influenza

Influenza is a highly contagious viral infection of the respiratory tract caused by influenza viruses, primarily types A, B, and C, with type A being responsible for seasonal epidemics and global pandemics ^[1]. The virus spreads through respiratory droplets and aerosols generated when infected individuals cough, sneeze, or talk, and can also be transmitted via contaminated surfaces ^[2]. With an incubation period of about 1–4 days, people can be contagious even before symptoms appear, contributing to its rapid spread, especially in crowded indoor settings during colder months ^[3]. Typical symptoms include sudden onset of high fever, chills, muscle aches, headache, fatigue, dry cough, sore throat, and nasal congestion, distinguishing it from the milder and more gradual presentation of the common cold, which is often caused by rhinoviruses ^[4]. While most healthy individuals recover within one to two weeks, influenza can lead to severe complications such as pneumonia, bronchitis, and acute respiratory distress syndrome, particularly in high-risk groups like the elderly, young children, pregnant women, and those with chronic conditions such as asthma, chronic obstructive pulmonary disease, or diabetes ^[5]. The virus's ability to undergo antigenic changes—through antigenic drift and antigenic shift—allows it to evade immune detection, necessitating annual updates to the influenza vaccine ^[6]. Global surveillance systems like the Global Influenza Surveillance and Response System, coordinated by the World Health Organization, monitor viral evolution and guide vaccine composition each year ^[7]. Preventive measures include annual vaccination, hand hygiene, respiratory etiquette, and in some cases, the use of antiviral drugs such as oseltamivir or zanamivir, especially in high-risk individuals ^[8]. The development of a universal influenza vaccine remains a key research goal to provide long-lasting protection against diverse strains ^[9].

Virology and Viral Types

Influenza viruses belong to the family Orthomyxoviridae, a group of enveloped viruses with a segmented, single-stranded, negative-sense RNA genome. These viruses are classified into four main types: A, B, C, and D, with types A, B, and C being the most relevant to human disease. Each type exhibits distinct structural, biological, and epidemiological characteristics that influence their transmission, clinical impact, and role in seasonal epidemics and global pandemics ^[10].

Structural and Genetic Features

All influenza viruses share a common structural framework: a lipid envelope derived from the host cell membrane, studded with glycoprotein spikes, and enclosing a helical nucleocapsid that houses the viral RNA segments. The genome of influenza A and B viruses consists of eight RNA segments, while influenza C has only seven, due to the fusion of the hemagglutinin and neuraminidase genes into a single gene encoding the hemagglutinin-esterase-fusion (HEF) protein ^[11].

The surface glycoproteins are critical for viral entry and release. Influenza A and B viruses express two major glycoproteins: hemagglutinin (HA) and neuraminidase (NA). HA mediates viral attachment to host cell receptors containing sialic acid, determining tissue and species tropism, while NA facilitates the release of newly formed virions by cleaving sialic acid residues, preventing viral aggregation on the cell surface ^[12]. Influenza A viruses exhibit extensive antigenic diversity, with 18 known HA subtypes (H1–H18) and 11 NA subtypes (N1–N11), enabling combinations such as H1N1 or H3N2 ^[10]. In contrast, influenza B viruses do not have subtypes but are divided into two main antigenic lineages: Victoria and Yamagata ^[1].

Influenza C virus expresses a single surface glycoprotein, HEF, which combines the receptor-binding and esterase functions of HA and NA, respectively. This structural simplicity correlates with its limited pathogenicity and lack of significant epidemic potential ^[10]. Influenza D, primarily affecting cattle, is not known to cause illness in humans and is not considered a public health threat.

Biological Differences and Host Range

The host range and zoonotic potential of influenza viruses vary significantly among types. Influenza A has the broadest host spectrum, infecting humans, birds, pigs, horses, and other mammals. Wild aquatic birds, particularly ducks and geese, serve as the natural reservoir for all known influenza A subtypes, allowing for continuous viral circulation and evolution in nature ^[10]. This zoonotic capacity enables cross-species transmission and genetic reassortment, particularly in intermediate hosts like swine, which possess receptors for both avian and human influenza viruses, making them ideal “mixer” hosts for the emergence of novel pandemic strains ^[17].

Influenza B viruses are almost exclusively restricted to humans, with no known animal reservoir. Their evolution is slower and driven primarily by antigenic drift, leading to seasonal epidemics but not pandemics ^[1]. Influenza C infects both humans and swine but causes only mild or asymptomatic infections, with no association with seasonal epidemics or severe disease ^[19].

Antigenic Variation: Drift and Shift

The ability of influenza viruses to evade host immunity is largely due to antigenic variation, which occurs through two mechanisms: antigenic drift and antigenic shift. Antigenic drift refers to the accumulation of point mutations in the genes encoding HA and NA, particularly in influenza A and B viruses. These gradual changes allow the virus to partially escape pre-existing immunity, necessitating annual updates to the influenza vaccine to match circulating strains ^[10].

Antigenic shift, exclusive to influenza A, is a more dramatic process involving the reassortment of genomic segments when two different influenza A viruses co-infect the same cell. This can result in a novel virus with a new HA and/or NA subtype, to which the human population has little or no immunity, potentially triggering a pandemic. A notable example is the 1957 pandemic, caused by the emergence of A(H2N2) through reassortment between human and avian viruses ^[21].

Viral Replication Cycle

The replication of influenza viruses occurs in the nucleus of host cells, a unique feature among RNA viruses. The cycle begins with HA-mediated attachment to sialic acid receptors on respiratory epithelial cells, followed by clathrin-mediated endocytosis. Acidification of the endosome triggers a conformational change in HA, leading to membrane fusion and the release of viral ribonucleoproteins into the cytoplasm, which are then transported to the nucleus ^[22].

