Influenza (Deadly Diseases and Epidemics)

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INFLUENZA

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Anthrax

Meningitis

Avian Flu

Mononucleosis

Botulism Campylobacteriosis

Pelvic Inflammatory Disease

Cholera

Plague

Ebola

Polio

Encephalitis

Salmonella

Escherichia coli Infections

SARS

Gonorrhea Hepatitis Herpes HIV/AIDS Influenza Leprosy Lyme Disease

Smallpox Streptococcus (Group A) Staphylococcus aureus Infections Syphilis Toxic Shock Syndrome

Mad Cow Disease Tuberculosis (Bovine Spongiform Typhoid Fever Encephalopathy) Malaria

West Nile Virus

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INFLUENZA

Donald Emmeluth CONSULTING EDITOR

I. Edward Alcamo Distinguished Teaching Professor of Microbiology, SUNY Farmingdale FOREWORD BY

David Heymann World Health Organization

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Dedication We dedicate the books in the DEADLY DISEASES AND EPIDEMICS series to Ed Alcamo, whose wit, ch a rm, i n tell i gence, and commitm ent to bi o l ogy edu c a ti on were second to none.

Influenza Copyright © 2003 by Infobase Publishing All rights re s erved . No part of this book may be reprodu ced or uti l i zed in any form or by any means, electronic or mech a n i c a l , including photocopying, record i n g, or by any inform a ti on stora ge or retri eval systems, without perm i s s i on in writing from the publisher. For information contact: Chelsea House An imprint of Infobase Publishing 132 West 31st Street New York NY 10001 Library of Congress Cataloging-in-Publication Data Emmeluth, Donald. Influenza / Donald Emmeluth. v. cm. —(Deadly diseases and epidemics) Includes index. Contents: Deadly world traveler—What is a virus? —Viral replication —I’ve got the flu. What can I do?— Diagnosis—Influenza: nature’s frequent flyer: prevention—Dealing with complications—What may the future bring?: the past and future concerns—The future: hopes and dreams. ISBN 0-7910-7305-X 1. Influenza —Juvenile literature. [1. Influenza. 2. Diseases.] I. Title. II. Series. RC150 .E466 2003 616.2'03 —dc21 2002155110 Chelsea House books are available at special discounts when purchased in bulk quantities for businesses, associations, institutions, or sales promotions. Please call our Special Sales Dep a rtment in New York at (212) 967-8800 or (800) 322-8755. You can find Chelsea House on the World Wide Web at http://www.chelseahouse.com Series design by Terry Mallon Cover design by Takeshi Takahashi Printed in the United States of America Lake 21C 10 9 8 7 6 5 4 3 2 This book is printed on acid-free paper.

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Table of Contents Foreword David Heymann, World Health Organization

6

1.

Deadly World Traveler

8

2.

What is a Virus?

14

3.

Viral Replication

24

4.

“I’ve Got the Flu. What Can I Do?”

36

5.

Diagnosis

44

6.

I n f l u e n za— Nature’s Frequent Flyer: Prevention

52

7.

Dealing with Complications

64

8.

What May the Future Bring? The Past and Future Concerns

82

The Future: Hopes and Dreams

96

9.

Glossary

110

Bibliography

116

Index

123

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Foreword In the 1960s, infectious diseases—which had terrorized generations—

were tamed. Building on a century of discoveries, the leading killers of Americans both young and old were being prevented with new vaccines or cured with new medicines. The risk of death from pneumonia, tuberculosis, meningitis, influenza, whooping cough, and diphtheria declined dramatically. New vaccines lifted the fear that su m m er would bring polio and a gl obal campaign was approaching the global eradication of smallpox. New pesticides like DDT cleared mosquitoes from homes and fields, thus reducing the incidence of malaria which was present in the southern United States and a leading killer of children worldwide. New technologies produced safe drinking water and removed the risk of cholera and other water-borne diseases. Science seemed unstoppable. Disease seemed destined to almost disappear. But the euphoria of the 1960s has evaporated. Microbes fight back . Those causing diseases like TB and malaria evolvedre s i s t a n ce to cheap and ef fective dru gs . The mosqu i to evolved the abi l i ty to defuse pe s ticides. New diseases emer ged including AIDS, Legionnaires, and Lyme disease. And diseases which haven’t been seen in decades re-emerged, as the hantavirus did in the Navajo Nation in 1993. Technology itself actually created new health risks. The global transportation network, for example, meant that diseases like West Nile virus could spread beyond isolated regions in distant countries and quickly become global threats. Even modern public health protecti ons sometimes failed, as they did in Mi lw a u kee, Wisconsin in 1993 which resulted in 400,000 cases of the digestive system illness cryptosporidiosis. And, more recently, the threat from smallpox, a disease completely eradicated, has returned along with other potential bioterrorism weapons such as anthrax. The lesson is that the fight against infectious diseases wi ll n ever en d . In this constant struggle against disease, we as individuals have a weapon that does not require vaccines or drugs, the warehouse of k n owledge. We learn from the history of science that “m odern” beliefs can be wrong. In this series of books, for example, you will learn that diseases like syphilis were once thought to be caused by 6

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e a ting po t a toes. The inven ti on of the microscope set science on the ri ght path. Th ere are more po s i tive lessons from history. For example, smallpox was eliminated by vaccinating everyone who had come in contact with an infected person. This “ring” approach to controlling smallpox is still the preferred method for confronting a smallpox outbreak should the disease be intentionally reintroduced. At the same time, we are constantly adding new drugs, new vaccines, and new information to the warehouse. Recently, the entire human genome was decoded. So too was the genome of the parasite that causes malaria. Perhaps by looking at the m i c robe and the victim thro u gh the lens of genetics we will to be able to discover new ways of fighting malaria, still the leading killer of children in many countries. Because of the knowl ed ge ga i n ed abo ut diseases su ch as A I D S , en ti re new classes of a n ti - retrovi ral dru gs have been developed. But resistance to all these drugs has already been detected , so we know that AIDS drug devel opm en t must con ti nu e . Education, experimentation, and the discoveries which grow out of them are the best tools to protect health. Opening this book may put you on the path of discovery. I hope so, because new vaccines, new antibiotics, new technologies and, most importantly, new scientists are needed now more than ever if we are to remain on the winning side of this struggle with microbes. David Heymann Executive Director Communicable Diseases Section World Health Organization Geneva, Switzerland

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1 Deadly World Traveler We live in a time of marvelous medical achievements. Scientists have

identified and copied many of our genes and have inserted some of them into bacteria to produce, for example, the insulin that diabetics need. They have even genetically engineered bananas and potatoes so that one day we may be vaccinated while eating them. They have also begun using viruses as carriers of genetic information in gene therapy experiments. Despite these magnificent achievements, one disease continues to kill at least 20,000 Americans each year. Thousands more lose valuable time away from work or school. Everyone who reads this book will know of someone who has been afflicted by this disease. It is influenza, or, as it is commonly called, the flu. No one knows when or where influenza began. The Greek physician Hippocrates documented an outbreak of a flu-like disease about 412 B.C. in a region that is now part of Turkey. Two hu n d red ye a rs later, the h i s torian Livy described a disease that struck the Roman army which might have been influenza. Recorded history is unclear as to when the next outbreak of influenza took place. Some evidence suggests that in the late Middle Ages influenza was spread by the Crusaders. Indeed, the name “influenza” was first used a bo ut this ti m e . People thought that the disease was caused by som e c a tastrophic or cosmic “influences.” Epidemics of disease in Italy in 1357 and 1387 were soon being described as influenza. During the 1500s, three major outbreaks of influenza occurred in Eu rope. The outbreak of 1580 prob a bly qualified as a worl dwi de epidemic or pandemic. In the 1620s there were reports of influenza in both Virginia and New England, and the first recorded epidemic of influenza in North

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Figure 1.1 Martinus Beijerinck, pictured here working in his laboratory, laid the foundations for the study of viruses. In 1899, Beijerinck was investigating tobacco mosaic disease, and discovered that a “living fluid,” which was not part of the plant itself, was responsible for causing the disease. He hypothesized that other plant diseases could also be caused by a similar agent.

America occurred in 1647. Hi s torical reports suggest that influenza was present from South Carolina to New England during most of the 1700s. The epidemic of 1759 was particularly devastating to the elderly population. In 1790, President G eor ge Wa s h i n g ton was stru ck by influ en z a , and his own doctor predicted Washington’s death. But Washington’s fever broke, and he survived. A few months later, Thomas Jefferson and James Madison developed the disease, and Jefferson was

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INFLUENZA

said to have suffered with terrible headaches for more than a month. Fortunately, all the leaders of the new nation survived. The epidemic in the United States was relatively minor com p a red to the pandemic that swept thro u gh Eu rope in the early 1780s. Historical records show that two-thirds of the population of Rome and three-fourths of the population of Britain were afflicted with the disease. But so far, no one had any idea of the cause. During the 1800s, s c i en ce and technology com bined to find answers to many medical questi on s . Al t h o u gh the causes of m a ny diseases were discovered, the cause of i n f lu en z a rem a i n ed unknown. Some physicians believed that a virus could be the cause, espec i a lly since our knowl ed ge of viruses was growing at the end of the 1800s. In 1898, t wo inve s ti gators named Fri ed ri ch Loeffler and P. Fro s ch were stu dying an animal skin disease known as foo t - a n d - m o uth disease. Th ey were su rprised that the agent of the disease was small er than bacteria because it was able to pass thro u gh filters de s i gned to trap the smallest bacteria. The fo llowing year, in 1899, a Dutch microbi o l ogist, Ma rti nus Beij eri n ck (Figure 1.1), was trying to find the cause of tob acco mosaic disease, a disease that afflicts tob acco p l a n t s . He call ed the agent he found in the sick plants a “contagium vivum fluidum” or con t a gious l iving fluid, a name that ref l ected his uncertainty abo ut the true natu re of a virus. This agent ulti m a tely did tu rn out to be a virus. Beij eri n ck recogn i zed that he was dealing with a different form of microbe (minute life form), and he predicted that a similar agent might cause other plant diseases. Hi s insights became the building bl ocks for the field of virology. In 1900, Wa l ter Reed discovered that a virus caused yell ow fever in humans. An understanding of the viral basis of m a ny diseases was now becoming cl e a rer. However, it would be a n o t h er 33 ye a rs before scientists saw the influ enza virus by using an electron micro s cope.

