aria

Forewords . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

About the Author . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Acute Respiratory Infections: Making Inroads Against a Forgotten Pandemic . . . . . . . . . . . . . . . . . 8Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

The Forgotten Pandemic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Solutions within Reach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Part 1: Understanding Acute Respiratory Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

How Infection Occurs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Pathogens That Cause Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Preventing Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Treating Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

HIV and Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

The Influenza Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Drift and Shift: How Influenza Viruses Evolve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Influenza Pandemics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

H1N1: The First 21st-Century Flu Pandemic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Influenza Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Preventing Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Treating Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Respiratory Syncytial Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Treating TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Tuberculosis and HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Future Threats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Profile: The SARS Story . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

PUBLISHED BY WORLD LUNG FOUNDATION61 Broadway, Suite 2800New York, NY 10006worldlungfoundation .org

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Contents

WLF_Part1_BH_0824.indd 2-3 8/31/10 11:03 AM

Antibiotics and Antiviral Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

How Drug Resistance Develops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

The Research and Development Drought . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

Preventing Drug Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

Access to Health Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

Gaps in Health Care Spending . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

Primary Care in Rural and Urban Settings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

Growing the Health Workforce . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

Profile: Treating Severe Pneumonia in Malawi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

Part 4: Making ARIs a Global Priority . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88Identifying and Meeting the Worldwide Challenge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

ARIs Are Significantly Underfunded . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

More Information Is Needed About ARIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

Health and Governance Infrastructure Is Often Weak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Global Initiatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

APPendICeS Appendix A: World Regions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Appendix B: Mechanisms of Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Pathogens:Agents of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

What Is a Virus? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

What Are Bacteria? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

What Is a Fungus? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

How the Body Defends Itself . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

Appendix C: Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Appendix d: Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

Appendix e: Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Part 2: drivers of Acute Respiratory Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Malnutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

How Nutritional Deficiencies Affect the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

Linking ARIs and Malnutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Micronutrients: Zinc, Vitamin D, and Vitamin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

How the International Community Can Help . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

Air Pollution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Particulates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

How Pollutants Affect the Body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

Indoor Air Pollution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Home Cooking and Heating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Indoor Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Outdoor Air Pollution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Motor Vehicles Emissions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Ozone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Profile: Air Pollution in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Tobacco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

Adult Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Environmental Tobacco Smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Overcrowding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

Profile: The Hajj . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Part 3: Prevention, diagnoses, and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Preventing ARIs with Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Immunization Disparities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Financing Immunization Campaigns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Promoting Wider Vaccine Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

diagnoses and Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Diagnosing ARIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Surveillance Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Profile: Integrated Approaches to Reduce ARIs in India . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77


6The drivers of ARIs can be largely addressed through poverty reduction strategies, evidence-based public policies, medical knowledge, and funding.Three themes have consistently emerged during my 30 years fighting lung disease across the globe . The first: Lung diseases take a much greater toll than is recognized . Ten million people around the world will die this year alone, some from ancient diseases such as tuberculosis, others from 21st-century strains of influenza .

The second theme is that the worlds poorest people bear an overwhelming share of the lung disease burden . Acute respiratory infections thrive where people go hungry, live in overcrowded conditions, earn less than two dollars a day, and have inadequately funded health systems . Many who die could not afford a doctor or medicine .

The third theme is that so much of this death and suffering is preventable . The drivers of ARIs, such as malnutrition, air pollution, and tobacco use, can be largely addressed through poverty reduction strategies, evidence-based public policies, medical knowledge, and funding .

That is why this Atlas is vitally important . It is the first scientific publication to weave together all of these themes in ways that motivate action by those who can make a difference .

The team behind the Atlas and ARIAtlas .org has made an important contribution to the need to address ARIs, and I congratulate its members on this tremendous accomplishment . For more than a century, the Union has been on the frontlines of global lung health issues . We hope that those who pick up this book will feel compelled to join us in our work .

Dr . Nils Billo, MD, MPHExecutive Director

International Union Against Tuberculosis and Lung Disease

Reducing ARIs begins with increased knowledge, global commitment, and partnerships.Advances in medical knowledge and technology, though considerable, have not rid the world of age-old respiratory infections such as pneumonia and influenza, which are especially devastating in poverty-stricken countries . Increasing the availability of public health and health care services is part of the solution, but the perspectives of sociology, urban planning, nutrition, environmental sciences, and economics are also essential .

This Atlas offers a new way of understanding and tackling this global problem by presenting these diseases as a group of acute respiratory infections (ARIs) with common symptoms, drivers, and methods of prevention and treatment . Dramatic reductions in ARIs, which claim 4 .25 million lives every year, can be achieved by raising living standards and addressing malnutrition, pollution, and overcrowding, especially in low- and middle-income nations .

With this Atlas, World Lung Foundation (WLF) takes an important step to inform and empower policymakers, journalists, and other public health advocates, presenting the most up-to-date data in the most accessible manner . Accompanying this book is ARIAtlas .org, a dynamic and interactive resource for advancing discussions on ARI research and policy issues .

WLF is pleased to introduce this Atlas to the public health, policy, journalism, and philanthropic communities . Through global commitment and partnerships, we can dramatically reduce the toll of ARIs and help to better the lives of people around the world . Peter Baldini Chief Executive Officer and President World Lung Foundation

About the AuthorNEIL W . SCHLUGER, MD, is the Chief Scientific Officer of World Lung Foundation . Dr . Schluger received his undergraduate degree from Harvard University and his medical degree from the University of Pennsylvania School of Medicine . He completed training in pulmonary and critical care medicine at the Cornell University Medical Center in New York City, with research training at Rockefeller University and the National Institutes of Health .

Dr . Schluger began his academic career at the New York University School of Medicine and Bellevue Hospital Center, where he directed the Tuberculosis Clinic and led research programs designed to develop new diagnostics and treatments for tuberculosis . He also led innovative pro-grams designed to improve delivery of services to patients with tuberculosis . In 1998 Dr . Schluger was recruited to Columbia University, where he is currently Professor of Medicine, Epidemiology and Environmental Health Sciences, and Chief of the Division of Pulmonary, Allergy and Critical Care Medicine . He has an active research career in lung disease and is the Steering Committee Chairman of the Tuberculosis Trials Consortium, an international research collaboration supported by the U .S . Centers for Disease Control and Prevention . He has long been involved in advocacy for lung health and has served as President of the American Lung Association of the City of New York . Dr . Schluger is author of more than 100 scientific publications about lung disease and is an internationally recognized authority on lung infections .

AcknowledgmentsWorld Lung Foundation (WLF) is grateful for the generous contributions of many individuals who made the Acute Respiratory Infections Atlas possible . Karyn Feiden masterfully synthesized reams of complex research into clear narrative and was a core part of the team assembled to tell the ARI story . Kimberly Sebek dedicated countless hours to the collection and analysis of global lung health data and was unwavering in her commitment to accuracy and thoroughness .