Inside the nucleus, the viral RNA-dependent RNA polymerase (composed of PB1, PB2, and PA subunits) transcribes viral mRNA and replicates the genome. Newly synthesized viral proteins are exported to the cytoplasm or plasma membrane, while progeny vRNA segments are exported via the nuclear export protein (NEP). Virion assembly occurs at the plasma membrane, where HA, NA, and M2 proteins cluster, and budding is facilitated by NA’s enzymatic activity ^[23].

Clinical and Epidemiological Implications

The virological differences among influenza types translate into distinct clinical and epidemiological profiles. Influenza A is responsible for most seasonal epidemics and all known pandemics due to its antigenic variability and zoonotic potential. It is generally associated with more severe disease and higher complication rates, particularly in high-risk groups such as the elderly, young children, and individuals with chronic conditions ^[24].

Influenza B causes seasonal outbreaks with clinical manifestations similar to influenza A, though often considered slightly less severe. However, it can still lead to significant morbidity and complications, especially in children ^[25]. Influenza C typically causes mild upper respiratory tract infections, often indistinguishable from the common cold, and is not targeted by seasonal vaccines ^[26].

The continuous evolution of influenza A viruses through antigenic drift and shift underscores the importance of global surveillance systems such as the Global Influenza Surveillance and Response System, coordinated by the World Health Organization, to monitor viral changes and guide vaccine composition ^[7]. Understanding the virology of influenza is essential for developing effective prevention strategies, including the pursuit of a universal influenza vaccine that targets conserved viral epitopes to provide broad and long-lasting protection ^[9].

Transmission and Contagiousness

Influenza is a highly contagious viral infection primarily transmitted through respiratory droplets and aerosols generated when infected individuals cough, sneeze, or talk ^[29]. The virus spreads efficiently in close proximity, as these respiratory particles—ranging from larger droplets to smaller aerosols of 1–4 microns—can be inhaled directly by nearby individuals or settle on surfaces, leading to indirect transmission when contaminated hands touch the eyes, nose, or mouth ^[19]. This mode of transmission underscores the importance of respiratory etiquette and hand hygiene in curbing viral spread ^[31].

The transmission of influenza is particularly efficient in enclosed, poorly ventilated environments where people are in close contact, such as homes, schools, workplaces, and healthcare facilities ^[32]. Studies have shown that the virus remains more stable and transmissible under cold, dry conditions typical of winter months, which contributes to its pronounced seasonality in temperate climates ^[19]. In the Northern Hemisphere, influenza activity typically peaks between December and February, while in the Southern Hemisphere, it occurs from June to August ^[34].

Contagious Period and Incubation

A key factor in the rapid spread of influenza is that individuals can be contagious before they develop symptoms. The incubation period—the time between exposure to the virus and the onset of symptoms—is generally short, averaging about two days, with a range of 1 to 4 days ^[3]. Notably, people infected with influenza can begin shedding the virus and transmitting it to others approximately one day before symptom onset ^[36]. This asymptomatic and presymptomatic transmission makes containment challenging and contributes significantly to community spread, especially in crowded indoor settings during colder seasons ^[31].

The contagious period typically lasts 5 to 7 days after symptoms begin, but it can extend longer in certain populations. In young children and individuals with compromised immune systems, such as those with immunodeficiencies or undergoing chemotherapy, viral shedding may persist for more than 10 days, increasing the risk of transmission ^[36]. This prolonged infectiousness highlights the importance of isolation and preventive measures in households and healthcare settings.

Viral Types and Transmission Efficiency

Among the different types of influenza viruses, influenzavirus A and influenzavirus B are the most transmissible among humans, with a basic reproduction number (R0) estimated between 1.2 and 2.0, meaning each infected person can infect 1 to 2 others on average ^[19]. In contrast, influenzavirus C causes milder infections and has much lower transmissibility, rarely leading to epidemics ^[19]. The high transmissibility of type A is further amplified by its ability to infect multiple species, including birds and swine, which act as reservoirs and "mixing vessels" for genetic reassortment, potentially giving rise to novel strains with pandemic potential ^[17].

The efficiency of transmission is also influenced by viral load and host behavior. Activities that increase respiratory particle emission—such as talking, singing, or physical exertion—can enhance spread, particularly in poorly ventilated spaces. This has led public health authorities to recommend measures such as improving indoor air quality through ventilation and the use of HEPA filters, as well as wearing face masks during peak influenza seasons or in high-risk settings ^[2].

In summary, the transmission of influenza is driven by a combination of biological, environmental, and behavioral factors. Its high contagiousness, facilitated by presymptomatic shedding and efficient spread in crowded indoor environments, makes it a significant public health challenge. Preventive strategies, including annual vaccination, respiratory hygiene, and environmental controls, are essential to reduce transmission, particularly among high-risk groups such as the elderly, young children, and those with chronic conditions ^[43].

Symptoms and Clinical Presentation

Influenza is characterized by a sudden and intense onset of systemic symptoms that distinguish it from other common respiratory infections. Unlike milder illnesses such as the common cold, which develops gradually, influenza strikes abruptly and is typically more severe in its presentation ^[4]. The clinical picture involves a constellation of symptoms affecting multiple body systems, with a pronounced impact on general well-being and physical function.

Core Symptoms of Influenza

The hallmark of influenza is its acute onset, with symptoms often appearing within 1–4 days after exposure, following a short incubation period ^[3]. The primary symptoms include:

• High fever, frequently exceeding 38°C, which is a key differentiator from the common cold where fever is rare or mild ^[19].
• Chills and sweating, commonly accompanying the fever and contributing to patient discomfort ^[24].
• Muscle aches (myalgia) and joint pain (arthralgia), which are often severe and debilitating, affecting the back, arms, and legs ^[48].
• Headache, typically frontal or temporal, which can be intense and persistent ^[19].
• Dry cough, which is usually non-productive and can linger for several weeks after other symptoms resolve ^[19].
• Sore throat and nasal congestion, though these upper respiratory symptoms are generally less prominent than in the common cold ^[51].
• General malaise and fatigue, a profound sense of exhaustion and weakness that can persist long after the acute phase of the illness ^[24].

