research paper on flu shot

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Influenza and Influenza Vaccine: A Review

Affiliations.

1 Nurse-Midwifery and Women's Health Nurse Practitioner Programs, University of Cincinnati, Cincinnati, Ohio.
2 Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, Ohio.
3 Family Nurse Practitioner Program, University of Cincinnati, Cincinnati, Ohio.
PMID: 33522695
PMCID: PMC8014756
DOI: 10.1111/jmwh.13203

Influenza is a highly contagious, deadly virus, killing nearly half a million people yearly worldwide. The classic symptoms of influenza are fever, fatigue, cough, and body aches. In the outpatient setting, diagnosis can be made by clinical presentation with optional confirmatory diagnostic testing. Antiviral medications should be initiated as soon as possible, preferably within 24 hours of initiation of symptoms. The primary preventive measure against influenza is vaccination, which is recommended for all people 6 months of age or older, including pregnant and postpartum women, unless the individual has a contraindication. Vaccination should occur at the beginning of flu season, which typically begins in October. It takes approximately 14 days after vaccination for a healthy adult to reach peak antibody protection. There are challenges associated with vaccine composition and vaccine uptake. It takes approximately 6 to 8 months to identify and predict which influenza strains to include in the upcoming season's vaccine. During this time, the influenza virus may undergo antigenic drift, that is, mutating to avoid a host immune response. Antigenic drift makes the vaccine less effective in some seasons. The influenza virus occasionally undergoes antigenic shift, in which it changes to a novel virus, creating potential for a pandemic. There are also barriers to vaccine uptake, including lack of or limited access to care and misconceptions about receiving the vaccine. Interventions that improve access to and uptake of the influenza vaccine must be initiated, targeting multiple levels, including health care policy, patients, health care systems, and the health care team. This article reviews information about influenza identification, management, and prevention.

Keywords: diagnostic tests; influenza; pregnancy; screening; vaccination.

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Vaccines against influenza: WHO position paper – May 2022

Weekly Epidemiological Record, 2022, vol. 97, 19 [‎full issue]‎

This position paper is concerned with vaccines and vaccination against seasonal (epidemic) influenza. In recent years, there have been important developments in the field of influenza vaccines, e.g. new data have emerged on the epidemiology of influenza in developing and tropical countries, quadrivalent influenza vaccines (QIVs) have been introduced and new vaccine technologies have been developed, including the use of cell culture, recombinant protein vaccines and adjuvanted and high-dose vaccines for use in older adults.

In addition, reviews have been published of the consequences of influenza virus infection in certain population groups and of the impact of repeat influenza vaccinations on vaccine effectiveness (VE). This document replaces the 2012 WHO position paper on influenza vaccines. Recommendations on the use of influenza vaccines were discussed by SAGE at its meeting in October 2021.

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Research Article

Examining the potential benefits of the influenza vaccine against SARS-CoV-2: A retrospective cohort analysis of 74,754 patients

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

¶ ‡ Denotes equal contribution as co-first authors.

Affiliation Division of Plastic & Reconstructive Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America

Roles Project administration, Resources, Software, Supervision, Writing – review & editing

Affiliation Anne Arundel Medical Center, Annapolis, Maryland, United States of America

Roles Conceptualization, Investigation, Methodology, Project administration, Supervision, Writing – review & editing

* E-mail: [email protected]

Susan M. Taghioff,
Benjamin R. Slavin,
Tripp Holton,
Devinder Singh

Published: August 3, 2021
https://doi.org/10.1371/journal.pone.0255541
Reader Comments

Introduction

Recently, several single center studies have suggested a protective effect of the influenza vaccine against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This study utilizes a continuously updated Electronic Medical Record (EMR) network to assess the possible benefits of influenza vaccination mitigating critical adverse outcomes in SARS-CoV-2 positive patients from 56 healthcare organizations (HCOs).

The de-identified records of 73,346,583 patients were retrospectively screened. Two cohorts of 37,377 patients, having either received or not received influenza vaccination six months–two weeks prior to SARS-CoV-2 positive diagnosis, were created using Common Procedural Terminology (CPT) and logical observation identifiers names and codes (LOINC) codes. Adverse outcomes within 30, 60, 90, and 120 days of positive SARS-CoV-2 diagnosis were compared between cohorts. Outcomes were assessed with stringent propensity score matching including age, race, ethnicity, gender, hypertension, diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), obesity, heart disease, and lifestyle habits such as smoking.

SARS-CoV-2-positive patients who received the influenza vaccine experienced decreased sepsis (p<0.01, Risk Ratio: 1.361–1.450, 95% CI:1.123–1.699, NNT:286) and stroke (p<0.02, RR: 1.451–1.580, 95% CI:1.075–2.034, NNT:625) across all time points. ICU admissions were lower in SARS-CoV-2-positive patients receiving the influenza vaccine at 30, 90, and 120 days (p<0.03, RR: 1.174–1.200, 95% CI:1.003–1.385, NNT:435), while approaching significance at 60 days (p = 0.0509, RR: 1.156, 95% CI:0.999–1.338). Patients who received the influenza vaccine experienced fewer DVTs 60–120 days after positive SARS-CoV-2 diagnosis (p<0.02, RR:1.41–1.530, 95% CI:1.082–2.076, NNT:1000) and experienced fewer emergency department (ED) visits 90–120 days post SARS-CoV-2-positive diagnosis (p<0.01, RR:1.204–1.580, 95% CI: 1.050–1.476, NNT:176).

Our analysis outlines the potential protective effect of influenza vaccination in SARS-CoV-2-positive patients against adverse outcomes within 30, 60, 90, and 120 days of a positive diagnosis. Significant findings favoring influenza vaccination mitigating the risks of sepsis, stroke, deep vein thrombosis (DVT), emergency department (ED) & Intensive Care Unit (ICU) admissions suggest a potential protective effect that could benefit populations without readily available access to SARS-CoV-2 vaccination. Thus further investigation with future prospective studies is warranted.

Citation: Taghioff SM, Slavin BR, Holton T, Singh D (2021) Examining the potential benefits of the influenza vaccine against SARS-CoV-2: A retrospective cohort analysis of 74,754 patients. PLoS ONE 16(8): e0255541. https://doi.org/10.1371/journal.pone.0255541

Editor: Corstiaan den Uil, Erasmus Medical Centre: Erasmus MC, NETHERLANDS

Received: April 29, 2021; Accepted: July 17, 2021; Published: August 3, 2021

Copyright: © 2021 Taghioff et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper.

Funding: The authors received no specific funding for this work.

Competing interests: Dr. Holton serves as a consultant for Acelity/3M and Stryker. Dr. Slavin, Ms. Taghioff, and Dr. Singh have no relevant disclosures. The authors have not received any consulting fees, stock options, research funding, capital equipment, or educational grants from TriNetX.

With cases in excess of 140 million and a death toll over 3 million, COVID-19 has greatly impacted the global community [ 1 ]. In the nascency of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), demand for rapid, yet accurate data was voracious [ 2 ]. As the world continues to attempt to overcome the current pandemic and readies itself to combat a future one, the need for expeditious clinical answers remains paramount.

Federated electronic medical record (EMR) networks, such as TriNetX (TriNetX Inc, Cambridge, MA), aggregate the de-identified records of millions of patients from participating healthcare organizations (HCOs) into an accessible and searchable database in real-time [ 3 , 4 ]. Several publications have already demonstrated the utility of federated EMR networks in addressing research questions regarding the implications of SARS-CoV-2 on maladies including obesity, rheumatological disease, gastrointestinal bleeding, and psychiatric illness [ 5 – 8 ]. The efficiency and speed with which these previous retrospective studies were able to examine topics of interest, using real-time EMRs, allows for the collective advancement of COVID-19 knowledge in hopes of optimizing prevention and management.

