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Research needs for

the Battle against

Respiratory Viruses

(BRaVe)

Background document

2013

Research needs for the Battle against Respiratory Viruses (BRaVe) ii | P a g e

World Health Organization 2013

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Research needs for the Battle against Respiratory Viruses (BRaVe) iii | P a g e

Acknowledgements

The World Health Organization (WHO) would like to thank the Wellcome Trust and the Fondation

Mrieux 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

Research needs for the Battle against Respiratory Viruses (BRaVe) iv | P a g e

Contents

Acknowledgements iii

Abbreviations and acronyms v

Foreword vi

Introduction: needs for a research agenda 1

1. Defining the burden of disease of respiratory viral infections 6

2. Understanding disease pathogenesis and host dynamics of respiratory viral infections 12

3. Expanding treatment options for respiratory viral infections 16

4. Improving SARI diagnosis and diagnostic tests 20

5. Improving clinical management of SARI and CAP 23

6. Optimizing public health strategies 26

Full reference list 29

Research needs for the Battle against Respiratory Viruses (BRaVe) v | P a g e

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

Research needs for the Battle against Respiratory Viruses (BRaVe) vi | P a g e

Foreword

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.

Research needs for the Battle against Respiratory Viruses (BRaVe) 1 | P a g e

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 (15 years) and the medium-to-long (510 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

3050% of CAP, 80% or more of asthma exacerbations, and 2060% 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.

Suboptimal management

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 viralviral and

viralbacterial) increase the complexity of pathogenhost interactions. Improved therapeutic strategies

for RVIs will depend on a better understanding of the mechanisms of disease in different syndromes and

target populations.


Syndromic approach

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

1 Available at http://www.who.int/wer/2012/wer8747.pdf


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.

Mitigation

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.

Opportunities

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.


References (Introduction)

1 World Health Organization. The global burden of disease: 2004 update. Geneva, WHO, 2008.

http://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf

2 World Health Organization. The World health report 2002: Reducing risks, promoting healthy life.

Geneva, WHO, 2002.

3 World Health Organization/United Nations Childrens Fund. Global Action Plan for Prevention

and Control of Pneumonia (GAPP). Geneva, WHO/UNICEF, 2009.

http://www.who.int/maternal_child_adolescent/documents/fch_cah_nch_09_04/en/index.html

4 Welkers MR, Dunning J, Wong CH et al. Current research on respiratory viral infections: XIIth

International Symposium. Antiviral Therapy, 2012, 17(1 Pt B):227-253. PM:22311667

5 Welkers M, Sutherland T, Osterhaus AD et al. Current research on respiratory viral infections: XIII

International Symposium on Respiratory Viral Infections: part 1. Future Virology, 2011,

6(10):1155-1160.

6 Sutherland TC, Welkers MRA, Osterhaus ADME et al. Current research on respiratory viral

infections: XIII International Symposium on Respiratory Viral Infections: part 2. Future Virology,

2011, 6(11):1283-1288. http://dx.doi.org/10.2217/fvl.11.102

7 Scott JA, Wonodi C, Mosi JC et al. The definition of pneumonia, the assessment of severity, and

clinical standardization in the Pneumonia Etiology Research for Child Health Study. Clinical

Infectious Diseases, 2012, 54(Suppl 2):S109-S116.

http://cid.oxfordjournals.org/content/54/suppl_2/S109.abstract

8 Ruuskanen O, Lahti E, Jennings LC et al. Viral pneumonia. Lancet, 2011, 377(9773):1264-1275.

PM:21435708

9 Ranieri VM, Rubenfeld GD, Thompson BT et al. Acute respiratory distress syndrome: the Berlin

Definition. JAMA : The Journal of the American Medical Association, 2012, 307(23):2526-2533.

http://www.ncbi.nlm.nih.gov/pubmed/22797452

10 Osterhaus AD. New respiratory viruses of humans. The Pediatric Infectious Disease Journal, 2008,

27(10 Suppl):S71-S74. PM:18820582

11 Nair H, Simooes EA, Rudan I et al. Global and regional burden of hospital admissions for severe

acute lower respiratory infections in young children in 2010: a systematic analysis. Lancet, 2013.

PM:23369797

12 Levine OS, O'Brien KL, Deloria-Knoll M et al. The Pneumonia Etiology Research for Child Health

Project: a 21st century childhood pneumonia etiology study. Clinical Infectious Diseases, 2012,

54(Suppl 2):S93-101. http://www.ncbi.nlm.nih.gov/pubmed/22403238

13 Jartti T, Jartti L, Ruuskanen O et al. New respiratory viral infections. Current Opinion in

Pulmonary Medicine, 2012, 18(3):271-278. PM:22366993

14 Gilani Z, Kwong YD, Levine OS et al. A literature review and survey of childhood pneumonia

etiology studies: 2000-2010. Clinical Infectious Diseases, 2012, 54(Suppl 2):S102-108.


15 Anderson LJ, Baric RS. Emerging human coronaviruses disease potential and preparedness.

New England Journal of Medicine, 2012. PM:23075144

16 Nair H, Nokes DJ, Gessner BD et al. Global burden of acute lower respiratory infections due to

respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet, 2010,

375(9725):1545-1555. PM:20399493


1. Defining the burden of disease of respiratory viral infections (16-31)

Respiratory illnesses, exemplified by pneumonia, are the leading cause of death from infectious diseases;

they account for approximately 20% of mortality in children under 5 years of age, particularly in

resource-limited settings. With improvements in diagnostic technologies, there has been an increase in

studies that specify the responsible viral pathogen. However, more research is needed to better estimate

the burden of RVI pathogens relative to bacterial or mixed etiologies in different settings.

These viruses also cause considerable morbidity in older children and adults, and mortality in older

adults and those with underlying conditions. For example, in the United States (US), 90% of seasonal

influenza and 78% of RSV-associated respiratory and circulatory deaths occur in adults aged 65 years and

older. Although many studies on RVIs focus on children under 5 years of age (Box 2) and elderly adults,

too little is known about the overall impact across the age spectrum. Similarly, population- or hospital-

based studies have highlighted the importance of specific RVIs such as influenza and RSV in causing

serious disease (Box 1).

The figures given in Box 1 do not include the contributions of other viruses to the global burden. Such

gaps in knowledge tend to hide the real burden of RVIs in the global population. Therefore, the

causative pathogens and particularly the contributions of RVIs need to be better characterized in

different clinical syndromes, settings and target populations.

Data on disease burden are unavailable from many countries, especially those that are under-resourced

and, at present, there is no globally integrated surveillance system for RVIs other than influenza.

Understanding the geographical patterns, seasonality and distributions of RVIs would allow for more

appropriate and targeted clinical management in situations where the burden of disease currently

remains hidden. Furthermore, the wider scale use of effective vaccines for viral infections (e.g. influenza)

and bacterial infections (e.g. Hib and pneumococcal conjugate) will probably lead to changes in the

etiologies and, perhaps, patterns of serious respiratory illnesses. For example, in older adults with high

uptake rates for influenza vaccine, the frequency of RSV-associated hospitalizations is comparable to

that caused by influenza.


