The respiratory tract is one of the main portals of entry for human viruses. Respiratory tract infections lead to enormous health and economic burdens and cause severe outcomes, including hospitalization and death, especially in developing countries [1,2,3,4]. In 2013, the WHO’s Battle against Respiratory Viruses initiative (BRaVe) recognized acute respiratory infection as a major global public health issue [5]. Unfortunately, nearly ten years later, respiratory infections are still a global health security threat, exemplified by the recent coronavirus outbreak in 2020 [3].

Viral respiratory tract infections (vRTIs) can be due to several families of viruses, such as picornaviruses (human rhinoviruses (HRV)), coronaviruses (CoV), ortho- and paramyxoviruses (influenza virus, parainfluenza virus (PIV or HPIV for human), human metapneumovirus (HMPV) and respiratory syncytial virus (RSV)), adenoviruses and herpes viruses [1,6]. Since the beginning of the 21st century, the world has faced several episodes of epidemic or pandemic respiratory illnesses due to the emergence of new respiratory viruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003, H1N1 influenza in 2009, avian influenza A viruses, such as H5N1 and H7N9, middle east respiratory syndrome coronavirus (MERS-CoV) in 2012, and the recent SARS-CoV-2 in 2019. These reemerging and highly pathogenic pandemic viruses have been one of the leading causes of morbidity and mortality worldwide and are known to cause acute respiratory infections in all age groups globally and all year round [7,8,9,10]. In 2017, it was estimated that more than 54 million lower respiratory tract infection (LRI) episodes were due to influenza worldwide, leading to more than 9 million hospitalizations and 145,000 deaths among all ages [11]. Even though all age groups are susceptible to influenza, children up to 5 years, pregnant women, the elderly and individuals with specific chronic medical conditions are considered at-risk populations. Alike influenza-virus-associated infections, RSV caused around 1.5 million episodes of acute LRIs in 2015 in the elderly, specifically those aged 50–64 years [12]. Although other respiratory viruses, such as adenovirus and rhinovirus, cause lower mortality, they are associated with significant morbidity, which causes a huge economic burden. Increased respiratory viral infections worldwide necessitate searching for safe and effective antiviral drugs to counteract these massive healthcare problems.

The transmission of viral pathogens occurs mainly by the respiratory route, characterized by aerosol emission or droplets primarily during a cough or sneezing episode [6,13]. In most cases, these vRTIs are limited to the upper respiratory tract but can lead to acute lower respiratory tract infections as well, particularly in the case of RSV, influenza virus, PIV and SARS-CoV2 [14,15,16]. The symptoms of viral respiratory infections can include congestion of either the nasal sinuses or lungs, runny nose, cough, sore throat, body aches, fatigue (Figure 1).

In the most severe cases, symptoms can be chills, difficulty in breathing, dizziness, bronchiolitis, asthma exacerbations, pneumonia, respiratory distress syndromes and chronic obstructive pulmonary disease (COPD) [5,17]. The propagation of several respiratory viruses has also been reported from the respiratory tract to the central nervous system (CNS) [18].

Although some viruses may be associated with defined clinical signs and symptoms, there is also some intersection in the correspondence of pathology and the responsible pathogen. It is thus difficult to define viral respiratory diseases because the symptoms related to vRTI commonly overlap [6]. For example, the common cold may originate from different etiologic agents, such as rhinoviruses or coronaviruses. Similarly, influenza may be caused by the influenza virus, but also by RSV, Haemophilus influenzae type b, or Streptococcus pneumoniae [11].

Symptomatic therapies or antiviral medications are still the major tools to treat vRTIs [19] as vaccines are currently not yet available for most of the respiratory viruses [20] except against influenza, adenovirus and more recently, against SARS-CoV-2. However, it is also important to notice that such vaccines will face several specific hurdles: (i) they could be restricted to some countries and dedicated personnel, as evidenced by the adenovirus vaccine available only to military personnel in the US; (ii) their mild efficacy (from 30% to 60% for the influenza vaccine) and need for annual revaccination due to emerging new variants [6] and (iii) high-cost and need for specific cold chain suppliers as observed with recent mRNA vaccines against SARS-CoV-2. Although developing vaccine strategies against the respiratory diseases still remain an outstanding priority, it questions the availability of these vaccines in developing countries in a timely manner, where cost-effective antiviral therapies could be preferred.