Recently, several studies have suggested a possible protective effect of the influenza vaccine against SARS-CoV-2 [ 9 – 12 ]. Although no cross-reactivity between influenza-induced antibodies and SARS-CoV-2 protection has been demonstrated, several theorized mechanisms of the potential protective effect of influenza vaccination have been proposed in the recent literature [ 9 , 13 , 14 ]. The first hypothesis centers around the presence of MF59 in the influenza vaccine: an oil-in-water squalene emulsion that has been shown to assist in potentiating an immune response to SARS-CoV variants [ 14 ]. Alternatively, influenza vaccination’s potential protective effect may be explained by its ability to stimulate the activation of natural killer cells, the levels of which have been found to be considerably decreased in moderate and severe SARS-CoV-2 cases [ 15 , 16 ]. Another proposed mechanism was described in a recent case-control study of 261 healthcare workers. The authors noted several prior studies that suggested both coronaviruses and influenza viruses engage with the angiotensin-converting enzyme 2 (ACE-2) and tetraspanin antibodies. Thus, there is belief that ACE-2 and tetraspanin antibodies may inhibit both coronavirus and low-pathogenic influenza A virus infections. Outcomes of this study pointed to a potential protective effect in those with influenza vaccination [ 11 ]. Additional studies reported that the influenza vaccine may lead to decreased risk of cardiovascular events due to potential interaction with immune and inflammatory systems to promote plaque stabilization [ 17 , 18 ]. It has also been recently reported that influenza vaccine-induced antibodies may interact with the bradykinin 2 receptor, leading to an anti-inflammatory effect secondary to increasing nitric oxide [ 18 , 19 ].

In a single-center study of 2,005 patients, Yang et al. were the first to perform a retrospective review highlighting a potential protective effect of influenza vaccination against adverse outcomes associated with SARS-CoV-2. Only 10.7% of patients in this study were considered up to date on their influenza immunization. The authors reported a 2.44 greater odds ratio (OR) for hospitalization and 3.29 greater OR for intensive care unit (ICU) admission indicating a protective effect for SARS-CoV-2 positive patients who were up to date on their influenza immunization [ 9 ].

This investigation seeks to explore the potential protective effects of influenza vaccination against SARS-CoV-2 using the TriNetX database. Specifically, this study aims to assess the possible benefit of influenza vaccination in mitigating critical adverse outcomes in SARS-CoV-2 positive patients using 73 million deidentified EMRs from 56 HCOs provided by a continuously updated network.

At the time of our search in January 2021, the analytics subset contained EMRs from 56 HCOs distributed predominantly throughout the United States of America, but also with participating institutions in the United Kingdom, Italy, Germany, Israel, and Singapore. Within the US, the geographic distribution of HCOs is 6% in the Northwest, 33% in the Midwest, 42% in the South, and 19% in the West [ 3 ]. The deidentified records of 73,346,583 patients were retrospectively screened using the TriNetX platform ( Fig 1 ).

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https://doi.org/10.1371/journal.pone.0255541.g001

In order to ensure accuracy, logical observation identifiers names and codes (LOINCs), the universal standard for identification of medical laboratory data, were used to identify patients positive for SARS-CoV-2 (LOINC 94500–6). CPT codes were used to identify patients who had received either the trivalent live intranasal (90660) or inactivated intramuscular influenza vaccine (90653) within a timeframe of six months–two weeks prior to receiving a SARS-CoV2-positive diagnosis. Additionally, Medicare patients receiving either the intranasal or intramuscular influenza vaccine were captured using the corresponding healthcare common procedure coding system (HCPCS) code (G0008). Any EMRs belonging to patients that were pregnant, incarcerated, experienced an outcome outside of a 120-day post-SARS-CoV-2 diagnosis window, or not meeting all of the aforementioned criteria by CPT code were excluded. Following application of inclusion and exclusion criteria, a cohort of 2,814,377 patients who had not received the influenza vaccine six months–two weeks prior to a positive SARS-CoV-2 diagnosis was compared to a second cohort of 37,377, patients who had received the influenza vaccine six months–two weeks prior to a positive SARS-CoV-2 diagnosis. We selected two weeks as the minimum end of our study’s timespan as it takes approximately two weeks for the immune system to fully develop antibodies following influenza vaccination. Conversely, six months was chosen as the maximum end of the timespan between influenza vaccination and SARS-CoV-2-positive diagnosis because the accepted standard for adequate protection without a waning effect is six months [ 20 ].

Following the creation of these two cohorts, we used the TriNetX platform to facilitate propensity score matching between cohorts with ICD-10 codes for numerous factors including age, race, gender, ethnicity, diabetes mellitus (E08-E13), elevated BMI status (E65-E68), hypertension (I10-I16), chronic ischemic heart disease (I25), heart failure (I50), COPD (J44), musculoskeletal disease (M00-M99), and factors influencing health status and contact with human services (Z00-Z99) which includes factors influencing health status including tobacco use, body mass index (BMI), and socioeconomic status. After propensity score matching, a cohort of 37,377 SARS-CoV-2 positive patients without influenza vaccination was paired with a second cohort of 37,377 SARS-CoV-2 positive patients, comparable in demographics and co-morbidities, that had received influenza vaccination within the aforementioned time frame.

Propensity score 1:1 balancing was completed within the TriNetX platform via logistic regression utilizing version 3.7 of Python Software Foundation’s Scikit-Learn package (Python Software Foundation, Delaware, USA). A greedy nearest neighbor matching algorithm approach was used, setting standard differences to a value of less than 0.1 to indicate appropriate matching. To eliminate record order bias, randomization of the record order in a covariate matrix occurs before matching. Baseline characteristics with a standardized mean difference between cohorts lower than 0.1 were considered well balanced.

Following optimization of the two cohorts for direct comparison, adverse outcomes were identified with ICD-10 or CPT codes as sepsis (A41.9), deep vein thrombosis (DVT) (I82.220, I82.40-I82.89, I82.A19), pulmonary embolism (I26), acute myocardial infarction (I21), stroke(I63), arthralgia(M25.5), ICU admission (99291, 1013729, 1014309), ED visits (1013711), hospital admission (1013659, 1013660, 1013699), renal failure (N19), acute respiratory distress syndrome (J80), acute respiratory failure (J96), anorexia (R63), pneumonia (J18), and death. Following identification, adverse outcomes within 30, 60, 90, and 120 days of SARS-CoV-2-positive diagnosis were analyzed and compared between the two cohorts. 120 days was made the maximum endpoint of our study window to account for the presence of the poorly understood Post-Acute Covid Syndrome (PACS), an autonomic dysfunction phenomenon observed in many patients after recovering from SARS-CoV-2 [ 17 ].

Using the TriNetX platform’s Analytics function, statistical analysis and logistical regression were performed by comparing indices and relative risks of outcomes following the successful matching of cohorts with a p-value greater than 0.05. Outcomes for all measures were calculated using 95% confidence intervals (CIs). All p-values were two-sided and the alpha level was set at 0.05. Risk ratio was defined in this study as the ratio of the probability of an adverse SARS-CoV-2-related event occurring without history of up-to-date influenza vaccination versus the probability of the same adverse SARS-CoV-2-related event occurring in a patient with history of up-to-date influenza vaccination [ 21 ].

Subsequently, Absolute Risk Reduction (ARR), defined as the difference in risk of an adverse SARS-CoV-2-related outcome between the influenza-vaccinated group and non-influenza-vaccinated group, was calculated for each adverse outcome. The reciprocal of ARR was then obtained to determine number needed to treat, henceforth referred to in this study as number needed to vaccinate (NNV), for all statistically significant variables. The NNV is a calculation specifying the average number of patients who needed to be up-to-date on their influenza vaccination in order to have prevented one adverse SARS-CoV-2-related outcome [ 22 , 23 ].