We would also like to thank our peers who lent their expertise and guidance to the Atlas:

Otto Braendli, MD, President, Swiss Lung Foundation; E . Jane Carter, MD, Associate Professor, Alpert School of Medicine, Brown University; Penny Enarson, MD, Head of Child Lung Health Division, International Union Against Tuberculosis and Lung Disease (The Union); Paula I . Fujiwara, MD, MPH, Senior Technical Advisor, The Union; Patrick Kinney, ScD, Professor of Environmental Health Sciences, Columbia University Mailman School of Public Health; Keith Klugman, MB BCh, PhD, FRCPath, Professor of Global Health, Rollins School of Public Health, Emory University; Ram Koppaka, MD, MPH, Senior Advisor, Epidemiology and Analysis Program Office, U .S . Centers for Disease Control and Prevention .

We gratefully acknowledge the support of these individuals, yet we do not hold them responsible for the views expressed within .

Additional acknowledgment goes to the World Health Organization for providing a large portion of the data that appears in this book .UNICEF, the World Bank, the Stop TB Partnership, and others also provided essential data .

A special thanks to Mego Lien for her meticulous editing of the manuscript, and to Stephen Hamill for his invaluable art direction . WLF is also grateful to its many other colleagues who contributed their talent and expertise to the review, editing, and design of the Atlas, as well as those who oversaw project management, promotion, and distribution of the book: Jorge Alday, Yvette Chang, Chun-Yu Huang, Alexey Kotov, Sandra Mullin, Rebecca Perl, and Stephan Rabimov . We would also like to thank other team members at WLF for their unwavering support of this project: Peter Baldini, Jos Castro, and Joanna Thomas .

We also extend our appreciation to Sarah Fedota, Rob Levin, and the staff of Bookhouse Group, Inc . for their hard work on the design, layout, and printing of the Atlas .

7


8Acute Respiratory Infections:Making Inroads Against a Forgotten Pandemic

World Lung Foundation Acute Respiratory Infections Atlas

9

This Atlas offers an in-depth look at a forgotten pandemic that kills more than four million people every year. And yet the core message is hopeful: Progress lies within reach.Acute respiratory infections, or ARIs, are a group of diseases that impose an enormous burden on vulnerable populations around the world, yet they have rarely risen to the top of the global health priority list . This Atlas seeks to change that .

Pneumonia need not claim the lives of 1 .6 million children every year . The toll of influenza, which causes three to five million severe infections annually, and respiratory syncytial virus (RSV), which results in three million hospitalizations, can be dramatically reduced . All it takes is adequate resources, collaborative partnerships, and broad global commitment .

Part 1: Understanding Acute Respiratory Infections describes three major ARIspneumonia, influenza, and RSVas well as the emerging infections that loom as further threats . It also provides an overview of tuberculosis (TB), which has many characteristics of ARIs . This section includes information about the bacterial and viral pathogens that cause these infections and how they evolve, the risk of coinfections, the role of the health system, and the opportunities to intervene at every disease stage .

1 Ischemic heart disease 12 .2%

2 Cerebrovascular disease 9 .7%

3 Lower respiratory infection (accounts for most ARIs)

7 .1%

4 Chronic obstructive pulmonary disease

5 .1%

5 Diarrheal diseases 3 .7%

6 HIV/AIDS 3 .5%

7 Tuberculosis 2 .5%

8 Trachea, bronchus, lung cancers 2 .3%

9 Road traffic accidents 2 .2%

10 Prematurity and low birthweight 2 .0%

Top Ten Causes of Death: Worldwide

1 Lower respiratory infection (accounts for most ARIs)

11 .2%

2 Ischemic heart disease 9 .4%

3 Diarrheal diseases 6 .9%

4 HIV/AIDS 5 .7%

5 Cerebrovascular disease 5 .6%

6 Chronic obstructive pulmonary disease

3 .6%

7 Tuberculosis 3 .5%

8 Neonatal infections 3 .4%

9 Malaria 3 .3%

10 Prematurity and low birthweight 3 .2%

Top Ten Causes of Death: Developing World

Part 2: drivers of Acute Respiratory Infections examines the environmental conditions that foster ARIs and considers how they can be altered . Poverty, malnutrition, air pollution, tobacco, and overcrowding allow pathogens to flourish, while improved standards of living can vanquish many of them . The Atlas gives special emphasis to proven interventions, such as the use of cleaner cooking fuels, emissions controls, breastfeeding and other nutritional strategies, tobacco regulations, and community development .

Part 3: Prevention, diagnoses, and Treatment reviews the therapeutic and policy tools that can halt the spread of ARIs or control them when they occur: a strong vaccine infrastructure, the widespread availability of diagnostic tools, comprehensive surveillance, strategies to maintain the effectiveness of existing antibiotics, research to develop new ones, and improved access to health care, especially in poor urban and rural areas .

Part 4: Making ARIs a Global Priority is a call to action for governments and the international community . Far less funding is dedicated to ARIs than to HIV/AIDS or malaria, relative to their global burden . A lack of basic data limits the ability to set program priorities and measure success . Weak health systems, workforce shortages, fragmented policymaking, and governance challenges further delay progress . But the good news is that strategic, carefully planned changes can have a dramatic impact .

Appendices provide an overview of illness-causing pathogens and the bodys defenses, a glossary, extensive country-level and regional data about the ARI burden and its drivers, and source lists .

Percent of total deaths Percent of total deaths


10


11

Acute respiratory infections (ARIs), a group of diseases that includes pneumonia, influenza, and respiratory syncytial virus (RSV), result in 4 .25 million deaths worldwide every year . ARIs are also the leading cause of illness in children and their leading killer . These diseases are responsible for at least six percent of the worlds disability and death .

While the immediate bacterial or viral triggers of ARIs are unique, the underlying drivers are often the same and can include some combination of malnutrition, pollution, overcrowding, and tobacco use . Poverty is also an underlying risk factor, as evidenced by the disproportionate impact of ARIs on developing countries and vulnerable populations: The death rate from pneumonia is 215 times higher in low-income countries than in high-income countries .

Despite the tremendous public health burden, acute respiratory infections are not generally recognized as a collective global threat, and far too little is being done to prevent or treat them . Yet the good news is that many solutions lie within reach .

Overview

despite the tremendous public health burden, acute respiratory infections are not generally recognized as a collective global threat, and far too little is being done to prevent or treat them. Yet the good news is that many solutions lie within reach.

More than 4,250,000 people will die this year from ARIs. Acute respiratory infections: Sickenandkillchildren. Twenty to 40 percent of all hospitalizations

among children are due to acute respiratory infections . Pneumonia alone is responsible for almost 1 .6 million deaths a year in children under five, making it the leading global killer in that age group .

Sickenandkilladults. ARIs annually kill 1 .65 million adults 60 or older and more than half a million people from ages 15 to 59 . Three to five million severe influenza infections occur every year, killing some 250,000 to 500,000 people. More than three million people are hospi-talized annually with illness caused by respiratory syncytial virus.