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Deadly World Traveler

As the twentieth century began, the United States was actively pursuing a policy of expansion and becoming more interested in the events in the rest of the world. Economically and politically, the United States was increasing its influence throughout the world. Unfortunately, that expansion would bring involvement in the Great Influenza Pandemic as travelers spread the virus across the globe. In f lu enza arrived on the su n ny northern coast of Spain in Febru a ry 1918. Al t h o u gh the we a t h er was warm , a n i n c reasing nu m ber of people were swe a ting not from the heat but from the high fevers assoc i a ted with the disease. In s p i te of a ll the ef forts by health of f i c i a l s , the disease spre ad . Be a utiful San Sebastian, Spain, an attractive city and pop u l a r to u rist de s tinati on , was where the first wave of influenza struck. The great pandemic to foll ow would be known as the “ Spanish Flu .” Two months later, it seem ed that all of Spain was affected . Hi s torians have su gge s ted that ei gh t m i ll i on peop l e , i n cluding the king, were ill although on ly a few hu n d red died. G overn m ent of f i ces were forced to cl o s e , and vehicular traffic came to a standsti ll . The troop s c a ll ed it the “t h ree - d ay fever,” although the after-effects l a s ted at least a week. The “Spanish Flu” spre ad thro u gh o ut Europe, Asia, and the United States. Millions of people in all walks of l i fe were affected . The Great In f lu enza Pa ndem i c will be examined in Ch a pter 8. In 1957, a new strain of i n f lu enza virus was isolated in Peking, Ch i n a . Some su gge s ted that the disease had started in Russia. In early April, the virus re ach ed Hong Kong after stopping to infect large numbers of people in Singapore and Ja p a n . The pandemic invo lved 22 million cases and became known as the Asian Flu. Th en , in 1968 –1969, a new Hong Kong flu cl a i m ed 700,000 lives globally. About 34,000 people died in the Un i ted States. In 1976, a new influ enza virus was identified in an Army recruit at Fort Dix, New Jers ey. It was known as the swine flu,

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Figure 1.2 During the second half of the twentieth century, Asian Flu claimed the lives of more than 700,000 people around the world. The epidemic was so severe that colleges set up temporary infirmaries to house the patients, such as this one in the ballroom at the University of Massachusetts.

and it was feared that this flu was rel a ted to the influ en z a strain of 1918 –1919. The government began a massive influenza immunization program. Luckily, the swine flu never materi a l i zed.

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Deadly World Traveler

Th en in 1997, a n o t h er Hong Kong flu em er ged . Ei gh teen people became ill, and six died. This flu was unique because it seem ed to be carried by ch i ckens and moved direct ly from ch i ckens to peop l e . To stop the outbre a k , m ore than a mill i on ch i ckens were slaugh tered in Hong Kon g. Al t h o u gh this was cruel, it was the smart way to stop a pandemic and was n ece s s a ry from a public health point of view. It is now the t wen ty - f i rst century. When and wh ere wi ll this de adly travel er a rrive next? This and nu m erous other qu e s ti ons wi ll be answered in the fo ll owing chapters .

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2 What is a Virus? Viruses have always been difficult to define. Recall that in Chapter 1, the

Dutch microbiologist Beijerinck thought the disease agent he called a virus was a contagious, living fluid. Louis Pasteur, the French chemist/ microbiologist, used the term “virus” in 1885. He took the name from the Latin word for poison. By 1908, scientists knew that viruses could cause diseases of p l a n t s , a n i m a l s , and even hu m a n s . By 1940, s c i en ti s t s were taking pictu res of viruses thro u gh the tra n s m i s s i on electron m i c ro s cope, a micro s cope using electrons rather than vi s i ble light to produce magnified images. What is a virus? Is it like a cell? For som ething to be con s i dered a cell, t h ree cri teria must be met. First, there needs to be a membrane serving as a bo u n d a ry for the s tru ctu re. Second, a fluid environment must exist in which biochemic a l re acti ons occur; this is su rro u n ded by the mem brane. Th i rd, the cell must contain genetic inform a ti on in the form of DNA. The DNA is a rranged into one or more ch rom o s omes and contains the inform a ti on codes for the cell. Eu k a ryotic cells, such as plants, animals, fungi, and pro tists whose cells contain a distinct mem brane-bound nucleus, m ay have additional or ga n elles inside the fluid environ m en t . Pro tists are or ganisms that are , with few excepti ons, m i c ro s cop i c . They are divi ded i n to three su b gro u p s . The animal-like pro tists are known as pro tozoa . P l a n t - l i ke pro tists are algae, and pro tists that are funga l - l i ke i n clu de water molds and slime molds. Pro k a ryo tic cells su ch as b acteria, wh i ch do not contain a distinct membrane-bound nu cl eu s , do not have these additional or ga n ell e s . Does a virus meet the cri teria for being a cell? If a virus does not qualify as a cell, it cannot be con s i dered a l ive. The cell theory tells us that all living things are com po s ed of on e

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or more cells. The cell is the basic unit of l i fe . Th erefore , if a virus does not qualify as a cell, can we con s i der it a living thing? Can we call it an or ganism? Before these questi ons can be answered a look at the stru ctu re of a typical virus and then the stru ctu re of the influ enza virus is necessary. VIRAL BASICS The structu ral parts that make up a virus have been known since the 1930s. Viruses conti nue to surprise us with their d ivers i ty and their unique soluti ons to the probl ems of su rvival. A virus contains a single type of nu cl eic acid, either DNA or RNA . It cannot contain bo t h . The DNA or R NA may be do u ble-stranded or single-stranded. This core of nu cleic acid is known as the viral genome and is covered by a pro tein coat called a capsid . The genetic information in the DNA or RNA contains the codes for producing and assembling more viruses. The capsid is composed of protein su bunits called capsomeres . Vi ruses that consist on ly of a capsid and a nu cleic acid are called nucleocapsids, or n a ked viruses. Some viruses have an additi onal outer covering called an e n v e l o p e . The envel ope is com po s ed of ph o s ph o l i p i d s and glycopro teins in most viruses. Remember that the cell m em brane consists of ph o s pholipids and glycopro tei n s . Phospholipids are molecules made by combining ph o s ph a te groups (H 2PO4) with different types of fatty acids. G lycopro teins are com bi n a ti ons of simple su gars and pro teins. (The prefix “glyco” refers to su gars). As new virus parti cl e s a re being assembled and finally leave their host cell or the cell that houses them, they take some of the membrane materials with them. The virus may also add some of its own glycopro teins to the envelope. Some of these may appear as s p i ke s . A virus with an envelope, with or without spike s , is called an enveloped vi ru s . As can be seen , vi ruses lack the stru ctu res that we

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n ormally assoc i a te with cells. In addition, viruses have no metabolic mach i n ery of their own. Th ey cannot carry out any of the functi ons we assoc i a te with living things unless t h ey are inside a host cell . Vi ruses use the raw materi a l s and the metabolic machinery of their host to direct the produ cti on and assem bly of n ew viruses. One could con s i der a virus an intracellular (meaning within a cell) parasite. Si n ce viruses depend on their host cells for replication (making exact copies of themselve s ) , they can be difficult to grow in the laboratory. In order to do re s e a rch and te s ting on viruses, scientists must grow the viruses in animal cells, su ch as ch i cken eggs . STRUCTURE OF THE INFLUENZA VIRUS The influ enza virus is an envel oped virus. This envel ope is com po s ed mainly of a lipid bi l ayer and is lined with a type of pro tein known as the matrix pro tein. This com binati on of lipids and pro tein is som etimes call ed the matrix protein m em b ra n e. The outer su rface is covered with two types of spikes made of glycopro teins and em bed ded in the envel ope. The first type is known as hemagglutinin, abbreviated as HA. The name refers to the fact that the influ enza virus can attach itself to red bl ood cells and cause them to clump or a ggluti n a te. This same HA glyco - pro tein is re s pon s i ble for the attach m ent of the virus to the host cell and for beginning the process of i n fecting the cell . The second type of glycoprotein spike is called neuraminidase, or NA. The “-ase” ending on its name indicates that it is an enzyme. NA’s major job seems to be all owing the newly formed viruses to leave the host cell without sti cking to each other or the host cell. Th ere are abo ut four to five times more HA pro teins than NA pro teins in the lipid envelope. There are three types of influenza viruses. Type A contains m a ny subtypes and has been the major culprit in causing epidemics and pandemics in the last 100 years. Type B has been

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What is a Virus?

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Figure 2.1 The viral material of influenza is surrounded by a special protein coat. The coat is covered by a lipid bilayer. Notice the spikes on the outer surface of the coat, or envelope, of the Influenza Type A culture in this picture.

responsible for some regional level epidemics. Type C seldom creates major problems and is found only in humans. Neither Type B nor Type C has any known subtypes. Differences in the three types of viruses are caused by differences in the HA and NA proteins, the viral genetic information the virus contains, and the matrix protein.

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INFLUENZA INFLUENZA GENOMES The influ enza gen omes (a gen ome is the com p l ete gene complem ent of an or ganism) for Types A and B In f lu enza virus consist of ei ght sep a ra te , s i n gl e - s tra n ded RNA segm en t s containing ten genes (Figure 2.2). Type C contains on ly seven RNA segm en t s . These RNA segm ents are coa ted by helical or s p i ral nu cl eo - proteins cre a ting segm ents som etimes known as ribonu cl eopro teins (RNPs ) . Recall that this com binati on of genome and pro tein covering is also known as the nu cl eocapsid. The nu cl eocapsid of i n f lu enza viruses is su rro u n ded by an envel ope . E ach of the RNA segm ents has the code for one or more of the viral pro teins. Ta ble 2.1 provides the current understanding of the influ enza virus genes and their functi on s . The influ enza virus is one of very few viruses to have its gen ome in separa te segm en t s . This segm en ting of the gen ome increases the likelihood that new gen etic sequ ences wi ll develop if t wo different strains of virus infect a cell at the same time. Gene segments from each of the strains may produce new combinations leading to a new strain of flu. On the po s i tive side, labora tory du p l i c a ti on of the gen om e segm ents may lead to new vaccine strains to inoc u l a te people against these viral strains. NAMING VIRAL STRAINS Type A subtypes are identified and named using a very specific s ys tem. The geographic locati on where the strain was first isolated is followed by a labora tory identificati on number that usually tells how many cases were identified and isolated. Th en comes the year of discovery and finally, in parentheses, the type of HA and NA the viral strain possesses. A typical example might be A / Hong Kong/156/97/(H5N1). Another example is A/Singapore/6/86/(H1N1). Scientists need to know this information so that they can prepare an appropri a te vaccine against the particular influ enza virus strain causing the most recent outbre a k .

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What is a Virus?

Figure 2.2 The genomes of Influenza Type A and Type B each contain eight single-stranded RNA segments. Influenza Type C only contains seven RNA segments. In addition, the three types contain diff e rent ion channels and surface proteins.

CHANGES IN THE VIRAL GENOME The influenza virus is constantly changing through mutations, re a s s o rt m e n t s , and recom bi n a ti on s . Di f ferent su btypes of Influenza A are found in the environment each winter. Therefore , a new flu vaccine must be produ ced each ye a r. Th ere a re two conditions that are frequently mentioned as the major reasons for the instability of the influenza virus. First, small ch a n ges in the gen etic sequ en ce of the HA or NA genes lead to a ch a n ge in the amino acid sequ en ce of the

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INFLUENZA

Table 2.1

GENES OF INFLUENZA A AND THEIR PRESUMED FUNCTIONS #1

PB2 gene

Codes for an RNA polymerase involved in cap binding (sealing end of molecule); part of transcriptase, which is an enzyme that converts DNA into types of RNA

#2

PB1 gene

Codes for an RNA polymerase involved in elongation of the molecule; part of transcriptase

#3

PA gene

Codes for an RNA polymerase that may serve as a protease; part of transcriptase

#4

HA gene

Codes for hemagglutinin; three distinct hemagglutinins are found in human infections (H1, H2, H3); at least nine others have been found in animal flu viruses

#5

NP gene

Codes for the nucleoproteins; Types A, B, and C have different nucleoproteins; part of transcriptase complex

#6

NA gene

Codes for neuraminidase; involved with release of virus from the host cell; two different neuraminidases have been found in human viruses (N1,N2); at least seven others in other animals, e.g., chickens, pigs, ducks

#7

M1 gene M2 gene

Matrix protein; different sections of the genetic code of the gene are read to produce the two proteins that open channels in the cell membrane and allow charged atoms or molecules (ions) to pass through

#8

NS1 gene NS2 gene

Codes for two different nonstructural proteins whose function is still unknown; as above, d i ff e rent sections of the code are used for each

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What is a Virus?

