Insights from respiratory virus co-infections

Abstract

Respiratory viral co-infections present significant challenges in clinical settings due to their impact on disease severity and patient outcomes. Current diagnostic methods often miss these co-infections, complicating the epidemiology and management of these cases. Research, primarily conducted in vitro and in vivo, suggests that co-infections can lead to more severe illnesses, increased hospitalization rates, and greater healthcare utilization, especially in high-risk groups such as children, the elderly, and immunocompromised individuals. Common co-infection patterns, risk factors, and their impact on disease dynamics highlight the need for advanced diagnostic techniques and tailored therapeutic strategies. Understanding the virological interactions and immune response modulation during co-infections is crucial for developing effective public health interventions and improving patient outcomes. Future research should focus on the molecular mechanisms of co-infection and the development of specific therapies to mitigate the adverse effects of these complex infections.

Key Words: Respiratory viral co-infections; Disease severity; Diagnostic challenges; Immune response modulation; Public health strategies

Core Tip: Respiratory viral co-infections significantly complicate clinical management due to their impact on disease severity and patient outcomes. Current diagnostic techniques often miss these co-infections, making it difficult to accurately define their epidemiology and management strategies. Research suggests that co-infections can exacerbate illnesses, leading to higher hospitalization rates and increased healthcare utilization, particularly among high-risk groups such as children, the elderly, and immunocompromised individuals. Thus, advancing diagnostic methods and developing targeted therapeutic strategies are essential for improving public health interventions and patient outcomes. Understanding the virological interactions and immune response during co-infections is crucial for these advancements.

INTRODUCTION

While viral-viral co-infections can be studied in the clinical setting, it is difficult to ascertain the true incidence of specific co-infections and almost impossible to assess the effects of co-infection on disease severity and patient outcomes. Due to the insensitivity of current diagnosis methods and the non-specific clinical presentation of viral respiratory tract infections, many co-infections go unnoticed or receive incorrect diagnoses[1]. These limitations make the epidemiology of co-infection difficult to define, even in controlled prospective studies[2]. As a result, a significant portion of current research on respiratory viral co-infections takes place in vitro using cell culture and in vivo using animal models. These methods enable controlled infection and identification of pathogens, resulting in a wealth of data. However, extrapolating these findings to humans is challenging, and the data have raised more questions than answers[3].

Respiratory viruses are important causes of morbidity and mortality worldwide[4]. In addition to the threat of emerging infections, there is concern about the implications of co-infections between respiratory viruses in certain groups in the population, such as young children, the elderly, and the immunocompromised[5]. Co-infection is defined as the simultaneous infection of a single host by two or more pathogens, and because of shared routes of transmission, it is a common occurrence with both respiratory viruses and bacteria[6]. The availability of molecular diagnostics has unveiled the greater than anticipated incidence of viral-viral co-infections[7]. A recent study identified an etiological viral agent in 85% of children with lower respiratory tract infections[7]. Researchers have estimated the average detection rates at 20%–40% using viral culture and antigen detection methods[8]. Similarly, in asymptomatic individuals and individuals with infections not involving the respiratory tract, molecular methods have revealed a high incidence of respiratory viral infections[9]. This increased awareness has raised many questions about the epidemiology, pathogenesis, and management of viral co-infections[10].

CO-INFECTION PATTERNS

Researchers have described respiratory virus co-infection as an independent risk factor for severe illness. Several studies have shown that co-infection leads to increased disease severity, with more severe symptoms and acute respiratory tract infections being the most common outcomes[11]. The admission rate for lower respiratory tract illness is 70.5% for cases of single viral infection compared to 92% for viral-viral co-infection and 95% for viral-bacterial co-infection[12]. Eighty-six percent of people who had more than one respiratory virus infection needed extra oxygen, while only 52% of people who had a single respiratory virus infection did[13]. Another study revealed that hospital admission rates for children with single virus detections were lower than those for co-infection cases (30% vs 57%)[14]. According to these studies, people who have more than one infection were more likely to be hospitalized and need oxygen therapy. This may be because the symptoms get worse when different respiratory pathogens interact with each other[15]. This is of particular significance for respiratory virus co-infections among the elderly and other high-risk groups who already have underlying health conditions. In these cases, co-infection may lead to rapid health deterioration with added complications, greater healthcare utilization, and increased morbidity and mortality[16]. High-risk groups are also more susceptible to respiratory virus co-infection due to the increased prevalence of these viruses among them and high-risk factors such as immunocompromised states[17]. Studies have linked influenza virus co-infection to the exacerbation of chronic diseases, often resulting in hospitalization and death[18].