Propensity score matching resulted in 37,377 patients in each cohort. Prior to matching, all between-groups factors were found to be significantly different (p<0.0001). However, following matching, all demographic and diagnostic factors were no longer significant (p>0·05) ( Table 1 ), indicating successful balancing.

https://doi.org/10.1371/journal.pone.0255541.t001

Following propensity score matching by the TriNetX system, statistical analysis was performed for all adverse outcomes of interest at 4 time points: 30, 60, 90, and 120 days following a SARS-CoV-2-positive diagnosis (Tables 2 – 5 ).

https://doi.org/10.1371/journal.pone.0255541.t002

https://doi.org/10.1371/journal.pone.0255541.t003

https://doi.org/10.1371/journal.pone.0255541.t004

https://doi.org/10.1371/journal.pone.0255541.t005

SARS-CoV-2-positive patients who received the influenza vaccine experienced significantly decreased sepsis (p = 0.0001–0.0020, Risk Ratio: 1.361–1.450, 95% CI: 1.123–1.699) and stroke (p = 0.0003–0.0154, Risk Ratio: 1.451–1.580, 95% CI: 1.075–2.034) across all time points. ICU admissions were significantly lower in SARS-CoV-2-positive patients receiving the influenza vaccine at 30, 90, and 120 days (p = 0.0073–0.0240, Risk Ratio: 1.174–1.200, 95% CI: 1.003–1.385), while approaching significance at 60 days (p = 0.0509, Risk Ratio: 1.156, 95% CI: 0.999–1.338) ( Fig 2A ).

Significant adverse outcome trends 30–120 days (a), 60–120 days (b) & 90–120 days (c) (p<0.05). ** ICU Admissions Within 60 Days approaching significance (p = 0.0509, 95%).

https://doi.org/10.1371/journal.pone.0255541.g002

Patients who received influenza vaccination experienced significantly fewer DVTs 60–120 days after positive SARS-CoV-2 diagnosis (p = 0.0058–0.0108, Risk Ratio: 1.411–1.530, 95% CI: 1.082–2.076) ( Fig 2B ) and experienced significantly fewer ED visits 90–120 days post SARS-CoV-2-positive diagnosis (p = 0.0001–0.0076, Risk Ratio: 1.204–1.580, 95% CI: 1.050–1.476) ( Fig 2C ).

Additional findings included patients up-to-date on their influenza vaccination experiencing significantly less anorexia within 90 days of SARS-CoV-2-positive diagnosis (p = 0.0486, Risk Ratio: 1.276, 95% CI: 1.001–1.627) as well as decreased arthralgia within 120 days of SARS-CoV-2-positive diagnosis (p = 0.0041, Risk Ratio: 1.218, 95% CI: 1.064–1.395).

NNV with influenza vaccination to prevent one adverse SARS-CoV-2-related outcome calculations for significant findings for sepsis, stroke, and ICU Admission within 30, 60, 90, and 120 days of positive SARS-CoV-2 diagnosis are illustrated in Fig 3 , along with NNV to prevent DVT within 60–120 days, and NNV to prevent ED Visits within 90–120 days ( Fig 3 ).

https://doi.org/10.1371/journal.pone.0255541.g003

This study underscores the utility of federated EMR networks as a potential solution for the need for urgent clinical data, particularly during health crises such as pandemics. While the work of retrospective single-center studies continues to have advantages such as detailed historical patient information that deidentified EMR networks cannot provide, the ability to scan, in minutes, the charts of 73 million patients from 56 HCOs in real-time to guide clinical decision-making is invaluable.

EMRs included in our study monitored patients with positive SARS-CoV-2 diagnoses for adverse outcomes during a period of 120 days. This time window was chosen intentionally to account for the possible presence of PACS. Although poorly understood, previous studies of PACS have reported orthostatic intolerance, often without objective hemodynamic abnormalities upon testing, as well as new illness-related fatigue to be the most common presentations. Development of these symptoms was found to occur between 0–122 days and 29–71 days post-SARS-CoV-2 diagnosis respectively [ 24 , 25 ].

By focusing on rates of hospitalization and ICU admission, the study of Yang et al., garnered a sizable amount of media coverage [ 23 , 24 ]. This study most closely mirrors this study’s aim of appraising the potential impact of influenza vaccination on adverse outcomes associated with SARS-CoV-2. Prior to comparing findings between these two studies, it is important to note several key differences in methodology [ 9 ]. While both studies relied on medical coding to identify SARS-CoV-2 positivity and influenza vaccination status, the timeframes were different, with this study encompassing the first full year of SARS-CoV-2 cases globally from January 2020-January 2021 [ 1 , 25 ]. This timespan enabled our study to include data from the 2019–2020 influenza vaccine formulation as well as the most recent 2020–2021 influenza season formulation. This contrasts with the timespan of the previously mentioned study, as well as the recently published retrospective review of 27,000 patients by Conlon et al. Both of these studies analyzed SARS-CoV-2 cases between March-August 2020, a period overlapping between two different influenza vaccinations and seasons which excludes peak influenza season, and did not set a 2 week– 6 month time limit for influenza vaccine being “current/active” [ 9 , 12 ]. Additionally, the Yang and Conlon study timeframes began 6 months after the CDC’s recommended influenza vaccination time in October, therefore the vaccine antibodies were likely already waning [ 9 , 12 , 20 ].

Our study found no association between influenza vaccination and risk of death in SARS-CoV-2-positive patients. This confirms the previous findings of Umasabor-Bubu et al., Pedote et al. and Ragni et al., which found that a history of influenza vaccination did not confer protection against death in reviews of 558, 664, and 17,600 patients respectively [ 26 – 28 ].

Alternatively, two macro-scale studies have found there to be conflicting relationships between influenza vaccination and mortality in the elderly population. In a large scale study of over 2,000 counties in the United States, Zanettini et al. demonstrated a potential protective effect of influenza vaccination on SARS-CoV-2 mortality [ 29 ]. Conversely, Wehenkel et al. performed a macro-scale study of association between influenza vaccination rate and SARS-CoV-2 deaths in an examination of over 500,000 patients across 39 countries [ 30 ]. This study showed a positive association between COVID-19 deaths and influenza vaccination rates in elderly people 65 years of age and older. The conflicting findings of these studies may be attributable to their large scale nature and lack of analysis of individual patient EMRs, thereby further increasing the need for prospective randomized control studies to better define the potential protective effect of influenza vaccination against SARS-CoV-2.

In light of the over 140 million confirmed positive cases worldwide 1 , the use of NNV calculations allows for a deeper appreciation of the potential benefit of influenza vaccination. In addition to guarding against a possible “twindemic” of simultaneous outbreaks of influenza and SARS-CoV-2 [ 31 ], the NNV trends observed within 30–120 days of SARS-CoV-2 diagnosis for sepsis, stroke, ICU admission, DVT, and ED visits further strengthen the case in favor of a protective effect of influenza vaccination ( Fig 3 ). Specifically, in order to prevent one individual from visiting the ED, developing sepsis, being admitted to the ICU, suffering a stroke, or having a DVT within 120 days of positive SARS-CoV-2 diagnosis, 176, 286, 435, 625, and 1,000 people respectively would need to have been up-to-date with their influenza vaccination. When considered on a global scale, the NNVs calculated in this study may serve to benefit not only those that will be infected with SARS-CoV-2, a diagnosis that has already affected over 140 million to date, but also the finances and resources of the health systems responsible should patients suffer these adverse outcomes [ 32 ]. Even more encouraging, apart from DVT for which NNV remained stable, the NNVs for sepsis, stroke, ICU Admissions, and ED Visits were down trending at the 120-day mark, implying that the NNV and thus potential protective benefit of influenza vaccination may be even stronger than observed in the present study.

Expanding upon our prospective understanding of the relationship between influenza vaccination and protection against adverse outcomes during SARS-CoV-2 is the work of Pawlowski et al. This retrospective review found that a history of eight different vaccines including Polio, H. influenzae type-B, measles-mumps-rubella, and Varicella, amongst others, within the past one, two, or five years is associated with decreased SARS-CoV-2 infection rates, even after cohort balancing [ 33 ]. This suggests that the protective effect observed by our group and others against SARS-CoV-2 may not be unique to influenza vaccination.

This study has the benefits of large cohort size and a tightly matched patient population, however reliance on a global database also introduces limitations that must be acknowledged. These limitations include our study’s retrospective nature, absence of detailed historical patient data, and lack of ability to follow up regarding new symptoms. Our search query’s reliance on the CPT, ICD-10, and LOINC coding of individual HCOs is another potential source of confounding as the accuracy of these factors is inherent to the EMRs comprising the database. This statement is particularly of interest as relates to false positive and false negative cases of SARS-CoV-2, which relies on the specificity and sensitivity of PCR and rapid antigen testing.