Burdenhealthcaresystems.Acute respiratory infections are the most common reason that people access health services around the world .

Threatenaglobalcatastrophe.Bacteria and viruses can mutate, as the H1N1 influenza virus demonstrates, and new pathogens, such as the one that caused severe acute respiratory syndrome (SARS), can emerge to infect unprotected populations . Both have unpredictable consequences .

>200

101-200

51-100

31-50

21-30

11-20

0-10

no data

ARI death rates are highest in sub-Saharan Africa and parts of Asia .

ARI death rate, per 100,000 (2004)


12 13

World Lung Foundation Acute Respiratory Infections AtlasOverview

The Forgotten Pandemic Despite their toll, acute respiratory infections have been called the forgotten pandemic because they have not attracted sufficient attention from governments, the global health community, donors, the pharmaceutical industry, or the public .

The clinical conditions that comprise ARIs are not uniformly defined, and they draw only a fraction of the resources dedicated to other global health challenges . For example, only about one percent of the funds dedicated to pharmaceutical research and development in 2007 were spent on bacterial pneumonia, while HIV/AIDS, malaria, and tuberculosis accounted for 80 percent of that total .

In part, this skewed resource allocation reflects a tendency to view every acute respiratory infection discretely, rather than as an interrelated group of diseases with similar clinical presentation and a degree of common cause . This Atlas brings the package of ARIs together in a single volume for the first time so that the many linked challenges and opportunities can be considered comprehensively .

Acute respiratory infections are

the leading killer of children under five.

More children under five die of pneumonia worldwide than any other cause .

Diarrheal diseases 17%

Others 10%

Pneumonia 19%

Severe neonatal infections (mainly pneumonia/sepsis)

10%

Birth asphyxia 8%

Malaria 8%

Measles 4%

Injuries 3%

HIV/AIDS 3%

Preterm birth 10%

Congenital anomalies 3%

Neonatal tetanus 2%

Neonatal other 2%Neonatal diarrheal diseases

1%

The burden of disease linked to ARIs falls most heavily on the developing world .

>5,000

3,001-5,000

1,001-3,000

401-1,000

201-400

101-200

0-100

no data

Disability-adjusted life years, or DALYs, are a measure of the burden of disease, calculated both by lost years of life and lost years of healthy life .

Death Rate from All Causes among Children under Five

>150

101-150

51-100

11-50

0-10

Deaths per 1,000 live births (2008)

DALYs lost to ARIs, per 100,000 (2004)



15

Overview

14

Global Impact Acute respiratory infections are the leading cause of illness

worldwide and the leading killer of children . ARIs account for 30 to 50 percent of pediatric visits to medical providers and 20 to 40 percent of all hospitalizations among children .

ARIs are a forgotten pandemic . They have not attracted the global attention that would enable proven low-cost interventions to be implemented on a scale that could transform patterns of disease and death .

ARIs garner considerably less funding, relative to their impact on health, than HIV/AIDS, malaria or tuberculosis . In 2007, bacterial pneumonia received about one percent of the US$2 .56 billion invested in pharmaceutical R&D in developing countries . By comparison, HIV/AIDS received 42 percent, malaria received 18 percent, and TB 16 percent .

Solutions within ReachFortunately, cost-effective solutions are within reach (see Prevention, Diagnoses and Treatment, p . 66) . Wider use of existing vaccines can prevent some acute respiratory infections altogether . Breastfeeding, im-proved nutrition, and pollution and tobacco controls are also essential tools of prevention . Close surveillance and timely diagnosis allow acute respiratory infections to be recognized and curbed before they spread or become more severe . When ARIs do occur, they can often be cured with antibioticsif these are readily available, prescribed appropriately, and taken as directed .

Better access to health care, especially in poor urban communities and remote rural areas, is crucial to prevention and treatment . Other priorities are public health education, research and development to bring more vaccines and new antibiotics to market, drug-use practices that minimize antibiotic resistance, and reliable studies to inform interventions .

Significant progress to reduce or prevent ARIs is also possiblebut it demands more awareness and commitment from donors, national governments, industry, and the international public health community (see Making ARIs a Global Priority, p . 88) .

0

Declines in U .S . Child Mortality Rate from Influenza and Pneumonia

ARIs can be controlled with better housing, better nutrition, and antibiotics .

5

10

15

20

25

1900 1920 1940 1960

Rate

per

1,0

00 ch

ild ye

ars

Influenza pandemic

Younger than age oneAges one to four

Antibiotics introduced

In parts of the developing world, the death rate from ARIs alone is ten times higher than the global median death rate from all causes .

500

450

400

350

300

250

200

150

100

50

0

Glob

al Med

ian AR

I deat

h Rate

Proven strategies exist, but we are failing to act globally.

Of 2 .5 million child deaths preventable by vaccines in 2002, more than half were caused

by ARI-related pathogens .

Other vaccine-preventable diseases

1%

Tetanus 8%

Pertussis 11%

Haemophilus influenzae type b

15%

Pneumococcal diseases

28%

Measles 21%

Rotavirus 16%

ARI

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s (20

04)

Actions That Make a Difference Expanding access to vaccines, improving nutrition (including better

breastfeeding practices), mitigating air pollution, and controlling tobacco use can prevent many acute respiratory infections, and pharmaceutical therapies can cure others .

Reducing global poverty would lessen some of the key drivers of acute respiratory infections while also improving access to care . These drivers include malnutrition, air pollution associated with wood-burning cookstoves and motor vehicles, and overcrowding in urban areas .

Fostering broad-based commitment from governments, increased donor funding, and more engagement by the public, the global health community, and the pharmaceutical industry are crucial to lessen the toll of acute respiratory infections .

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16

Acute respiratory infections cause atleastsixpercentofthedisabilityanddeatharoundtheglobe,affectingthemostvulnerablepopulations,especiallytheyoung,theold,theailing,andthepoor.

Pneumonia is the leading global killer of children under five, responsible for almost 1 .6 million deaths a year, most of them in developing nations .

Influenza causes three to five million severe infections in a typical year and could create a global emergency if a new and virulent influenza virus were to spread rapidly.

Respiratory syncytial virus (RSV) is the most common source of severe respiratory illness in infants and children worldwide.

Acute respiratory infections can occur in either the upper or lower respiratory tract (see Appendix B, p . 100, for more information on infectious agents and the bodys defense system) . Lower respiratory tract infections, which include pneumonia, influenza, and RSV and typically involve the lungs, are the primary focus of this Atlas .

Because tuberculosis (TB) can be mistaken for pneumonia and affects the lower respiratory tract, it is included in this Atlas, even though symptoms tend to develop more gradually and it is not a classic ARI . TB causes nine million symptomatic cases and two million deaths annually .