Impact on disease severity

While co-infections affect disease severity, more research is necessary to determine the exact nature of this relationship and the underlying mechanisms[19]. There are several factors that may influence the observed effect of co-infections on disease severity. These include the study population's age and nature, case definition and outcome measures, as well as the spectrum of pathogens and methods used for pathogen detection[20]. The relationship between co-infection and exacerbation of pre-existing cardiopulmonary disease is also difficult to assess. It may be that viruses are particularly associated with exacerbations, but it is also possible that patients with chronic lung disease are simply more susceptible to viral infections[21].

Several recent epidemiological studies have investigated this issue in a more organized way by comparing the severity of disease in people with a single virus infection vs people with dual virus infections using standard measures of severity, such as hospitalization, certain clinical parameters, and sometimes death[22]. Whereas some studies have found an association between dual infections and increased disease severity, others have found no association, and a few have found that co-infected patients have milder disease[23].

In humans, co-infection patterns can have an impact on disease presentation and outcome. However, deciphering the precise contribution of individual pathogens to the clinical syndrome in co-infected patients is often difficult[24]. Concurrent respiratory virus infections have long been considered a cause of increased disease severity, particularly in the pediatric population. Evidence to support this contention, however, has been largely anecdotal, derived from small case studies or series, and is thus inconclusive[25].

Co-infection combinations

Co-infection of a single population with different disease-causing agents can occur by a variety of methods. A study elegantly demonstrated this for human metapneumovirus (hMPV) and respiratory syncytial virus (RSV), using sequence information to establish molecular clocks and the likely R0 for each virus. The study suggested that the R0 of HMPV was insufficient for the virus to co-evolve with humans separately from RSV. Instead, researchers believed that hMPV spread to humans through zoonoses from RSV, and it only survived by co-infecting populations already infected with RSV[26].

Animal models may provide more detailed virological insights. Mouse studies have shown that a mild respiratory viral infection can lead to more severe disease upon secondary infection with RSV or other respiratory viruses[27]. However, models of RSV and hMPV in cotton rats showed no obvious increase in pathogenicity or virus load upon simultaneous infection with both viruses[28]. Common co-infection combinations may occur by chance, but they are more likely the result of complex immune responses to different infections[23]. A thorough understanding of why certain viruses tend to co-infect will help in designing preventative and treatment strategies. Molecular epidemiological studies suggest that RSV co-infection with hMPV or influenza is more common than it would occur by chance[29].

Risk factors for co-infections

The types and number of pathogens infecting an individual host are typically a result of the host's exposure to those pathogens balanced against the defenses mounted against them. Environmental factors have a major role in determining infection risks, an example being the seasonality and climate in temperate regions that result in marked annual peaks of viral respiratory infections but with different pathogens predominant in the winter and summer months[30]. Exposure to pollutants, cigarette smoke, and other harmful particulates impairs mucociliary clearance and alveolar macrophage function while also irritating the airways and increasing the susceptibility to infection[31]. Animal models and, in some cases, following controlled human infections, have demonstrated their ability to increase susceptibility to and severity of respiratory viral infections[32]. There is a significant association between smoking and viral respiratory infections[33]. Institutions, schools, military establishments, and households have long been associated with increased risks of respiratory infections such as the common cold, primarily due to increased opportunities for interpersonal contact and fomite transmission[34]. This is also true of increased social contact, which is a likely reason why school-aged children are known to be major transmitters of many infections to household contacts[35]. Globalization and international travel have made the world a smaller place, increasing the risk of emerging infections and the spread of infections to new areas and host populations[36]. The disease burden of RSV infection in infants in the United States is significantly higher than the hospitalization rate for RSV infection in infants in England, despite consistent monitoring of National Health Service hospitalization data indicating similar hospital admission criteria[37]. This may be due to differences in social and housing conditions between the two countries or unspecified differences in the use of health care services. Travel has also resulted in an increasing number of reports of travel-associated pneumonia due to a variety of pathogens, which can be difficult to precisely diagnose due to co-infection possibilities[38]. An example of Avian influenza infections in humans has demonstrated that higher intensity and nature of contact with animal populations can increase the risk of zoonotic infections[39]. Some viral infections can have indirect effects on immune system function. For instance, influenza virus or RSV infection of respiratory epithelial cells triggers the production of pro-inflammatory cytokines, which can predispose people to bacterial infections by up-regulating adhesion molecule expression and promoting the influx of inflammatory cells[40]. Chronic infections or the transmission of certain viruses can increase the risk of co-infections for a long time[41]. Immune suppression is a well-recognized risk factor for many infections and has led to greatly increased rates of various co-infections, particularly in the context of the HIV pandemic[42].