Federated EMR networks, such as TriNetX, have vast potential to challenge or verify scientific findings using sample sizes and turnaround times unachievable by individual centers, particularly during health crises such as pandemics. Our study was able to verify and challenge the relatively large difference in the potential protective effect of influenza vaccination observed by the previous study with a much more modest effect backed by nearly 75,000 global EMRs [ 9 ]. The potential protective effects of the vaccine against sepsis, stroke, DVT, ED visits, and ICU admissions at 30, 60, 90, and 120 days following SARS-CoV-2-positive diagnosis reaffirms the importance of annual influenza immunization.

While this observed potential protective effect is relatively small, the stringently matched cohort balancing and sample size afforded by TriNetX substantially increases our confidence in the fidelity of our findings. In the context of over 140 million cases globally, the potential protective benefits further elucidated by the NNV calculations for these same adverse outcomes suggests that a concerted effort to continue ramping up influenza vaccination in parallel with SARS-CoV-2 vaccination is strongly worth consideration. Although production and distribution of SARS-CoV-2 vaccines continues to increase daily, the fact remains that certain populations in the global community may still have to wait a long period of time before they are vaccinated and could therefore benefit from a more readily available source of even marginally increased protection [ 34 ]. That being said, less than half of US adults receive influenza vaccination each year, with Non-Hispanic Black, Hispanic, and American Indian/Alaskan Native individuals having had the lowest influenza vaccination coverage while also being disproportionately affected by SARS-CoV-2 [ 35 ].

The influenza vaccine may be a viable option to attenuate the adverse effects of SARS-CoV-2 worldwide, with a specific potential to benefit populations struggling with access to or distribution of SARS-CoV-2 vaccination. Even patients who have already received SARS-CoV-2 vaccination may stand to benefit given that the SARS-CoV-2 vaccine does not convey complete immunity, although further research into the relationship and potential interaction between influenza vaccination and SARS-CoV-2 vaccination should be performed.

Using a federated EMR network of over 73 million patients across 56 global HCOs, this analysis examines the potential protective effect of the influenza vaccine against various adverse outcomes at 30, 60, 90, and 120 days of SARS-CoV-2-positive diagnosis. Significant findings in favor of the influenza vaccine in mitigating the risks of sepsis, stroke, DVT, ED visits, and ICU admissions suggest a protective effect that merits further investigation. Limitations include this study’s retrospective nature and its reliance on the accuracy of medical coding. Future prospective controlled studies to validate these findings and determine if an increased emphasis on influenza vaccination will improve adverse outcomes in SARS-CoV-2-positive patients will be beneficial.

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dark green surface with striations of orange virus attached below

Universal Influenza Vaccine Research

A key focus of NIAID’s influenza research program is developing a universal flu vaccine, or a vaccine that provides robust, long-lasting protection against multiple subtypes of flu, rather than a select few. Such a vaccine would eliminate the need to update and administer the seasonal flu vaccine each year and could provide protection against newly emerging flu strains, potentially including those that could cause a flu pandemic.

Flu viruses are classified by two proteins on the outer surface of the virus: hemagglutinin (H) and neuraminidase (N). There are 18 different H subtypes and 11 different N subtypes, and viruses can be further broken down into different strains within those subtypes. For example, there are various strains of H1N1 influenza virus. The H protein (also called HA) enables the flu virus to enter a human cell. It is made up of a head and a stem. Seasonal flu vaccines fight infection by inducing antibodies that target the HA head. This region varies season to season, which is why flu vaccines must be updated each year. However, scientists discovered the stem typically remains unchanged, making it an ideal target for antibodies induced by a universal flu vaccine.

Universal flu vaccine should: be min 75% effective, protect against group 1 and 2 influenza A; durable protection & last at least 1 year; suitable for all ages

NIAID Universal Influenza Vaccine Strategic Plan

In February 2018, NIAID released its Universal Influenza Vaccine Strategic Plan outlining the institute’s research priorities. It focuses on three specific research areas to simultaneously broaden knowledge around basic influenza immunity and advance translational research efforts to drive universal influenza vaccine development by:

Improving knowledge of transmission, natural history and pathogenesis of influenza infection to help understand factors that contribute to the spread, severity and diversity of influenza, and to identify measures to improve disease control.
Characterizing influenza immunity and immune correlates of protection through the study of immune responses to natural influenza infection and vaccination over time that can be used to identify measurable immune factors critical to vaccine design.
Supporting rational design of universal influenza vaccines through the development and iterative clinical testing of immunogens, adjuvants, diverse platforms, and alternative vaccine delivery methods. NIAID will continue to build resources (Box 1) to lay the foundation of knowledge needed to answer fundamental questions in these research areas and to test new products. These resources will provide the building blocks critical to attaining the research area objectives outlined in the plan with an ultimate goal of rationally designing next-generation influenza vaccines.

Box 1. Universal influenza vaccine resources development: Establish longitudinal human cohorts of varying birth generations; Increase human challenge study capacity and capability; Develop systems biology approaches; Develop animal models; Engineer standardized, validated assays

Achieving these goals will require a global collaborative effort among government agencies, industry, philanthropic organizations, and academia that incorporates interdisciplinary approaches and new technological tools, such as gene-based vaccination, to aid in the development of vaccine candidates.

Leading Vaccine Strategies and Candidates

NIAID is studying various strategies to create a vaccine that elicits antibodies targeting the HA stem. For example, NIAID scientists designed an experimental vaccine featuring the protein ferritin, which can self-assemble into microscopic pieces called nanoparticles, as a key component. The vaccine showed promise in animal testing and is being evaluated for future trials in humans.

In another approach to a universal flu vaccine, NIAID scientists developed a vaccine incorporating four subtypes of the H protein into one vaccine. The vaccine is made from non-infectious virus-like particles that stimulate an immune response but cannot replicate or cause disease. Results have been promising in animal studies and may advance to human trials.

NIAID Vaccine Research Center scientists have initiated Phase 1/2 studies of a universal flu vaccine strategy that includes an investigational DNA-based vaccine (called a DNA “prime”) followed by a licensed seasonal influenza vaccine (“boost”) to improve the potency and durability of seasonal influenza vaccines.

In May 2018, NIAID launched a Phase 2 clinical trial of a universal influenza vaccine called M-001. The vaccine, which was developed and produced by BiondVax Pharmaceuticals based in Ness Ziona, Israel, contains antigenic peptide sequences shared among many different influenza strains.

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NATURE BRIEFING
17 May 2022

Daily briefing: Flu vaccine might also prevent COVID-19

Flora Graham

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An elderly woman holds her arm after receiving a flu vaccine and a man waits in a chair next to her

People in Santiago are vaccinated against influenza. Credit: Ivan Alvarado/Reuters/Alamy

Flu vaccine could cut COVID risk

Influenza vaccines might prevent COVID-19, particularly in its most severe forms. A preprint study of more than 30,000 health-care workers in Qatar found that those who got a flu shot were nearly 90% less likely to develop severe COVID-19 over the next few months, compared with those who hadn’t been recently vaccinated against flu. It’s unclear why flu vaccines — which are composed of killed influenza viruses — would also protect against COVID-19 or how long this protection lasts.

Nature | 4 min read

Reference: medRxiv preprint (not peer reviewed)

Far-UVC disinfection works in real rooms

Real-world tests confirm that short-wavelength ultraviolet light, known as far-UVC, can disinfect air without harming people. Researchers found that far-UVC lamps effectively wiped out airborne Staphylococcus aureus bacteria in a room-sized chamber. Even when the bacteria were continuously released into the room, the lamps — combined with typical ventilation of around three air changes per hour — reduced the amount in the room by 92%, equivalent to 35 air changes per hour . Far-UVC light has long shown promise against airborne pathogens — including SARS-CoV-2 — in the laboratory. And, unlike other forms of UV light, it doesn’t damage human skin or eyes, or cause cancer.