HA or NA pro tei n s . This happens because the order or s equ en ce of amino acids, wh i ch make up a pro tein, determine what type of pro tein will be produced. These ch a n ges of ten occur because the influ enza virus is an RNA virus. R NA viruses, with few excepti on s , a re con s t a n t ly making “s pelling errors” in their gen etic sequ en ces wh en they are being cop i ed. The RNA copying process is flawed. This lead s to new gen etic sequ en ce s . New gen etic sequ en ce s , in tu rn, l e ad to new amino acids being put into place in the cre a tion of a pro tein. This usu a lly leads to a new or altered pro tein. This series of continual changes is known as genetic drift. The HA pro tein plays a large role in sti mulating immu n i ty ( pro tecti on against infectious disease); thus ch a n ges in this protein may cause a loss of immunity to the virus. NA protein p l ays a very minor role in immu n i ty. A second condition, known as genetic shift, is an exten s i on of the genetic drift. Continual small changes in the HA and NA proteins may accumulate, and over time they create major changes in the proteins. This may lead to production of new HA or NA proteins unlike any previously known and to new viral strains against which the population has no immunity. When two strains of virus infect a cell at the same time, the genetic information may not only be copied incorrectly but may also be reassorted or recombined in new ways. This also could lead to strains of virus that could cause major epidemics or pandemics because the population has no protection against these new strains. Changes in different influenza genes can also create problems. The Septem ber 7, 2001, issue of S ci ence m a gazine contains an article that describes a change in the PB2 gene. In the table pres en ted earl i er (Table 2.1), rec a ll that PB2 is found on segm en t #1. Researchers tested the A/Hong Kong/97/(H5N1) strain in mice and found, by a system of elimination, that the PB2 gene was responsible for giving this virus its potency. Although they are unsure as to the exact function of the gene, scientists believe

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that it directs the producti on of an enzyme that forces the host cell to make more viruses. This change in the PB2 gene is significant because it changed a form of chicken flu into a strain deadly to humans in Hong Kong in 1997. DETERMINATION OF NEW VACCINE COMPONENTS The World Health Orga n i z a ti on (WHO) makes the dec i s i on as to which strains of the vi rus to inclu de in the new vacc i n e . Th ey a n a ly ze inform a ti on that is provi ded by WHO labora tories in Atlanta, Geor gi a ; Lon don, England; Mel bourne, Austalia; and To kyo, Japan. These labora tories ob s erve the dominant stra i n s that were circ u l a ting the previous wi n ter. Th ey also look for eviden ce of n ew strains with the po ten tial to spre ad , p a rti c ul a rly if the current vaccines do not provi de pro tecti on aga i n s t these new stra i n s . A new vaccine would norm a lly contain three com pon ents: t wo su btypes of In f lu enza Type A and one of Influenza Type B. In Febru a ry 2002, the WHO announced that a new strain of influenza vi rus had been isolated . The strain, called subtype A/(H1N2), appe a rs to be a combination of two human subtypes that have been causing sickness for a nu m ber of years. This new s train probably has ari s en from the reassortment of gen etic information in the subtypes A/(H1N1 and H3N2). This new strain was identi f i ed in China in 1988 –1989, but there was no spre ad of the vi rus at that time. This new subtype A/(H1N2) strain has been isolated from people in England, Wales, Is rael, and Egypt. Because this new subtype is a combination of gen etic inform ation from A/(H1N1) and A/(H3N2), people who have been previously vaccinated against these two strains should have a h i gh level of immu n i ty. Even those indivi duals who have not been previ o u s ly vaccinated should have some immu n i ty because these strains have been around for a number of years. The composition of the influ enza vaccine for the 2002 –2003 season was announced by the WHO on February 6, 2002. This

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What is a Virus?

vaccine is designed to be used for the wi n ter months in the Nort h ern Hem i s ph ere. The contents of the vaccine wi ll inclu de : • an A/New Caledonia/20/99 (H1N1)-like virus • an A/Moscow/10/99 (H3N2)-like virus (the widely used vaccine strain is A/Panama/2007/99) • a B/Hong Kong/330/2001 – a B Victoria-like virus

The first two compon ents are the same as those found in the 2002 vaccine. Scientists feel that they will provide good protection against this new strain. Recommendations for the vaccine which needed to be produced for the Souther n Hemisphere was made by WHO in September 2002. This is the vaccine that will be used in May 2003 through October 2003 in the Southern Hemisphere. How do viruses produce copies of themselves in our cells? Should you get vaccinated? Should ever yone get vaccinated? Are there any dangers in getting vaccinated? These are a few of the questions that will be answered in future chapters.

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3 Viral Replication A virus is an enclosed particle of nucleic acid. It depends on a living cell

to carry out the functions we identify with life . It replicates on ly after taking over a living cell. Recall the discussion in Chapter 2 which defined a virus as an intracellular parasite. A viral genome contains either DNA or RNA but never both. All viruses follow a fairly standardized sequence of actions that allows them to enter host cells. STEPS IN VIRAL REPLICATION Th ere are a nu m ber of s i m i l a ri ties bet ween the way vi ruses infect bacteri a , plants, and animals. The sequ ence of steps involves: (1) attachment or adsorption; (2) penetration; (3) uncoating (most bacterial viruses inject only their nucleic acid and not the entire virus); (4) synthesis of viral enzymes, nucleic acids, and proteins; (5) assembly and packaging; and finally, (6) release of n ewly form ed vi ruses from the cell . Here concentration focuses on how viruses infect animal cells. The first part of this process requ i res that the vi rus come into contact with the su rf ace of the host cell, find a way to sti ck to that su rface , and introduce the viral gen ome into the cell (Figure 3.1). This first step is u sua lly call ed attachment or adsorption. Ad s orption means to ad h ere or sti ck to a su rf ace. To be su ccessful, the vi rus must come into contact with a proper receptor protein em bed ded in the host cell ’s mem brane. A proper receptor is one whose shape is complementary to some part of the vi ra l outer coveri n g. Not all vi ruses can infect all types of cells because the proper receptors are found only on certain cells. Genetic information on how to make these protein receptor sites is inherited; thus a person with missing or defective inform a ti on may be less susceptible to certain vi ral disorders.

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Figure 3.1 A virus can enter a cell one of two ways. On the left, the virus fuses with the cell wall. Receptor sites on the outside of the cell wall attach to the virus and the virus is sucked onto the cell. The other method of entry is called receptor-mediated endocytosis, shown on the right side of the diagram. The host cell forms “arms” that surround the virus and pulls it inside the cell. In both methods, after the virus has entered the cell, it loses its protein coating and is ready for replication.

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This is true rega rding the attach m ent site for the hu m a n immunodeficiency virus ( HIV). Persons lacking or having imperfect receptor sites on their wh i te blood cells will not convert from being HIV-positive (also known as antibodypositive or virus-positive) to having acquired immunodeficiency syndrome (A I D S ). The HIV cannot enter the white blood cell or other types of cells such as nerve cells that lack the proper receptors. Dru gs that can bl ock or prevent en tra n ce of the vi rus into the receptor sites are curren t ly under inve s ti ga ti on for several viral diseases. The second step is usually called penetration. In the case of infection of animal cells, the enti re virus is taken inside the cell. The viral envelope may fuse with the host cell membrane, thereby causing the lipids in the membrane of the host cell to rearrange. This rearrangement allows the nucleocapsid to enter the cytoplasm of the host cell. A different penetration method occurs when the host cell creates a little pocket or invagination in the membrane and surrounds and encloses the attached virus. This method of enclosure is called receptor-mediated endocytosis, and the virus is enclosed in a structure sometimes known as a coated vesicle or an endosome. Figure 3.1 shows both methods. Finally, the viral nucleic acid is separated from the protein capsid, a process known as uncoating. In some viruses, digestive enzymes released by the lysosomes of the host cell aid the uncoating. Recall that lysosomes are organelles found in eukaryotic cells. The lysosomes contain a variety of hydrolytic or dige s tive en z ymes. Depending on viral type, the processes of attachment, penetrati on , and uncoating may take from minutes to as long as 36 hours. At this poi n t , d i f feren ces occur in the way the DNAcontaining vi ruses and the RNA-containing vi ruses con ti nue the process. Figure 3.2 shows how DNA-containing vi ruses proceed . D NA viruses contain all the genetic information nece s s a ry to produ ce the en z ymes that direct the synthesis of the vi ra l com ponents. The vi rus wi ll use molecules provi ded by the host

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Viral Replication

Figure 3.2 After the virus has successfully entered the host cell, it begins to replicate. Using the host cell’s machinery, the viral DNA unwinds and each strand is copied. This p rocess is aided by two enzymes, polymerase and ligase. Each new set of viral DNA is packaged into a capsule and released from the host cell. These new viruses can now infect other cells and continue the replication process.

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cell to con s tru ct more vi ruses. Some DNA vi ruses carry out this process com p l etely in the host cell ’s cytoplasm. Ot h er DNA vi ru s e s , like the aden ovi ruses that cause the common cold, divide the work. Vi ral DNA is cop i ed in the nu cl eus of the host cell , while the vi ral proteins are produ ced in the cytoplasm. As the vi ral gen ome is being copied, synthesis of materials that would be used by the host cell is halted . The proteins that wi ll form the capsid of the vi rus en ter the nu cl eus and com bine wi t h the newly cop i ed DNA of the vi ral gen ome. A new vi ral parti cl e or virion is form ed. The formati on of n ew vi ri ons is call ed a s sem bly or maturation. The new vi ri ons then force their way thro u gh the mem branes. The mem brane is pushed in front of t h em and, as the vi rus is rel e a s ed from the cell , some of the mem brane is rem oved and forms the new envel ope of the virus. This process of forcing the vi ri on thro u gh the mem brane is call ed budding and usu a lly kills the host cell. RNA-containing vi ruses have a va ri ety of d i f ferent pattern s of synthesis. Some RNA viruses are single-s tranded (ssRNA ) and some are double-stranded (dsRNA ) . In some ssRNA viruses, the RNA strand is used directly as a messenger RNA (mRNA) molecule that conveys information on how to make proteins. Such a virus is said to have “sense” or is called a sense or (+) positive-stranded RNA virus. The viruses that cause polio, hepatitis A, and the common cold all are (+) stranded RNA viruses. These viruses are able to supply the genetic information as soon as they have penetrated and uncoated. Some of the newly formed viral proteins inhibit the synthesis activities of the host cell. Other ssRNA viruses synthesize a complementary strand of RNA. The newly created strand is used as a messenger RNA to guide protein synthesis. Multiple copies of this new (+) strand are usually made. The rules followed in virology suggest that the strand that serves as the mRNA is alw ays said to be plus (+). The enzyme, RNA polymerase, also known as replicase, is used to synthesize this complementary strand. The