Box 1: Disease burden of respiratory infections (8, 16, 25, 32, 33)

A. Estimated global impacts of RVI in pneumonia and SARI:

CAP cases per year: 429.2 million

o 200 million cases of viral CAP per year

o Approximately 3.54 million deaths (7% of total annual mortality)

o Economic costs of US$ 17 billion per year in the US alone

CAP cases in children per year: 156 million

o 151 million CAP cases in developing countries

o RVI in 4367% of paediatric CAP cases

o 14.6 million SARI + severe CAP cases

o 1.4 million deaths in developing countries (>95% in developing countries)

B. Specific viral pathogens in children


Box 2: Paediatric ALRI episodes in children under 5 years of age

Millions/year

ALRI, acute lower respiratory infection; Hib, Haemophilus influenzae type B; RSV, respiratory syncytial virus (16, 25, 26, 30)

Further information is needed on the role of RVIs in causing other clinical syndromes, in order to

improve strategies to reduce the overall morbidity and mortality of acute respiratory disease. Available

evidence indicates that respiratory viruses are the primary agents involved in multiple common

respiratory syndromes (e.g. rhinosinusitis, ILI, bronchiolitis, laryngotracheobronchitis, acute bronchitis,

exacerbations of asthma and COPD), and that they either directly cause other illnesses affecting the

upper respiratory tract (e.g. otitis media and sinusitis) and lower respiratory tract (e.g. pneumonia), or

foster secondary bacterial infections at these sites. In addition, some RVIs particularly influenza and

adenovirus have been associated with severe illnesses involving other organ systems (e.g.

encephalopathyencephalitis and myocarditis). RVIs also cause serious worsening or complications of

non-respiratory conditions (e.g. myocardial infarction, congestive heart failure, stroke and diabetes) that

contribute heavily to the burden of RVI-associated hospitalizations and mortality.

It appears that RVIs may sometimes also be associated with chronic sequelae, such as the development

of asthma. The role of viruses in the development of specific cancers is well-understood; for example, in

relation to the role of human papilloma virus (HPV) in cervical cancer, and of hepatitis viruses B and C in

liver cancers. However, little is known about any potential association between RVIs and malignancy.

Human adenoviruses are oncogenic in other animals, but are not known to be so in humans. Whatever

this situation, given that lung cancer is one of the leading non-communicable causes of death, further

knowledge could be of crucial importance.

0

5

10

15

20

25

30

35

Pneumococcal ALRI Hib ALRI RSV ALRI Influenza ALRI


More research is needed to define the age-related burden of RVIs and what might be achieved with

more effective interventions. Both hospital-based and community-based surveillance systems are

required to provide quality data that link RVI and bacterial etiologies with outcomes. Where possible, the

synergies between increased surveillance and vaccine or antiviral probe studies are likely to improve the

overall strength of results.

Priority research questions

1.1 Assess the overall burden of disease generated by respiratory viruses, including their economic

consequences, by:

identifying the key respiratory viruses responsible for the major burden on health-care systems

in different settings (e.g. rural versus urban, tropical versus temperate), and seasons or times of

the year;

assessing the proportions of specific viral, bacterial and mixed-pathogen infections in pneumonia

and other serious acute lower respiratory infection (ALRI) syndromes in different age groups and

settings;

assessing the proportion of specific viral pathogen infections in exacerbation of other underlying

conditions, particularly asthma, COPD and cardiovascular disease (CVD);

assessing the interactions between acute respiratory viral infections and other infectious

diseases, including human immunodeficiency virus (HIV) and tuberculosis (TB).

1.2 Characterize the dynamics of respiratory virus transmission, the associated factors and their

impact at:

individual, household and institutional levels, and assess the utility of selected non-

pharmaceutical interventions;

population level (including factors in seasonality, interference and routes of transmission).

1.3 Assess the occurrence of respiratory virus infection and infectiousness in nosocomial settings,

and identify cost-effective means to prevent transmission.

1.4 Determine the longer term consequences of respiratory viral infections in infants and young

children (e.g. development of asthma or chronic lung disease).

1.5 Evaluate the potential reductions in burden of disease and the potential health-care effects

gained or realized in treating respiratory viral diseases.

1.6 Measure the comparative advantage (e.g. in terms of technical demands and costs) of reducing

disease burden with different combinations of preventive and therapeutic measures (e.g. individual

hygiene measures, vitamins, oxygen therapy, antiviral therapies and intensive care) for known

pathogens.


References (Section 1)


PM:21435708



375(9725):1545-1555. PM:20399493

17 Dawood F, Iuliano A, Reed C et al. Estimated global mortality associated with the first 12 months

of 2009 pandemic influenza A H1N1 virus circulation: a modelling study. The Lancet Infectious

Diseases, 2012. http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(12)70121-

4/abstract

18 Falsey AR, Hennessey PA, Formica MA et al. Respiratory syncytial virus infection in elderly and

high-risk adults. New England Journal of Medicine, 2005, 352(17):1749-1759. PM:15858184

19 Hammitt LL, Kazungu S, Morpeth SC et al. A preliminary study of pneumonia etiology among

hospitalized children in Kenya. Clinical Infectious Diseases, 2012, 54(Suppl 2):S190-S199.

PM:22403235

20 Liu L, Johnson HL, Cousens S et al. Global, regional, and national causes of child mortality: an

updated systematic analysis for 2010 with time trends since 2000. Lancet, 2012, 379(9832):2151-

2161. PM:22579125

21 Lunelli A, Rizzo C, Puzelli S et al. Understanding the dynamics of seasonal influenza in Italy:

incidence, transmissibility and population susceptibility in a 9-year period. Influenza and Other

Respiratory Viruses, 2012. PM:22694182

22 Mermond S, Zurawski V, D'Ortenzio E et al. Lower respiratory infections among hospitalized

children in New Caledonia: a pilot study for the Pneumonia Etiology Research for Child Health

project. Clinical Infectious Diseases, 2012, 54(Suppl 2):S180-S189. PM:22403234

23 Miller EK, Lu X, Erdman DD et al. Rhinovirus-associated hospitalizations in young children. The

Journal of Infectious Diseases, 2007, 195(6):773-781. PM:17299706

24 Murata Y. Respiratory syncytial virus infection in adults. Current Opinion in Pulmonary Medicine,

2008, 14(3):235-240. PM:18427247

25 Nair H, Brooks WA, Katz M et al. Global burden of respiratory infections due to seasonal

influenza in young children: a systematic review and meta-analysis. Lancet, 2011,

378(9807):1917-1930. PM:22078723

26 O'Brien KL, Wolfson LJ, Watt JP et al. Burden of disease caused by Streptococcus pneumoniae in

children younger than 5 years: global estimate. Lancet, 2009, 374(9693):893-902. PM:19748398

27 Shrestha SS, Swerdlow DL, Borse RH et al. Estimating the burden of 2009 pandemic influenza A

(H1N1) in the United States (April 2009April 2010). Clinical Infectious Diseases, 2011, 52(Suppl

1):S75-S82. PM:21342903

28 Thompson WW, Shay DK, Weintraub E et al. Mortality associated with influenza and respiratory

syncytial virus in the United States. JAMA : The Journal of the American Medical Association,

2003, 289(2):179-186. PM:12517228

29 van Asten L, van den Wijngaard C, van PW et al. Mortality attributable to 9 common infections:

Significant effect of influenza A, respiratory syncytial virus, influenza B, norovirus, and

parainfluenza in elderly persons. The Journal of Infectious Diseases, 2012. PM:22723641


30 Watt JP, Wolfson LJ, O'Brien KL et al. Burden of disease caused by Haemophilus influenzae type b

in children younger than 5 years: global estimates. Lancet, 2009, 374(9693):903-911.