Physics World | 5 min read

Reference: Scientific Reports paper

First plants grown in Moon soil

For the first time, plants have been grown in soil brought back from the Moon . Researchers grew thale cress ( Arabidopsis thaliana ) in samples gathered by the Apollo 11, 12 and 17 missions. The plants sprouted eagerly but didn’t thrive and ended up stunted.

BBC | 3 min read

Reference: Communications Biology paper

Features & opinion

Decolonizing science in south africa.

In the third of an eight-part podcast series, Science in Africa , two researchers at the University of Cape Town discuss the movement that grew around the removal of a campus statue of nineteenth-century imperialist Cecil Rhodes in April 2015. Environmental geographer Paballo Chauke, who is Black, and anthropologist Shannon Morreira, who is white, tell host Akin Jimoh, chief editor of Nature Africa , that seeing the statue come down was both an anti-climax and a catalyst for change . “People must know that ‘Rhodes must fall’ was a thinking movement,” says Chauke. “There was theory and practice behind why the statue must fall.” Nevertheless, the moment itself was overwhelmingly emotional. “That day, it was ‘Oh my god.’ It was like a release, there was a cascading moment like a waterfall.”

Nature Careers Podcast | 26 min listen

Subscribe to the Nature Podcast on Apple Podcasts , Google Podcasts or Spotify .

The shadow pandemic: tuberculosis

In 2020, while all eyes were on COVID-19, tuberculosis (TB) killed 1.5 million people — the first year since 2005 that the number of deaths from the disease had risen. In her new book, The Phantom Plague , global-health reporter Vidya Krishnan reminds us that the threat of drug-resistant TB still hangs over the globe , with the poorest people bearing the heaviest burden. “Poverty is the disease,” she writes; “TB the symptom.”

Nature | 5 min read

‘He brought calm’

Physicist and civil servant Bernard Bigot, who led the jaw-droppingly ambitious ITER project, has died aged 72. Bigot took on the experimental fusion reactor in 2015 and is widely credited with bringing soaring budget and scheduling overruns to heel . Bigot was known for his gentle charm and firm grasp of international diplomacy — essential skills at a multibillion-dollar project that involves every major world power. He was “one of the great leaders in turn-of-the-21st-century science”, says fusion physicist Steven Cowley.

Science | 5 min read

Image of the week

This image was taken by Mast Camera (Mastcam) onboard NASA's Mars rover Curiosity on Sol 3466 (2022-05-07 07:58:16 UTC).

This image taken on Mars by NASA’s Curiosity rover earlier this month shows a rock feature that looks like a door! It’s definitely not a door, though. “It’s just the space between two fractures in a rock,” says NASA geophysicist Ashwin Vasavada. ( Gizmodo | 5 min read )

QUOTE OF THE DAY

“we are not rooted in ideology; we are rooted in making the dream of fusion power a benefit for all of humankind, regardless of country or political party. we are all in this journey together.”.

ITER director-general Bernard Bigot spoke to Nature Physics in 2020 about the status of the project and the future of fusion energy. ( 14 min read )

doi: https://doi.org/10.1038/d41586-022-01406-7

Just when I thought I couldn’t love banana bread more, the European Space Agency (ESA) publishes a recipe that contains the main chemical elements found on the Moon. (It’s a tangential homage to ESA’s participation in the Artemis crewed Moon mission.) It has chocolate, oats and somehow also comes out looking a lot like the Moon ? Give it a try and tag ESA on your favourite social network for a chance to win prizes from them — or send me a photo of your creation to win eternal gratitude from me.

Thanks for reading!

Flora Graham, senior editor, Nature Briefing

With contributions by Smriti Mallapaty

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Iran J Med Sci
v.42(1); 2017 Jan

A Narrative Review of Influenza: A Seasonal and Pandemic Disease

Mohsen moghadami.

Non-Communicable Diseases Research Center, Shiraz University of Medical Sciences, Shiraz Iran

Influenza is an acute respiratory disease caused by the influenza A or B virus. It often occurs in outbreaks and epidemics worldwide, mainly during the winter season. Significant numbers of influenza virus particles are present in the respiratory secretions of infected persons, so infection can be transmitted by sneezing and coughing via large particle droplets. The mean duration of influenza virus shedding in immunocompetent adult patients is around 5 days but may continue for up to 10 days or more—particularly in children, elderly adults, patients with chronic illnesses, and immunocompromised hosts. Influenza typically begins with the abrupt onset of high-grade fever, myalgia, headache, and malaise. These manifestations are accompanied by symptoms of respiratory tract illnesses such as nonproductive cough, sore throat, and nasal discharge. After a typical course, influenza can affect other organs such as the lungs, brain, and heart more than it can affect the respiratory tract and cause hospitalization. The best way to prevent influenza is to administer annual vaccinations. Among severely ill patients, an early commencement of antiviral treatment (<2 d from illness onset) is associated with reduced morbidity and mortality, with greater benefits allied to an earlier initiation of treatment. Given the significance of the disease burden, we reviewed the latest findings in the diagnosis and management of influenza.

What’s Known

Epidemiology, clinical manifestations, and high-risk group management are known as regards influenza.

What’s New

We underscore the recent emphasis on the management of pregnant women without severe manifestations or the management beyond 48 hours of the clinical onset of flue. We also review data on drug resistance and various diagnostic tests and indications thereof.

Introduction

Influenza (mostly referred to as “flu”) is a contagious viral infection caused primarily by the influenza virus A or B. It affects mainly the upper respiratory organs (i.e., the nose, throat, bronchi, and infrequently, lungs) but other organs such as the heart, brain, and muscles can be involved. It occurs worldwide and causes considerable morbidity and mortality with pandemic, epidemic, or seasonal patterns. Epidemics of flu happen annually during autumn and winter in temperate areas and produce significant mortality and morbidity each year. 1 The virus is transmitted from person to person with respiratory droplets produced when the patient coughs or sneezes. Close contact (<1 m) is frequently needed to get infected. Individuals usually recover after a few days, but influenza can give rise to complications and even lead to death—especially in high-risk groups like pregnant women and those with an underlying immunodeficiency state. The symptoms include high fever, body ache, headache, severe malaise, dry cough, sore throat, and runny nose. It should be differentiated from the common cold by clinical presentations.

There are some unique features for influenza such as the epidemic nature of the disease due to its persistent antigenic changes and mortality, caused in part by pulmonary complications. 2

We aimed to review different clinical aspects of the influenza infection vis-à-vis its annual incidence, significant mortality, and burden.

The influenza virus has caused recurrent epidemics of acute febrile syndrome every 1 to 4 years for at least the recent centuries. The first epidemic report of an influenza-like illness was noted in 1173–74, 3 but the first definitive epidemic was reported in 1694. 4 The greatest pandemic in recorded history occurred between 1918 and 1919, when approximately 21 million deaths were recorded worldwide. 5 It was among the deadliest events in reported human history. Afterward, 3 other pandemics occurred in the 20th century: the 1957 H2N2 pandemic, the 1968 H3N2 pandemic, and the 2009 influenza A (H1N1) virus (pH1N1) pandemic. In the most recent event, an influenza strain with a combination of gene segments not previously reported in the swine or human influenza virus strains was identified firstly in Mexico and then in the United States of America. 6 After the involvement of many countries, the pandemic was declared to be over in August 2010. 7

Influenza viruses belong to the family of viruses termed “ Orthomyxoviridae ”, an RNA type virus with diverse antigenic characteristics. They are divided into 3 main types: A, B, and C. Most of the epidemics and outbreaks of flu are caused by types A and B, with type C being generally responsible for sporadic mild upper respiratory symptoms. 8 , 9

Viruses have spherical or filamentous shapes with an envelope, containing glycoproteins and a single stranded RNA gene. The 2 most important glycoproteins over the outer layer of the flu virus are hemagglutinin (H, or HA) and neuraminidase (N, or NA). Both of them have important roles in the pathogenesis of the disease.