VIROLOGICAL INTERACTIONS

A study on dengue virus co-infection revealed an unfavorable effect on viral clearance, primarily due to a competitive interaction. This interaction showed that having two infections with similar viral loads increased the risk of getting dengue hemorrhagic fever and dengue shock syndrome for people who already had another infection[43]. This has an underlying significance. A study of competitive and cooperative interactions between RSV and influenza in a mouse model demonstrated their unfavorable effects and potential prolongation of the disease[44]. In this case, both viruses caused more illness and made it last longer in some cases. This was true even though they only slightly affected the second virus's ability to replicate, and only one infection was found to speed up viral clearance and disease resolution. With little concrete evidence regarding the effect of co-infection on viral interactions, it is important to first establish theoretical scenarios based on known immunological and virological principles[45]. Despite a potential interaction period during the initial co-infection of both viruses, it is likely that the overall dominance of one virus over the other would lead to a primarily competitive interaction. When the second virus introduces itself during the first virus's infection, it perpetuates the co-infection's effects on viral clearance, prolonging the period of incomplete immunity against one of the viruses[46].

Dynamics of viral replication

Due to its higher prevalence rate in the community and the greater knowledge of in vitro studies already conducted, influenza is another likely candidate for RSV co-infection. RSV replication primarily occurs in the respiratory epithelium, but influenza can infect both the upper respiratory tract and type II pneumocytes in the lungs[47]. Because influenza tropism is so complicated, there are many ways that co-infection can happen. It is important to think about how co-infection with influenza, which can be mild or severe, might affect the spread of RSV replication. An example of this is the impact of influenza infection on RSV replication, which may not hinder the migration of RSV-infected cells from the lower respiratory tract to the upper mucosal areas. Additionally, the co-infection of RSV and influenza on type II pneumocytes can significantly influence RSV replication, though it is challenging to evaluate in an in vivo setting[48].

Extrinsic and intrinsic factors combine to determine the viral replication dynamics. It's important to know how to spread target cells and how cell tropism affects the overall viral load in an infected person[27]. It is also important to know how likely it is for cells to become co-infected. As RSV is well known to infect ciliated and goblet cells within the respiratory tract, it is highly likely for RSV to be involved in a co-infection scenario with either itself in the form of re-infection or with another virus. Researchers have extensively studied co-infection in vivo between RSV and hMPV[23]. Because the symptoms of both viruses are similar and the rates of infection in similar age groups are known, hMPV is a great candidate to study in the context of RSV co-infection to identify new subtle ways that they interact[49].

Immune response modulation

Scientists showed that infecting a BALB/c mouse model with a recombinant RSV strain activated a T-helper 2 (Th2) response, leading to eosinophilia and the airway becoming more reactive[50]. Researchers have obtained similar results from hMPV infections[28]. It was found that using an inactivated RSV vaccine to treat the infection improved eosinophilia, T-helper 1 (Th1)-biased cytokine and antibody responses. It was found that this vaccine-related disease was caused by immune complex formation. The researchers inhibited disease in mice by removing their complement[24]. Vaccine-enhanced disease has hindered the successful development of both RSV and hMPV vaccines[32].

Researchers have found that increasing a Th1 immune response helps stop the spread of viruses like RSV and hMPV in lab experiments[45]. However, increasing a Th2 immune response makes the disease worse, as shown by higher eosinophilia, mucus production in the airways, and disease severity[51].

The local response to a respiratory virus infection is quite varied, depending on the infecting virus. Antiviral and pro-inflammatory activities classify the immune response. The immune response starts with the production of interferon and virus-specific cytotoxic T lymphocytes[28]. Th1 cytokine and IgG2a antibody production is also indicative of a protective immune response[52]. Table 1 summarizes the virological interaction in co-infections.