PM:19748399

31 Wonodi CB, Deloria-Knoll M, Feikin DR et al. Evaluation of risk factors for severe pneumonia in

children: The Pneumonia Etiology Research for Child Health Study. Clinical Infectious Diseases,

2012, 54(Suppl 2):S124-S131. http://cid.oxfordjournals.org/content/54/suppl_2/S124.abstract

32 World Health Organization. World health statistics. Geneva, WHO, 2012.

http://www.who.int/gho/publications/world_health_statistics/2012/en/index.html

33 Hall CB, Weinberg GA, Iwane MK et al. The burden of respiratory syncytial virus infection in

young children. New England Journal of Medicine, 2009, 360(6):588-598.



2. Understanding disease pathogenesis and host dynamics of respiratory

viral infections (34-49)

To develop more effective treatments and public health interventions, we need better understanding of

the mechanisms by which respiratory viruses are transmitted and cause disease. Little is known about

the pathogenesis of RVIs, and it is likely that interactions between virus, host and environment vary

among specific pathogens and among key patient groups. For example, viral replication patterns and

innate immune responses differ between mild upper respiratory infections and severe lower respiratory

infections, and between patient groups at high risk of complications (e.g. infants, pregnant women,

elderly adults and immunocompromised hosts). Data on the kinetics of viral replication would be a useful

first step in determining infection control measures. Disease severity following infection depends on

multiple factors, including pre-existing immunity, host genetic factors and underlying conditions, viral

replication kinetics in the upper and lower respiratory tract, inefficient or aberrant host innate and

adaptive immune responses triggered by viral replication, environmental conditions, and virulence

factors related to mutations in key viral proteins.

Specific data on viral replication dynamics and host pro-inflammatory and immune responses (especially

in the lower respiratory tract) in key patient groups are important to determine the nature, timing

(initiation and cessation), and potency of candidate immunomodulatory and host-directed therapeutic

interventions. Such data may also serve to discourage use of potentially harmful interventions. For

example, systemic corticosteroids have been commonly used in management of RSV-associated

bronchiolitis and of influenza-associated acute lung injury or acute respiratory distress syndrome (ARDS).

However, available data do not indicate benefit and, in the case of influenza, actually appear to indicate

harm in terms of prolongation of viral replication, adverse drug effects, and increased risks of nosocomial

infections and mortality.

Elevated temperatures have been associated with host-defense immunological mechanisms against

influenza infection, such as the proliferative response of lymphocytes or the increased production and

activity of cytokines. Animal models reveal an increased risk of mortality associated with antipyretics

during influenza infection. Although antipyretics are widely used in humans, there is little evidence on

their potential adverse events. More research on these practices is therefore important.

Viruses and (commensal) bacteria are often present together in the respiratory tract, but relatively little

is known about their interplay and how this affects transmission and disease pathogenesis. The

importance of bacterial pneumonias and, sometimes, bloodstream infections following influenza is well

documented. Various mechanisms have been implicated in promoting secondary bacterial infections,

including increased bacterial adherence, altered tracheobronchial clearance, inhibition of functions of

polymorphonuclear leukocytes (PMN) and macrophages, anergy of pattern recognition receptors, and

viral virulence factors such as PB1-F2. Animal model studies of pneumococcal pneumonia following

influenza suggest that antiviral therapy can lessen disease severity and that some commonly used

antibiotics might enhance adverse inflammatory responses.


The frequency of bacterial complications and the mechanisms involved following other RVIs are less well

studied. Furthermore, many common respiratory viruses such as human rhinovirus (HRV), RSV and

human coronavirus (HCoV) are associated with mixed viralbacterial infections involving sites in the

upper respiratory tract (e.g. otitis media and sinusitis), in part related to altered Eustachian tube function

and inadequate sinus drainage. Further understanding of the processes involved in secondary bacterial

infections may help to improve strategies for prevention and management.

Sensitive methods for nucleic acid detection have led to the frequent detection of multiple viral

pathogens in respiratory samples, especially in infants and young children. Two or three respiratory

viruses are detected in 1020% of paediatric pneumonia cases (Box 3). The pathogenic consequences of

these viral co-infections have not yet been clarified, but may depend on the particular viruses involved,

the timing of acquisition (concurrent or sequential), the interval between acquisition, and host factors.

Improved understanding of virushost interactions in key patient groups is fundamental to developing

rationally designed therapeutics and vaccines. This includes understanding the basis of transmission and

the pathology associated with infection, as well as the basis of mechanisms and consequences of viral

and bacterial co-infections. Complementary basic and clinical research approaches will be required.



2.1 Understand the interactions of different respiratory viruses with host-cell pathways, and their

roles in pathogenesis and as potential targets for intervention.

2.2 Characterize viral and bacterial replication dynamics and host immune responses in the upper

and lower respiratory tracts during infection in key patient groups.

2.3 Understand the interplay between viral, bacterial (including the human microbiome) and host

factors in disease pathogenesis.

2.4 Understand the effect of the virus on immune responses, including the basis of protection and

the role of viruses in inhibiting effective responses.

2.5 Understand the pathogen, host and environmental factors and mechanisms that determine viral

and bacterial transmission.

2.6 Clarify the issue of disease causation for different viruses (e.g. frequency of subclinical infection,

and significance of viral ribonucleic acid [RNA] detection), and the contributory roles of specific

pathogens during infection with multiple agents.

2.7 Identify host genetic factors that determine susceptibility to respiratory viral infections and the

severity of such infections, and assess the implications for therapeutic interventions.

2.8 Determine the underlying mechanisms for established major risk factors in the host (e.g.

pregnancy, obesity, smoking and comorbidities) and the environment (e.g. passive smoking and indoor

air pollution) associated with increased disease severity.

2.9 Promote efforts to obtain etiology and pathogenesis data from fatal cases, through strategic use

of limited postmortem sampling (e.g. needle biopsies of affected and unaffected lungs).





34 Agrati C, Gioia C, Lalle E et al. Association of profoundly impaired immune competence in H1N1v-

infected patients with a severe or fatal clinical course. The Journal of Infectious Diseases, 2010,

202(5):681-689. PM:20670171

35 Bezerra PG, Britto MC, Correia JB et al. Viral and atypical bacterial detection in acute respiratory

infection in children under five years. PloS One, 2011, 6(4):e18928. PM:21533115

36 Collins PL, Graham BS. Viral and host factors in human respiratory syncytial virus pathogenesis.

Journal of Virology, 2008, 82(5):2040-2055. PM:17928346

37 El Saleeby CM, Bush AJ, Harrison LM et al. Respiratory syncytial virus load, viral dynamics, and

disease severity in previously healthy naturally infected children. The Journal of Infectious

Diseases, 2011, 204(7):996-1002. PM:21881113

38 Everitt AR, Clare S, Pertel T et al. IFITM3 restricts the morbidity and mortality associated with

influenza. Nature, 2012, 484(7395):519-523. PM:22446628


39 Eyers S, Weatherall M, Shirtcliffe P et al. The effect on mortality of antipyretics in the treatment

of influenza infection: systematic review and meta-analysis. Journal of the Royal Society of

Medicine, 2010, 103(10):403-411. PM:20929891

40 Gern JE. The ABCs of rhinoviruses, wheezing, and asthma. Journal of Virology, 2010, 84(15):7418-

7426. PM:20375160

41 Horby P, Sudoyo H, Viprakasit V et al. What is the evidence of a role for host genetics in

susceptibility to influenza A/H5N1? Epidemiology and Infection., 2010, 138(11):1550-1558.