For influenza type A, at least 16 highly variable hemagglutinins (H1 to H16) and 9 distinct NAs (N1 to N9) have been recognized so far. With the aid of these different antigens, the influenza type A virus is further subdivided into subtypes on the basis of variable combination patterns of their own specific H or N proteins (e.g., H1N1 or H3N2). Nonetheless, in the nomenclature of the viruses, other variables such as the place of initial isolation and the year of isolation are included. 10

The influenza B virus has a similar viral structure to type A; however, due to the fixed antigenic characters of HA and NA, there are no subtypes in this virus. Still, some small antigenic variabilities have been reported since 1970 in this virus, with the virus having started to diverge into 2 antigenically distinguishable lineages. 11

Epidemiology

Flu occurs in distinct outbreaks of varying extension and intensity every year. This epidemiologic pattern of influenza is based on multiple factors such as the changing nature of the antigenic properties of the virus, transmissibility power of the virus, and the susceptibility of the population. The susceptibility of community is one of the most important factors in the strength of epidemics and its mortality or morbidity effects in specific. For example, in a recent pandemic due to the presence of baseline partial immunity in the Iranian community, the country did not have a high mortality rate. 12

The influenza A virus, in particular, has a specific ability to undergo periodic changes in the antigenic characteristics of its surface glycoproteins, hemagglutinin, and neuraminidase. Major changes in these proteins are termed “antigenic shifts”, and minor changes are termed “antigenic drifts”. Antigenic shifts are associated with the epidemics and pandemics of influenza A, whereas antigenic drifts are responsible for more localized outbreaks of varying extent.

Due to the segmented pattern of the influenza virus gene and the high rates of reassorment on its genome, the emergence of pandemic strains usually has been caused by animal- and human-type reassorment and the resultant antigenic shifts.

Between the years of antigenic shifts, antigenic drifts have happened almost annually and have resulted in outbreaks of variable extent and severity. The outbreaks of antigenic drifts are usually less extensive and severe than the epidemics or pandemics associated with antigenic shifts. Antigenic drifts are resulted from point mutations in the RNA gene segments that are responsible for hemagglutinin or neuraminidase; accordingly, they occur sequentially as the virus spreads through susceptible populations. 13

Influenza usually has the highest attack rates among young people, while high mortality rates are reported among older adults. In addition to the elderly, mortality and morbidity are specifically high in those with definite high-risk medical conditions—including extreme of ages, cardiovascular diseases, and metabolic diseases such as diabetes mellitus. A summary of these conditions are shown in table 1 . Specifically, the increased risk of influenza morbidity and mortality during pregnancy were observed during the 2009 pandemic. 14 Also, the data from previous pandemics and seasonal influenza outbreaks suggest that the risk of influenza complications may be higher in the 2nd and 3rd trimesters of pregnancy in comparison to the 1st trimester. 15

Groups at risk of influenza complications

Unvaccinated infants aged 12–24 months

Persons with asthma or other chronic pulmonary diseases such as cystic fibrosis in children or chronic obstructive pulmonary disease in adults

Persons with hemodynamically significant cardiac disease

Persons who have immunosuppressive disorders or who are receiving immunosuppressive therapy HIVinfected persons

Persons with sickle-cell anemia and other hemoglobinopathies

Persons with diseases requiring long-term aspirin therapy such as rheumatoid arthritis

Persons with chronic renal dysfunction

Persons with cancer

Persons with chronic metabolic diseases such as diabetes mellitus Persons with neuromuscular disorders, seizure disorders, or cognitive dysfunction—which may compromise the handling of respiratory secretions

Adults aged>65 years

Residents of any age of nursing homes or other long-term care institutions

Transmission

In the respiratory secretion of the patients suffering from influenza, large amounts of virus load are often present and, as a result, each infected person can be transmitting infection to other individuals by sneezing and coughing. It has been posited that the disease is transmitted primarily via large particle droplets (>5 µ). 16

Owing to the large size of infectious droplets, close contact is needed for the acquisition of the disease. These large particles usually do not remain suspended in the air for a long time and they travel only short distances. Airborne transmission is, therefore, not often considered for disease spread. 17 However, limited data show that small particle respiratory droplets, which become aerosolized and can stay suspended in the air for a long time, also contain the influenza virus and can potentially cause disease spread. 18 In a recent study, aerosol transmission accounted for around half of all the transmission events. This suggests that activities to reduce transmission by contact or large droplets may not be enough to control the transmission of the influenza A virus in households or communities. 19 Thus, the prevention strategies that are drawn upon routinely in hospitals require further re-evaluation.

Moreover, contact with contaminated surfaces containing respiratory droplets is another potential source of disease transmission. In adults without other underlying diseases, the shedding of virus starts from 24 to 48 hours before disease manifestation and the shedding stops after 6 or 7 days according to most studies and after 10 days according to some other investigations. 20 It should be considered that longer periods of shedding and infectiousness can occur in children, elderly adults, immunocompromised hosts, and patients with chronic illnesses. 21 , 22

Clinical Manifestations

Uncomplicated influenza.

Influenza typically begins with the abrupt onset of symptoms following an incubation period of 1 to 2 days. Primarily, these symptoms are systemic and consist of fever sensation, true chills, headache, severe myalgia, malaise, and anorexia. Mostly headache, myalgia, and fever determine the severity of the disease insofar as they are more prominent. 23 Myalgia is prominent in the calf muscle (especially in children) and the paravertebral and back muscles, but all striated muscles may become involved such as the extraocular muscle, which causes painful eye movement. These symptoms are mostly accompanied by the manifestations of respiratory tract illnesses such as dry cough, nasal discharge, and sore throat. Often, so abrupt is the onset that the patient can remember the precise onset of the disease. However, the manifestations of influenza infections can range from afebrile respiratory illnesses similar to the common cold, to diseases in which systemic signs and symptoms predominate with relatively little respiratory tract infection symptoms. 24 , 25 In the early days, the patient has high-grade fever and on the 2nd and 3rd days, the fever decreases and diminishes gradually. It may, nonetheless, last for 4 to 8 days. Early in the course of the disease, the patient’s face is plethoric with watery and red eyes. A convalescent period of some weeks may ensue, during which dry cough and malaise are the most salient complaints of the patient.

Complications of Influenza

The most important and common complication of influenza is pneumonia, not least in high-risk individuals. Pneumonia may happen as a continuum of the acute influenza syndrome when caused by the influenza virus (primary pneumonia) or as a mixed viral and bacterial infection after a gap of a few days (secondary pneumonia).

Primary Influenza Viral Pneumonia

The illness occurs after the typical course of flu with a rapid progression of fever, dyspnea, cough, cyanosis, and difficult breathing. It happens predominantly among individuals with cardiovascular or underlying pulmonary diseases such as asthma. Physical examination is in favor of bilateral lung involvement, and imaging findings in the lungs constitute reticular or reticulonodular opacities with or without superimposed consolidation. Sometimes the radiological appearance of primary influenza pneumonia can be difficult to distinguish from pulmonary edema because of the presence of perihilar congestion and hazy opacification, at least in the lower lobes. Less frequently, radiographs show focal areas of infiltration. Commonly used pneumonia severity assessment tools such as the CURB65 or the Pneumonia Severity Index are not useful in determining which patients to hospitalize due to primary influenza pneumonia since these tools have not been developed and validated during an influenza pandemic. 26 Thus, careful history taking and examination, determination of pregnancy or hypotension, and early identification of young patients with decreased oxygen saturation, respiratory rate >25 per minute, and concomitant diarrhea are crucial for admission decision-making. The typical radiographic findings of primary influenza pneumonia are bilateral reticular or reticulonodular opacities, sometimes accompanied by superimposed consolidation. Less frequently, radiographs show focal areas of consolidation without reticular opacities. High-resolution computed tomography often shows multifocal peribronchovascular or subpleural consolidation with or without ground-glass opacities. 27 The most severe cases progress rapidly to acute respiratory distress syndrome and multilobar alveolar infiltrations. These patients usually present with progressive dyspnea and severe hypoxemia 2 to 5 days after the onset of typical influenza symptoms. Hypoxemia increases rapidly and causes respiratory failure, requiring intubation and mechanical ventilation, maybe after only 1 day of hospitalization. 28

Secondary Bacterial Pneumonia

The incidence of secondary bacterial pneumonia ranged from 2% to 18% during the influenza pandemic in 1957–58. 29 A threefold increase in the incidence of secondary Staphylococcus aureus pneumonia during the influenza pandemic of 1968–9 compared to a non-epidemic period of pneumonia etiologies was observed. 30 Recently, community–acquired methicillin-resistant Staphylococcus aureus was determined after seasonal influenza, 31 but another very common etiologic bacterium is Streptococcus pneumonia . The patient has a classic influenza disease, followed by an improvement period lasting maximally 2 weeks. The recurrence of the symptoms such as fever, productive cough, and dyspnea and findings of new consolidations in chest imaging can be found in involved patients. Accordingly, a biphasic pattern of signs and symptoms in influenza-labeled patients should be considered as secondary superimposed bacterial pneumonia.