Table 1 Virological interactions in co-infections.

Co-infection combination	Interaction type	Impact on disease progression
Dengue virus + secondary virus	Competitive	Increased risk of severe dengue outcomes (DHF, DSS)
RSV + influenza	Cooperative/competitive	Prolongs disease, increases severity and duration in some cases
RSV + other respiratory viruses (e.g., hMPV)	Varies; neutral in some models	Little to no increase in pathogenicity in some animal models

DHF: Dengue hemorrhagic fever; DSS: Dengue shock syndrome; hMPV: Human metapneumovirus; RSV: Respiratory syncytial virus.

CLINICAL IMPLICATIONS

For patients presenting to the hospital with respiratory viral infections, one study found that patients positive for influenza have similar characteristics to those with community-acquired pneumonia (CAP)[53]. Another study specifically on patients with CAP requiring intensive care unit admission produced some interesting findings. In the multivariate analysis, influenza was the only independent factor associated with death when comparing the viral etiology of pneumonia[54]. Therefore, finding influenza in respiratory viral infection patients is even more important, and finding a specific respiratory virus instead of just a clinical diagnosis could change how different lung infections are treated and how well they do. An observational study on cellular viral loads in immunosuppressed patients diagnosed with pneumonia found that patients with a lower respiratory illness and a positive respiratory virus PCR had an attributable mortality of 26% for respiratory viral infections and improved antivirals could reduce mortality outcomes[55]. In the United States, influenza virus infects 20% of the population annually, and during a circulating influenza outbreak, many clinicians diagnose influenza-like illness (ILI) as influenza and initiate treatment with oseltamivir or zanamivir in a hospital or community setting[56]. A recent systematic Cochrane review, encompassing 20 trials of oseltamivir and zanamivir treatment in adult and pediatric outpatients, determined the clinical effectiveness of ILI treatment to be modestly beneficial, at best reducing the duration of illness by 1 day[57]. Initiating treatment within the first 48 hours of symptoms enhances the clinical effectiveness of these antivirals. A specific diagnosis of influenza and a high level of illness severity yield the best results. Data on hospitalized adult patients who can have very severe outcomes from respiratory viral infections are lacking. High costs for individual patients, particularly in third-world countries, are problematic. For instance, respiratory viral infections exacerbate heart failure exacerbations and chronic obstructive pulmonary disease, frequently leading to hospital admissions for ILI patients. The clinical effectiveness of antivirals, particularly in high-risk groups such as the elderly and those with co-morbidities, remains an important issue[58]. Because ILI is highly non-specific, many respiratory virus infections cluster around this case definition, making a specific diagnosis and a decision on how to manage the patient frequently difficult. Without virological testing, a specific diagnosis remains rare, even in the best of clinical settings[34].

Diagnosis challenges

The lack of compelling evidence for the clinical implications of viral interactions on disease severity is likely to reflect the methodological limitations impacting the success of future virus-virus interaction studies. Observational studies or traditional statistical methods in existing datasets pose many difficulties in definitively diagnosing the viruses involved, specifying the timing, order, and type of infection, establishing a causative association between infection and disease, and controlling for confounding factors[59].

While rapid progress in diagnostic technology has been a major contributor to the recent discoveries of viral prevalence, incidence, and etiology in the population, it has also generated a wealth of information describing simple viral shedding or presence. An example of this is the frequency of detection of all viruses within a diagnostic test, even when multiple specimens are not available from every patient at the time of disease incidence. Epidemiologists have interpreted this to mean a surrogation of clinical disease, with the most severe symptoms being attributable to the virus. However, tests detect all levels of virus RNA or antigen, including asymptomatic shedding, and detection of viruses often continues well after cessation of symptoms[60].

Viral vaccination studies have convincingly demonstrated the important implications of identifying virus-specific etiologies of disease for public health and global health issues[61].

Treatment considerations

The lack of specific antiviral therapies for many viruses is a limitation, and more broad-spectrum anti-infective agents have increased potential for drug-drug interactions and may have unknown effects on a second virus. These points highlight the complex issues regarding the treatment of co-infections and the need for further research to determine the optimum management strategies[45]. At present, many treatment regimens are based on specific etiologies. However, for many viral pathogens, effective therapies are lacking and management is often supportive. If co-infections occur, it may be unclear which virus is the causative agent, and treatment regimens may overlap, potentially exacerbating a treatment-induced adverse event[48].