The abrupt onset and severity of these systemic symptoms are critical clinical clues. While the common cold primarily affects the upper respiratory tract with symptoms like runny nose and sneezing, influenza presents with a broader, more intense systemic illness ^[53].

Age-Specific and Atypical Manifestations

The clinical presentation of influenza can vary significantly depending on the age and health status of the individual. In children, particularly those under five years of age, the illness may be accompanied by gastrointestinal symptoms such as nausea, vomiting, and diarrhea, which are uncommon in adult cases ^[54]. These symptoms can sometimes lead to misdiagnosis as a gastrointestinal infection.

Conversely, in older adults, the classic symptom of high fever may be absent or only mild, making diagnosis more challenging ^[51]. Instead, elderly patients may present with atypical symptoms such as confusion, dizziness, or a general decline in functional status, which can be mistaken for other age-related conditions. This underscores the importance of considering influenza in the differential diagnosis for any acute illness in this high-risk population, even in the absence of typical symptoms.

Distinguishing Influenza from Other Respiratory Infections

During peak respiratory virus seasons, differentiating influenza from other infections is crucial for appropriate management. Key differentiators include:

• Versus the common cold: The common cold, often caused by rhinoviruses, has a gradual onset and is dominated by nasal symptoms like congestion and runny nose. Fever and systemic symptoms like severe muscle aches are rare ^[56].
• Versus respiratory syncytial virus (RSV): RSV often presents with prominent respiratory distress, wheezing, and a persistent cough, particularly in infants where it can cause bronchiolitis. Systemic symptoms like high fever and severe myalgia are less common ^[57].
• Versus SARS-CoV-2 (COVID-19): While the symptoms of influenza and COVID-19 can overlap significantly, the loss of taste and smell (anosmia) is a more specific feature of COVID-19 ^[58]. However, definitive diagnosis often requires laboratory testing due to the clinical similarities.

The presence of sudden high fever, severe muscle pain, and profound fatigue should raise a strong clinical suspicion of influenza, especially during known epidemic periods. Early recognition is vital, as it enables the timely initiation of antiviral therapy with agents like oseltamivir, which is most effective when started within 48 hours of symptom onset ^[59]. This prompt intervention can reduce the duration of illness and lower the risk of developing serious complications such as pneumonia or acute respiratory distress syndrome.

High-Risk Groups and Complications

Influenza, while often self-limiting in healthy individuals, can lead to severe and potentially life-threatening complications, particularly in certain high-risk populations. These groups are more susceptible due to age-related physiological changes, underlying health conditions, or altered immune responses. The most common complications include pneumonia, bronchitis, and acute respiratory distress syndrome, with more rare but serious outcomes such as encephalitis, myocarditis, and sepsis ^[60]. The virus can also exacerbate pre-existing chronic diseases, leading to hospitalization and increased mortality. Preventive measures, particularly annual influenza vaccination, are crucial for mitigating these risks in vulnerable individuals ^[61].

High-Risk Groups

Several distinct populations are at an elevated risk of developing severe influenza and its complications. These groups are the primary focus of public health recommendations for vaccination and early antiviral treatment.

Elderly individuals (aged 60 years and older) are among the most vulnerable. The natural decline of the immune system with age, known as immunosenescence, combined with a high prevalence of comorbidities, significantly increases the risk of severe outcomes ^[19]. Studies show that older adults with chronic conditions have a substantially higher risk of hospitalization and adverse outcomes, making them a key target for preventive strategies ^[63].

Young children, especially those under the age of 5, are another high-risk group. Their immune systems are still developing, and they are frequently exposed to the virus in crowded settings like daycare centers and schools ^[64]. Common complications in children include otitis media, bronchitis, croup, febrile seizures, and pneumonia ^[65]. Infants between 6 months and 2 years are at particular risk for severe respiratory illness.

Pregnant women experience significant physiological changes in their cardiovascular system, respiratory system, and immune system, which increase their susceptibility to severe influenza ^[66]. They face a higher risk of complications such as pneumonia, which can lead to serious obstetric outcomes, including preterm birth, low birth weight, and spontaneous abortion. Vaccination is strongly recommended to protect both the mother and the fetus ^[67].

Individuals with chronic medical conditions are at a significantly elevated risk. This includes people with:

• chronic obstructive pulmonary disease and asthma
• cardiovascular disease and hypertension
• diabetes mellitus and other metabolic disorders
• chronic kidney disease and chronic liver disease
• cancer and other immunocompromising conditions ^[68]

Influenza can severely exacerbate these pre-existing conditions, leading to hospitalization and death ^[69].

Immunocompromised individuals, whether due to disease (e.g., HIV) or medical treatments (e.g., chemotherapy or immunosuppressive drugs), have a weakened ability to fight the virus. This makes them more susceptible to severe and prolonged infections, as well as secondary bacterial pneumonias ^[70].

Finally, residents of long-term care facilities (e.g., nursing homes) are at high risk due to a combination of advanced age, multiple comorbidities, and close living quarters, which facilitate rapid transmission of the virus ^[71].

Common and Severe Complications

The most frequent complication of influenza is pneumonia, which can be either viral, caused directly by the influenza virus, or bacterial, as a secondary infection. Bacterial pneumonias are often caused by pathogens like Streptococcus pneumoniae and Staphylococcus aureus ^[72]. This can lead to respiratory failure, necessitating intensive care and mechanical ventilation.