PM:20236573

42 Jagger BW, Wise HM, Kash JC et al. An overlapping protein-coding region in influenza A virus

segment 3 modulates the host response. Science, 2012. PM:22745253

43 Lee N, Chan PK, Wong CK et al. Viral clearance and inflammatory response patterns in adults

hospitalized for pandemic 2009 influenza A(H1N1) virus pneumonia. Antiviral Therapy, 2011,

16(2):237-247. PM:21447873

44 Lee N, Wong CK, Chan PK et al. Cytokine response patterns in severe pandemic 2009 H1N1 and

seasonal influenza among hospitalized adults. PloS One, 2011, 6(10):e26050. PM:22022504

45 Melendi GA, Laham FR, Monsalvo AC et al. Cytokine profiles in the respiratory tract during

primary infection with human metapneumovirus, respiratory syncytial virus, or influenza virus in

infants. Pediatrics, 2007, 120(2):e410-e415. PM:17671045

46 Mizgerd JP. Acute lower respiratory tract infection. New England Journal of Medicine, 2008,

358(7):716-727. PM:18272895

47 Peiris JS, Cheung CY, Leung CY et al. Innate immune responses to influenza A H5N1: friend or foe?

Trends in Immunology, 2009, 30(12):574-584. PM:19864182

48 Sullivan JE, Farrar HC. Fever and antipyretic use in children. Pediatrics, 2011, 127(3):580-587.

PM:21357332

49 Zaas AK, Chen M, Varkey J et al. Gene expression signatures diagnose influenza and other

symptomatic respiratory viral infections in humans. Cell host and Microbe, 2009, 6(3):207-217.

PM:19664979

50 Pavia AT. Viral infections of the lower respiratory tract: old viruses, new viruses, and the role of

diagnosis. Clinical Infectious Diseases, 2011, 52(Suppl 4):S284-289.



3. Expanding treatment options for respiratory viral infections (51-61)

A number of antivirals have been tested for treatment of RVIs; they include interferons, ribavirin,

amantadine, oseltamivir, zanamivir, antibody preparations for RSV and capsid-binding anti-HRV

compounds. The agents of proven therapeutic value are mainly those for influenza, such as oseltamivir,

which reduces disease severity and mortality. For example, during the (H1N1) 2009 pandemic in Japan,

the combination of early diagnosis, rapid testing and oseltamivir treatment, in addition to other factors,

resulted in the lowest mortality rate in the world, with no influenza deaths in pregnant women. However,

oseltamivir fails to adequately control viral replication in some patients, and resistance is emerging as a

problem H1N1 virus resistant to oseltamivir was circulating globally in 200709. Consequently, more

potent antiviral combinations, especially for seriously ill persons, are needed.

In addition to oseltamivir, other neuraminidase inhibitors, including intravenous and long-acting inhaled

formulations, are in clinical development, as are several agents with novel mechanisms of anti-influenza

action (e.g. DAS181, favipiravir, nitazoxanide and AVI-7100). Recent reports of results with inhaled

interferon-beta or an oral anti-HRV inhibitor are promising, with reduced rhinovirusassociated cold

symptoms and modulated risk of exacerbations in asthmatic patients. However, there are no drugs to

treat most RVIs, and the relatively high cost of anti-influenza agents hinders their optimal use, especially

in low- and middle-income countries.

Most antiviral drugs have been developed by identifying viral proteins that can be inhibited by small

molecular chemical entities or, in some instances, larger biotherapeutics. Consequently, most approved

antiviral drugs are highly specific for a particular virus or family of viruses (e.g. neuraminidase inhibitors

and adamantanes for influenza). The advantage of this strategy is selectivity, and it may lower the risk of

adverse host effects. The disadvantages are a limited antiviral spectrum, the risk of antiviral resistance

and limitations on the number of virus-encoded proteins with properties suitable for developing

pharmaceutically acceptable inhibitors.

Recent non-clinical studies using ribonucleic acid interference (RNAi) screens have examined the cellular

interactions of selected viruses, and determined that large numbers of host-cell functions are essential

to viral replication. Through this approach, host-directed therapies could be identified and used as short-

term inhibitors. In some instances, a particular host function or pathway is required for the replication of

many different viruses. This raises the possibility of developing antiviral drugs with broad-spectrum

activity.

A related area of research is understanding and modulating host innate immune and other inflammatory

responses to RVIs. These host responses are thought to account for much of the symptomatology of

acute RVIs, and, in some cases, contribute to tissue damage in key target organs like the lung. However,

more information is needed on RVI pathogenesis in different syndromes and patient groups. Some of the

pathways involved in these host responses are also those necessary for efficient viral replication.

Consequently, a drug has the potential to inhibit viral replication and potentially deleterious host

responses. There is also evidence of inadequate host responses in some RVIs (e.g. deficient interferon


responses in severe influenza pneumonia and perhaps RSV infections), which may open the possibility of

therapeutic intervention.

For some RVIs, prophylaxis is a viable option. Vaccination is an effective intervention for influenza,

although protective efficacy varies across patient groups and seasons, and vaccine availability may be

severely limited during a pandemic. Influenza antivirals are effective for chemoprophylaxis but

prophylactic use has been limited by cost and, in some target groups, concerns about the emergence of

resistance. For RSV, there is currently no vaccine or chemoprophylaxis, but passive immunization with

either human immunoglobulin or anti-F monoclonal antibody (e.g. palivizumab) during the RSV season is

partially protective in high-risk groups such as preterm infants. The available RSV interventions are too

expensive for broad use in developing countries, although imminent patent expiry may mean more

affordable versions of these products will be developed.

More research is needed to expand treatment options across the range of respiratory viral pathogens.

Data from seasonal burden-of-disease studies indicate that therapeutics for RSV and HRV infections

should be prioritized. New data from burden-of-disease and pathogenesis studies will also inform

prioritization. Antiviral resistance and human pharmacokinetics, including pharmacokinetic

pharmacodynamic relationships and drugdrug interactions for combinations, are cross-cutting issues

that need to be integrated in therapeutic development strategies.



3.1 Develop and test new antivirals and combinations of antivirals for major respiratory viral

pathogens according to their burden:

given current burden-of-disease data, prioritize the development of inhibitors for RSV and

rhinovirus infections;

given concerns about resistance to adamantane and neuraminidase inhibitors (NAIs), also

prioritize development of influenza inhibitors with novel mechanisms of action;

test the effectiveness of combination antiviral therapy in seriously ill, hospitalized patients with

influenza.

3.2 Develop novel antiviral modalities and test their effectiveness in relevant target populations;

test:

existing broad-spectrum antivirals (e.g. favpiravir and nitazoxanide);

broad-spectrum antivirals against emerging viral threats (e.g. interferons for novel coronavirus);

host pathway-directed therapies, particularly those potentially inhibiting replication of multiple

viral pathogens.

3.3 Determine the host factors (e.g. genetic differences in drug metabolism) and drug

pharmacokinetic factors that predict responses to antiviral treatment, risk of adverse events and risk of

emergence of resistance.