Non-Pulmonary Complications

In addition to its respiratory effects, the virus can exert effects on other body systems such as the musculoskeletal, cardiac, and neurologic systems. Myocarditis and pericarditis constitute unusual but significant complications of seasonal or pandemic flu. In a prospective study, half of adult flu patients without cardiac complaints had abnormal ECG findings at presentation. 32 Myocarditismostly resolves by 28 days, and the patients has a good heart-muscle function without a reduced ejection fraction. Significant myositis and rhabdomyolysis have rarely been reported with seasonal influenza, 25 but different amounts of creatine phosphokinase elevation have been reported in many studies after seasonal or pandemic flues. 33 - 35 Mild myositis and myoglobinuria with tender leg or back muscles can mainly be seen in children, although they can occur in adults and be accompanied by symptoms of painful walking or standing. Other rare complications such as the Guillain–Barré syndrome, encephalitis, acute liver failure, and the Reye syndrome may happen after influenza A infection.

The majority of influenza cases are diagnosed by their clinical manifestations and there is no need for laboratory tests. Be that as it may, in special circumstances, the diagnosis of flu necessitates laboratory confirmation using available tests such as nucleic acid tests (e.g., polymerase chain reaction [PCR]) or rapid diagnosis kits or rarely virus isolation by culture methods.

Rapid Diagnosis Influenza Tests

Rapid influenza diagnostic tests detect influenza viral antigens and screen patients with suspected influenza in a timely manner in comparison to other diagnostic modalities. The most widely used technique is based on the detection of viral antigens in the respiratory secretions of patients by immunologic methods. All rapid tests are performed with ease and can provide results within 30 minutes. Each test varies with regard to whether it can distinguish between influenza A and B. Nevertheless, these tests have thus far been unable to specify types of influenza A such as H1N1 and H3N2. The overall specificities achieved by these tests are high and comparable between the manufacturers. However, their sensitivities have shown great heterogeneity across studies depending on the nature of the samples tested and the patients, ranging from 4.4% to 80% in comparison to cell culture as a gold standard test. 36 - 38 As a general concept, sensitivity in adults is less than that reported in younger patients. Also, the sensitivity may be higher at the onset of the disease, when a higher load of the virus exists. Economic studies comparing rapid testing to the clinical diagnosis of influenza remain inconclusive. Indeed, some studies have suggested that, in most cases, clinical judgment combined with antiviral treatment is the most cost-effective strategy, 39 while new studies have suggested that testing may be the most cost-effective strategy and shown that oseltamivir treatment based on the point-of-care (POC) test is a dominant option compared to conventional approaches without screening tests in the baseline scenario and that they could be cost-effective in 80% of cases according to the cost-effectiveness acceptability curve. 39 Furthermore, influenza antiviral treatment based on POC could be cost-effective in specific conditions of performance, price, and disease prevalence. 40

Molecular Tests

Due to the limitation in other diagnostic modalities in influenza detection, molecular assays have increasingly been considered the gold standard diagnostic method for the detection of the influenza virus in hospital-based diagnostic laboratories. Although several amplification methods have been developed, the majority of the current assays—particularly those used in clinical laboratories—are based on the PCR amplification method. These tests have the ability to check several targets concurrently and thereby provide type and subtype information for each virus. Additionally, they have the ability to be adapted rapidly for the detection of novel targets; these features 41 played a critical role during the influenza pandemic of 2009. PCR is potentially more sensitive than cell culture, and it can detect the nonviable virus in samples. The sensitivity of these tests is dependent on the sample site of the patient and is similar to that of the rapid tests. Higher sensitivity can be obtained by swab samples of a nasopharyngeal origin. PCR-based molecular assays have yielded excellent clinical utility for the detection and identification of influenza viruses at bedside as POC, and numerous Food and Drug Administration (FDA)-cleared commercial devices are now available. 42 - 44

Role of the Laboratory Diagnosis of Flu in Clinical Case Management

Given the self-limiting nature of the disease in otherwise healthy individuals, there is no need for diagnostic tests in all presenting cases. Diagnostic tests should be conducted if the results of the test are thought to be able to influence subsequent clinical management and if the results of the test are deemed influential in decisions on the initiation of specific antiviral treatment, impact on other diagnostic tests, antibiotic treatment decision-making, and infection control practices. 45 In addition, duringinfluenzaseasons, hospitalized individuals of any age with fever and severe respiratory symptoms—including those with a diagnosis of community-acquired pneumonia—need laboratory testing irrespective of time from illness onset.

Currently, at least 4 antiviral drugs are available for the treatment and prevention of influenza. It is deserving of note that in healthy immunocompetent individuals with intact immunity, there is a rapid limitation in the ability of the influenza virus; therefore, the anti-replication power of antiviral drugs is limited and has no theoretical effect. Also, no study to date has demonstrated a beneficial effect for antiviral agents starting beyond 48 hours of symptom onset. The greatest effect is classically seen when therapy is started in the first 24 hours. Treatment is recommended for both adults and children with the influenza virus infection with the following criteria: 46

1) Persons with laboratory-confirmed or highly suspected influenza virus infection in high-risk groups ( table 1 ), within 48 hours after symptom onset
2) Patients requiring hospitalization for laboratory-confirmed or highly suspected influenza disease, regardless of underlying illnesses, if treatment can be initiated within 48 hours after symptom onset
3) Outpatients at high risk of complications ( table 1 ) with an illness that is not improving and outpatients with a positive influenza test result from a specimen obtained >48 hours after symptom onset.

Individuals whose onset of symptoms is >48 hours before presentation with persisting moderate-to-severe illness.

During the last pandemic wave, neuraminidase inhibitors (NAIs)—primarily oseltamivir and zanamivir—were widely prescribed for patients with confirmed or suspected A H1N1pdm09 infection. 47 , 48 However, before the 2009–10 pandemic, evidence of their effectiveness in seasonal influenza, while strong for modest symptom reduction, was less strong for decreases in pneumonia incidence or pneumonia outcome improvment. 49 - 52 Recent data demonstrated that patients with influenza-related pneumonia treated early (≤48 h after illness onset) with an NAI experienced around one-third lower likelihood of dying or requiring ventilator assistance compared to those treated at later hours. 53 Influenza viruses and their susceptibilities to available antiviral medications are changing rapidly. Clinicians should be aware of the local patterns of influenza circulations and susceptibilities. For instance, a meta-analysis showed that NAIs were able to lessen mortality in patients admitted to the hospital with A H1N1pdm09 infection. 30 Sporadic oseltamivir-resistant infections have been identified, together with rare episodes of limited transmission. 54 Given the currently circulating influenza A (H3N2) and 2009 H1N1 virus resistance to adamantanes, these medications are not recommended for use against influenza A virus-induced infections. However, most influenza A and B virus strains are still susceptible to neuraminidases such as oseltamivir and zanamivir, with these drugs being selected for treatment in indicated persons ( table 2 ). In addition, it should be considered that the development of resistance to oseltamivir during treatment was more common among seasonal influenza A (H1N1) virus infections (27%) than among seasonal influenza A (H3N2) (3%) or B (0%) virus infections in a recent study. 55