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Viral Replication

host cells do not produce the RNA polymerase used by these viruses. The virus must bring in this version of the enzyme when it penetrates the host cell. The original viral strand is said to have “antisense,” and the virus is said to be an antisense virus or (-) negative-stranded RNA virus. The rabies, Ebola, and influenza viruses are (-) stranded RNA viruses. The group of s i n gl e - s tra n ded RNA viruses known as retrovi ruses inclu des agents that cause va rious kinds of cancer and AIDS. These vi ruses convert their RNA into DNA but go thro u gh an interm ed i a teDNA stage. The ssRNA is converted into s s D NA , which is then converted into dsDNA ; this can now produce mRNA. The unique en z yme requ i red to convert RNA into DNA is known as reverse tra n scriptase. The process of converting DNA into mRNA is norm a lly call ed transcription and, as can be seen, vi ruses go through several additional steps to bring this about. The host cell does not produce the en z yme call ed reverse transcriptase; thus, the retrovi ruses carry the reverse tra nscriptase enzyme in their virion (the complete viral particle). REPLICATION OF THE INFLUENZA VIRUS The influenza virus is a (-) negative-stranded, enveloped RNA virus that will multiply on ly in a vertebrate host. It is a member of the family Orthomyxovi ri d ae and the orthomy xovi rus group (any vi rus bel on ging to that family ) . Ch a pter 2 pointed out that there are three major types of the influenza virus — A, B, and C. The influ enza vi rus invades the cells lining the respiratory tract. The specificity of this relationship is the re sult of the receptor molecules on the a t t ach m en t s i tes of the host cells that cl o s ely match the protein molecules ex tending from the su rface of the virus. Also recall from Chapter 2 that eight linear sections of RNA, containing ten genes, comprise the viral genome of influenza vi ruses A and B. Type C has on ly seven RNA s egm en t s . Thu s , t h e i n f lu enza gen ome is said to be a segmented genome. An envelope con s i s ting of several virus-s pecific pro tein spike s

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and lipids derived from host cells covers the nu cl eocapsid of the influ enza virus. The viral g lycoprotein spikes known as hemagg lutinin (HA) accomplish the initial attachment of the influenza virus to receptive cells in the respiratory tract. These HAs attach to a molecule of sugar called sialic acid. Sialic acid is derived from neuraminic acid and is a part of the glycoproteins embedded in the host cell membrane. Immunity to influenza occurs when these HA molecules are prevented from attaching to sialic acid by antibodies. At t ach m ent indu ces the host cell to engulf the vi rus thro u gh receptor-mediated en doc ytosis. The mem brane of the vesicle or en dosome, wh i ch has en cl o s ed the vi rus, fuses with the vi ra l outer su rf ace and all ows the vi ri on to en ter the host cell . Critical ex periments in the 1980s showed that this fusion could not occur unless the pH in the en do s ome was low, a bo ut 5.0. The low pH causes the HA proteins to unfold and ch a n ge thei r shape. This all ows the lipoprotein envelope of the vi rus to fuse with the lipid-bilayer mem brane of the en dosome. As part of this proce s s , the RNA of the vi ri on is rel e a s ed into the cytoplasm of the host cell and migra tes to the nu cl eus. A protein in the membrane of the endosome forms a channel that all ows protons (hydrogen ions) to en ter the vi ri on. These protons aid in the release of pro teins binding the nu cl eocapsid and all ow the nu cl eocapsid to be moved to the nu cl eus of the host cell . Internal proteins, including RNA po lym erase, s oon fo ll ow the migrati on ro ute . Within the host cell nu cl eu s , (-) negative stra n ded RNA makes a complementary copy of its gen om e , wh i ch becomes mRNA. This mRNA can be used to make more proteins and more copies of the vi ral gen om e . Figure 3.3 shows an overvi ew of the process. The influ enza virus uses the host cell DNA to produce mRNA and then removes part of this newly formed mRNA to attach to its own viral mRNA . These ad ded sequ en ce s , s om etimes known as caps, a ll ow the viral mRNA to move

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Viral Replication

Figure 3.3 This diagram summarizes the viral replication process. First, the virus must enter the host cell. Next, the virus will shed its p rotein coat and begin replication. While the genetic material is replicating, the virus will also produce a new glycoprotein coat. Finally, the new copies of the virus are assembled and released from the cell.

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i n to the cytoplasm and use the host’s ri bo s omes to produce more viral pro teins. The In f lu enza Type A virus uses the internal mach i n ery of the nu cl eus in another way as well. Two of the eight RNA segments in the virus contain geneti c

SPREADING THE WEALTH The cells most frequently attacked by the influenza viruses are cells in the lungs and throat. The reason is simple. These cells contain receptors that allow the hemagglutinin (HA) a site for attachment. HA is one of the two major proteins that are p a rt of the viral envelope. To form this attachment, the HA needs to be cut into two pieces. This is accomplished by enzymes called proteases, common in the lungs and throat but not in other parts of the body. This is why influenza is usually just a respiratory disease. If the HA is not split by the proteases, the virus cannot infect the host cell. R e s e a rchers at the University of Wisconsin, led by Dr. Yoshihiro Kawaoka, have discovered that the most deadly forms of Influenza Type A use an additional enzyme to infect cells t h roughout the body, not just in the lungs and throat. The additional enzyme is called “plasmin” and is found in all sorts of tissue. The second major protein making up the envelope is an enzyme protein known as neuraminidase (NA). The NA of these deadly flu strains collects and attaches a molecule called plasminogen. Plasminogen is converted into plasmin. Thus, the virus is providing itself with a high concentration of a molecule that will allow it to infect cells throughout the body. Kawaoka and his group tested ten other strains of flu and could not find the same enzyme being used. Only the form that was a descendant of the 1918 pandemic strain used the enzyme plasmin. The re s e a rchers hope that this information may provide a means of testing individuals to see if they are harboring the most dangerous forms of influenza. Perhaps a new target for d rug therapy may also come from this information.

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i n formati on wh i ch produ ces mRNA molecules that can be s p l i ced together. The host cell nu cl eus has the mach i n ery to do this splicing. When mRNA molecules are spliced together, a new message is cre a ted, all owing the cell to make a different pro tein. The end re sult of this splicing process is that the eight RNA segm ents can produ ce up to ten viral mRNAs . As s em bly of the new viruses occ u rs wh en the capsid pro teins su rround the newly formed viral RNA molecules. Together with other pro teins, the new virions move tow a rd the host cell membrane. Some of the proteins that the vi rus has instru cted the host cell to make become glycoproteins for the envel ope of the new vi rions. These proteins fo ll ow the standard route of con s tru ction on the ri bosomes, wh i ch are attach ed to a series of m em bra n e channels known as the en doplasmic reti c u lum (ER) of the host cell . This ro u gh ER, as it is known , produ ces a protein ch a n n el to the interior of the ER wh en con s tru cti on of the protein has been com p l eted on the ri bo s ome. A research team led by Thomas Ra poport of Harva rd Univers i ty discovered these pro tein translocation channels. Their results were reported in the journal Cell on Novem ber 5, 1996. As the newly form ed protein en ters the ER, a porti on of the pro tein is enzymatically rem oved. This rem oval causes the channel to close. The portion of the protein that is rem oved had been serving as a signal to the ER membra n e . The protein is pack a ged by lipids in the ER and sen t to the organelle known as Golgi. Within the Golgi apparatus the appropriate suga rs are ad ded , thus forming the new glycoprotei n s , wh i ch are tra n s ported to the host cell mem brane and become embedded within it. The glycoproteins, along with the vi ral pro tei n s , h em a gglutinin, and neuraminidase, become part of a new viral envelope. The newly form ed vi ri ons are now re ady to leave the host cell . This process, known as budding, may take as long as six h o u rs . The cell is not kill ed immed i a tely but even tu a lly dies owing to the disru ption of its normal synthesis of va ri o u s

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essen tial molec u l e s . The nu cl eocapsids of the new vi ruses bind to the inner su rf ace of the host cell membra n e . Rem em ber that the vi rus ori gi n a lly attach ed to the host mem brane by binding to sialic acid (neu raminic acid). The host mem brane is stu d ded with these molecules, and the newly form ed vi rions now have t h em attach ed to their su rf aces. If these sialic acid molecules are not rem oved from the host cell mem brane and the outside of the vi rions, the vi rions wi ll sti ck to each other and to the host cell membra n e . The protein neuraminidase is an en z yme that breaks down sialic acid (neuramininic acid) in both the host cell membrane and on the su rf ace of the new vi rions. Rem oval of the sialic acid molecule all ows the vi rus to leave the host cell in wh i ch it was form ed. As shown in Figure 3.4, this budding process takes some of the cell membrane and the embedded proteins to form the new viral envelope. Nine different forms of n eu raminidase have been iden ti f i edfor Influenza A vi ru s . About a third of the amino acid sequ en ce of the neuraminidase molecule is the same in a ll nine forms. This amino acid sequ ence provi des the stru cture of the portion of the enzyme that binds to the sialic acid molecule. If a drug could be produced to bl ock that site of attach m ent, the viruses would not be able to leave the cell to i nvade other cells and would sti ck to each other. Some have suggested that viruses are simple structures. Perhaps, but they need to look more carefully at how complex these so-call ed simple stru ctu res re a lly are . In the next three ch a pters, this text wi ll fo ll ow a co ll ege freshman as he com e s i n to contact with some unwanted invaders, the influenza viruses. These chapters will focus on treatment possibilities, diagnostic tests available, and ways to prevent the influenza virus from making one sick. Subsequent chapters will explore the possible complications that can arise when one becomes infected and ways that the body tries to protect and defend itself. The last chapter will focus on concerns and hopes for the future regarding influenza viruses.

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Viral Replication

Figure 3.4 This electron micrograph of the HIV-1 viru s shows the budding stage of replication. Budding is the way in which newly created viruses are released from the host cells. These new viruses contain all the genetic material of the original virus and can infect new cells and continue to replicate.

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4 “I’ve Got the Flu. What Can I Do?” Friday night’s concert was great. Even though it was November and cold

outside, thousands had jammed together to hear “Dice and the Slicers,” the latest singing rage. Jim and his friends left the Civic Center hoarse from yelling. They stopped at their usual hangout, Paul’s Pizza Palace and rejoined some of their friends. The ice-cold soda and piping-hot sausage and mu s h room pizza tasted won derful. On Sa turday Jim finally got up at 1 P.M. The rest of Saturday was a blur. Sunday evening was devoted to finishing up some homework and studying for his Principles of Biology class. There was a big lab exam coming up on Thursday. On Monday, the alarm went off at 6 A.M. It sounded like a giant gong banging inside Jim’s head. Turning on the light nearly blinded him and added to the pain of his pounding head. Jim’s throat was dry and had a tickling sensation. When he coughed, it was a dry, sometimes raspy, cough. Jim started to shiver and realized that most of his muscles ached. He felt hot and was ex h a u s ted. “Wh a t’s going on?” groaned Jim. “What did I eat to cause this feeling?” Jim tried to stand up but felt l i ke he had been be a ten with a baseb a ll bat. He fell back into bed and immediately regretted that move. His head was pounding like the drummer on Friday night. Only this time, his head was the drum. BE SURE IT’S REALLY THE FLU Jim is showing most of the classic sym ptoms of influ en za—the “f lu .” ( F i g u re 4.1) Did you recogn i ze the symptoms? He ad ach e , fever, ch i lls, dry cough, fatigue, and really achy mu s cles are the starting symptoms. There

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Figure 4.1 Flu symptoms diminish over the course of the disease, usually four days. A flu patient may experience sore t h roat, cough, headache, high fever, muscle aches, and fatigue during the first two days of the illness. The sore throat, muscle aches, and chest pain will most likely lessen over the next few days. The number of antibodies also decreases, following the same pattern. Both trends can be seen on this graph.

are many diseases that cause flu - l i ke symptoms. Some are bacterial, some are fungal, and some are vi ra l . If a person can get up and go to work or school, it is very unlikely that he or she has the flu. Jim doesn’t sound like he is going anywhere very soon. He won dered if he had eaten something to cause these sym ptoms. People sometimes use the term “stomach flu.” This condition can be caused by one of s everal vi ruses. The rotavi rus causes “stomach flu” which occurs during the same time of the year as the influenza virus. Other enteric (intestinal) viruses and the Norwalk virus all cause “stomach flu.” Norwalk viruses cause a vomiting disease during the winter, and all “stomach flu” vi ruses cause vomiting and/or diarrh e a . So far, these unpleasant symptoms have not been ad ded to Ji m’s list. Another disease sometimes diagnosed as “stomach flu” is actu a lly ga s troen teri tis,

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which is usually caused by bacteria. “Stomach flu” is sometimes misdiagnosed as viral gastroenteritis as well. Could Jim have a cold or a strep throat (throat infection caused by bacteria)? The table of comparisons shown below may help to answer part of that question. Cold symptoms normally include stu f f y, ru n ny nose, s n ee z i n g, s ore throa t , and co u gh . Sym ptoms of a co l d usually do not include a fever or body aches. Jim does not have these symptoms. Strep throat symptoms include a high fever, difficulty swallowing, headache, fatigue, and coughing. Strep throat is caused by a bacterium of the genus Streptococcus. Jim

HOW TO TELL IF IT IS A COLD OR THE FLU SYMPTOMS

COLD

FLU

How did the illness occur?