Pertussis, which is preventable with vaccines, is another potentially dangerous ARI . In developing countries, 40 deaths occur for every 1,000 pertussis cases (compared with one death in the developed world) . The overall ARI-related data collected by the World Health Organization (WHO) and others, and presented in this Atlas, do not include pertussis, but it is mentioned in several sections of this book .

Strategies to curb ARIs include: Emphasizingacuterespiratoryinfectionsasaninterrelatedpackage

of health challenges that can be addressed with low-cost prevention and treatment strategies .

Strongerdatacollectionandmonitoringsystemstomeasurethe

incidence of acute respiratory infections and to evaluate prevention, diagnostic, and treatment strategies .

Improvingaccesstocare,distributingeffectivevaccinesmore

widely, encouraging appropriate use of antimicrobials, and under-taking more vaccine development and drug research .

Publichealtheducationpromotingbreastfeeding,infectioncontrol,

tobacco control, and spreading knowledge about the warning signs of serious disease .

Adequateresourcesforsurveillanceinordertoidentifynew

pathogens quickly, when more opportunities exist to control them .

Initiativesthataddressglobalpoverty,includingmalnutrition,

overcrowding, and other living conditions that are directly linked to ARIs .

Part 1Understanding Acute Respiratory Infections


17


18 19


Pneumonia is the leading global killer of children under five, respon-sible for almost 1 .6 million deaths per year. In that vulnerable popula-tion, it is a disease of poverty and occurs most commonly when a childs still-developing defense system is weakened by malnutrition, air pollution, coinfections with HIV/AIDS and measles, and low birth-weight. In wealthier nations, adults over 65 years old and people with chronic health problems bear the greater burden of pneumonia .

An estimated 156 million new cases of pneumonia occur each year, 97 percent of them in the developing world, and seven to 13 percent of them severe enough to require hospitalization . Seventy-four percent of those cases occur in just 15 countries, mostly in Asia and sub-Saharan Africa, with 43 million cases in India alone.

Pneumonia occurs when the sacs of the lungs, known as alveoli, become filled with pus and fluid, limiting oxygen intake and making it hard to breathe . A bacterial or viral pathogen can be the primary cause of pneumonia, or it can be a complication of other infections, including influenza, measles, tuberculosis, or HIV .

Pneumonia is responsible for nearly 20 percent of child deaths globally .

PneumoniaVaccines, breastfeeding, improved living standards, and swift treatment can curb pneumonia, the leading global killer of children under five.

Global Impact Almost1.6milliondeathsfrompneumoniaoccurannually

in children under five, about one-fifth of all pediatric deaths around the world (based on 8 .8 million pediatric deaths from all causes in 2008) . By contrast, 732,000 children die from malaria and 200,000 from HIV/AIDS each year .

Everyyear,anestimated156millionnewcasesofpneumonia

occur, 97 percent of them in the developing world . Seventy-four percent of those cases occur in just 15 countries, mostly in South Asia and sub-Saharan Africa, with 43 million cases in India alone .

Improvedlivingstandardsandaccesstoantibioticstransformed

the trajectory of pneumonia in the developed world during the 20th century . In the United States, pneumonia-related deaths among children fell by 97 percent between 1939 and 1996 .

>19 .9%

15-19 .9%

10-14 .9%

2-9 .9%

20 21


How Infection OccursMost severe cases of pneumonia, whether acquired in the community or the hospital, result from bacterial infections, although viruses or fungi can sometimes be the cause . These pathogens may travel as airborne particles or droplets, causing infection after they are inhaled, or they may colonize the nose or throat, where they reside harmlessly until they have an opportunity to penetrate the bodys defense system and travel into the lungs . Newborns can also become infected by exposure to microbes in the birth canal or during delivery.

Often, pneumonia is the result of a coinfection process, in which one pathogen damages the bodys tissues or immune system, making it easier for other pathogens to cause secondary infection in the lungs . For example, pneumonia can cause death among the 30 to 40 million children infected by measles every year, and within the same country, people living with HIV are 20 to 40 times more likely to become infected with tuberculosis.

Pathogens That Cause PneumoniaBacteria: Streptococcus pneumoniae, usually called pneumococcus, is the most common cause of bacterial pneumonia worldwide, accounting for about 30 percent of the total pneumonia caseload and at least half the cases in the developing world . In 2000, almost 14 million pneumococcal pneumonia cases occurred in children younger than five . Pneumococcus is also a leading cause of meningitis in that age group.

Haemophilus influenzae type b (Hib) is implicated in as many as 20 percent of the worlds severe pneumonia cases. These bacteria, which also cause meningitis and other severe infections, were responsible for 7 .9 million cases of pneumonia in 2000, resulting in the deaths of an estimated 300,000 children under age five.

Hospital-acquired bacterial pneumonia is typically caused by Staphylo-coccus aureus or gram-negative bacteria (including Legionella spp, which causes Legionnaires disease) . These infections are also increasing in the community, especially antibiotic-resistant staph . Pneumonia can also result from tuberculosis, which is caused by Mycobacterium tuberculosis .

Viruses: If left untreated, influenza virus, respiratory syncytial virus, parainfluenza virus, and the measles virus can all lead to pneumonia .

Fungi: Individuals with compromised immune systems, especially those who are HIV-positive, are susceptible to Pneumocystis jiroveci pneumonia . Other types of fungus-linked pneumonia occur among individuals in certain geographic locations, including the American Southwest .

Preventing PneumoniaIn the United States, pneumonia-related deaths among children fell by 97 percent between 1939 and 1996dramatic evidence of what effective clinical and public health measures can accomplish .

Vaccines: Vaccines to prevent diseases associated with Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae type b are remarkably effective . Children in countries without these vaccines are 40 times more likely to die than those in countries that administer them routinely . Wider use of the measles vaccine, which covered three-quarters of the worlds children in 2004, could also lessen pediat-ric pneumonia significantly .

Pneumococcus: The pneumococcal conjugate vaccine (PCV13), approved in the United States in 2010, protects infants, children and adults against 13 of the most common pneumococcal strains, known as serotypes (20 serotypes cause most pneumococcal infections worldwide) . PCV13 replaces PCV7, which has been available since 2000 . Earlier generations of vaccines, first distributed in the mid-1970s, were not safe for children younger than two years old .

The potential benefit to developing countries is highlighted by the effectiveness of a vaccine that was tested in Gambia and was designed to provide protection against the nine pneumococcal serotypes most prevalent in the country . On the basis of a four-year study of

3%

21%21%15%15%14%13%

20%

19%2%

0% 10% 20% 30% 40% 50%

South Asia

Sub-Saharan Africa

Middle East and North Africa

East Asia and Pacific

Latin America and CaribbeanCentral and Eastern Europe and the

Commonwealth of Independent States

Developing countries

Industrialized world

World

Percent of total deaths in children under five from pneumonia(excludes severe neonatal infections, some of which are pneumonia)

World Bank Income Group (2004)

The lower a countrys income, the more child deaths from pneumonia .