Other common complications include acute bronchitis and the worsening of underlying chronic conditions. For instance, influenza can trigger an acute exacerbation of COPD or lead to a cardiovascular event, such as a heart attack or stroke, in individuals with pre-existing heart disease.

Severe complications, though less common, are life-threatening. Acute respiratory distress syndrome (ARDS) is a major cause of death in severe influenza cases, particularly during pandemics like the 2009 H1N1 outbreak ^[73]. This condition requires advanced respiratory support, such as high PEEP ventilation or even extracorporeal membrane oxygenation (ECMO) ^[74]. Myocarditis (inflammation of the heart muscle) and encephalitis (inflammation of the brain) are rare but serious neurological and cardiac complications ^[60].

Clinical Management and Hospitalization Criteria

The decision to hospitalize a patient with influenza is based on a clinical assessment of disease severity, the presence of complications, and the patient's risk profile. Key criteria for hospitalization include signs of acute respiratory distress, such as tachypnea (respiratory rate >24 breaths/min), hypoxia (SpO₂ <92% on room air), or cyanosis ^[76]. Rapid clinical deterioration after an initial period of illness is a red flag for complications like secondary bacterial pneumonia or sepsis.

Patients with severe complications such as ARDS, septic shock, or multi-organ failure require intensive care. The management of influenza-related ARDS differs from simple viral pneumonia, requiring lung-protective ventilation with low tidal volumes and high levels of positive end-expiratory pressure (PEEP) ^[77]. In refractory cases, VV-ECMO may be a life-saving intervention ^[74].

Early antiviral therapy with oseltamivir or zanamivir is strongly recommended for all hospitalized patients and those at high risk of complications, ideally within 48 hours of symptom onset ^[79]. This treatment has been shown to reduce symptom duration, the risk of complications, and mortality ^[80]. The use of corticosteroids in severe cases is controversial and not routinely recommended, except in specific situations like refractory septic shock. The integration of national surveillance systems, such as Italy's RespiVirNet, helps monitor severe cases and guide public health responses ^[81].

Influenza vs. Other Respiratory Infections

Distinguishing influenza from other respiratory infections is crucial for appropriate clinical management, timely use of antiviral therapy, and effective public health interventions. While several viral pathogens cause respiratory illness with overlapping symptoms, influenza is characterized by a distinct clinical profile, greater systemic involvement, and a higher risk of severe complications compared to milder infections such as the common cold. Accurate differentiation relies on symptom patterns, disease onset, and epidemiological context.

Clinical Presentation and Symptom Onset

One of the most reliable ways to differentiate influenza from other respiratory infections is the sudden and intense onset of symptoms. Influenza typically presents abruptly, with high fever, chills, and profound systemic symptoms developing within hours ^[4]. In contrast, the common cold, primarily caused by rhinoviruses and other viruses, develops gradually over a few days and is dominated by upper respiratory tract symptoms such as nasal congestion, runny nose, and sneezing ^[56].

Key distinguishing symptoms of influenza include:

• High fever (>38°C), often accompanied by chills and sweating ^[19]
• Severe muscle and joint pain (myalgia and arthralgia), which are rare or mild in the common cold
• Intense headache and generalized malaise or prostration
• Dry, persistent cough, which may become productive later
• Fatigue and weakness that can last for weeks

While both influenza and the common cold may cause sore throat and nasal symptoms, these are more prominent and often the primary complaints in the common cold, whereas in influenza they are secondary to systemic manifestations ^[53].

Comparison with Other Respiratory Viruses

Influenza must also be differentiated from other respiratory viruses such as the respiratory syncytial virus, which commonly causes bronchiolitis in infants and respiratory illness in older adults. RSV typically presents with cough, wheezing, and respiratory distress, but fever and systemic symptoms like myalgia are usually less severe than in influenza ^[57]. In young children, RSV is a leading cause of hospitalization due to lower respiratory tract involvement.

Another important differential is with SARS-CoV-2, the virus responsible for COVID-19. The clinical features of influenza and COVID-19 overlap significantly, including fever, cough, fatigue, and myalgia. However, certain symptoms are more suggestive of SARS-CoV-2 infection, such as loss of taste or smell (anosmia), which is uncommon in influenza ^[58]. Additionally, while both can progress to severe pneumonia and acute respiratory distress syndrome, the incubation period for SARS-CoV-2 is generally longer (2–14 days) compared to influenza (1–4 days) ^[3].

Duration and Complications

The duration and potential complications further distinguish influenza from other respiratory infections. The common cold is typically self-limiting, resolving within 3–7 days, with complications being rare ^[56]. In contrast, influenza symptoms, especially fatigue and cough, can persist for 10–14 days or longer, particularly in vulnerable populations ^[90].

Influenza carries a significantly higher risk of severe complications compared to the common cold. These include:

• pneumonia, either viral or secondary bacterial
• bronchitis
• Exacerbations of underlying chronic conditions such as asthma or chronic obstructive pulmonary disease
• Rare but serious complications like encephalitis, myocarditis, or sepsis ^[60]

Such complications are uncommon in typical colds but may occur in vulnerable individuals with RSV or SARS-CoV-2 infections.

Role of Epidemiological Context and Diagnostic Tools

During seasonal peaks, the epidemiological context aids in clinical differentiation. Influenza activity typically rises in colder months, with predictable seasonal patterns in both the northern and southern hemispheres ^[92]. Surveillance systems such as Influnet in Italy and the Global Influenza Surveillance and Response System coordinated by the World Health Organization provide real-time data on circulating strains, supporting clinical suspicion ^[93].

While clinical diagnosis is often sufficient during peak seasons, laboratory confirmation using polymerase chain reaction testing can distinguish influenza from other pathogens, especially when antiviral treatment decisions are critical ^[79]. Rapid antigen tests are also available but are less sensitive than PCR.