Gradually

Suddenly

Do you have a fever?

Rarely

May be higher than 101°F (38°C) and last 3-4 days

Do you feel exhausted?

Never or only a little

Ve ry and happened suddenly

Is your throat sore ?

Usually

Not usually

A re you coughing?

A hacking, sometimes A dry, hoarse, or severe cough raspy cough

A re you sneezing?

Usually

Sometimes

Do you have aches and pains?

Occasional aches and pains

Frequently achy, sometimes very sore

Do you have a headache?

Not usually

It is strong and nasty

Do you have a runny nose?

Yes

No, usually dry and clear

Do you have chills?

No

Yes

How is your appetite?

Normal

Decreased

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“I’ve Got the Flu. What Can I Do?”

cert a i n ly has those sym ptom s . S trep throat pati ents also have swollen lymph glands and a red, raw appearance to the back of the throat. If Jim could get to the doctor, he could find out which disease he has. There are a number of rapid tests that can be done in the doctor’s office for identification of strep i n fections. Si n ce there are a high nu m ber of cases of flu in the community at the present time, Jim’s doctor will probably suggest that Jim does in fact have the flu. A quick call to some of his friends from the concert showed that three of them had the same s ym ptoms as Ji m . Th eir doctors also diagn o s ed t h eir illnesses as the flu. I’VE GOT THE FLU It seems that almost all doctors agree what you should do when you have the flu. First, be sure to get plenty of bed rest. Don’t try to be a hero and drag yourself to work or school. If you come into contact with other people, you are a menace in a number of ways: going to work or school, while you are there, and on your way home. You could become sleepy while driving or while at work or sch oo l . You also could be spre ad i n g influenza to your work or school mates. Second, drink plenty of fluids. Try to drink water and not alcoholic or caffeinated drinks. Th i rd , take over- t h e - co u n ter medications to relieve the major sym ptoms (Figure 4.2). Rem em ber that these medicati ons redu ce your discomfort. Th ey do not treat the vi ral infection itself. Most physicians recommend acetaminophenbased products to relieve the fever and aches. The fever may last from two to five days. These products, such as Tylenol®, are less likely to irritate the stomach. Aspirin and aspirin-based produ cts som etimes irri t a te the stom ach lining. They may also play a role in the development of a rare liver and central nervous sys tem con d i ti on known as Reye’s syndrom e . This condition shows up most frequently in children under 18 years of age. It may cause vomiting, convulsions, brain damage, and even death. If your flu symptoms include con gestion,

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Figure 4.2 Medications can be used to treat certain types of influenza and to relieve symptoms. Cough suppressants, pain relievers, and throat lozenges can help to make the flu patient feel more comfortable while the body fights the disease. New anti-viral medications such Tamiflu® and Relenza® may help to shorten the course of the disease.

coughing, and a runny nose, you may also take decongestants and antihistamines. There are a number of over-the-counter flu remedies that contain both of these ingredients. TREATMENT REGIMES — PRESCRIPTION DRUGS It is important that you see your doctor within 48 hours of having noticed your symptoms. There are some new antiviral drugs

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“I’ve Got the Flu. What Can I Do?”

available that can reduce both the severity and length of the disease. These drugs must be given within 48 hours of the appearance of symptoms for maximum effectiveness and require a doctor’s prescription. The first of these drugs is amantadine. It goes by the brand name of Symmetrel®. The second drug is known as rimantadine, or the brand name Flumadine®. Both of these drugs work only on Type A influenza virus and will not work on Types B or C. Flumadine is less toxic. Individuals with cases of uncomplicated Type A Influenza may be given amantadine for five days. The usual dose is 200 mg. Rimantadine is usually given in 100 mg doses twi ce a day for five days . Recen t ly, Type A viruses resistant to both of these drugs have been found, usually in young children treated with the drug. Two other drugs that have been developed recen t ly can be used to treat both Types A and B influ en z a . These drugs, z a n a m ivir (Rel enza) and osel t a m ivir (Ta m i f lu ) , a re part of a group of drugs that attack a different site on the virus. You may wish to go back to Chapter 2 and review the structu re of the influ enza vi ru s . Rel enza and Ta m i f lu attack and i n h i bit the en z yme neu ra m i n i d a s e , wh i ch is a prom i n en t part of the viral coat. Relenza is ava i l a ble in nasal spray form on ly, whereas Tamiflu can be taken orally. Both have been s h own to have very few clinical side effects. Relenza can be used as a treatm ent for those who are 12 ye a rs of age and older. Tamiflu is used as a treatment for those who are 18 ye a rs of a ge and older. Ta m i f lu can be given preven tively to indivi duals who are 13 years of age or older to prevent them from coming down with flu . Relenza is not used as a preven t a tive . Tamiflu is curren t ly the most widely pre s c ribed antiviral med i c a ti on for influ en z a . Unfortu n a tely, it is also more ex pen s ive than Sym m etrel and Flu m ad i n e . It is not a good idea to call your doctor to ask for an anti bi o tic unless you know you are dealing with a bacterial infecti on . Antibiotics do not work a gainst viruses.

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INFLUENZA YOU AND YOUR DOCTOR It is important to see the doctor when symptoms first appear. Only in this way can a strep or another infection be ruled o ut . If it is a strep infecti on , appropriate anti bi o tics can be pre s c ribed. If it is the flu, the doctor may prescribe one of the previously mentioned antiviral medications. Sometimes infection with the influenza virus can be complicated by other viruses, bacteria, or fungi. If the pati ent becomes breathless

INFLUENZA AND RELATED DISEASES On May 11, 1997, a three-year-old boy in Hong Kong was having d i fficulty breathing. He was hospitalized on May 15 and diagnosed as having pneumonia and Reye’s syndrome. One of the problems associated with influenza is the damage that it does to lung tissue. The tissue becomes swollen and inflamed. This damage is usually slight and heals within a few weeks. However, the immune system of a young child often responds slowly to the rapid growth of the virus. Pneumonia is an inflammation of the lungs caused by diff e rent viruses or bacteria. Reye’s syndrome affects the brain and liver of a child who is recovering from a viral infection like influenza. Nausea and vomiting are followed by confusion and delirium. As the liver breaks down, the chemistry of the blood begins to change. Most victims of Reye’s syndrome sustain some degree of brain damage. This syndrome is associated with taking aspirin-based products. Therefore, aspirin should NEVER be given to children under 12 years of age who are suffering from flu-like symptoms. On May 21, 1997, the young boy died. It was reported that he had died from complications of the flu. He was the first victim in the 1997 group of individuals who died from a strain of influenza found in chickens. This was the first time that this strain showed up in humans. By November of 1997, more cases appeared, and the world was made aware of a new type of flu.

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“I’ve Got the Flu. What Can I Do?”

or begins to slip in and out of consciousness, c a ll the doctor. If he or she becomes con f u s ed or delirious, call the doctor. As is true with most diseases, the patient has a better chance of recovering com p l etely and rapidly if he or she takes positive action to treat the disease and its symptoms. Could Jim have prevented getting the flu? What could he have done? What should he do in the future? These are some of the questions that are addressed in the next chapter.

In May 2002, several members of the United Kingdom task force serving in Afghanistan fell ill. Their symptoms included fever, headache, and general gastroenteritis. Since medical diagnosis and care are difficult to obtain in a war zone, the individuals were sent to either an American hospital in Germany or back to England. At least three individuals who had been in contact with the original seven members also became ill. The initial diagnosis suggested that a Norwalk-like virus (NLV) was the cause. NLV seems to cause a common gut infection in England, with as many as one million cases each year. Outbreaks occur in places where people are closely confined and in constant contact with each other, such as schools or hospitals. Military personnel working in close quarters during wartime are also prime candidates. Many cases occurred during the Gulf War (1990 –1991). NLV is seldom dangerous, but unfortunately it is always unpleasant. Diarrhea and explosive fits of vomiting may last from 24 to 48 hours. No specific treatment exists other than making sure that the patient does not become dehydrated. Most people recover within a few days. The virus is spread when particles from an infected person get into the gut of another person. Poor personal hygiene and particles that become airborne during fits of vomiting are the major means of transfer.

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5 Diagnosis How do doctors determine what disease a patient actually has? Remember

in the last ch a pter that Jim had sym ptoms that su ggested the flu but migh t have been strep throat as well . Knowing wh et h er the disease is caused by a vi rus or a bacteria can redu ce the probl em of taking dru gs that might be useless and could cause other unfore s een problems. Bacteri a l , but not vi ra l , diseases should be tre a ted with the proper anti biotic, but antibiotics are not ef fective against viruses. One of the bi ggest ch a llen ges faced in medicine tod ay is the nu mber of s trains of b acteria that are resistant to one or more antibiotics. The abuse, overuse, and misuse of antibiotics has led to the development of dozens of resistant strains of pathogenic bacteria. If the disease is vi ra l , proper antivi ral thera py should be administered when or if available. Because many indivi du a l s , including some of Jim’s friends, had similar sym ptom s , the doctor su gge s ted that Jim prob a bly had the f lu . Wh en there is an outbreak of s ome re s p i ra tory sickness in the immediate area, it makes sense to test some of the sick patients to determine if influenza is the cause. The signs of the illness, k n own as the clinical symptoms, are often used to make a pre sumptive diagnosis. Un fortu n a tely, a nu m ber of diseases have flu-like sym ptoms, t hus redu c i n g the accuracy of a diagnosis based only on the symptoms. TYPES OF DIAGNOSTIC TESTS AVAILABLE There are a number of tests that can aid in the diagnosis of influenza. In recent ye a rs , rapid diagnostic tests have been devel oped that can be performed on an outpatient basis. Laboratory re sults can be given in 30 minutes or less. As might be suspected, these tests differ in terms of which viruses they can detect. Some detect only Type A Influenza virus,

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whereas others can detect both Type A and Type B. Most of these rapid tests have a lower sensitivity than other, longer tests. Thus, a negative result received from one of these rapid tests should still be con f i rmed with one of the other tests available. Some of these rapid tests are shown below No matter what type of test is being used , the proper collection of materials to be tested is the most important factor in the procedu re. Proper collecti on tech n i ques are nece s s a ry to provi de an uncontaminated sample for te s ti n g. In this way, vi rologists can determine the strain of vi rus causing the disease s ym ptoms and devel op the most beneficial treatment. They can also determine if new, previously uniden tified, s trains of the vi ru s are in circulation. This inform a ti on can then be used to make dec i s i ons about the type of future vaccine to devel op. Th ree major types of samples are collected for testing:

TYPES OF DIAGNOSTIC TESTS TEST NAME

SENSITIVITY SPECIFICITY

TIME

TYPE

SPECIMEN

Directigen™ (Becton-Dickinson)

67-96%

88-100%

<30 min.