3.4 Optimize dose regimens of existing antivirals for particular target populations.

3.5 Assess the effectiveness and safety of low-cost adjunctive therapies with regard to potential to

modulate the course of infection and of illness, including host immune responses. Therapies to test

include:

vitamin and mineral supplements (e.g. probiotics, selenium, vitamin A, vitamin D and zinc),

especially in populations with deficiencies;

immunomodulatory interventions (e.g. corticosteroids, cyclo-oxygenase 2 inhibitors, glitazones

and statins), particularly for treatment in conjunction with antivirals in severe illness;

commonly used medications for symptom relief (e.g. non-steroidal anti-inflammatory drugs

NSAIDs).

3.6 Define the criteria for using combinations of treatments, especially for antivirals and antibiotics,

and for antivirals and immunomodulatory agents.

3.7 Develop affordable prophylactic interventions (e.g. vitamin and mineral supplements) for high-

risk groups, to determine the ability of such interventions to reduce the vulnerability of patients before

infection.



51 DeVincenzo JP. The promise, pitfalls and progress of RNA-interference-based antiviral therapy

for respiratory viruses. Antiviral Therapy, 2012, 17(1 Pt B):213-225. PM:22311654

52 Geevarghese B, Simoes EA. Antibodies for prevention and treatment of respiratory syncytial

virus infections in children. Antiviral Therapy, 2012, 17(1 Pt B):201-211. PM:22311607

53 Hayden FG. Experimental human influenza: observations from studies of influenza antivirals.

Antiviral Therapy, 2012, 17(1 Pt B):133-141. PM:22311616

54 Ludwig S. Disruption of virus-host cell interactions and cell signaling pathways as an anti-viral

approach against influenza virus infections. Biological Chemistry, 2011, 392(10):837-847.

PM:21823902

55 McCarthy MK, Weinberg JB. Eicosanoids and respiratory viral infection: coordinators of

inflammation and potential therapeutic targets. Mediators of Inflammation, 2012, 2012:236345.

PM:22665949

56 Nguyen HT, Fry AM, Gubareva LV. Neuraminidase inhibitor resistance in influenza viruses and

laboratory testing methods. Antiviral Therapy, 2012, 17(1 Pt B):159-173. PM:22311680

57 Nichols WG, Peck Campbell AJ, Boeckh M. Respiratory viruses other than influenza virus: impact

and therapeutic advances. Clinical Microbiol Reviews, 2008, 21(2):274-290, table. PM:18400797

58 Renaud C, Englund JA. Antiviral therapy of respiratory viruses in haematopoietic stem cell

transplant recipients. Antiviral Therapy, 2012, 17(1 Pt B):175-191. PM:22311587

59 Shaw ML. The host interactome of influenza virus presents new potential targets for antiviral

drugs. Reviews in Medical Virology, 2011, 21(6):358-369. PM:21823192

60 Smith SB, Dampier W, Tozeren A et al. Identification of common biological pathways and drug

targets across multiple respiratory viruses based on human host gene expression analysis. PloS

One, 2012, 7(3):e33174. PM:22432004

61 Tan EL, Ooi EE, Lin CY et al. Inhibition of SARS coronavirus infection in vitro with clinically

approved antiviral drugs. Emerging Infectious Diseases, 2004, 10(4):581-586. PM:15200845


4. Improving SARI diagnosis and diagnostic tests (62-73)

RVIs are often unrecognized or ignored by clinicians, especially in developing countries, because of the

lack of rapid, inexpensive and reliable diagnostic tests, and the sense that no effective treatments are

available. To reduce the burden of RVIs, good diagnostic tests are needed, especially at the point of care.

Such tests would raise awareness of health-care workers about the viral etiology of the disease, guide

therapeutic choices and improve clinical management of RVIs.

Establishing the etiology of RVIs remains challenging, although new molecular technologies in

particular multiplex nucleic acid amplification tests (NAATs) are promising tools that can be used in

developing country settings. Compared to older tests, NAATs are better able to detect fastidious or non-

cultivable pathogens such as human metapneumovirus (huMPV), HCoV and HRV, or low quantities of

pathogens, but results can be difficult to interpret. Detecting viral RNA at the same time as pneumonia

or SARI may indicate direct causality (e.g. bronchiolitis or viral pneumonia), indirect or predisposing

causality (e.g. secondary bacterial or mixed infection) or an unrelated incidental finding. The high

prevalence of RNA for some respiratory viruses (e.g. HRV) in apparently healthy infants and young

children (detected by qualitative assays) may represent subclinical or mild infections, or prolonged

excretion after a recent illness. Determining background rates in control groups and quantitative RNA

levels in the respiratory tract or other sites (e.g. blood) may therefore be important.

In resource-limited settings, other issues related to NAATs include high start-up equipment costs,

sensitivity to extreme environmental conditions, and access to reliable power supply, reagents and

technical support. Studies of the etiology of paediatric pneumonia (e.g. using RNA detection methods)

will help in assessing some of these issues; such studies include the Pneumonia Etiology Research for

Child Health (PERCH) and the Global Approach for Biological Research on Infectious Epidemics in Low

income countries (GABRIEL).

Another area of active investigation is the measurement of biomarkers that may distinguish patients

with bacterial etiologies from those with viral or non-bacterial etiologies. Such biomarkers may help to

inform clinical decision-making. For example, serum procalcitonin (PCT) levels are elevated in patients

with bacterial pneumonia and septic shock, whereas they are generally not elevated in those with RVI,

unless there is secondary bacterial or mixed infection. PCT levels are more dynamic and increase faster

than other markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels in

bacterial infections. Rapid decreases in PCT appear to indicate prompt response to antibiotic therapy and

the potential for short antibiotic courses, but confirmatory studies are needed. Other studies suggest

that, in patients with influenza, CRP levels may be informative for assessing risk of progression or

bacterial complications.

Improved diagnostic methods over the past decade present a much more complicated picture of

respiratory infections. Work on diagnostic tests should focus on three main goals: improving clinical

management of patients; assisting surveillance and burden-of-disease determinations; and supporting

other areas of RVI research (e.g. the evaluation of novel therapeutics). Platforms applicable to multiple


pathogens and sample types should be developed as a priority. The priority research questions for this

section are aimed at better assessment and understanding of the complexity of respiratory infection.


4.1 Develop reference reagents and performance standards to promote diagnostic development and

to assure accurate test performance.

4.2 Strengthen comprehensive characterization of respiratory specimens to inform diagnostic test

development, validation and interpretation, through deep sequencing and public posting of genetic and

epidemiologic findings.

4.3 Evaluate existing specimen collection techniques and devices, and develop new methods that

improve diagnosis of respiratory diseases.

4.4 Develop simple, accurate, low-cost nucleic acid amplification tests (NAATs) for acute respiratory

diseases.

4.5 Identify early biomarkers of the etiology and prognosis of pneumonia and ALRIs.

4.6 Develop protocols, algorithms and tools for rapid identification and characterization of emerging

respiratory infections.


