,500/µL [OR 4.27, 95% CI (1.92-9.50) P < .001] and the presence of hypertension [OR 2.69, 95% CI (1.13-6.36) P = .025] as confounding variables. Respiratory viruses' detection by using PCR in respiratory samples of nontransplanted postoperative septic patients is frequent. These preliminary results revealed that the presence of lymphopenia on sepsis diagnosis is independently associated to a positive virus result, which is not related to a higher 28-day mortality.

Influenza B Lineages Have More in Common Than Meets the Eye. Trivalent Influenza Vaccines Trigger Heterotypic Antibodies Against Both Influenza B Viruses.

Influenza B is accountable for an important burden during flu epidemics, causing special impact in children and the elderly. Vaccination is the best approach to address influenza infections. However, one of the main problems of this virus is that two different lineages circulate together, Victoria and Yamagata; and trivalent vaccines, that only contain one of these lineages, are still in use. For that reason, if during an epidemic, the lineage not included in the vaccine predominates, a mismatch would occur, and the vaccine effectiveness will be very poor. In this work, we evaluated the cross-protection given by the trivalent Influenza vaccine and compared serological profiles based on age, sex, and the type of vaccine used. We performed a retrospective analysis of serum samples obtained before and after seasonal influenza vaccination during 20 seasons (1998-2018). The results showed that heterotypic reactivity between both influenza B lineages is common, but always lower than the homologous response. Age is a relevant factor for this cross-reactivity between both lineages, while the sex and the type of vaccine not. Vaccination with trivalent influenza vaccines elicits cross-reactive antibodies against both lineages, however, this response might not be enough to provide an appropriate serological protection in case of mismatch.

Growth Arrest-Specific Factor 6 (GAS6) Is Increased in COVID-19 Patients and Predicts Clinical Outcome.

BACKGROUND: Growth arrest-specific factor 6 (GAS6) and the Tyro3, AXL, and MERTK (TAM) receptors counterbalance pro-inflammatory responses. AXL is a candidate receptor for SARS-CoV-2, particularly in the respiratory system, and the GAS6/AXL axis is targeted in current clinical trials against COVID-19. However, GAS6 and TAMs have not been evaluated in COVID-19 patients at emergency admission. METHODS: Plasma GAS6, AXL, and MERTK were analyzed in 132 patients consecutively admitted to the emergency ward during the first peak of COVID-19. RESULTS: GAS6 levels were higher in the SARS-CoV-2-positive patients, increasing progressively with the severity of the disease. Patients with initial GAS6 at the highest quartile had the worst outcome, with a 3-month survival of 65%, compared to a 90% survival for the rest. Soluble AXL exhibited higher plasma concentration in deceased patients, without significant differences in MERTK among SARS-CoV-2-positive groups. GAS6 mRNA was mainly expressed in alveolar cells and AXL in airway macrophages. Remarkably, THP-1 human macrophage differentiation neatly induces AXL, and its inhibition (bemcentinib) reduced cytokine production in human macrophages after LPS challenge. CONCLUSIONS: Plasma GAS6 and AXL levels reflect COVID-19 severity and could be early markers of disease prognosis, supporting a relevant role of the GAS6/AXL system in the immune response in COVID-19.

Diagnostic challenges in influenza. / Retos diagnósticos de la gripe.

In 2018 there are still microbiology laboratories that do not subtype or detect influenza viruses, one of the main agents of community-acquired pneumonia. A major challenge is to introduce multiplex-type technologies into most clinical virological diagnostic laboratories, increasing the feasibility of timely etiological diagnosis of influenza and other respiratory viruses whenever required and thus limiting antibiotic treatments. Other diagnostic tools such as markers of severity and the detection of resistance are pending challenges to complete and expand. Viral culture, an essential tool in the epidemiological surveillance of viruses, has been relegated by more sensitive and affordable molecular techniques. Sequencing of the influenza virus together with the antigenic characterisation and detection techniques of antibodies against hemagglutinin and neuraminidase will, in future, be used in tandem with other techniques to detect antibodies against other structural proteins, helping to elucidate the complicated epidemiology of these viruses and the production of new vaccines and their evaluation. Supplement information: This article is part of a supplement entitled «SEIMC External Quality Control Programme. Year 2016¼, which is sponsored by Roche, Vircell Microbiologists, Abbott Molecular and Francisco Soria Melguizo, S.A. © 2019 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosasy Microbiología Clínica. All rights reserved.

Comparative study of the prevalence of the human papilloma virus in Spanish and foreign women participating in a population screening programme in Castilla y León. / Estudio comparativo de la prevalencia de virus de papiloma humano en las mujeres españolas y extranjeras, participantes en un programa de cribado poblacional en Castilla y León.

INTRODUCTION: The objective of this study was to compare the prevalence of human papilloma virus (HPV) in Spanish and foreign women in a cervical cancer screening programme of Castilla y León and foreign women living in the community who participated in the programme. METHODS: This was an observational, descriptive, cross - sectional, retrospective study of period prevalence. The sample consisted of all the women included in the cervical cancer prevention programme of the Regional Ministry of Health of the Junta de Castilla y León who were screened for cervical cancer during the period from 2012 to 2014, aged between 25 and 64 years of age. RESULTS: Of the 190,203 cervical smear samples collected, 10.2% were foreign (n=19,329). The prevalence of HPV in the foreign women was 23.51%, significantly higher than in the Spanish women (P<.001). The presence of morphological and microbiological changes in the foreign women was also greater. CONCLUSIONS: This study makes an important contribution, since it comprised a voluminous population screening sample. The prevalence of HPV in the foreign women was significantly higher than in the women born in Spain. It is important to continue studying this type of population, who are difficult to recruit for cultural reasons.