20%

15%

10%

5%

0%

Low-i

ncome

Lowe

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Upper

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High-i

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The burden of pneumonia in the developing world is nearly ten times that of the developed world .

Pneumonia


22 23

World Lung Foundation Acute Respiratory Infections AtlasPneumonia

17,000 children, researchers determined that the vaccine had lowered rates of X-ray-confirmed pneumonia by 37 percent and had reduced mortality by 16 percent . Gambia, Rwanda and South Africa now include the vaccine as part of their routine vaccination programs .

Haemophilus influenzae type b (Hib): Ninety-two percent of children in developed countries received Hib conjugate vaccines in 2003, compared with 42 percent in the developing world and just eight percent in the least-developed countries . The Hib vaccine is highly effective in reducing infections in countries where it is widely used, even among unvaccinated people, presumably because it lessens the chance that people will be exposed to the bacteria (a phenomenon known as herd immunity). Broader use of the Hib vaccine could save 400,000 lives.

The bottom line is clear: Vaccines can transform patterns of pneumonia in developing countries, as they have in the developed world . But increasing immunization depends on a strong vaccine delivery infrastructure, leadership and political will, and a much greater commitment from the international community (see Preventing ARIs with Vaccines, p . 68) .

Projected Lives Saved with Proven Pneumonia Interventions among Countdown to 2015Countries (see Countdown to 2015 Initiative p . 96 .)

Deaths from childhood pneumonia can be dramatically reduced with a package of proven interventions .

100%

80%

60%

40%

20%

0%2009 2010 2011 2012 2013 2014 2015

Aver

age c

over

age o

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year

(%)

Child deaths prevented annually(x 100,000)

20

15

10

5

0

Post-neonatal pneumonia deaths Neonatal pneumonia/sepsis deaths

Pathogens That Cause Pneumonia

Half the severe cases of pneumonia among children in developing countries are caused by

pathogens that can be stopped by vaccines .

S. pneumoniae

H. influenzaeRSV and other

respiratory viruses

No pathogen identified

S. aureus

Gram-negativebacteria

M. tuberculosis

Breastfeeding:Breastfeeding provides all the nutrients an infant needs in the first six months of life . It remains an essential nutritional source until at least age two and contributes significantly to the development of a healthy immune system, making it one of the most important tools available to prevent pneumonia (see Breastfeeding, p . 50) .

Improved living standards: Like other acute respiratory infections, pneumonia targets the worlds most vulnerable children . Malnutrition, crowded housing, smoking, and polluted air, especially in households that cook with wood and other biofuels, have all been linked to higher incidences of pneumonia (see Drivers of Acute Respiratory Infections, p . 44) .

Improvements in health care, nutrition, and the environment are independent interventions that can significantly reduce the incidence of pneumonia . But a broad and integrated commitment on the part of the international community to improving living standards world-wide is the true foundation of prevention (see Making ARIs a Global Priority, p . 88) .

Treating PneumoniaAppropriate therapies, administered promptly, will cure most cases of pediatric bacterial pneumonia . But many children go untreated, and as many as 20 percent of them will die as a result, sometimes within three days of the onset of illness.

Diagnoses: A first step in treatment is to recognize the warning signs and to seek immediate attention from a health care provider . But in the developing world, only 54 percent of caregivers recognize the need to take a child who is breathing quickly, or with difficulty, to an appropriate provider, even though these are classic indicators of pneumonia .

To provide optimal therapy, it is ideal for clinicians to identify the pathogen involved, but this is often impossible, especially in resource-poor countries without adequate laboratories . Conventional diagnostic techniques, including blood tests and cultures taken from blood and sputa, may not be available . Even if they are, these tests are less definitive than using the much more costly tools of microbiology, such as DNA-based techniques that identify specific pathogenic strains . If resources allow for an intensive investigation, multiple infectious agents can still make the cause difficult to pinpoint.

Treatments: Antibiotics are the treatment of choice for bacterial pneumo-nia . They can cure most cases, and if they were given to all children under age five with pneumonia, as many as 600,000 lives could be saved annu-ally. Yet a 2008 report indicated that only about one-third of all children under five with suspected pneumonia received an antibiotic in the 68 countries that have the highest levels of childhood and maternal deaths (see Antibiotics and Antiviral Therapy, p . 78) . Providing universal antibi-otic treatment in sub-Saharan Africa and South Asia, where the great majority of pediatric deaths occur, would cost US$200 million per year .

Systems for delivering supplemental oxygen to children with pneumonia can also save lives, but deficits in equipment, supplies, and staff training have meant that this critical component of care is often unavailable in developing countries . Investments in oxygen systems should be a more prominent priority of those concerned about treating pneumonia .

Most caregivers dont know when to seek care for child pneumonia. Just 17 percent know that fast breathing is a sign to seek immediate care, and just 21 percent recognize that difficult breathing demands the same attention.

Case management of pneumonia

Hib vaccine

Breastfeeding counseling

Pneumococcal vaccine


24 25


HIV and PneumoniaCommon bacterial pneumonia, pneumonia associated with tuberculosis, and fungal pneumonia caused by Pneumocystis jiroveci all have a greater impact on HIV-infected people because their immune systems are so weakened. HIV-infected children are 40 to 50 times more likely than children without HIV infection to develop pneumonia and are less likely to respond to treatment . Likewise, the fungus may reside harmlessly in the lungs of healthy people, but it causes one-quarter of all deaths among HIV-positive infants younger than six months and is often the first indication that an infant is carrying the virus.

Prevention and treatments: Vaccines designed to prevent bacterial pneumonia are less effective in HIV-infected populations, but they still have the power to save lives . For example, under the controlled conditions of a clinical trial, the conjugate pneumococcal vaccine provided protection to 65 percent of HIV-infected children (compared with 83 percent among uninfected people) . The Haemophilus influenzae type b vaccine provided protection to 55 percent of infected children (compared with 91 percent among those without HIV). HIV-infected populations are generally advised to have both vaccines, as well as to be immunized against influenza.

Some of the clinical interventions used to treat HIV can also be effective in preventing pneumonia, including highly active antiretroviral therapy (HAART) . The combination of drugs used in HAART reduces by fourfold the risk of opportunistic infectionsthose that can gain a foothold in the body because the immune system is damagedamong HIV-infected children. Cotrimoxazole, a combination of two

Pneumonia

20,000

5,000-19,999

2,000-4,999

500-1,999

100-499

20-99

26 27


InfluenzaSurveillance, vaccines, and infection control can curb influenza, which causes three to five million severe infections annually.

The Influenza VirusInfluenza can be caused by three major classes of RNA viruses grouped by their genetic characteristics . Influenza A and B are associated primarily with diseases in humans, while influenza C primarily infects animals .

These classes are further delineated by the nature of the two large proteins on the viral surfacehemagglutinin (HA) and neuraminidase (NA) . There are 16 HA and nine NA subtypes, although relatively few cause human infection. The proteins largely define the behavior of viruses, which are named according to the combinations of protein they contain . For example, the influenza A viruses currently circulating in the human population include the subtypes H1N1 and H3N2 .