Summary of Key Differences

Feature	Influenza	Common Cold	RSV	SARS-CoV-2 (COVID-19)
Onset	Sudden	Gradual	Gradual to sudden	Variable
Fever	High (>38°C), common	Low or absent	Moderate or absent	High, variable
Myalgia	Severe	Mild or absent	Mild	Moderate to severe
Cough	Dry, persistent	Mild, occasional	Persistent, often with wheezing	Dry, often persistent
Systemic symptoms	Prominent (malaise, headache)	Minimal	Moderate	Moderate to severe
Anosmia	Rare	Absent	Absent	Common
Duration	7–14 days	3–7 days	1–2 weeks	Variable, may be prolonged
Complications	Frequent in high-risk groups	Rare	Common in infants and elderly	Frequent, including thrombotic events

^[51], ^[96]

In summary, influenza is distinguished from other respiratory infections by its abrupt onset, high fever, severe systemic symptoms, and potential for serious complications. Accurate clinical assessment, supported by epidemiological data and, when necessary, laboratory testing, enables timely use of antivirals like oseltamivir and appropriate patient management ^[59].

Prevention and Vaccination Strategies

Preventing influenza and mitigating its impact relies on a multifaceted approach combining annual vaccination, personal hygiene, and public health measures. The cornerstone of prevention is the influenza vaccine, which is updated annually to match circulating strains due to the virus’s capacity for antigenic changes through antigenic drift and, in the case of type A, antigenic shift ^[6]. Vaccination is strongly recommended for all individuals aged six months and older, particularly for high-risk groups such as those aged 60 years or older, pregnant women, young children, and individuals with chronic conditions like asthma, chronic obstructive pulmonary disease, or diabetes ^[99].

Annual Influenza Vaccination and Strain Selection

The development of seasonal influenza vaccines is guided by global surveillance coordinated by the World Health Organization through the Global Influenza Surveillance and Response System ^[7]. Twice a year, WHO recommends the composition of vaccines for the Northern and Southern Hemispheres based on data from over 170 national influenza centers in 127 countries ^[101]. For the 2025–2026 season, the recommended strains include A/Missouri/11/2025 (H1N1)pdm09-like, A/Singapore/GP20238/2024 (H3N2)-like, and B/Austria/1359417/2021 (B/Victoria lineage) ^[102]. The European Medicines Agency and national agencies like the Agenzia Italiana del Farmaco adopt these recommendations to authorize updated formulations ^[103].

For the 2025–2026 season, 11 influenza vaccines have been authorized in Italy, most of which are quadrivalent, offering protection against two influenza A subtypes and two B lineages (Victoria and Yamagata) ^[104]. The exclusion of the B/Yamagata lineage in some formulations reflects its minimal global circulation since 2020 ^[48]. Vaccine production typically takes about six months using either egg-based or cell-based technologies, with adjuvanted or high-dose versions developed to enhance immunogenicity in vulnerable populations ^[106].

Vaccination Efficacy and Target Populations

Vaccine effectiveness varies annually depending on the match between vaccine strains and circulating viruses, with estimates ranging from 23% to 93% ^[107]. Despite this variability, vaccination significantly reduces the risk of severe outcomes, hospitalization, and death, especially among high-risk groups. In Italy, influenza vaccination coverage among individuals aged 65 and older was 52.5% during the 2024–2025 season, below the European target of 75% ^[108].

To improve protection in the elderly, who experience immunosenescence, high-dose or adjuvanted vaccines such as Fluad (containing the MF59 adjuvant) are used. These formulations enhance immune responses and have demonstrated superior efficacy in reducing hospitalizations and healthcare costs ^[109]. For children, both inactivated vaccines and live attenuated nasal sprays like Fluenz are available, with the latter approved for children aged two years and older ^[110].

Non-Pharmaceutical Preventive Measures

In addition to vaccination, non-pharmaceutical interventions are critical for limiting transmission. These include frequent handwashing with soap or alcohol-based solutions, respiratory etiquette (covering coughs and sneezes with the elbow or a tissue), and avoiding close contact with infected individuals ^[8]. During peak influenza seasons, wearing masks in crowded indoor settings is recommended, especially when symptoms are present or when interacting with vulnerable individuals ^[112].

Environmental factors such as low humidity and cold temperatures favor virus stability and transmission, particularly in enclosed, poorly ventilated spaces where people congregate during winter months ^[19]. Therefore, improving indoor ventilation and reducing crowding can help curb outbreaks. The Italian Ministry of Health promotes these measures as part of integrated prevention strategies, especially in schools, workplaces, and healthcare facilities ^[114].

Challenges and Innovations in Vaccine Development

Despite advances, challenges remain in developing a universal influenza vaccine that provides long-lasting protection against diverse strains. The primary obstacles include the virus’s high antigenic variability and the phenomenon of original antigenic sin, where prior exposures bias immune responses and limit reactivity to new strains ^[115]. Current research focuses on targeting conserved viral proteins such as the M2e ectodomain, nucleoprotein (NP), and the stalk region of hemagglutinin (HA), which are less prone to mutation ^[116].

Innovative platforms such as mRNA vaccines are being explored for their potential to induce broader and more durable immunity. Clinical trials of mRNA-based influenza vaccines, including Moderna’s mRNA-1010, have shown promising immunogenicity and safety profiles, prompting the U.S. Food and Drug Administration to initiate review processes ^[117]. These technologies may enable faster adaptation to emerging strains and pave the way for universal vaccines capable of protecting against both seasonal and pandemic influenza threats ^[118].

Evaluation of Public Health Impact

The effectiveness of mass vaccination programs is assessed through multiple indicators, including vaccination coverage rates, vaccine effectiveness (VE), and reductions in morbidity and mortality. Surveillance systems such as Influnet and RespiVirNet in Italy, coordinated by the Istituto Superiore di Sanità, provide real-time data on influenza activity, enabling timely public health responses ^[93]. These systems integrate clinical, virological, and epidemiological data to estimate incidence, identify outbreaks, and evaluate the impact of interventions ^[120].