62 Zimmerman O, Rogowski O, Aviram G et al. C-reactive protein serum levels as an early predictor

of outcome in patients with pandemic H1N1 influenza A virus infection. BMC Infectious Diseases,

2010, 10:288. PM:20920320

63 Murdoch DR, O'Brien KL, Driscoll AJ et al. Laboratory methods for determining pneumonia

etiology in children. Clinical Infectious Diseases, 2012, 54(Suppl 2):S146-S152. PM:22403229

64 Loens K, Van HL, Malhotra-Kumar S et al. Optimal sampling sites and methods for detection of

pathogens possibly causing community-acquired lower respiratory tract infections. Journal of

Clinical Microbiology, 2009, 47(1):21-31. PM:19020070

65 Lieberman D, Shimoni A, Keren-Naus A et al. Identification of respiratory viruses in adults:

nasopharyngeal versus oropharyngeal sampling. Journal of Clinical Microbiology, 2009,

47(11):3439-3443. PM:19726607

66 Hammitt LL, Murdoch DR, Scott JA et al. Specimen collection for the diagnosis of pediatric

pneumonia. Clinical Infectious Diseases, 2012, 54(Suppl 2):S132-S139. PM:22403227

67 Ginocchio CC. Strengths and weaknesses of FDA-approved/cleared diagnostic devices for the

molecular detection of respiratory pathogens. Clinical Infectious Diseases, 2011, 52(Suppl

4):S312-S325. PM:21460290

68 Gilbert DN. Procalcitonin as a biomarker in respiratory tract infection. Clinical Infectious Diseases,

2011, 52(Suppl 4):S346-S350. PM:21460294


69 Chartrand C, Leeflang MM, Minion J et al. Accuracy of rapid influenza diagnostic tests: a meta-

analysis. Annals of internal medicine, 2012, 156(7):500-511.


70 Bhat N, O'Brien KL, Karron RA et al. Use and evaluation of molecular diagnostics for pneumonia

etiology studies. Clinical Infectious Diseases, 2012, 54(Suppl 2):S153-S158. PM:22403230

71 Bartlett JG. Diagnostic tests for agents of community-acquired pneumonia. Clinical Infectious

Diseases, 2011, 52(Suppl 4):S296-S304. PM:21460288

72 American Academy of Microbiology. Bringing the lab to the patient: Developing point-of-care

diagnostics for resource limited settings. American Society for Microbiology, 2012.

http://www.finddiagnostics.org/resource-

centre/reports_brochures/bringing_the_lab_to_the_patient_2012.html

73 An unmet medical need: rapid molecular diagnostics tests for respiratory tract infections. Clinical

Infectious Diseases, 2011, 52(Suppl 4):S384-S395. PM:21460300


5. Improving clinical management of SARI and CAP (50, 74-87)

In all resource settings, timely and appropriate clinical management can reduce morbidity and,

potentially, mortality related to RVIs. Better evaluation algorithms, diagnostics, and safe and effective

treatments are needed. Identifying valid prognostic markers and scoring systems can help to determine

the correct type and level of care. Supportive-care interventions, such as oxygenation, rehydration and

(sometimes) non-invasive ventilation, may provide benefit in ALRI by preventing progression to severe

illness and death, especially in settings lacking modern intensive care capacities. However, there is an

insufficient evidence base for such basic supportive-care measures.

Some well-known effective interventions, such as oxygen therapy, are rarely used in many developing

countries. Every year, 1120 million children are admitted with pneumonia. At least 13.3% (1.5

2.7 million) have hypoxemia, which contributes to the more than 1.2 million deaths caused by

pneumonia. Investment in oxygen systems to improve detection and management of hypoxemia should

be part of health system support. However, there are many obstacles to using oxygen therapy. Scientific

evidence is still lacking on the efficacy and cost-effectiveness of oxygen use in low-resource settings. This

has prevented the publication of guidelines on oxygen use using the Grading of Recommendations

Assessment, Development and Evaluation (GRADE) approach1 and the inclusion of oxygen on the global

essential list of medicines2. Also, despite advances in technology for oxygen concentrators and pulse

oximeters, and the increased affordability of such devices, more innovation is needed to reach resource-

limited settings and ensure sustainable use of these techniques.

In many practice settings, antibiotics (including over-the-counter ones obtained by patients or their

family members) are frequently used to treat probable RVIs. Inappropriate antibiotic use drives

resistance; it also raises the costs of care and the risk of adverse events. Clinicians are often poorly

informed on the appropriate use of available antivirals and on the avoidance of interventions such as

systemic corticosteroids that might cause harm in certain RVIs (e.g. influenza and viral pneumonia).

More research is needed to improve clinical management strategies, and to help health professionals

adopt new attitudes to and practices in RVIs. The rapid communication of clinical management guidance

during the pandemic (H1N1) 2009 appeared to affect practice patterns. However, follow-up studies have

found reversion to pre-pandemic patterns; for example, delayed antiviral use for severe influenza in

1 http://www.who.int/kms/guidelines_review_committee/en/index.html

2 http://www.who.int/medicines/services/essmedicines_def/en/index.html


multiple countries, and associated increases in mortality. These examples show that it is crucial to forge

and sustain a paradigm shift regarding health-care workers beliefs and practices on clinical management

of RVIs.

Better integration of research activities and clinical practice is crucial in developing the most relevant

evidence base for policy decisions. All ages and settings must be considered in improving clinical

management practices. Clinical research can be undertaken, with designs ranging from observational

studies to randomized controlled trials (traditional or adaptive). Improved clinical research design,

combined with advances in basic science, will to help to identify those ARI patients who are most ill and

require intervention; assess and develop effective interventions for SARI and CAP; and promote more

timely exchange of data and knowledge.


5.1 Develop algorithms to identify high-risk patients and prognostic markers at an early stage of the

disease.

5.2 Validate specific protocols, including supportive-care interventions such as rehydration and

oxygen, to reduce the risk of severe outcomes. For instance, the use of a pulse oximeter for early

diagnosis and case management of hypoxemia warrants more study.

5.3 Develop and validate clinical management algorithms for optimizing SARI outcomes in resource-

limited settings, including use of a range of therapeutics and supportive or adjunct therapies.

5.4 Develop further evidence on oxygen therapy (protocols for use and benefits), to enable its

inclusion in the WHO list of essential medicines.

5.5 Promote research on oxygen delivery and dispensing devices that are better adapted to all

settings (including household and low-resource settings), particularly low-cost and easy-to-maintain

ventilatory support systems.

5.6 Determine feasible approaches to reducing risks of nosocomial transmission of viral respiratory

infections in health-care and household settings.

5.7 Compare the riskbenefit and cost-effectiveness of various therapeutic strategies (e.g. treatment

of mild cases, versus all cases, versus severe cases only).

5.8 Assess the conditions in the health-care systems to ensure the optimal implementation of

recommended changes.

5.9 Promote innovative clinical research design, and sharing of data and knowledge.



50 Pavia AT. Viral infections of the lower respiratory tract: old viruses, new viruses, and the role of

diagnosis. Clinical Infectious Diseases, 2011, 52(Suppl 4):S284-289.


74 Voiriot G, Dury S, Parrot A et al. Nonsteroidal antiinflammatory drugs may affect the

presentation and course of community-acquired pneumonia. Chest, 2011, 139(2):387-394.