Once an influenza virus has invaded the body and attached itself to cells lining the respiratory tract, it incubates for one to seven days before symptoms appear . An infected individual may be able to infect others prior to and during the symptomatic period . One study of the pandemic H1N1 virus showed that children and young adults remained infectious for ten days or longer, while individuals with compromised immune systems might be capable of infecting others for weeks . Influenza can survive for hours outside a human host, further aiding its capacity to spread.

The many types of influenza virus infect anywhere from five to 30 percent of the worlds population during a typical year . Most cases of flu are mild, primarily affecting the nasal passages, throat, and pharynx in the upper respiratory tract . But every year three to five million severe infections occur, generally in the lower respiratory tract (see The Airways and the Lungs, p . 103) . Influenza kills 250,000 to 500,000 people annually .

Influenza tends to get more attention in wealthier countries, where infants and individuals over age 65 are typically at greatest risk be-cause of their lessened immunity and underlying health conditions . In developing countries, where so many other health problems compete for attention, influenza is sometimes overlookedyet it imposes a heavy disease burden, especially among populations that are malnourished or immunocompromised .

The flu virus can travel on inhaled airborne particles, sprayed droplets that are projected onto mucous membranes, or a contaminated hand that touches the nose or mouth . In temperate regions of both hemi-spheres, peak flu activity occurs in the winter season, while in the trop-ics, influenza occurs throughout the year.

Global Impact Worldwide,threetofivemillionsevereinfluenzainfectionsoccur

annually, killing between 250,000 and 500,000 people . While influenza is a burden everywhere, it tends to be overlooked in de-veloping countries, where inadequate laboratory facilities impede diagnoses, and other health challenges compete for attention .

Vaccinesarethemosteffectivestrategyavailableforpreventing

influenza, but the wealthier nations dominate production, and worldwide capacity is limited to 900 million doses .

Manyinfluenzavirusesareresistanttoantiviraltherapies,and

those that remain effective are not being manufactured in ad-equate volume .

Most developing countries lack the ability to diagnose and report influenza .

Actions That Make a Difference Rigoroussurveillancecansendanearlywarningsignalabout

the emergence of new viral strains, providing a window of opportunity for control . Effective surveillance requires adequate resources and international cooperation (see Surveillance Techniques, p . 75) .

Researchisneededonmoreefficientwaystomanufacture

vaccines, distribution systems to poor countries should be strengthened, and more equitable access to a limited vaccine supply is essential (see Preventing ARIs with Vaccines, p . 68) .

Publiceducationabouthand-washingtechniques,coughand

sneeze safeguards, and limiting social contact are essential to curbing the spread of flu . In health care settings, compliance with proper infection control procedures is also crucial, so that infections do not spread from patient to health care worker to patient .

Insevereepidemics,itmaybecomenecessarytousepublic

policies that restrict public interaction and minimize the spread of infection .

Newantiviraltherapiesareneededtocountergrowingdrug

resistance . For example, oseltamivir (Tamiflu) has largely lost its value against a seasonal form of H1N1 . Tamiflu remains effective against the pandemic strain of H1N1 that arose in 2009, but production capacity should be increased from the 220 million doses currently available around the world (see Antibiotics and Antiviral Therapy, p . 78) .

Influenza has been overlooked in develop-ing counries, but it imposes a heavy burden, especially among malnourished and immunocompromised populations.

>10,000

3,001-10,000

1,001-3,000

101-1,000

0-100

no data

Number of laboratory- confirmed flu cases (2009)

Structure of an Influenza Virus

HA

NA


28 29

World Lung Foundation Acute Respiratory Infections AtlasInfluenza

1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010

Drift and Shift: How Influenza Viruses EvolveInfluenza viruses can mutate swiftlyone million times faster than vertebrates can mutateand can swap genetic components with other viruses . Many influenza viruses are believed to originate in the tropics before being exported to the more temperate northern and southern hemispheres, although this pattern is not fully understood.

In a process known as antigenic drift, the proteins on the surface of the flu virus make frequent minor changes in their genetic structure . The resulting new strains can evade the human defense system, even among populations previously infected by, or vaccinated with, a related strain.

At unpredictable intervals, flu viruses with the power to infect humans undergo antigenic shift, a more significant genetic alteration that typically results from a merger with viruses residing in reservoirs of poultry, water fowl, pigs, or other mammals . If the recombined virus is zoonotic, or capable of traveling from animal to human populations, humans are unlikely to have any immunity .

Influenza A and B viruses are subject to antigenic drift, while only influenza A undergoes antigenic shift. The H1N1 pandemic of 2009-10 is an example of a significant viral antigenic shift.

Influenza PandemicsA pandemic is the widespread transmission of a pathogen to populations around the world . Influenza pandemics are inevitable but unpredictable, and they generally occur with the emergence of a virus that is either novel or has not circulated for many decades . Pandemic flu infects far more people than a typical seasonal flu, although the illness is not necessarily more severe .

Pandemics of the past: Three influenza pandemics occurred in the 20th century, each resulting from antigenic shifts in the influenza A virus .

The Spanish flu of 1918, believed to be the most devastating in human history, infected between one-third and one-half the worlds population and killed tens of millions of people . Milder pandemics occurred in 1957, when Asian influenza killed two million people, and in 1968, when the Hong Kong influenza was responsible for one million deaths .

Human influenza pandemics are inevitable, but unpredictable, in the extent of the death they cause .

H1N1Spanish flu

as many as 50 million deaths

H2N2 Asian flu

2 million deaths

H3N2Hong Kong flu

1 million deaths

H5N1

H7N2

H9N2H5N1H7N7H7N2H9N2

H5N1H7N3

H10N7

H1N118,000 deaths

Antigenic DRIFT

Antigenic SHIFT

Antigenic Drift and Shift

The Spanish flu pandemic may have involved an avian virus that adapted to become able to infect humans directly, while the Asian and Hong Kong pandemics were caused by a reassortment of human and avian viruses. In each case, younger populations faced greater-than-usual risks, possibly because they had no exposure to earlier versions of the pathogenindividuals younger than 65 were 20 times more likely to die during one of these pandemics than they were during a normal flu season . Elderly populations, who are inherently more vulnerable, may have already built up some immunological protection and did not face special additional risks .

Spanishfluof1918: The 1918 pandemic occurred in three waves around the world. After a first round of mild infections in the spring, the Spanish flu returned with deadly power in the late summer, causing acute lung inflammation and progressing rapidly to lethal pneumonia . A third wave in early 1919 was also deadly, although less so . Mortality data are inconsistent, but most sources estimate that between 20 and 50 million deaths occurred . Global population growth remained depressed for a decade afterward .

Researchers have called the Spanish flu the mother of all pandemics because the genetic structure of most subsequent influenza A viruses can be traced back to it . Many of todays efforts to prepare for a potential new pandemic consider the severity of that event in their calculations, although the vagaries of biology, coupled with todays ease of travel, ac-cess to health care, and improved nutrition, make extrapolation difficult .