A only

NP* swab, throat swab,

Directigen™ A+B (Becton-Dickinson)

81-86%

90-99%

<30 min.

A&B

NP swab, throat swab

FLU OIA® (Biostar/Biota)

62-88%

52-90%

<30 min.

A&B

NP swab, throat swab

ZstatFlu® (ZymeTx)

62-70%

92-99% < 30 min.

A&B

Throat swab

Quick-Vue® (Quidel)

73-82%

95-99%

<30 min.

A&B

NP swab, nasal wash,

~99% 2-4 hours

A&B

NP swab, nasal wash

D i rect Fluorescent Antibody

~90%

Numbers for sensitivity and specificity vary by state— current figures represent ranges of values; * NP = nasopharyngeal.

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Figure 5.1 Taking a culture from the back of the throat is one way to test for the influenza virus. This diagram depicts how a throat culture is obtained. A doctor swabs the back of the patient’s throat with a cotton swab to collect cells. The cotton swab is then sterilely transported to a lab where the cells can be tested for the presence of the influenza virus.

th roat swabs, nasal swabs or washes, and nasoph a ry n geal washes. Ex peri m ental evi dence suggests that nasopharyngeal washes are more ef fective than throat swabs in producing findings . Figure 5.1 shows the reg ion of the throat where a throat swab would be used. A throat culture should be taken before any antiviral medication is given. The patient is asked to open his or her mouth and say “ah.” The tongue is gently pressed down with a tongue blade. The patient’s throat should be well-lit and visible. Using a swab that has been moistened with a solution that will pick up the viruses, the physician gently rubs the swab over the back of the patient’s throat. He tries to avoid touching the patient’s tongue, cheek, or lips with the swab. Af ter the material is co llected, the swab is placed in a s terile container and sent to the laboratory. A nasal swab invo lves a sligh t ly moisten ed cotton, D ac ron®, or polyester swab such as a Q-tips® swab. It is used to get a sample of nasal mucus that may contain bacteria or viruses.

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Figure 5.2 Sometimes a doctor will take a nasal culture instead of a throat culture. Nasal cultures are perf o rmed by swabbing the nasal passage with a moist cotton swab. Generally, the patient is asked to cough and then tilt his or her head. The doctor will insert the swab through the nostrils and to the nasal cavity and rotate the swab to collect a sufficient sample. The cotton swab is then sterilely transported to a lab where the cells can be tested for the presence of the influenza virus.

The swab is inserted abo ut 1 cm (~½ inch) into the nasal c avity and gently rotated. After removal, the sample is placed in a sterile container for transport to the laboratory. Figure 5.2 shows the position of the cotton or po lyester swab for a nasopharyngeal culture. The patient is asked to co u gh before the test and tilt his or her head . The sterile swab is inserted and left in place for about a minute. It passes thro u gh the nostri l and into the nasoph a ry n x . Note from the figure that this is the area over the roof of the mouth. A nasopharyngeal wash requ i res first that the patient’s head be ti l ted backward at abo ut a 70° angle. A syri n ge fill ed with sterile saline has a small piece of tubing attach ed to its tip. The tubing is used to allow the saline to enter the nostril. The nasal secretions should be removed

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immediately by a su cti on devi ce or the patient may tilt his or her h e ad forward and drain the spec i m en into a sterile con t a i n er. VIRAL ISOLATION Any test used to isolate and grow vi ral cultures relies on specimen samples taken by any of the previously indicated methods. There are some suggestions in the literature that nasal washings provi de the best specimens. Specimen samples may be inoculated into the amniotic cavi ty of 10- to 12-day-old embryonated chicken eggs or tissue cultures. Using fertilized chicken eggs as a medium for vi ral cultivation was first propo s ed by Alice M. Woodruff and Ernest W. Goodpasture in 1931. Viral particles wi ll replicate inside the cells of the amniotic membrane, releasing large numbers of vi ruses into the amniotic fluid. Figure 5.3 shows the various sites within the chicken egg that may be inoculated for the cultivation of different vi ruses. Incubation usually takes 48 to 72 hours. Viruses in the amniotic fluid can be detected after they are mixed with a sample of red blood cells taken from chickens, guinea pigs, or humans. Rhesus monkey cells provide the most sensitive cells for tissue culture, although chicken and human kidney cells are also used. Influenza vi ruses isolated by either technique can be identi f i ed as to type by va rious serologic (serum) and molecular tests. Identifying influenza viruses as to subtypes and strains is the job of the World Health Organization reference laboratories. SEROLOGIC TESTS Often the actual cause of a disease may be difficult to isolate and grow in a culture solution. This is true whether the disease is caused by bacteria or by viruses. It is possible to determine whether one has been in contact with the infectious agent by a simple blood test. Serology is the study of the portion of the blood known as the serum. Usually, tests using the serum are designed to detect the presence of antibodies (Ab) to a specific disease or strain of disease. If the body has been infected with bacteria or viruses in sufficient numbers, the immune system will recogn i ze the foreign parti cles, cells, or molecules and

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Figure 5.3 It is difficult to grow viral cultures in a dish in the lab because viruses need a host cell to use for replication. Therefore, v i ruses are often grown in chicken eggs during the embryonic stage (the egg had been fertilized 10 –12 days prior to receiving the virus). The viral sample can be inserted into the egg at several locations. Many of the locations are displayed in this diagram. Viruses can then be collected from the amniotic fluid.

respond to their presence. Antibodies are specific pro teins produced by one type of wh i te bl ood cell when a foreign i nvader is recogn i zed. The production of antibodies is a multistep process undertaken by the immune system. Cells of the immune sys tem, usually mod i f i ed wh i te bl ood cell s , must first recogn i ze the forei gn invader. Af ter these cell s recogn i ze and make con t act with the forei gn invader, a series of chemicals, u su a lly pro tei n s , are rel e a s ed to communicate this i n form a ti on to other parts of the immune sys tem . F i n a lly, acti on is taken , in this case produ cti on of a n ti bodies specific to this forei gn invader. This RCA sequen ce (Recogn i ti on , Com munication, Acti on), or some vers i on of it, constitutes the most com m on immune re s ponse. Thu s , a strain of influenza wi ll cause infected individuals to produ ce anti bodies specific to that strain. This provi des the “foo tpri n t s” of the foreign invader.

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Individuals who have antibodies specific to that strain when tested are said to be seropositive. Additional information about the immune response is found in Chapter 7. It might be useful to revi ew the stru cture of blood at this time. Blood consists of a cellular component, som etimes call ed the “formed elem en t s .” First are the familiar red bl ood cell s (erythroc ytes), responsible for carrying oxygen to our body’s cells and carbon diox i de aw ay from the cells. Second are the white blood cells (leukoc ytes), which are involved in constantly monitoring the body sites for forei gn molecules or cells and also involved in the immune response. Some wh i te blood cells are involved in the rejection of forei gn ti s sues or organs. Finally, the platel ets (thromboc ytes) are involved in the process of blood coagulation or cl o t ti n g. The remainder of the blood is the liqu i d portion known as the “plasma.” The plasma is about 90 percen t w a ter. Di s s o lved inor ganic ion s , or ganic su b s t a n ce s , a n d proteins make up the remainder. Two of the major protein type s , fibrinogen and prothrombin, are involved in blood clotting. If we remove the form ed el ements and the clotting factors , the straw-colored liquid portion that remains is called the serum. Serologic tests can be used to diagnose influenza using a number of antibody or antigen detection tests. One test, k n own as the HAI or hemaggluti n i n - i n h i bi ti on te s t , looks for antibodies produced against one type of spike in the viral envelope. One of the rapid tests menti on ed earlier, ZstatFlu is designed to detect neuraminidase, the other type of protein enzyme found in the spikes of the envelope. An even more rapid determination can be made by looking for viral antigens. An antigen is a molecule, such as a protein, or a cell part, su ch as a bacterial cell wall, that the host determines is foreign to the body. All of the other rapid test procedures prev iously mentioned attempt to detect viral antigens. Viral antigens can be detected in nasal secretions by an immunofluorescence test. In this procedu re, fluorescen t -tagged molecules will attach only to specific antigens, allowing them to be visualized under a microscope . Al t h o u gh the test can be

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conducted fairly rapidly, not all labora tories have the capabi l i ty to carry it out. Some researchers question the specificity of certain parts of this process and of ten find the interpret a ti on of results difficult because of back ground co l ori n g. Th ere appe a rs to be a great deal of su bj ectivi ty in the interpret a ti on of the results. The po lymerase chain reaction (PCR) technique can also be used to detect the presence of antigens. The PCR procedure allows scientists to take a small amount of nucleic acid and make mu l tiple copies of it. In many ways, the PCR machine functi ons like a copying machine. PCR testing of influenza vi rus RNA is currently available, but it is of limited use in a typical laboratory set ti n g. Many clinicians feel that the ELISA (known as enzymel i n ked immunosorbent assay) or EAI test is the best and probably should be the first test used to see if an individual is positive for the suspected viral agent. ELISA or EAI can be used to test for specific antigens or for antigen-specific antibodies. The presence of antigens or antibodies in solution causes the solution to change color. This co l or ch a n ge is sti mu l a ted by an en z ym e . Enzyme immunoa s s ays can be performed rapidly, usually within two hours. There is much less subjectivity in the interpretation of the results, and the test is widely available. The only drawback to the technique is that predictions made from results are not very reliable when the number of a n ti gens or antibodies in the original sample is very low. The Howard Hughes Medical Institute has a virtual labora tory at their online site that enables people to run their own ELISA tests.1 All serologic tests have some level of false-positive results caused by a va ri ety of factors. Both the sensitivi ty and specificity of test results for influenza vary according to the type of sample used, the type of test chosen, and the laboratory person n el who carry out the test. Test results should supplement any other type s of clinical information that is available to the physician. Now that it has been seen how influenza can be treated and diagnosed, atten ti on must turn to methods available to prevent its spread. 1. Howard Hughs Medical Institute’s Bio Interactive website: http://www.hhmi.org/ biointeractive/vlabs/index.htm

