Introduction

The ever-evolving nature of influenza continues to perplex mankind. Significant progress has been made in comprehending the pathophysiology of the influenza virus, its interaction with bacterial illnesses, and diagnostic techniques over the twenty-first century. Nevertheless, there are still obstacles that need to be addressed. These include the search for a cost-effective and dependable point-of-care test suitable for implementation in developing nations, the development of more effective antiviral medications, the exploration of strategies to address the emergence of antiviral resistance and the creation of vaccines that can be manufactured in a shorter timeframe or can eliminate the requirement for annual matching with the circulating strains of influenza. India, being a country that had the greatest fatality rate during the influenza pandemic of 1918, is faced with a pressing imperative to enhance our current level of readiness for any future pandemics that may arise at any given moment.¹

Influenza virus

In the Orthomyxoviridae family, influenza viruses A, B, and C are classified as enveloped negative-strand RNA viruses. Negative signifies the presence of RNA with contrasting polarity, which serves as the template for protein synthesis necessary for viral replication. While it is true that the three viruses have the same genetic makeup, it is important to note that genetic reassortment is confined to the single viral genus rather than extending across other kinds.

The virus' envelope contains surface glycoproteins, namely hemagglutinin (HA) and neuraminidase (NA), which are crucial in their development and serve as the primary targets for neutralizing antibodies against the virus.

In 1980, the World Health Organization (WHO) introduced a standardised system of naming for influenza viruses. The composition of the virus includes the antigenic type (A, B, or C), host of origin (if it has not been isolated from humans), geographical region of origin, number of lineages, year of isolation, and, for Influenza A viruses only, the HA and NA subtypes, which are described by letter and number, ranging from H1 to H16 as of now, and N1 to N9. As an illustration, the Influenza A pandemic in 2009, refers to Influenza type A, This strain was initially isolated in California and has a lineage number of 04, belongs to the year 2009, and is classified as H1N1.¹

Pathogenesis

Hyaluronic acid (HA) has an affinity for the sialic acid residues that are present on the columnar epithelial cells of the respiratory tract, as well as the alveolar type II cells. Avian influenza viruses specifically attach to sialic acids through alpha 2,3 links seen on type II pneumocyte cells in the epithelium of the lung tissues. On the other hand, human influenza viruses attach to 2,6 linked sialic acids found in the upper respiratory tract epithelium (this includes the nose, mouth, throat, and voice box). The transmission risk of human influenza viruses is higher compared to avian flu due to their localisation mostly in the upper respiratory tract.

Nevertheless, strains capable of infecting the lower respiratory tract (this includes the windpipe and the structures that make up the lungs which are the alveoli, bronchi, and bronchioles) elicit heightened inflammation and give rise to more advanced problems. As an illustration, the H1N1 pandemic flu of 1918 had characteristics of high transmissibility and virulence, whereas the 2009 H1N1 pandemic demonstrated high transmissibility but moderate virulence. In contrast, it has been shown that H5N1 and H7N9 exhibit limited transmissibility but cause some who were infected to become severely ill.

The attachment of the HA complex leads to the process of endocytosis of the virus particle (virion), resulting in its fusion with the endoplasmic membrane of the epithelial cell. This fusion then triggers the activation of the matrix protein 2 (M2) ion channel. M2 enables the entrance of the virion into the host nucleus to promote replication. The Influenza A viruses possess a total of eight segments of negative-sense RNA. Consequently, the replication of these negative sense RNAs onto the template necessitates the presence of RNA polymerase, which is transported alongside the virus into the host cell. The reproduction process of viruses encompasses three distinct stages: assembly, budding, and scission. Nicotine anhydrase (NA) facilitates the liberation of recently generated virions, which are then ejected via droplet discharges and invade neighbouring cells. Thus, the virus propagates from one cell to another.

Cell apoptosis (programmed cell death) can occur due to the host's immunological response aimed at eliminating the virus. In instances of heightened severity, the alveolar epithelium may undergo necrosis (accidental cell death), resulting in the manifestation of acute respiratory distress. The severity of the sickness can be attributed to either compromised viral clearance or heightened host immunological response.¹

Influenza-induced hyperthermia, stress, and bacterial dissemination

Stringent downregulation of virulence factors facilitates bacterial colonisation and biofilm formation by reducing the production of epithelial pro-inflammatory cytokine responses, hence enabling immune evasion. In the context of influenza infection, the presence of pyrogenic cytokines (a substance secreted by cells that provoke fever) leads to hyperthermia, which in turn triggers the activation of bacterial virulence genes. This, in turn, facilitates the release of bacteria from the biofilms that inhabit the nasopharynx, therefore enabling microaspiration and invasion. Moreover, influenza elevates levels of glucose, ATP, and noradrenaline, which, although crucial for activating lymphocytes and eliminating viruses, lead to an excessive presence of bacteria, pneumonia, and otitis media (infection of the ears) in mice that are otherwise stable in their colonisation.

