[Source: World Health Organization, full PDF document: (LINK). Introduction, excerpt.]
Research needs for the Battle against Respiratory Viruses (BRaVe)
© World Health Organization 2013
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The World Health Organization (WHO) would like to thank the Wellcome Trust and the Fondation Mérieux for their support for the two Informal Technical Consultations, in July and November 2012, which contributed to the development of this research agenda.
Find out more on the Battle against Respiratory Viruses (BRaVe) initiative on the WHO web site: www.who.int/influenza/patient_care/clinical/brave/en/index.html
Abbreviations and acronyms
- ALRI acute lower respiratory infection
- ARDS acute respiratory distress syndrome
- ARI acute respiratory infections
- CAP community-acquired pneumonia
- COPD chronic obstructive pulmonary disease
- CRP C-reactive protein
- DALY disability adjusted life years
- HCoV human coronavirus
- Hib Haemophilus influenzae type B
- HIV human immunodeficiency virus
- HRV human rhinovirus
- huMPV human metapneumovirus
- ILI influenza-like illness
- NAAT nucleic acid amplification test
- PCT procalcitonin
- PIV parainfluenza virus
- RNA ribonucleic acid
- RSV respiratory syncytial virus
- RVI respiratory viral infection
- SARI severe acute respiratory infection
- WHO World Health Organization
Battle against respiratory viruses: the timing is right
Acute respiratory infections are a major global public health problem. Despite progress made in the 20th century with the introduction of antibiotics, vaccines and (recently) antivirals, there are no specific interventions for most respiratory infections of viral origin. These infections continue to cause frequent morbidity, and sometimes cause severe outcomes including death, especially in developing countries. Current practices for treating these illnesses (e.g. the frequent use of antibiotics) are ineffective and often result in adverse consequences, including antimicrobial resistance.
The discovery of antiviral medicines in the late 20th century led to significant breakthroughs in the fight against infectious diseases. Progress in molecular biology, genetic engineering and other disciplines has enabled scientists to design and produce antivirals that target key viral proteins, or block critical processes involved in viral replication. For example, there are effective antivirals for human immunodeficiency virus (HIV), influenza, herpes, and hepatitis B and C viruses. These antiviral therapies have been introduced widely into clinical practice in some countries, illustrating their potential value in reducing morbidity and mortality. When these medications are combined with advances in diagnostics tests and improvements in clinical management, it seems that effective treatment of respiratory viral infections (RVIs) is a real possibility.
Although advances in the development of influenza vaccines and therapeutics have shown the potential for mitigating the impact of seasonal and pandemic influenza, effective strategies that combine vaccines, therapeutics and improved clinical management are currently lacking for most RVIs. Targeting such infections will be a key challenge of the 21st century. We now have the research tools to develop effective modalities against respiratory viruses. However, how can this new knowledge be rapidly and effectively incorporated into public health strategies?
To succeed in the battle against respiratory viruses, we need to develop and implement a coherent, integrated research agenda. Only through collective engagement can we assemble the ideas and resources to find new weapons, particularly vaccines and therapeutics, against respiratory viruses, and make them available to those in need. This research agenda will be the framework by which the research and public health communities will identify gaps, and work together to fill those gaps.
Introduction: needs for a research agenda (1-15)
Recent decades have seen many important studies on respiratory viral infections (RVIs), yet there is still only a limited evidence base for understanding the burden of such infections, and for mitigating their impact, and there are few effective pharmacologic interventions other than for influenza. We need to know more about specific areas and to develop new interventions, to support the strategy of reducing the health impacts of these pathogens, particularly the severe illnesses that cause hospitalizations and deaths. The principal objectives of this research agenda are to:
- identify the specific research needed to improve medical and public health responses to RVIs and their sequelae over both the short-to-medium (1–5 years) and the medium-to-long (5–10 years) term;
- provide a framework – reflecting public health research priorities – for allocating research resources, including studies applicable in under-resourced countries and those addressing areas that have been relatively less studied (e.g. operational and social sciences research);
- facilitate discussion, coordination and interactions among fundamental and clinical investigators from both public and private sectors, funders, pharmaceutical industry representatives and public health professionals;
- highlight the need and the potential benefits of a multidisciplinary approach to addressing knowledge gaps in prevention and treatment of RVIs.
This document will help in targeting funding towards priority areas, monitoring the progress in filling knowledge gaps, and facilitating the development of evidence-based policies to prevent and mitigate RVIs. The following section outlines important factors to take into account in considering the rationale and scope of such a research agenda.
Respiratory viral infections are common and widespread
RVI is one of the most common health conditions globally, and has enormous but under recognized impacts on public health. Everyone has experienced colds or influenza-like illness (ILI), and young children average up to a dozen episodes per year. In addition to their high frequency, RVIs are major causes of severe acute respiratory infection (SARI), which can lead to severe outcomes including hospitalization and death (Box 1). RVIs are implicated in approximately 50% of community-acquired pneumonia (CAP) in young children, over 90% of bronchiolitis cases in infants and young children seeking medical attention, and over 90% of asthma exacerbations in children. In adults, they are implicated in 30–50% of CAP, 80% or more of asthma exacerbations, and 20–60% of exacerbations of chronic obstructive pulmonary disease (COPD). In addition, RVIs predispose those infected to a range of secondary bacterial infections including otitis media, sinusitis and CAP. Acute lower respiratory infections (ALRIs) are estimated to cause 3.9 million deaths per year, and pneumonia alone is the leading single cause of mortality in children under 5 years of age, with approximately 1.2 million children dying each year. Estimates indicate that about 99% of these deaths occur in developing countries, and 80% occur out of hospital.