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6 Influenza—Nature’s Frequent Flyer: Prevention Remember Jim? He recovered from his bout with the flu. It took about a

week before he was feeling well en o u gh to go back to school. He wondered , though, what he could do to prevent ever getting the flu again. Are there ways that all of us can decrease our chances of coming into contact with the influenza viruses? HOW ARE INFLUENZA VIRUSES SPREAD? It is parti c u l a rly difficult to prevent coming into con t act with either cold or flu vi ruses after som eone near you sneezes or coughs because the viruses pass easily through the air. In f lu enza is a respiratory disease and is very con t a gi o u s . As can be seen in the ph o togra ph of t h e s n eezing man (Figure 6.1), these ti ny drop l ets can travel for lon g d i st a n ces in the air and remain there to be inhaled by unsu specti n g vi cti m s . These re s p i ra tory drop l ets can land on va rious su rf aces and tem pora ri ly con t a m i n a te them , making it po s s i ble to pick up the virus by to u ch . Du ring the wi n ter months, we tend to stay i n s i de m ore of ten , and major holidays bring toget h er fri ends and fami ly m em bers from distant areas. O f ten these friends or relatives have spent s everal hours in airplanes with indivi duals who are infected wi t h the influ enza vi rus and may not show any immed i a te sym ptom s . With limited air rep l acem ent in the plane, d i s persal of vi ruses into

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Figure 6.1 Why is it so important to cover your mouth and nose when you sneeze? Each sneeze forces thousands of tiny, invisible respiratory droplets into the air. Influenza is a re s p i r a t o ry disease and can travel in these droplets. The sneeze in this picture was photographed at a very high speed to demonstrate how re s p i r a t o ry diseases can spre a d .

the air and on va rious su rf aces prom o tes con t act with the p a ss en gers . The viral frequ ent flyers stri ke again. HOW TO KEEP THE FLU FROM CATCHING YOU Th ere are a nu m ber of simple measu res that can redu ce the l i kel i h ood of c a tching the flu . Com m on sense immed i a tely su ggests two basic ide as — avoi d a n ce and good pers on a l hygi ene. If you know that a pers on has the flu, avoid him or her. Talk to him or her on the telephone or send an e-mail

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but re s trict your personal con t act. G oing to shopping malls, singing in the chu rch or sch ool ch oir or ch orus, or joi n i n g your friends at an indoor music or sporting event all represent poten tial sites for the spre ad and dispersal of i n f lu enza viruses. It is important that newborn infants stay away from c rowds because their immune sys tems are not su f f i c i en t ly devel oped to pro tect them . Two major su rf aces that should be cleaned regularly to prevent vi ral contamination and su b s equ ent infection of people are telephones and door handles. Both are well-known sites for viral contaminants. There are a number of commercially available products that are effective in destroying viruses on various surfaces. You could also use a ten percent solution of bleach to destroy the viruses.

COLD AND FLU IN ALASKA Imagine sitting inside an airplane for four and one half hours. This is not unusual on a cross-country trip; however, the people on this particular trip in Alaska never got off the runway. It was March in Homer, Alaska. It was freezing outside and there f o re the pilot turned off the ventilation system, allowing the cabin to remain comfortable thanks to the body heat of the 49 passengers and five crew members. Among the passengers, a woman with a hacking cough was beginning to show the symptoms of the flu. The air was filled with her influenza viruses. The plane finally took off and reached its final destination, Kodiak, Alaska, the next day. Within a day or two, 38 of the 54 persons who had been on that plane came down with the same strain of the influenza virus. The town’s only doctor treated all of the sick patients. This 1977 episode re p resents the only documented incident of its type; an unplanned, contro l l e d experiment with people who became sick from being confined in the same space with a particular virus.

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Influenza — Nature’s Frequent Flyer: Prevention

Covering your mouth wh en you co u gh or snee ze has always been an effective way to minimize the spre ad of respira tory viruses. It is important to make su re that you wash yo u r hands after you co u gh or snee ze . If you shake hands with s om eone who has the flu , if you use a teleph one in a public place, if you open doors in public insti tuti ons or even at h om e , wash your hands. Most people wash their hands after they have ch a n ged a baby ’s diaper but not after they snee ze or co u gh. Re s e a rch has shown that the simple act of washing your hands with soap and water for at least 15 seconds is the single most effective way of dec reasing the spre ad of viruses. Try to avoid touching your nose, mouth, or eyes until you have had a ch a n ce to wash your hands, because these are portals that all ow the virus to enter the body. Rem em ber that you may become ill by coming into con t act with som eon e curren t ly infected with the influ enza virus even though the pers on is not showing any sym ptom s . Th ere is usu a lly a delay of abo ut two or three days bet ween the time you becom e i n fected and wh en you begin to show symptom s . You may recall that Jim and his fri ends went to the con cert Fri d ay n i ght in the packed Civic Cen ter and by early Mon d ay m orn i n g, Jim was showing his sym ptom s . An infected person may be con t a gious the day before symptoms first appear and continue to be contagious for another three to f ive days after the sym ptoms su rf ace . ANTIVIRAL MEDICATIONS You may recall from Chapter 4 that some of the medications used to fight the flu may also be given ahead of time to prevent getting the flu. These pre s c ription drugs provide pro tection for indivi duals who cannot or have not been vacc i n a ted . However, these medications should not be used as a substitute for vacc i n a ti on . Amantadine, also known as Sym m etrel, was approved for use as a preventive agent against Influenza Type A in 1966.

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INFLUENZA

In 1976, its use was expanded to inclu de adults and ch i l d ren older than one year of age. Rimantadine, or Flumadine, is rel a ted to amantadine and in 1993 was approved for use against In f luenza Type A. Neither of these dru gs works against Influenza Type B. In 2000, oseltamivi r, or Tamiflu, was approved for use against both Influenza Types A and B vi rus for pers ons 13 and older. It is a useful med i c a ti on if taken before ex po sure or even after ex po sure to the vi ru s . This ch a racteri s tic makes Ta m i f lu an i m portant drug for indivi duals who conti nu a lly find them s elves su rro u n ded by ill people during the flu season. In spite of the effectiveness of these antiviral agents, the best ch oi ce for prevention continues to be vaccination.

SOMETHING TO SNEEZE ABOUT n M a rg a ret Aimes opened the door to her home and began to sneeze, and she kept sneezing nonstop for more than 200 hours. She tried every known remedy to stop the sneezing. she finally stopped sneezing after she discovered that cheap cologne from her husband’s friend was the cause. n Not many people know that the very first copyrighted motion p i c t u re was made by one of Thomas Edison’s assistants in 1894. The subject and title of the film were “The Sneeze,” and it starred Fred Ott, an Edison employee. Mr. Ott was well known for his comical antics and ability to sneeze on cue (Figure 6.2). The pictures of Mr. Ott sneezing show the distribution of aerosol particles released from the nose and mouth. The sneeze leaves the nose and mouth at about 100 miles per hour. Sneezes are powerful because the muscles of the face, throat, and chest are all involved. n Sneezes occur because nerve endings of the mucous membranes in the nose become irritated. The irritants may be dust, insects, bacteria, viruses, or almost any sort of foreign object. Even light may trigger an attack of sneezing.

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Figure 6.2 What does a sneeze look like in slow motion? This kinetograph, produced by one of Thomas Edison’s assistants, shows the progress of a sneeze.

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INFLUENZA VACCINATION — WHO SHOULD BE VACCINATED? Th ere is nearly worldwi de agreem ent abo ut the need for people to be vaccinated against influ enza (Figure 6.3). In the Un i ted States, the Cen ters for Disease Con trol and Preven ti on (CDC ) , the Food and Drug Ad m i n i s tra ti on (FDA ) , the Na ti on a l Institutes of Health (NIH), and various groups such as the Am erican Lung As s ociation (ALA) have issu ed guidelines as to who should and should not receive the annual vaccine. The Public Health Servi ces of co u n tries su ch as England, Austra l i a , New Zealand, Germany, and Sweden, to name only a few, are also in agreement with the United States organizations. Who should be vaccinated? It is clear that anyone who would like to decrease the chance of getting the flu should be vaccinated. The only exceptions are c hildren less than six months of age and people who may be allergic to som e component of the vaccine. Since the year 2000, the CDC has recommended that a nyone aged 50 or older should be vacc i n a ted ye a rly. It is su gge s ted that this group should also receive a pn eu m on i a vaccine that would con fer lifel ong pro tecti on . Another gro u p that should def i n i tely be vacc i n a ted is health care workers . Anyone who comes into con t act with pers ons who are p a rti c u l a rly su s ceptible to influenza should be vacc i n a ted so that the risk of tra n s m i t ting the disease to these people is dec re a s ed. Doctors, nurses, hospital personnel, nursing home employees, and those who work in chronic-care facilities and clinics are all obvious rec i p i en t s . Home care nu rses and vo lu n teers, those who work in assisted living and other senior residences, as well as children and others who live with people at high risk for the flu also qualify. Who is con s i dered to be at high risk? On April 12, 2002, the CDC publ i s h ed new influenza guidelines. The guidelines su ggest that pri ori ty should be given to indivi duals wh o are older than 65 ye a rs of age. People who have long-term or ch ronic medical con d i ti ons that might devel op into

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Figure 6.3 Vaccination is recommended by the Centers for Disease Control and Prevention (CDC) as an effective way to protect oneself from getting the flu. People who are at high risk for catching the flu are especially encouraged to get vaccinated. High risk groups include the elderly, health care workers, people with c e rtain diseases or disorders (diabetes, asthma, kidney or liver disease, or impaired immune systems, for example). People who are allergic to any component of the vaccine should talk with their doctors about alternative options.

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complications that could be life - t h re a tening are also to be given priority. Examples inclu de those with ch ronic anemia, diabete s , kidney or liver disease, long-term heart disorders, and lung con d i ti ons su ch as asthma. Any person wh o s e i m mune sys tem is com prom i s ed or whose immu n i ty is l owered as a re sult of diseases su ch as human immunodeficiency vi rus or leu kemia or who is receiving ch em o t h era py or radiati on tre a tments should be vacc i n a ted. As we poi n ted out in Chapter 4, children under the age of 18 who use aspirin to relieve flu symptoms might develop Reye’s syndrome. Therefore, persons aged six months to 18 ye a rs of age should be vacc i n a ted so that they wi ll not develop influ en z a and thus not need aspirin thera py. Pregnant wom en who will be at or beyond their fourteenth week of pregnancy du ring influ enza season should be vacc i n a ted . Pregn a n t wom en who have medical con d i tions that could increase the l i kelihood of com p l i c a tions from influ enza also should be vacc i n a ted before the flu season if possible, no matter what their stage of pregnancy. There are a few other groups that should strongly consider getting the flu vaccine. Viruses of all types are “frequent flyers” that fly for free on airlines that visit all parts of the globe . Travelers vary in their risk of exposure to influenza, depending on their travel de s ti n a ti on and the time of the year they are traveling. Influenza occurs all year long in the trop i c s . In the tem perate zone of the So ut h ern Hem i s ph ere , i n f lu en z a normally occurs from April thro u gh September. In the Nort h ern Hem i s ph ere , O ctober thro u gh Ma rch are the typical flu mon t h s . Ba s ed on this informati on , pers ons wh o plan to travel to the tropics or plan to travel with an organized to u rist group at any time of the year should be su re to be vaccinated ahead of time. If a trip to the Southern Hemisphere is planned bet ween April thro u gh September, the traveler should stron gly con s i der the flu vacc i n e . Com mu n i ty servi ces pers on n el su ch as firem en and

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police officers provide important activities that should not be disrupted by loss of personnel time. Teachers and religious leaders are surrounded by large numbers of people on a regular basis. Students at all levels of edu c a tion, parti c u l a rly those living in dormitory con d i tions, a re prime candidate s for con t act with respira tory infectious agents. In d ividuals who attend large indoor rallies, conventi on events, sporti n g even t s , or musical ga t h eri n gs are all su s cepti bl e . Du ri n g ep i dem i c s , the risk of i n fecti on is pre s ent even at large o utdoor parade ra ll i e s . All these indivi duals should be en co u ra ged to receive the vaccine to minimize their ch a n ce s of i n fecti on. VACCINATION — WHO SHOULD NOT BE VACCINATED? The influenza vaccine is a suspension of inactivated influenza viruses. A vaccine is designed to stimulate the immune system to produce antibodies that will recognize particular microbes or viruses whenever they enter the host’s body. This provides the host with long-term immunity against the specific microbe or virus. This type of immunity is known as active immunity. The specific viruses thought to be needed for the year’s vaccine are grown in eggs. There are three viral types used in the vaccine —two strains of Type A and one strain of Type B. The viruses are destroyed chemically and purified before the vaccine is com p l eted. This type of vaccine is said to be made of inactivated viruses. The vaccine is continuously tested to ensure its purity, safety, and ability to stimulate the immune system of humans. Small amounts of egg protein may remain in the vacc i n e ; therefore those individuals who may have all er gic re acti ons to ch i cken eggs should consult their physicians about other options. Typical allergic reactions might include welts or hives, swelling of the tongue or lymph nodes, difficulty breathing, or, most dramatically, a loss in blood pre s su re resulting in shock.