The Spanish flu pandemic may have involved an avian virus that adapted to become able to infect humans directly, while the Asian and Hong Kong pandemics were caused by a reassortment of human and avian viruses.

1918 1957 1968 2009

Improved surveillance has helped to identify emerginginfluenza strains that did not reach pandemic levels .


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The burden on many local health systems was significant, with spikes in the use of emergency rooms, hospitals, and outpatient care . Mexico, where the virus was first reported, estimated the cost of the outbreak at 57 billion pesos in 2009 (US$4 .29 billion), primarily from lost tourism. An adequate vaccine supply was slow to become available: Near the end of 2009, WHO said it would have 200 million donated doses available to 95 countries that are home to one-third of the global population; by contrast, the U .S . had already purchased 250 million doses for its residents.

Because the symptoms caused by the H1N1 pandemic have been relatively mild, at least thus far, global response capacity was not fully tested . Nonetheless, even an outbreak of limited virulence strained public health resources .

Avian flu watch: Aware that other influenza pandemics are inevitable, public health officials around the world conduct surveillance in order to identify new viral strains as soon as possible . A strain of H5N1 avian in-fluenza virus, first isolated in Asia in 2003, remains worrisome. As many as 150 million birds were culled to reduce transmission of the highly contagious virus, which is often fatal in domestic stocks of poultry, cats, and wild birds, but the virus nonetheless remains endemic in many parts of Asia .

To date, the H5N1 virus has had limited ability to cross the species barrier into human populations . From 2003 to May 2010, WHO reported fewer than 500 laboratory-confirmed human infections, although the death rate when infection does occur approaches 60 percent (and in Indonesia, 165 cases caused 136 deaths). Should the virus evolve to infect humans more readily, it could cause a devastating new pandemic .

H1N1: The First 21st-Century Flu PandemicOn June 11, 2009, two months after two cases of a new strain of in-fluenza A H1N1 were confirmed in the United States, WHO officially declared the first flu pandemic of the 21st century . By then, some 30,000 cases had been confirmed in 74 countries . Although the circulating virus was a novel combination of swine and avian influenza A viral strains, some components had circulated in the past, giving many adults born before 1956 a degree of immunity.

Areas with confirmed H5N1 human cases, since 2003

Avian Flu Watch: Will H5N1 cause the next epidemic?

A strain of H5n1 avian influenza virus, first isolated in Asia in 2003, is particularly worrisome. As many as 150 million birds were culled to reduce transmission of the highly contagious virus, but it nonetheless remains endemic in many parts of Asia.

At-risk groups: The majority of infections have occurred among individuals with an age range of 12 to 17 years, but the groups at highest risk for complications have been the elderly, children under five, pregnant women, and individuals with chronic health problems . As in a more traditional flu season, severe respiratory distress and coinfection with bacterial pneumonia can develop. As of May 2010, 18,000 laboratory-confirmed deaths from the pandemic form of H1N1 had been reported . However, the total death toll is undoubtedly much higher, as most cases are not confirmed .

Are we prepared? H1N1 has been a test case for global preparedness . WHO guided international surveillance efforts, and many nations declared the pandemic a public health emergency. Among those nations was the United States, which released stockpiles of antiviral medication and protective equipment but did not choose to exert the federal authority to impose border controls or mandate that public facilities be closed .


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Preventing Influenza Vaccines: The best protection against influenza is a vaccine well matched to the viral strains in circulation in any given season . Once developed, access remains a challenge and coverage rates are generally low, especially in less-developed countries . The vaccine supply is never sufficient to reach all those who need it: Even without a pandemic, some 1 .2 billion people around the globe are considered at high risk for flu, and many more are likely to be affected during a pandemic .

Only 900 million doses of vaccine can be produced worldwide, if all manufacturing facilities are operating at maximum capacity . More research is needed to overcome production bottlenecks, improve vaccine technology, and identify more efficient immunization strategies . Strengthening distribution systems and developing strategies to ensure more equitable access to limited vaccines are also essential, and manufacturers liability concerns may need to be addressed .

Because the vaccine designed for the 2009-10 flu season did not confer protection against the H1N1 virus that emerged to cause a pandemic, a new vaccine had to be developed, licensed and distributed in the months after its appearance . With supplies scarce, public health agencies in many countries initially limited immunization to first-responders and other priority populations . By the end of 2009, the United States had purchased adequate supplies for most of its residents, but WHO, relying on donated vaccines, had only 200 million vaccine doses for 95 countries with one-third of the worlds population.

Other prevention strategies: No vaccine confers 100 percent immunityfor example, a single dose of H1N1 vaccine generates a robust immune response in only 56 to 80 percent of adults 65 or older. Public education about hand-washing techniques and cough and sneeze safeguards is essential to preventing flu outbreaks or reducing the viruss spread in communities . In severe epidemics, the principles of social distancing, such as canceling public events and closing recreational facilities, may also be necessary . Compliance with proper infection-control procedures in health care settings limits spread among patients and staff, and prophylactic antiviral drugs may be appropriate for health care workers and others at high risk of complications .

Government mandates are another option for prevention . For example, some Asian countries have used quarantine and medical detention to curb H1N1 transmissionaggressive but controversial measures that appear to have slowed the spread of disease . Many other nations have developed pandemic preparedness plans, with containment strategies that include travel restrictions and prohibitions against mass gatherings .

Influenza Surveillance Worldwide monitoring of influenza provides best-guess information about the viral strains most likely to cause disease in a given year, so that a timely vaccine can be manufactured and distributed (some com-ponents of the vaccine change every year) . Surveillance is also essential for alerting public health authorities to illness surges so that they can act before a new, highly transmissible, or especially dangerous virus spreads in human populations .

Many surveillance strategies are available . These include case counts, based on specific laboratory tests and physician reports, monitoring do-mestic and wild animal populations, emergency room records, and even Google Flu Trends, which tracks regional patterns of online flu-related queries (see Surveillance Techniques, p . 75) .

WHOs Global Influenza Surveillance Network, established in 1952, is the primary vehicle for a coordinated, worldwide tracking effort.

As part of this network, designated National Influenza Centres at 134 institutions in 104 countries isolate and analyze some 175,000 viral samples every year and submit 2,000 of them to five WHO Collabo-ration Centers. These centers sequence the viruses to determine the extent and direction of their evolution away from previously identi-fied genetic structures . Through FluNet, the networks web-based data collection and reporting tool, tables, maps, graphs and reports are available to the public .

Many countries with the highest burden of acute respiratory infec-tions do not have their own National Influenza Centres because they lack the resources and technology to provide the necessary data . For example, of 46 countries in the WHO African region, only 18 have centers, and only 10 have the laboratory capacity to conduct sophisti-cated diagnostic testing.