Recommended dosages and durations of influenza antiviral medications for treatment or chemoprophylaxis

Antiviral agent	Use	Adults
Oseltamivir	Treatment (5 d)	75 mg twice daily
	Chemoprophylaxis (7 d)	75 mg once daily
Zanamivir	Treatment (5 d)	10 mg (two 5-mg inhalations) twice daily
	Chemoprophylaxis (7 d)	10 mg (two 5-mg inhalations) once daily

Due to the limitations in the current therapeutic options for the treatment of influenza virus infections, additional treatment options with a different mechanism of action have been investigated as treatment for individuals with severe influenza virus disease. For example, a handful of mAbs against influenza virus proteins are currently in the early phases of evaluation for human infection control. 56 These mAbs target the external portions (i.e. ectodomain) of the M2 protein (M2e). The M2e is an attractive target for influenza vaccines and therapeutic antibodies because of the extremely conserved nature of the amino acid sequences of its domains among isolates from different subtypes of influenza A viruses. 57

The mechanisms of anti-M2e Ab–mediated protection are not completely determined. Anti-M2 Abs do not have hemagglutination inhibition ability or in vitro virus neutralization properties. 58 It is supposed that the main target for the anti-M2e antibody is virus-infected human cells, which heavily express M2e on their surface. 59

Most studies have reported that corticosteroid therapy adversely influences influenza-related outcomes. During the 2009 influenza pandemic, 37% to 55% of the patients admitted to ICUs in Europe received corticosteroids as part of their treatment. 60 - 62 Nonetheless, in a recentmeta-analysis report, evidence from observational studies—albeit with important limitations—suggested that corticosteroid therapy for presumed influenza-associated complications was associated with increased mortality. 63

Vaccination

The most important strategy for the prevention of influenza and its severe outcomes is annual vaccination against seasonal influenza. The influenza virus is characterized for its high rate of mutation, beating the immune system’s function against new variants, 64 which is why new vaccines are produced annually to match circulating viruses. 65 The selection of influenza antigens to include in the vaccines is based upon the global surveillance of influenza viruses in circulation and the spread of new strains of the influenza virus around the world. 66 For the following influenza season in the southern hemisphere, recommendations are made in September and for the influenza season in the northern hemisphere in February because around 6 to 8 months are needed to manufacture and approve new vaccines. Recently, the World Health Organization (WHO) recommended that trivalent influenza vaccines for use in the 2016 southern hemisphere influenza season contain the following virus antigens: 67

An A/California/7/2009 (H1N1) pdm09-like virus
An A/Hong Kong/4801/2014 (H3N2)-like virus
A B/Brisbane/60/2008-like virus.

The WHO stresses that vaccination is especially important for individuals at higher risk of serious influenza complications, with the highest priority afforded to pregnant ladies—followed by children aged between 6 and 59 months, elderly and individuals with specific chronic medical conditions (e.g., renal failure and diabetes mellitus), and finally individuals at high risk (e.g., health staff). 68 In contrast in 2010, the United States’ Advisory Committee on Immunization Practices (ACIP) extended the recommendation for annual influenza vaccination to encompass all individuals 6 months of age and older individuals who did not have contraindications without any priority. 69

The outbreaks of influenza generally occur during the last autumn and whole winter months. A single dose (0.5 cc) of an influenza vaccine should be injected to adults annually, preferably by October in the northern hemisphere and May in the southern hemisphere. Children aged between 6 months and 8 years require 2 doses of influenza vaccine (with at least 4 weeks apart) during their 1st season of vaccination foroptimal response. 69

The vaccine effectiveness of influenza vaccines is a determinant of how much the seasonal influenza vaccine can prevent influenza virus infections in the given population during an influenza season. 70 Recently, the documentation of the antigenic drift from the vaccine strain in a majority of considered isolates raised concern that vaccine effectiveness might be suboptimal, especially in older ages or specific high-risk groups. TheCenters for Disease Control and Prevention (CDC) in the United Statesof America had an estimation of 23% of vaccine effectiveness for the northern hemisphere 2014–15 seasonal influenza vaccine due to a mismatch in the circulating viruses and vaccine contained viruses. 71 What should be taken into consideration is that even if a vaccine is not completely related to the predominant circulating virus, it can protect several different influenza viruses and can, as such, confer good protection and prevent influenza-related illnesses. It is also a fact that influenza vaccines are safe and are especially important for reducing severe disease in some high-risk populations. Accordingly, the WHO recommends seasonal influenza vaccines even if they are not closely related to the predominant circulating influenza viruses each year for the above-mentioned groups. 72

Chemoprophylaxis Strategy

Available antiviral drugs play an important role for patients who have not been immunized or who are nonresponsive to vaccines. Oseltamivir and zanamivir are the recommended drugs for the prevention of influenza based on their established efficacy and low rates of resistance in comparison to adamantanes. 73 Theseagentsare effective for the prevention of influenza in healthy individuals, persons at high risk of influenza complications, and those residing in long-term care facilities. The efficacy of oseltamivir and zanamivir has yet to be compared with each other. 74 It should be emphasized that when choosing a strategy of antiviral chemoprophylaxis, some parameters such as preventing complications in patients at high risk and reducing the risk of promoting antiviral drug resistance should be considered. There are, therefore, some indications for this approach, as follows: 18

1) Influenza prophylaxis during influenza outbreaks in long-term care centers in the elderly regardless of prior influenza vaccinations
2) In unvaccinated individuals at high risk of influenza complications who have been exposed to an individual with influenza infections within the previous 48 hours
3) Antiviral prophylaxis for vaccinated persons at high risk of influenza complications who have had close contact with an individual with influenza within the previous 48 hours when there is a poor match between the vaccine and circulating viruses in a given year
4) The United States’ ACIP recommends that antiviral chemoprophylaxis be considered in pregnant women and in women up to 2 weeks postpartum who have close contact with suspected or confirmed influenza A-infected individuals. Zanamivir may be the drug of choice for prophylaxis due to its limited systemic absorption. 75

Influenza epidemics and pandemics impose a heavy socioeconomic burden on all societies. Hospital admission and treatment and ICU care are more often necessary in high-risk individuals such as the elderly and pregnant ladies. However, the impact of influenza cannot be neglected even in young adults, mainly because of the loss of productivity.

Given the nature of the virus and the increasing patterns of the available antiviral drugs against the influenza virus, the best strategy is the vaccination of high-risk groups ( table 1 ) at appropriate times. Inactivated influenza vaccines are always well-tolerated, with the most common side effect being burning pain at the injection site. In clinical trials, serious adverse events have been reported in <1% of the individuals vaccinated. Consequently, the vaccination policy in high-risk groups should be the priority in the battle against flu.

With concerns over increasing resistance against both adamantanes and NAIs, the risk of the development of antiviral drug resistance should be considered if we opt to treat all patients who are labeled as suffering from flu. Individuals with suspected flue with severe disease such as those with signs and symptoms of lower respiratory tract infections (e.g., dyspnea, tachypnea, and low oxygen saturation) and those who have signs of rapid clinical deterioration or those at high risk of complications should receive antiviral therapy. In all cases, antivirals should be started <48 hours after symptom onset. In pregnant patients due to higher mortality, there is a suggestion that all patients with suspected or confirmed influenza—even those who present >48 hours after symptom onset—be treated provided that they are not improving. In addition, a new look at antiviral chemoprophylaxis and its appropriate use may effect a reduction in morbidity and mortality allied to flu in high-risk groups.

Conflict of Interest: None declared.

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A Narrative Review of Influenza: A Seasonal and Pandemic Disease

Introduction

Epidemiology

Transmission

Clinical Manifestations

Complications of Influenza

Primary Influenza Viral Pneumonia

Secondary Bacterial Pneumonia

Non-Pulmonary Complications

Rapid Diagnosis Influenza Tests

Molecular Tests

Role of the Laboratory Diagnosis of Flu in Clinical Case Management

Vaccination

Chemoprophylaxis Strategy

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