Mathematical modeling further supports public health decision-making by forecasting epidemic trends, estimating healthcare burden, and simulating the effects of vaccination campaigns and non-pharmaceutical measures ^[121]. Projects like Influcast on GitHub promote open-source collaboration in predictive modeling, enhancing transparency and responsiveness in influenza control ^[122].

In conclusion, preventing influenza requires a coordinated strategy that combines annual vaccination with robust hygiene practices and public health surveillance. While current vaccines are effective in reducing disease burden, ongoing research into universal vaccines and novel platforms promises to transform future prevention efforts, offering broader and longer-lasting protection against this ever-evolving virus ^[123].

Antiviral Treatments and Clinical Management

The clinical management of influenza focuses on early recognition, appropriate use of antiviral medications, and timely intervention to prevent complications, particularly in high-risk individuals. While most cases of influenza resolve with supportive care, antiviral therapy plays a critical role in reducing disease severity, shortening symptom duration, and preventing hospitalization, especially when initiated early in the course of illness.

Antiviral Medications: Neuraminidase Inhibitors

The primary class of antiviral drugs used to treat influenza are the neuraminidase inhibitors, which include oseltamivir (Tamiflu) and zanamivir (Relenza). These medications work by inhibiting the viral neuraminidase (NA) protein, a key enzyme that facilitates the release of newly formed virions from infected cells by cleaving sialic acid residues. By blocking this process, neuraminidase inhibitors limit the spread of the virus to adjacent respiratory epithelial cells ^[124].

The efficacy of these antivirals is maximized when treatment is initiated within the first 48 hours of symptom onset. Clinical studies have shown that early administration of oseltamivir or zanamivir reduces the duration of symptoms by approximately one day in both adults and children, and significantly lowers the risk of complications such as pneumonia, bronchitis, and hospitalization ^[80][126]. Even in patients presenting beyond 48 hours, antiviral therapy is still recommended if the illness is severe, progressive, or if the patient belongs to a high-risk group ^[127].

Oseltamivir is approved for treatment and prophylaxis of both influenza A and B in individuals aged one year and older ^[128]. It is administered orally, making it suitable for most patients. Zanamivir, delivered via inhalation, is indicated for treatment in patients aged five years and older and for prophylaxis in those five years and older; however, it is contraindicated in individuals with underlying chronic respiratory diseases such as asthma or chronic obstructive pulmonary disease due to the risk of bronchospasm ^[80].

Indications for Antiviral Therapy

Antiviral treatment is strongly recommended for patients with confirmed or suspected influenza who are at high risk of developing severe complications. These high-risk categories include:

• Hospitalized patients, regardless of symptom duration or confirmation status, due to the increased likelihood of severe outcomes ^[79].
• Individuals aged 60–65 years and older, who face higher risks of pneumonia, respiratory failure, and death ^[114].
• Children under 5 years of age, particularly those under 2, who are more susceptible to respiratory and neurological complications ^[80].
• Persons with chronic medical conditions, such as cardiovascular disease, diabetes mellitus, severe obesity (BMI ≥ 40), renal or hepatic disease, and respiratory disorders ^[133].
• Immunocompromised individuals, including those undergoing chemotherapy, organ transplant recipients, or people living with HIV, as influenza can lead to prolonged viral shedding and severe illness ^[134].
• Pregnant women and those in the postpartum period, due to physiological changes that increase vulnerability to severe respiratory infections ^[135].

In addition to treatment, antivirals may be used for prophylaxis in certain situations, such as during outbreaks in closed settings like nursing homes, or for unvaccinated individuals with high-risk conditions exposed to the virus.

Clinical Management of Severe Influenza

Severe influenza, particularly when complicated by respiratory failure, requires intensive clinical management. The two most common and life-threatening respiratory complications are viral pneumonia and acute respiratory distress syndrome (ARDS). Viral pneumonia results from direct invasion of the alveolar epithelium by the influenza virus, leading to inflammation, edema, and impaired gas exchange. It often presents with high fever, progressive dyspnea, and hypoxemia, and may be complicated by secondary bacterial infection ^[136].

ARDS is a more severe manifestation, characterized by diffuse alveolar damage, increased capillary permeability, and refractory hypoxemia. It is frequently associated with pandemic strains such as A/H1N1 and requires advanced respiratory support. Management of ARDS includes lung-protective mechanical ventilation with low tidal volumes (4–8 mL/kg predicted body weight) and controlled plateau pressures to prevent ventilator-induced lung injury ^[137]. High levels of positive end-expiratory pressure (PEEP) are used to maintain alveolar recruitment and improve oxygenation.

In refractory cases, veno-venous extracorporeal membrane oxygenation (VV-ECMO) may be employed as a life-saving intervention, especially in younger patients without significant comorbidities ^[74]. Adjunctive therapies such as neuromuscular blockers in the early phase of severe ARDS and corticosteroids in selected cases may also be considered, although evidence remains limited ^[139].

Differentiating Influenza from Other Respiratory Infections

Accurate clinical diagnosis is essential during peak respiratory seasons, when influenza co-circulates with other pathogens such as SARS-CoV-2, respiratory syncytial virus, and rhinoviruses. Influenza is distinguished by its sudden onset and prominent systemic symptoms, including high fever (>38°C), severe myalgia, headache, and profound malaise ^[51]. In contrast, the common cold typically presents with gradual onset, nasal congestion, sneezing, and minimal systemic involvement.