PM:20724739

75 Siempos II, Vardakas KZ, Kopterides P et al. Adjunctive therapies for community-acquired

pneumonia: a systematic review. The Journal of Antimicrobial Chemotherapy, 2008, 62(4):661-

668. PM:18641037

76 Rasmussen SA, Jamieson DJ. Influenza and pregnancy in the United States: before, during, and

after 2009 H1N1. Clinical obstetrics and gynecology, 2012, 55(2):487-497. PM:22510632

77 Panickar J, Lakhanpaul M, Lambert PC et al. Oral prednisolone for preschool children with acute

virus-induced wheezing. New England Journal of Medicine, 2009, 360(4):329-338. PM:19164186

78 Mytton OT, Rutter PD, Donaldson LJ. Influenza A(H1N1)pdm09 in England, 2009 to 2011: a

greater burden of severe illness in the year after the pandemic than in the pandemic year. Euro

Surveillance : European Communicable Disease Bulletin, 2012, 17(14). PM:22516004

79 McCullers JA. Preventing and treating secondary bacterial infections with antiviral agents.

Antiviral Therapy, 2011, 16(2):123-135. PM:21447860

80 Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American

Thoracic Society consensus guidelines on the management of community-acquired pneumonia in

adults. Clinical Infectious Diseases, 2007, 44(Suppl 2):S27-S72. PM:17278083

81 Lee N, Ison MG. Diagnosis, management and outcomes of adults hospitalized with influenza.

Antiviral Therapy, 2012, 17(1 Pt B):143-157. PM:22311561

82 Kramarz P, Monnet D, Nicoll A et al. Use of oseltamivir in 12 European countries between 2002

and 2007 lack of association with the appearance of oseltamivir-resistant influenza A(H1N1)

viruses. Euro Surveillance : European Communicable Disease Bulletin, 2009, 14(5). PM:19215715

83 Greene SK, Shay DK, Yin R et al. Patterns in influenza antiviral medication use before and during

the 2009 H1N1 pandemic, Vaccine Safety Datalink Project, 2000-2010. Influenza and Other


84 Garg S, Chaves SS, Perez A et al. Reduced influenza antiviral treatment among children and

adults hospitalized with laboratory-confirmed influenza infection in the year after the 2009

pandemic. Clinical Infectious Diseases, 2012, 55(3):e18-e21. PM:22543024

85 Ducharme FM, Lemire C, Noya FJ et al. Preemptive use of high-dose fluticasone for virus-induced

wheezing in young children. New England Journal of Medicine, 2009, 360(4):339-353.

PM:19164187

86 Corrales-Medina VF, Musher DM. Immunomodulatory agents in the treatment of community-

acquired pneumonia: a systematic review. The Journal of Infection, 2011, 63(3):187-199.

PM:21763343

87 Borders-Hemphill V, Mosholder A. U.S. utilization patterns of influenza antiviral medications

during the 2009 H1N1 influenza pandemic. Influenza and Other Respiratory Viruses, 2012.

PM:22681766


6. Optimizing public health strategies (88-102)

Vaccines remain at the heart of disease prevention and control strategies. However, among respiratory

viruses, only influenza has vaccines, and these are underused. Furthermore, the need for annual

immunization with current influenza vaccines, due to waning immunity and changing viral antigenicity,

highlights the importance of developing new vaccines with more durable and broader spectrum immune

responses. Development of vaccines against other respiratory viruses is a well-recognized research need,

and studies to develop vaccines for RSV and PIV have been ongoing for decades. Unfortunately, vaccine

development is a long process, and there are significant technical challenges with respiratory viruses.

Immune responses to infections by pathogens such as RSV, huMPV and PIV are incomplete, so

reinfections can occur. Consequently, effective vaccines will need to induce more effective protective

responses than natural infection. Both live-attenuated and subunit RSV vaccines are in development, but

it is uncertain whether vaccines will become available for RSV or other respiratory viruses within the next

510 years. Once available, maternal immunization, as shown for influenza vaccines, would offer the

possibility of protecting young infants.

Considering these potential limitations, further evidence is needed on effective implementation of public

health approaches, such as hand hygiene, cough etiquette and other population-based prevention

measures. Comparative scenarios weighting the cost-effectiveness of sets of measures to be

implemented would be an asset for policy makers, helping to transfer

knowledge into action.

Common misperceptions on RVIs are shared by health-care workers

and the general population. These misperceptions increase the

burden of RVI disease, because they are likely to delay or prevent

effective intervention. More high-quality data would provide policy

makers with strategies to help both groups comply with

recommended interventions and adhere to policies. Health-care

workers are especially important; they are a key group to mobilize

and educate the public, because they are generally trusted and seen

as reliable sources of information.

Another issue is that public health policies are increasingly

questioned by individuals in the media and general population. One

consequence is that adherence to recommended interventions may,

in certain situations, be very low in the population. In many countries,

recent decades have seen a switch from a paternalistic model, in which governmental guidance was

generally accepted and followed, to one based on individual choice and freedom of action as personal

rights.

Most common

misperceptions:

There is no effective

treatment for viruses;

Viral infections are not that

severe;

Vaccines are the only

approach possible for viral

infections;

Emerging viruses are most

likely to cause deadly

pandemics.


More research is needed on strategies to prevent and control RVIs, and on the timely and effective

integration of innovation and advances in science in decision-making and public health practices.

Particular attention should be given to communicating to different stakeholders, especially health-care

workers, who are pivotal in implementing change in health-care systems. Having better data on current

knowledge and practices will allow more refined strategies and improved local adaptation and

implementation. The link between evidence and practice should be emphasized.


6.1 Compile evidence to support the development of relevant public health strategies preventive

and responsive; individual and community-based to mitigate the impact of respiratory viral infections.

6.2 Survey the landscape of vaccines for non-influenza respiratory viruses, and promote efforts to

develop effective vaccines for key target groups.

6.3 Study knowledge, attitudes and practices of:

HCWs in relation to common and severe respiratory diseases in different settings;

the general public on respiratory viral infections, to increase adherence to public health

measures.

6.4 Assess the impact of various communication strategies to improve the management of

respiratory infections.

6.5 Develop mathematical models to guide decisions about the most effective combination of

measures to mitigate the impact of viral respiratory infections.

6.6 Assess and compare current decision-making processes related to respiratory viral infections in

different settings, health-care systems and risk groups.


88 Balinska M, Rizzo C. Behavioural responses to influenza pandemics: what do we know? PLoS

Currents, 2009, 1:RRN1037. PM:20025201

89 Barrett C, Bisset K, Leidig J et al. Economic and social impact of influenza mitigation strategies by

demographic class. Epidemics, 2011, 3(1):19-31. PM:21339828

90 Cohen AL, Hyde TB, Verani J et al. Integrating pneumonia prevention and treatment

interventions with immunization services in resource-poor countries. Bulletin of the World

Health Organization, 2012, 90(4):289-294. PM:22511825

91 Hollingsworth TD, Klinkenberg D, Heesterbeek H et al. Mitigation strategies for pandemic

influenza A: balancing conflicting policy objectives. PLoS Computational Biology, 2011,

7(2):e1001076. PM:21347316

92 Larson EL, Ferng YH, Wong-McLoughlin J et al. Impact of non-pharmaceutical interventions on

URIs and influenza in crowded, urban households. Public Health Reports, 2010, 125(2):178-191.

PM:20297744


93 Lau JT, Griffiths S, Choi KC et al. Avoidance behaviors and negative psychological responses in the

general population in the initial stage of the H1N1 pandemic in Hong Kong. BMC Infectious

Diseases, 2010, 10:139. PM:20509887

94 Lin Y, Huang L, Nie S et al. Knowledge, attitudes and practices (KAP) related to the pandemic

(H1N1) 2009 among Chinese general population: a telephone survey. BMC Infectious Diseases,

2011, 11:128. PM:21575222

95 McNulty C, Joshi P, Butler CC et al. Have the public's expectations for antibiotics for acute

uncomplicated respiratory tract infections changed since the H1N1 influenza pandemic? A

qualitative interview and quantitative questionnaire study. BMJ Open, 2012, 2(2):e000674.