In an era characterized by exceptional prospects for rapid influenza reassortment and worldwide transmission, escalating antibiotic resistance, and a rapid expansion of data to comprehend the dynamics between hosts and pathogens, the significance and capability to comprehend the mechanisms underlying co-infections between influenza and bacteria have reached unprecedented levels. Approximately one hundred years ago, the influenza pandemic of 1918 demonstrated the profound impact that can arise from a combination of influenza virus genotypes, prior influenza exposures, and bacterial infections. The enhancement and advancement of novel vaccines will play a crucial role in the first stages of defence. Nevertheless, because of the dynamic nature of viral and bacterial genomes and the fluctuating distributions of bacterial subtypes, the efficacy of vaccinations may be limited.

A comprehensive comprehension of the processes that underlie post-influenza bacterial infection is essential for the advancement of enhanced treatments to address the complex infections that are challenging, and in certain instances, fatal. An excessive and uncoordinated immune response, coupled with a failure to balance pathogen clearance with avoidance of host-tissue damage, is a significant factor contributing to severe illness and mortality in post-influenza infection. Therefore, the advancement of immunomodulatory medicines may offer greater advantages compared to traditional antimicrobial drugs in the treatment of complex co-infections. Enhancing comprehension about the utilization of combination treatments including antimicrobials and immunomodulatory drugs will play a crucial role in enhancing treatment efficacy and mitigating excessive fatality rates in forthcoming influenza seasons and worldwide pandemics.³

Long-term effects of the Influenza virus

It has long been known that severe influenza infection can lead to complications and even fatality in the most extreme cases. In fact, influenza is the cause of an estimated 300-500,000 deaths worldwide per year.⁵ One of the complications post-infection is exacerbating pre-existing chronic pulmonary conditions such as asthma and COPD.⁷

Apart from exacerbating pre-existing pulmonary conditions, there are a few incidences where cardiac issues arose after the initial influenza infection. One study found that 20 out of 344 hospitalisations for acute myocardial infarction occurred within a week after a positive test result for influenza, compared to just 6 out of 344 of those admitted for acute myocardial infarction who had a positive test result one year before or after their positive test result for influenza.⁶ This suggests there is a possible connection between influenza and acute myocardial infarction. 

Neurological issues have also been associated with the long-term effects of a severe influenza infection. Studies have shown that in children, neurological complications can accompany influenza in about 10-30% of these patients. The most common symptoms are seizures and encephalopathy of various degrees of severity.⁸

Challenges 

There are several factors contributing to the heterogeneity observed in hospitalisation rates. The level of influenza activity exhibits significant variation throughout different seasons and may even differ across geographic regions within a single season. Additional factors contributing to variance may encompass disparities in healthcare-seeking patterns, immunization rates, vaccine efficacy, and inconsistencies in the reasons for and the extent of influenza testing.²

Summary

In this comprehensive article, we delve into the multifaceted world of the influenza virus, exploring its pathogenesis, intricate interactions with bacterial infections, and the urgent need for preparedness in India. While significant strides have been made in understanding the virus and developing diagnostic tools, several challenges persist. Let’s break down the key points:

The influenza virus unveiled

• Our journey begins with a closer look at the influenza virus. We dissect its genetic structure, unravelling the blueprint that governs its behavior
• Pathogenesis—the intricate dance between the virus and our immune system—takes centre stage. How does the virus infiltrate our cells? What triggers the immune response? These questions guide our exploration.

The battle between influenza and bacterial coexistence

• Picture this: influenza and bacterial infections engaged in a high-stakes tango within our bodies. We explore their complex interactions—sometimes harmonious, often adversarial
• Hospitalisation rates during outbreaks reveal fascinating insights. Why do some individuals succumb more readily than others? The interplay of viral load, immune response, and bacterial co-infections holds the key

Hyperthermia, stress, and bacterial dissemination

• Fever—the body’s battle cry against invaders. But what happens when influenza-induced hyperthermia collides with stress? We dissect this delicate balance
• Bacterial dissemination—the silent accomplice. How does influenza pave the way for bacterial invaders? The answers lie in understanding the immune landscape

Immunomodulatory drugs: a ray of hope

• Amidst the chaos, hope emerges. Immunomodulatory drugs—our allies in the fight against post-influenza bacterial infections. We explore their potential, their limitations, and the road ahead
• Combination therapies beckon—a synergy of antivirals and immune boosters. Can we reduce mortality rates during influenza seasons and pandemics? The quest continues

India’s call to action

• India, with its historical vulnerability to influenza outbreaks, stands at a crossroads. In addition, India has one of the highest rates of antibiotic resistance in the world.⁴ Being prepared is not a luxury but a necessity
• As we navigate the ongoing challenges posed by influenza, research and innovation become our compass. Vaccines, diagnostics, and cost-effective point-of-care tests—our arsenal against a formidable foe