TRANSMISSION DYNAMICS

High co-infection rates can sustain an epidemic or lead to an outbreak of a particular virus if transmission rates between co-infections and single infections are significantly different. This was the case in RSV outbreak in a pediatric ward, where nosocomial transmission of multiple virus types, including RSV itself, caused prolonged ward closure[34]. In terms of acute respiratory infection, it is extremely rare for just one type of virus to be the sole cause, as exemplified by a study that showed 61% of cases tested negative for all virus types. However, prolonged viral shedding can complicate the classification of individuals as co-infected by PCR testing methods, potentially leading to the emergence of a second infection before clearing the first[38].

Co-infection transmission rates

This information is not yet available to respiratory virus agents. Co-infection is likely to increase viral transmission, as secondary strains are unlikely to evolve efficient transmission between humans without first increasing their prevalence. On the other hand, some viruses are known to speed up the spread of others through immunological or other means. For example, RSV speeds up the spread of Streptococcus pneumoniae in an animal model. This could be more important than any competitive effect between co-infecting strains[62].

Increasing transmission could also occur simply because of co-infection, increasing the overall disease burden on the host and making them more infectious in terms of contact rates with other individuals. An intriguing but neglected issue is the potential for complex interactions between different respiratory viruses in communal settings to affect each other's transmission. Schools play a crucial role in this context, as research indicates that children frequently contract multiple viruses simultaneously[63].

Mathematical models of infection for one specific virus often include a large number of simplifying assumptions about the host population, and it can be difficult to integrate multiple models for different viruses in a consistent way[64].

But adding information to these models from virological or epidemiological studies on how certain virus types can infect each other could help us understand how respiratory viruses spread in communities.

Role of co-infections in outbreaks

Large amounts of evidence from experiments with both animal models and in vitro systems with model viral infections show that how viruses interact with each other can have a big impact on how bad the disease is. It can be predicted that the potential net effect of virus-virus interaction can range from increased pathogenesis due to the reactivation of latent infection, where one or more viruses interact at the level of viral gene expression, to complete interference between two or more viruses in an attempt to establish a productive infection[65]. This can mean that one virus effectively outcompetes another virus for a susceptible host cell, resulting in the loss of a viral genetic lineage (extinction of one of the interacting viruses in a defined ecological niche). We now recognize these outcomes as potentially important in the natural ecology of virus infections, and it is challenging to study how they facilitate some of these events in humans, like viral reactivation and extinction. From a public health perspective, one of the most important consequences of virus-virus interactions is the exacerbation of acute disease manifestations. The most extreme example of this is the increased mortality seen with certain respiratory virus infections in the very young and/or elderly due to a variety of interacting infections.

PUBLIC HEALTH STRATEGIES

The majority of global morbidity from respiratory viruses occurs in developing countries, where infectious diseases significantly impact malnutrition and chronic diseases. Efforts here focus on identifying broad syndromes and developing interventions. Recent strategies using novel PCR techniques to identify viral causes of syndromes like fever in immunocompromised patients or acute respiratory infections in bone marrow transplant units show promise in understanding these infections' multifactorial impacts. In developed countries, public health surveillance emphasizes epidemiology and identifying etiological agents. Systems in the US and Canada linking pneumonia admissions to pathogen identification exemplify these efforts, which inform prevention and control strategies. Sentinel hospital networks monitoring pediatric respiratory virus infections correlate trends with broader morbidity data, proving effective in countries with good healthcare access. Advances in identification techniques highlight the global significance of respiratory viruses and the need for tailored public health strategies to address healthcare system disparities[66-68].

RNA-based molecular testing methods enhance the ability to define and characterize respiratory viral infections, improving recognition within communities and among patients. Despite effective antiviral therapy for influenza, presumptive diagnoses can be inaccurate, necessitating distinct management approaches. PCR testing and modern pneumococcal vaccines are expected to clarify the roles of respiratory viral infections and bacterial coinfections. Point-of-care PCR testing will facilitate accurate diagnoses similar to chest X-rays, aiding community physicians in recognizing respiratory viral infections. Real-time (RT)-PCR testing has high sensitivity and specificity, and it enables prompt diagnosis and detailed studies of disease burden and seasonality, crucial for understanding respiratory viral infections' impact on chronic disease exacerbations. Effective containment and treatment of respiratory viral infections rely on detecting the infecting agent and understanding its community impact. Traditional viral diagnosis methods like culture and serology are slow and often provide insufficient information[69-71].