PM:22457479

96 Poletti P, Ajelli M, Merler S. The effect of risk perception on the 2009 H1N1 pandemic influenza

dynamics. PloS One, 2011, 6(2):e16460. PM:21326878

97 Rudan I, El Arifeen S, Bhutta ZA et al. Setting research priorities to reduce global mortality from

childhood pneumonia by 2015. PLoS Medicine, 2011, 8(9):e1001099. PM:21980266

98 Ungchusak K, Sawanpanyalert P, Hanchoworakul W et al. Lessons learned from influenza

A(H1N1)pdm09 pandemic response in Thailand. Emerging Infectious Diseases, 2012, 18(7):1058-

1064. PM:22709628

99 van der Weerd W, Timmermans DR, Beaujean DJ et al. Monitoring the level of government trust,

risk perception and intention of the general public to adopt protective measures during the

influenza A (H1N1) pandemic in The Netherlands. BMC Public Health, 2011, 11:575.

PM:21771296

100 World Health Organization. Stream 3, Minimizing Impact: Minimizing the impact of pandemic,

zoonotic, and seasonal epidemic influenza. Geneva, WHO, 2010.

101 World Health Organization. Clinical management of influenza and other acute respiratory illness

in resource-limited settings: learning from the influenza pandemic (H1N1) 2009. Geneva, WHO,

2011.

102 Xue Y, Kristiansen IS, de Blasio BF. Modeling the cost of influenza: the impact of missing costs of

unreported complications and sick leave. BMC Public Health, 2010, 10:724. PM:21106057


Full reference list

1 World Health Organization. The global burden of disease: 2004 update. Geneva, WHO, 2008.

http://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf

2 World Health Organization. The World health report 2002: Reducing risks, promoting healthy life.

Geneva, WHO, 2002.

3 World Health Organization/United Nations Childrens Fund. Global Action Plan for Prevention

and Control of Pneumonia (GAPP). Geneva, WHO/UNICEF, 2009.

http://www.who.int/maternal_child_adolescent/documents/fch_cah_nch_09_04/en/index.html

4 Welkers MR, Dunning J, Wong CH et al. Current research on respiratory viral infections: XIIth

International Symposium. Antiviral Therapy, 2012, 17(1 Pt B):227-253. PM:22311667

5 Welkers M, Sutherland T, Osterhaus AD et al. Current research on respiratory viral infections: XIII

International Symposium on Respiratory Viral Infections: part 1. Future Virology, 2011,

6(10):1155-1160.

6 Sutherland TC, Welkers MRA, Osterhaus ADME et al. Current research on respiratory viral

infections: XIII International Symposium on Respiratory Viral Infections: part 2. Future Virology,

2011, 6(11):1283-1288. http://dx.doi.org/10.2217/fvl.11.102

7 Scott JA, Wonodi C, Mosi JC et al. The definition of pneumonia, the assessment of severity, and

clinical standardization in the Pneumonia Etiology Research for Child Health Study. Clinical

Infectious Diseases, 2012, 54(Suppl 2):S109-S116.

http://cid.oxfordjournals.org/content/54/suppl_2/S109.abstract


PM:21435708

9 Ranieri VM, Rubenfeld GD, Thompson BT et al. Acute respiratory distress syndrome: the Berlin

Definition. JAMA : The Journal of the American Medical Association, 2012, 307(23):2526-2533.


10 Osterhaus AD. New respiratory viruses of humans. The Pediatric Infectious Disease Journal, 2008,

27(10 Suppl):S71-S74. PM:18820582

11 Nair H, Simooes EA, Rudan I et al. Global and regional burden of hospital admissions for severe

acute lower respiratory infections in young children in 2010: a systematic analysis. Lancet, 2013.

PM:23369797

12 Levine OS, O'Brien KL, Deloria-Knoll M et al. The Pneumonia Etiology Research for Child Health

Project: a 21st century childhood pneumonia etiology study. Clinical Infectious Diseases, 2012,

54(Suppl 2):S93-101. http://www.ncbi.nlm.nih.gov/pubmed/22403238

13 Jartti T, Jartti L, Ruuskanen O et al. New respiratory viral infections. Current Opinion in

Pulmonary Medicine, 2012, 18(3):271-278. PM:22366993

14 Gilani Z, Kwong YD, Levine OS et al. A literature review and survey of childhood pneumonia

etiology studies: 2000-2010. Clinical Infectious Diseases, 2012, 54(Suppl 2):S102-108.


15 Anderson LJ, Baric RS. Emerging human coronaviruses disease potential and preparedness.

New England Journal of Medicine, 2012. PM:23075144




375(9725):1545-1555. PM:20399493

17 Dawood F, Iuliano A, Reed C et al. Estimated global mortality associated with the first 12 months

of 2009 pandemic influenza A H1N1 virus circulation: a modelling study. The Lancet Infectious

Diseases, 2012. http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(12)70121-

4/abstract

18 Falsey AR, Hennessey PA, Formica MA et al. Respiratory syncytial virus infection in elderly and

high-risk adults. New England Journal of Medicine, 2005, 352(17):1749-1759. PM:15858184

19 Hammitt LL, Kazungu S, Morpeth SC et al. A preliminary study of pneumonia etiology among

hospitalized children in Kenya. Clinical Infectious Diseases, 2012, 54(Suppl 2):S190-S199.

PM:22403235

20 Liu L, Johnson HL, Cousens S et al. Global, regional, and national causes of child mortality: an

updated systematic analysis for 2010 with time trends since 2000. Lancet, 2012, 379(9832):2151-

2161. PM:22579125

21 Lunelli A, Rizzo C, Puzelli S et al. Understanding the dynamics of seasonal influenza in Italy:

incidence, transmissibility and population susceptibility in a 9-year period. Influenza and Other





23 Miller EK, Lu X, Erdman DD et al. Rhinovirus-associated hospitalizations in young children. The

Journal of Infectious Diseases, 2007, 195(6):773-781. PM:17299706

24 Murata Y. Respiratory syncytial virus infection in adults. Current Opinion in Pulmonary Medicine,

2008, 14(3):235-240. PM:18427247

25 Nair H, Brooks WA, Katz M et al. Global burden of respiratory infections due to seasonal

influenza in young children: a systematic review and meta-analysis. Lancet, 2011,

378(9807):1917-1930. PM:22078723

26 O'Brien KL, Wolfson LJ, Watt JP et al. Burden of disease caused by Streptococcus pneumoniae in

children younger than 5 years: global estimate. Lancet, 2009, 374(9693):893-902. PM:19748398

27 Shrestha SS, Swerdlow DL, Borse RH et al. Estimating the burden of 2009 pandemic influenza A

(H1N1) in the United States (April 2009April 2010). Clinical Infectious Diseases, 2011, 52(Suppl

1):S75-S82. PM:21342903

28 Thompson WW, Shay DK, Weintraub E et al. Mortality associated with influenza and respiratory

syncytial virus in the United States. JAMA : The Journal of the American Medical Association,

2003, 289(2):179-186. PM:12517228

29 van Asten L, van den Wijngaard C, van PW et al. Mortality attributable to 9 common infections:

Significant effect of influenza A, respiratory syncytial virus, influenza B, norovirus,

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