Compared to RSV, which often causes wheezing and bronchiolitis in infants, influenza is more likely to produce generalized muscle pain and high fever. While SARS-CoV-2 shares many features with influenza, the presence of anosmia (loss of smell) or ageusia (loss of taste) is more suggestive of COVID-19 ^[58]. Diagnostic confirmation using rapid antigen tests or polymerase chain reaction (PCR) is recommended in high-risk patients or when clinical decisions depend on etiology.

Duration and Context of Treatment

The standard duration of antiviral therapy for uncomplicated influenza is 5 to 7 days, depending on clinical response and severity ^[142]. In hospitalized or immunocompromised patients, treatment may be extended beyond 7 days, particularly if viral shedding persists or clinical improvement is slow. During pandemics or in cases involving atypical influenza strains (e.g., H5N1), treatment strategies may be adapted based on emerging data on antiviral resistance and disease progression ^[143].

Resistance to oseltamivir has been documented, particularly in certain subtypes such as A(H1N1), with resistance rates exceeding 39% in some regions like France and Norway ^[144]. In such cases, zanamivir or alternative antivirals such as peramivir or laninamivir may be considered. Continuous virological surveillance is therefore essential to guide therapeutic choices and public health responses.

In summary, effective clinical management of influenza relies on early diagnosis, prompt initiation of neuraminidase inhibitors in high-risk individuals, and aggressive supportive care for severe cases. Integration of antiviral therapy with vaccination and public health measures remains essential to reduce morbidity and mortality during seasonal and pandemic influenza outbreaks.

Global Surveillance and Pandemic Preparedness

The global response to influenza relies heavily on coordinated surveillance systems and proactive pandemic preparedness strategies designed to detect emerging viral threats, guide public health interventions, and mitigate the impact of seasonal epidemics and potential pandemics. These efforts are underpinned by international collaboration, advanced genomic monitoring, and mathematical modeling, all aimed at enhancing early warning capabilities and ensuring rapid, evidence-based responses.

Global Influenza Surveillance and Response System (GISRS)

At the core of global influenza surveillance is the World Health Organization-coordinated Global Influenza Surveillance and Response System (GISRS), established in 1952. This network comprises over 170 national influenza centers across 127 countries, responsible for collecting, analyzing, and sharing virological and epidemiological data in real time ^[101]. GISRS plays a dual role: it informs the annual selection of influenza vaccine strains and identifies novel viruses with pandemic potential, triggering rapid response mechanisms ^[146]. The system enables the timely detection of antigenic changes in circulating strains, particularly in influenzavirus A, which is the only type capable of causing pandemics due to its zoonotic reservoirs and capacity for antigenic shift ^[10].

Genomic Surveillance and Viral Characterization

Advanced genomic surveillance is critical for monitoring the evolution of influenza viruses. The sequencing of viral genomes allows for precise identification of mutations in key surface proteins, especially emagglutinin (HA) and neuraminidase (NA), which are primary targets of the immune response ^[148]. This process detects antigenic drift—gradual mutations that necessitate annual vaccine updates—and identifies subclades such as A/H3N2 Subclade K, whose emergence can influence viral fitness and transmissibility ^[149]. Technologies like Oxford Nanopore sequencing have accelerated the speed and accuracy of genomic analysis, enabling near real-time outbreak tracking ^[150]. Data are shared globally through platforms such as the Global Initiative on Sharing All Influenza Data (GISAID), which supports phylogenetic analysis and international collaboration among public health institutions and research laboratories ^[151].

Vaccine Strain Selection and Seasonal Planning

The data generated by global surveillance directly inform the biannual recommendations for influenza vaccine composition issued by the WHO for the Northern and Southern Hemispheres. Experts from the WHO, the European Centre for Disease Prevention and Control (ECDC), the U.S. Food and Drug Administration (FDA), and other regulatory bodies analyze antigenic similarity, geographic spread, and epidemiological impact to select the most appropriate viral strains ^[152]. For the 2025–2026 season, updates included new variants of A(H3N2) and the B/Austria/1359417/2021-like strain, while the B/Yamagata lineage was excluded due to its absence from global circulation since 2020 ^[48]. National agencies such as the European Medicines Agency (EMA) and the Italian Medicines Agency (AIFA) then adopt these recommendations to authorize updated seasonal vaccines ^[103].

National and Regional Surveillance Networks

At the national level, countries implement integrated surveillance systems to complement global efforts. In Italy, the Istituto Superiore di Sanità (ISS) coordinates two key networks: Influnet, which uses data from sentinel physicians to estimate the incidence of influenza-like illness (ILI) and define epidemic thresholds using statistical methods like the Moving Epidemic Method (MEM), and RespiVirNet, a broader system that monitors multiple respiratory pathogens including SARS-CoV-2, respiratory syncytial virus (RSV), and rhinoviruses ^[93]. These systems enable timely detection of epidemic onset and intensity, supporting public health decisions on vaccination campaigns and containment measures ^[156]. In Europe, the ECDC consolidates data through the European Influenza Surveillance Network (EISN), publishing weekly reports on influenza activity and circulating variants to guide risk assessments and policy decisions ^[157].

Pandemic Preparedness and Response

Global surveillance is a cornerstone of pandemic preparedness. The early identification of novel influenza viruses with pandemic potential—such as those resulting from antigenic shift in influenzavirus A—triggers activation of national pandemic plans like Italy’s Piano Pandemico Influenzale (PanFlu). This plan outlines phases of alert, resource allocation, vaccine distribution strategies, and public communication protocols ^[158]. Preparedness also involves stockpiling antiviral drugs such as oseltamivir and zanamivir, which are critical for treatment and prophylaxis during the initial phase of a pandemic before a matched vaccine is available ^[79]. The 2009 H1N1 pandemic demonstrated both the value of rapid viral identification and the challenges of equitable vaccine distribution and risk communication ^[160].