Treating Influenza A class of antiviral therapies known as neuraminidase inhibitors, which include zanamivir (Relenza) and oseltamivir (Tamiflu), can reduce the severity of some types of influenza, but only if they are administered within 48 hours of the onset of illness . Treatment is generally recommended only for individuals at risk of complications and for those who have been hospitalized with flu symptoms, as the majority of the population can recover on its own .

Certain influenza strains have become resistant to an older class of antivirals known as adamantanes, and Tamiflu is no longer effective against a form of H1N1 influenza that circulates seasonally . While Tamiflu generally remained effective for the 2009 pandemic strain of H1N1, scattered reports of resistance raise concern (see How Drug Resistance Develops, p . 78) . Even if Tamiflu does retain its effectiveness, supplies are limited: In 2009, only about 220 million doses were available around the world.

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In adults, the distinctive feature of RSV is its disproportionate impact on vulnerable populations . Although three to seven percent of a healthy elderly population had active RSV infections in one study, they had gen-erally milder symptoms than those who had influenza, and they rarely needed to be hospitalized. By contrast, in a high-risk populationsuch as adults over 21 who had been diagnosed with congestive heart failure or chronic pulmonary diseaseRSV hospitalization and mortality rates were comparable to those of influenza . More than 10 percent of all pneumonia-related hospitalizations identified in this population over four winter seasons were caused by RSV.

Buildingimmunity: RSV exposure in infancy does not provide full protection against subsequent infection, so children may have repeated symptoms, especially until about age three . Older children and adults are less vulnerable, but the recurrence of symptoms in at-risk and elderly populations suggests that naturally acquired immunity to RSV is only partial . Moreover, the immune systems response to RSV is in itself a significant factor in the disease, promoting inflammation that may result in chronic lung-related problems .

Respiratory Syncytial VirusRSV is the most common source of severe respiratory illness in children worldwide, but a vaccine is not yet available.

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TuberculosisTB, which kills two million people annually, is not a classic ARI because it progresses more slowly, but many of the root causes, symptoms, and effective interventions overlap.

Countries with highest TB burden

Twenty-two countries incur 80 percent of all TB cases .

Global Impact TBcausesnearlytwomilliondeathsayear,makingittheworlds

seventh most common cause of mortality . More than two billion people are currently infected with Mycobacterium tuberculosis, and ten percent of them will develop active TB symptoms over their lifetimes . Though TB is not a classic ARI, the symptoms and drivers are similar, as are some of the effective interventions .

First-linetherapiestocureTBcancostaslittleasUS$20per personbut if the disease becomes resistant to those drugs, treatment costs can rise to US$5,000 or more . (A recent Kenyan study reported per-person costs of US$21,000 .)

FivepercentoftheglobalTBcaseloadisnowresistanttomultiple

antibiotics, and in some republics of the former Soviet Union, multidrug-resistant TB accounted for more than one-fifth of all new TB cases in 2008 .

In2008,1.4millionpeoplelivingwithHIVhadactiveTB. HIV-positive people are more likely to become infected with TB, more likely to have treatment-resistant forms of the disease, and more likely to die of it .

More than two billion peopleone-third of the worlds populationare infected with Mycobacterium tuberculosis . Tuberculosis can survive host defenses and remain hidden within the body for decades, and most people infected with TB are symptom-free .

But this reservoir of latent infections leads to more than nine million symptomatic cases of tuberculosis every year, and two million TB deaths annually . Eighty percent of active TB cases are found in 22 countries, most of them developing nations in Asia (with 55 percent of the worlds cases) and Africa (with 30 percent).

Directly observed therapy, short course, or DOTS, cures most TB in high-burden countries but only about two-thirds of active cases are ever detected .

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TB in children has been a neglected aspect of the disease, even though WHO estimates that 10 to 15 percent of the global caseload occurs in children under age 14 . In some countries, pediatric TB represents as many as 40 percent of all cases .

Treating TBTuberculosis can generally be cured with a four-drug cocktail, administered over six months, that can cost as little as US$20 per person . But more bacterial strains are becoming resistant to therapy (see How Drug Resistance Develops, p . 78), leaving increasing numbers of patients with limited treatment options, or none at all . If the disease becomes resistant to first-line therapies, medication and other treatment costs can rise to US$5,000, or much higher .

Treating TB effectively requires more investment in the diagnostic tools used to identify active infection, greater use of directly observed therapy, short course (DOTS)the proven technique of monitoring patients as they take their drugsand more pharmaceutical research to replace drugs that have stopped working .

Directlyobservedtherapy,shortcourse:One of the most important strategies for curing TB, and curbing the development of drug resistance, is a short course of directly observed therapy, in which patients take their drugs under supervision . More than half the worlds population lives in a region that has adopted DOTS, which has an 85 percent success rate .

Of course, a diagnosis is required before DOTS can be implemented, and this is a significant gap: Only about two-thirds of active TB cases are ever detected, mostly because modern diagnostic equipment is lacking in regions where TB is most common .

Drug-resistantTB:Five percent of the worlds tuberculosis cases are now multidrug-resistant (MDR-TB) and can no longer be treated effectively with rifampicin and isoniazid, two of the first-line therapies . In 2007, some 510,000 cases of MDR-TB occurred, and the problem seems to be growing.

The rise of multidrug resistance originates in a patients inability or failure to complete a full course of drug therapy, coupled with the bacterias capacity to mutate . A number of barriers make it difficult for patients to complete therapy, including inadequate or distant health care, coexisting social and medical challenges, cost, and the stigma associated with TB . A further complication is that patients must continue treatment after their symptoms subside .

Tuberculosis

The Stop TB StrategyWHOs Stop TB Strategy, with its goal of dramatically reducing the global burden of tuberculosis, was developed by a global partner-ship of governmental and private organizations, donors, and individuals . The six features of this strategic framework:

Pursue high-quality DOTS expansion and enhancement .

Address TB-HIV, multidrug-resistant TB, and the needs of poor and vulnerable populations .

Contribute to health-system strengthening based on primary care .

Engage all health care providers .

Empower people with TB and communities through partnerships .

Enable and promote research .

Though not traditionally considered an acute respiratory infection, TB can have similar symptoms and many of the same drivers (see Drivers of Acute Respiratory Infections, p . 44), and its huge global burden can be lessened with some of the same interventions . Once TB bacteria are activated, usually because the immune system is depressed, they can quickly cause serious illness . Symptoms include a long-lasting cough, which can produce blood or phlegm, fever, fatigue, weight loss, and chest or breathing pain . The majority of patients will die if they do not receive treatment, especially if they have HIV, severe malnourishment, or another underlying illness .

While substantial resources are being dedicated to TB, numerous research studies have documented the heightened vulnerability of poor, homeless, immigrant, and prison populations to TB exposure . As with acute respira-tory infections, greater risk for TB is associated with air pollution, tobacco smoke, overcrowded living conditions, and assaults against the immune system linked to HIV, drug us

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