Future molecular diagnostics will likely identify the ways in which respiratory virus exacerbate chronic lung disease, guiding prevention and treatment strategies. Effective public health strategies must be specific and practical, particularly for co-infections, which are under-researched. Evidence-based interventions can significantly improve health outcomes and reduce healthcare costs[72].

Therapeutic development

Developing therapies specific to co-infections can limit adverse outcomes for patients. One promising approach is altering the host cellular environment to prevent viral replication by modifying host cell proteins necessary for viral entry and replication. These findings can translate into drug therapies tested in animal models and clinical trials. Another strategy involves altering the ability of cells to produce proteins crucial for virus replication or modulating the immune response to prevent disease exacerbation. Further studies on host immune responses to virus-virus interactions, followed by animal models and human trials, can lead to the development of vaccines preventing respiratory virus co-infections[7,73].

Host immune response

While the immune response to single respiratory virus infections is well-studied, the effects of multiple viral infections are less understood. To comprehend the immune system's response to virus interactions, it is crucial to map the immune response sequence using animal models, followed by human clinical studies. Understanding these mechanisms can help develop therapies to prevent or limit co-infections, improving patient outcomes[74].

Current co-infection studies

Most studies use nucleic acid amplification to identify viruses present in a host, but they do not consider multiple strains of a single virus. Determining the in vivo significance of co-infection requires animal models to track the effects on viral replication, virulence, and host immune responses. These findings can then be applied to human clinical trials.

Understanding co-infection mechanisms

Co-infection mechanisms are poorly understood and often modeled in animals with viruses that do not naturally co-infect. For instance, RSV does not replicate well in mice, which can confound results[31]. Identifying replicated viruses vs marker viruses in these models is challenging, as highlighted in a study with murine gastroenteritis virus and transmissible gastroenteritis virus in pigs, where the data became blurred, complicating the understanding of co-infections on a molecular level[75].

Co-infection-specific therapies

Few antiviral agents have well-defined molecular mechanisms, and in vivo outcomes can vary based on administration timing and the host's immune status. While co-infection-tailored therapies are complex, they may be feasible. For instance, if a co-infection exacerbates disease by inhibiting IFN production, using IFN as a therapeutic agent might be effective. However, simplistic approaches, such as administering all antivirals simultaneously, should be avoided due to potential drug competition or pathway inhibition[76,77]. Table 2 summarizes public health strategies and recommendations.

Table 2 Public health strategies and recommendations.

Strategy	Recommendation
Enhanced surveillance systems	Focus on high-risk groups for better identification and control of co-infections
Targeted vaccination campaigns	Develop vaccines considering common co-infecting viruses, especially for high-risk groups
Multiplex PCR testing implementation	Implement in clinical settings for simultaneous diagnosis of multiple respiratory viruses
Education on infection control measures	Increase awareness among public and healthcare workers regarding transmission risks
Development of broad-spectrum antivirals	Encourage R&D for antivirals effective against multiple viruses to address co-infections

R&D: Research and Development.

CONCLUSION

Conclusion and future perspectives

In summary, respiratory viral co-infections pose significant challenges to clinical management due to their complex impact on disease severity and patient outcomes. Current diagnostic methods often fail to detect these co-infections, leading to underestimation of their prevalence and complicating the development of effective treatment strategies. There is an urgent need for advanced diagnostic techniques that can accurately identify co-infections and their specific viral combinations.

Future research should focus on elucidating the molecular mechanisms that underpin viral interactions during co-infections. A deeper understanding of these interactions will be crucial in developing targeted therapeutic strategies that can mitigate the exacerbation of symptoms caused by co-infections. Additionally, there is a pressing need to explore the role of the immune system in co-infections, particularly how it can be modulated to improve patient outcomes.

Public health strategies must also be adapted to address the challenges posed by respiratory viral co-infections. This includes improving surveillance systems to better capture data on co-infections and integrating this information into the development of vaccines and antiviral treatments. Ultimately, a multidisciplinary approach that combines clinical, virological, and epidemiological expertise will be essential to advance our understanding and management of respiratory viral co-infections, thereby reducing their burden on global health.