Direct and indirect costs of acute respiratory infections
Acute respiratory infections (ARIs) cause severe complications for patients, and impose an enormous burden on communities. Communities can be directly affected; for example, through the need for outpatient care and hospital services. One recent systematic analysis estimated that, in 2010, 14.9 million episodes of severe or very severe ALRI resulted in hospital admissions in young children worldwide, although only 62% of children with severe ALRI were hospitalized. Communities can also be indirectly affected; for example, ARIs are responsible each year for major losses in productivity, in part due to absenteeism. ALRIs are the leading cause of burden of disease worldwide, accounting for 94.5 million disability adjusted life years (DALYs), equivalent to 6.2% of total DALYs.
Current management of RVIs is suboptimal in most countries, and often results in both use of ineffective treatments and failure to use treatments of proven benefit. Because it is commonly thought that ARIs are caused by bacteria, most such infections are treated with antibiotics. Even when a viral etiology is diagnosed, the illness is unlikely to be treated with specific antivirals, because these are generally unavailable, except possibly for influenza treatments in some settings.
Inappropriate antibiotic use
Inappropriate antibiotic use for RVIs is a widely prevalent problem that increases the risks for antibiotic side-effects and emergence of antimicrobial resistance, as well as the cost of care. At the same time, RVIs are major causes of secondary infections with bacteria. Measures undertaken to prevent and treat the initiating RVIs could have major impacts on these adverse downstream consequences.
Innovative approaches targeting broad-spectrum pathogens are needed
With the availability of more sophisticated diagnostic tests, multiple respiratory viruses are now often detected in ARIs, especially in children. Such observations raise questions about disease causation, pathogenesis and the dynamics of infection with multiple agents; they also suggest that it would be beneficial to consider innovative therapeutic approaches that do not focus on a single virus.
Complex mechanisms of disease
Host responses to RVIs are important in disease pathogenesis, but such responses are diverse across population groups and are incompletely understood. Furthermore, mixed infections (both viral–viral and viral–bacterial) increase the complexity of pathogen–host interactions. Improved therapeutic strategies for RVIs will depend on a better understanding of the mechanisms of disease in different syndromes and target populations.
Except possibly during widespread outbreaks due to a specific virus (e.g. epidemic influenza), RVIs cannot be addressed effectively or efficiently with a vertical approach that focuses on one agent at a time from public health and clinical perspectives. A syndromic approach that addresses the pathogenesis, prevention and optimal management of clinical problems such as CAP and other forms of SARI makes most sense; it also allows for the introduction of technological advances in diagnostics and therapeutics to those in greatest need.
Global health security threat
Respiratory viruses are pathogens that may have a major effect on global health security. In recent years, we have witnessed the emergence and discovery of a number of new respiratory viruses including severe acute respiratory syndrome (SARS) and other coronaviruses, avian H5N1 influenza and pandemic (H1N1) 2009 influenza, and there is a high likelihood of new respiratory viruses emerging that could cause extensive disease and economic losses. The expectation is that the impact of these unpredictable events will be mitigated to some extent by non-pharmaceutical interventions, specific antiviral and potentially immunomodulatory therapies, and clinical management strategies effective for common RVIs. Studies in the period between pandemics can generate evidence that will inform responses to both recognized and novel RVI threats.
Treatments and vaccines
The treatment of RVIs will be an important complement to vaccination strategies directed at specific respiratory viruses and their secondary bacterial complications; for example, at Streptococcus pneumoniae and Haemophilus influenzae type B (Hib). Currently, we have vaccines for influenza, although these are incompletely protective and underused, and require annual administration. A recent position paper1 from a World Health Organization (WHO) Strategic Advisory Group of Experts (SAGE) on immunization promotes maternal immunization against influenza to protect both mother and infants, and this approach will be an important strategy to protect infants against respiratory syncytial virus (RSV) and possibly other RVIs, once effective vaccines are available.
Despite years of investigation, there are as yet no effective vaccines for RSV, picornavirus or other common respiratory viruses, except for several adenovirus serotypes. The large number of respiratory virus families, types and serotypes means that effective vaccines for most such viruses are unlikely to be developed in the foreseeable future. Consequently, it makes sense to pursue an integrated approach to RVIs by developing more effective therapeutics while continuing to pursue vaccine development for particular threats – for example, RSV and parainfluenza virus (PIV), and human metapneumovirus – and improving vaccines for influenza.
It is almost impossible to eradicate respiratory viruses because of their extraordinary diversity, complex evolution and ability to be maintained in human populations (in part through transmission by mild or subclinical infections). However, with the possible exception of measles infection, mitigation of the impacts of respiratory viruses is now achievable.
In spite of the issues outlined above, we are at a turning point. The prospects of new antivirals, new molecular diagnostics, novel vaccines and new management approaches offer opportunities to tackle RVIs, but to exploit these opportunities, we need new weapons and strategies, and particularly, a focus on scientific research. The overall goal for the proposed research agenda is to develop both the evidence and the tools needed to strengthen public health actions and decision-making, in order to limit the impact of acute RVIs and their consequences in both individuals and populations. In prioritizing research activities, both data-driven hypotheses and feasibility should be considered; hence, the ranking of particular projects is likely to evolve as better data or tools become available for addressing particular questions.
The research needs for viral respiratory infections encompass six key areas, which are covered in this document:
- 1. Defining the burden of disease
- 2. Understanding disease pathogenesis and host dynamics
- 3. Expanding treatment options
- 4. Improving SARI diagnosis and diagnostic tests
- 5. Improving clinical management of SARI and CAP
- 6. Optimizing public health strategies.
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(1) Available at http://www.who.int/wer/2012/wer8747.pdf