Mathematical Modeling and Public Health Decision-Making

Mathematical modeling plays a crucial role in supporting public health decisions during both seasonal and pandemic influenza. Models use surveillance data to forecast epidemic trajectories, estimate peak timing, and project healthcare burden, including demand for emergency services, hospital beds, and intensive care units ^[161]. These predictions help optimize resource allocation and prevent healthcare system overload. During the 2023–2024 season, integrated modeling accounted for the co-circulation of multiple respiratory pathogens, improving forecast accuracy ^[93]. In pandemic scenarios, models simulate transmission dynamics, estimate the basic reproduction number (R0), and evaluate the effectiveness of non-pharmaceutical interventions such as social distancing, mask use, and school closures ^[163]. Projects like Influcast, an open-source initiative on GitHub, promote collaborative model development and transparent data sharing to enhance predictive capacity ^[122].

One Health Approach and Zoonotic Threats

Given the zoonotic origins of pandemic influenza, a One Health approach is essential for effective surveillance and prevention. This framework recognizes the interconnection between human, animal, and environmental health. The primary natural reservoir for influenza A viruses is wild aquatic birds, particularly ducks and geese, which harbor all known subtypes and can transmit high-pathogenicity strains such as H5N1 to poultry and occasionally to humans ^[165]. Pigs serve as “mixing vessels” due to their susceptibility to both avian and human influenza viruses, enabling genetic reassortment and the emergence of novel pandemic strains, as seen with the 2009 H1N1 pandemic virus ^[17]. Surveillance in animal populations, especially in live bird markets and swine farms, is therefore critical for early detection of viruses with pandemic potential and for informing risk mitigation strategies ^[167]. Organizations such as the European Food Safety Authority (EFSA) advocate for integrated surveillance to prevent viral evolution at the animal-human interface ^[168].

Immune Response and Vaccine Efficacy

The immune response to influenza involves a coordinated interplay between the innate immune system and the adaptive immune system, each playing distinct but complementary roles in controlling infection and establishing long-term protection. The innate immune system provides the first line of defense, rapidly activated within hours of viral exposure, while the adaptive immune system develops a specific, durable response over several days ^[169]. Recognition of the influenza virus occurs through pattern recognition receptors, including Toll-like receptors and RIG-I-like receptors, which detect viral RNA and initiate signaling cascades leading to the production of type I interferons and pro-inflammatory cytokines ^[170]. These interferons induce an antiviral state in neighboring cells, inhibiting viral replication, and promote the activation of natural killer cells, macrophages, and neutrophils that help eliminate infected cells ^[171].

Adaptive Immunity and Immune Memory

The adaptive immune response, which begins approximately 5–7 days post-infection, is highly specific and generates immunological memory. It involves both humoral and cell-mediated arms. B lymphocytes differentiate into plasma cells that produce antibodies targeting the viral surface proteins, primarily hemagglutinin and neuraminidase ^[124]. Neutralizing antibodies against HA prevent viral attachment and entry into host cells, while those against NA inhibit viral release, limiting the spread of infection ^[173]. The adaptive response also includes T lymphocytes, with CD4+ T helper cells supporting B cell activation and antibody production, and CD8+ cytotoxic T cells directly recognizing and destroying infected cells presenting viral antigens via major histocompatibility complex molecules ^[174]. Notably, T cells often target more conserved internal viral proteins, such as the nucleoprotein, providing a degree of cross-protection against different influenza strains ^[175].

Cross-Protective Immunity and Its Significance

Cross-protective immunity refers to the ability of the immune system to confer protection against influenza strains not identical to those encountered previously through infection or vaccination ^[123]. This is primarily mediated by T cells recognizing conserved epitopes and by antibodies targeting less variable regions of HA, such as the stalk domain, rather than the highly mutable head ^[177]. While not always preventing infection, cross-protective immunity can significantly reduce disease severity, viral load, and the risk of complications like pneumonia or acute respiratory distress syndrome ^[178]. This is particularly important given the frequent antigenic mismatches between circulating strains and vaccine components. Vaccines enhanced with adjuvants such as MF59 or formulated as high-dose have been shown to elicit broader, more cross-reactive immune responses, improving protection in vulnerable populations ^[179].

Vaccine Efficacy Across Populations

Vaccine efficacy varies significantly across different population groups due to differences in immune competence. In older adults, immunosenescence leads to a diminished response to standard vaccines. To address this, high-dose and adjuvanted vaccines, such as Fluad and Efluelda, have been developed and demonstrate superior efficacy in reducing hospitalizations and severe outcomes in individuals aged 65 and over ^[180]. In children, especially those between 6 months and 2 years, inactivated vaccines like Fluad and Influvac are effective, while live attenuated vaccines like Fluenz are approved for older children ^[181]. For individuals with chronic diseases such as diabetes, chronic obstructive pulmonary disease, or immunosuppression, annual vaccination is strongly recommended and often provided free of charge, as it is associated with a significant reduction in adverse clinical outcomes ^[182].

Challenges and Innovations in Universal Vaccine Development

The development of a universal influenza vaccine faces major challenges, primarily due to the virus's high antigenic variability driven by antigenic drift and antigenic shift ^[10]. The phenomenon of original antigenic sin further complicates matters, as prior exposures can bias the immune response toward historical strains, limiting effectiveness against new variants ^[115]. Current research focuses on innovative strategies to overcome these obstacles, including targeting conserved viral proteins like the M2e protein, nucleoprotein, or the stalk of HA ^[185]. Advanced technologies such as mRNA vaccines and nanoparticle vaccines are being explored to deliver these conserved antigens and stimulate broader, longer-lasting immunity ^[186]. The use of novel adjuvants and computational design of consensus immunogens also holds promise for generating more robust and cross-protective responses ^[187]. These efforts, supported by global health initiatives like those from the World Health Organization, aim to create a vaccine that could provide long-term protection against diverse influenza strains, revolutionizing pandemic preparedness ^[118].

References