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People who are currently ill, particularly with upper respiratory tract infections, should wait until they have recovered before receiving the vaccine. In 1976, a limited number of people developed Guillain-Barre syndrome, a rare paralytic disorder, after being vacc i n a ted. There has been no incre a s e in risk of Gu i llain-Barre syndrom e’s being assoc i a ted with vaccination since 1977. The influenza vaccine is made from viruses that are no longer active; therefore you should not become infected or show signs of the flu. The most common side effect is soreness at the site of the injection, which may last for one to two days. Less than one third of the people who receive the shot have this reaction. Occasionally children may experience fever, fatigue, and muscle aches that start to occur six to twelve hours after the injection and last one to two days. SURVEILLANCE EFFORTS In 1947, doctors and medical researchers suggested forming a worldwi de watch (surveillance) for influ enza outbreaks. The World Health Organization was founded in 1948 and given the responsibility for this international effort. WHO keeps a constant watch for outbreaks of influ enza anywh ere in the world. To accomplish this task, there are a series of 110 centers or “sentinel” laboratories located in 83 countries. Additionally, there are four major WHO Co ll a borating Cen ters for Vi rus Referen ce and Re s e a rch. These major centers are loc a ted in Melbourne, Au s tra l i a ; To kyo, Ja p a n ; Lon don , E n gl a n d ; a n d the CDC h e ad qu a rters in At l a n t a , G eor gia. This network of laboratories monitors activity throughout the world, and when a new outbreak of influenza occurs, these laboratories isolate the virus and send it and all available information to the closest WHO Center for Virus Reference and Re s e a rch. The Cen ter then iden tifies the specific strain of virus involved in the outbreak. The Centers are constantly i s o l a ting influ enza vi ruses from humans and animals to

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determine which strains are current in the envi ron m ent. Consultations are held on a regular basis between the centers to review the information regarding which viruses are causing the current influ enza ep i s odes. This informati on makes it po s s i ble to recom m end wh i ch vi ral strains should be i n cluded in the vaccine com po s i ti on for the next flu season . In May 2002, WHO adopted the con tent of a Global Agenda for the Ma n a gement and Con trol of an In f lu enza Pa n demic. This doc u m ent and its con tents will be noted in the last ch a pters of the book as our con cerns, h opes, and dreams for the futu re are ex a m i n ed .

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7 Dealing with Complications For most people, including our friend Jim, a bout with the flu provides only

an unpleasant memory. Of course Jim is a healthy, 18-year-old college freshman. He has no predisposing illness or conditions and does not fit i n to any high-risk groups. He lives at home, eats regularly, exercises, and does not smoke or drink. Remember from Chapter 6 that there are a number of individuals, however, who are at high risk for influenza. Those over 65 years of age are particularly susceptible. Most of the complicati ons assoc i a ted with influ enza invo lve the l ower respiratory tract. F i g u re 7.1 provides a look at the respiratory system starting at the nose and mouth and working down into the lu n gs . The ori gin of the com p l i c a ti ons may be bacteri a l , vi ra l , or a combi n a ti on of the two. For some individuals, ex i s ting ch ronic diseases m ay become wors e . This is espec i a lly true for those su f fering from c a rd i op u l m onary diseases. TYPICAL SYMPTOMS The influenza vi ruses are spre ad by way of respiratory droplets, som etimes k n own as aero s o l s . The virus particles bind to cells of the respira tory epithelium by means of the hemagglutinin pro teins. The cells of the re s p i ra tory epithelium, specifically the simple ciliated columnar and the pseudo s tra ti f i ed ciliated co lumnar ep i t h el iu m , are fill ed with vi ra l receptors . As the newly form ed vi ruses are prep a ring to leave the host cell , the protein neu raminidase helps to sep a rate the vi ruses from each other and the host cell mem brane, t hus aiding the infectious process by releasing vi ru s

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Figure 7.1 Complications from influenza can affect the respiratory system. The virus enters through the mouth or nose and travels down to the lungs. Along the way, viral p a rticles can stick to the epithelial cells that line the re s p i r a t o ry tract. Lung tissues can swell and become painful, and pneumonia can occur. Other complications involve the muscular, circ u l a t o ry, and nervous systems.

parti cles that have been bound by the mucus pre s ent on the su rface of ep i t h elial cell s . (Figure 7.2) The usual symptoms of influenza appear after a ty pical incubation period of about 48 hours. A rapidly developing

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Figure 7.2 Cells in the wall of the trachea, seen here, contain hemagglutinin proteins. The airborne virus particles enter the re s p i r a t o ry system and bind to these proteins. A protein called neuraminidase helps the viruses to separate from one another, effectively releasing m o re particles into the body.

fever that may re ach over 101°F is matched by a splitting headache. The fever is usually present and lasts about three d ays . Th ere is usu a lly also shiveri n g, a dry ra s py co u gh , fatigue, and muscular aches and pains. Some indivi du a l s become sensitive to light, but this is not com m on to all.

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In f lu enza Type B infections are similar to those caused by Influenza Type A, but infections with Influenza Type C usually go unnoticed or are very mild in nature. COMPLICATIONS — RESPIRATORY Because the influ enza vi ruses norm a lly rep l i c a te in the lower, warmer, respiratory tract, the ti s sues of the lung of ten become swollen and inflamed. After the viruses have i nvaded the columnar epithelium, they begin replicati on , wh i ch re aches its peak one to three days after that initial infecti on . Damage occ u rs almost immed i a tely as cells start to die and swelling and inflammation begin, of ten spreading to the bron chioles (ex tensions of the bron chi) and alveoli (lung or air sacs). This inflammatory re s ponse cre a tes slight damage to the lungs, but they usu a lly heal within a few weeks. Th e epithelial cells normally begin their recovery within a week, but re s toration of full function for the cilia and for mu c u s produ ction may take two weeks. Mucus is produ ced by m od i f i ed epithel ium called gobl et or mu cous cells. Cilia are pro tein micro tu bules that ex tend thro u gh cell membranes and serve to sweep mucus-laden materials upward so they can be rem oved from the body. As shown in Figure 7.3, a variety of con d i ti ons and agents, including smoking and influ en z a , m ay damage or depress the cilia and prevent their proper functi oning. In those indivi duals with a depre s s ed , i m p a i red , or s l owed immune sys tem, com p l i c a ti ons may arise. The very young and the very old of ten have a slower than normal i m mune re s pon s e . The most com m on and po ten tially the most severe of the com p l i c a ti ons leads to pn eu m on i a . Pn eumonia is a general term for an inflammatory disease of the lungs. This inflammati on may lead to ti s sue damage. At this poi n t , the damaged cells release their fluid con tents into the lung area, further dec reasing su rface area for exch a n ge of ox ygen and carbon diox i de ga s e s .

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Figure 7.3 Smoking damages the epithelial cells of the lungs. Extra, unhealthy cells may grow in addition to, or even replace, normal healthy cells. The top diagram shows normal epithelial cells. Notice how the cilia lie on top to sweep away any foreign debris, and the cells lie flat against one another. In the middle diagram, extra basal cells have started to gro w next to the basement membrane. In the bottom diagram, the cilia have disappeared as well as the columnar cells. Squamous cells now grow in a random pattern and are damaged. They have also ruptured the basement membrane and begun to invade other tissues.

Pn eu m onia related to influ enza may have a bacterial or a viral origin. Bacterial pneumonia is considered to be the most common form, pure viral pneumonia the least comm on form, and a com binati on of both lies som ewh ere in bet ween. Ma ny of the bacteria re s pon s i ble for bacterial pn eu m onia are

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found as part of the normal flora of the nose and throa t . Wh en the influ enza virus damages and we a kens the lu n gs and the cilia in the trachea, these bacteria are able to de s cend i n to the lu n gs. Loss of ciliary functi on prevents mucus from being swept upw a rd and being rem oved from the body. This re sults in what is som etimes call ed a “su peri n fecti on ,” with bacteria that are part of the normal flora becom i n g opportunistic and creating damage to the host cells. The three bacterial species men tion ed most frequ en t ly in assoc i a tion with influ en z a - rel a ted pn eu m onia are St a p hyl o co ccus aureus, Streptococcus pneumoniae, and Haemophilus influenzae . Pa ti ents with bacterial pn eu m onia usu a lly re s pond favorably to tre a tm ent with anti bi o ti c s . Som etimes anti bi o tics are not effective because of bacterial re s i s t a n ce to the anti bi o tic. In patients with existing heart or lung disease, c i rc u l a tory failure may occur. If the immune system is severely depressed, toxins released by the bacteria may overwhelm the patient, leading to a lack of oxygen being carried to the body or to toxic shock syndrome. Toxic shock syndrome is caused by toxins released by specific strains of St a p hyl o co ccus aureus. Recent evidence suggests that the genetic information on how to m a ke these toxins was provided by viruses that infected the St a p hyl o cc u s bacteria. Wors ening of an alre ady existing con d i ti on known as COPD (ch ronic ob s tru ctive pulmon a ry disease) is not uncom m on with influ enza infecti on s . This COPD syndrom e may invo lve a com bi n a ti on of conditi on s , i n cluding chron i c bronchitis, asthma, emphysema, and cystic fibrosis. Any significant ob s tructi on of the air passages leads to co u ghing, wh ee z i n g, and painful bre a t h i n g, known as dys pn e a . COMPLICATIONS OTHER THAN RESPIRATORY Some of the other complications related to influenza may involve the heart and circulatory system, the muscles, and the central nervous system. Although cardiac complications have

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occurred in apparently healthy young adults, the bulk of cases i nvo lve older persons with pre - ex i s ting cardiopulmonary disease. A common cardiac complication in older persons is atrial fibrill a ti on, a con d i tion in which the con tractions of the right and left atria or auricles of the heart are out of rhythm and often twitch. This usually leads to lack of pumping action by this part of the heart. Even in a strong heart, atrial fibrillation may reduce pumping action by 20 – 30 percent. Pericarditis, inflammation of the membrane surrounding the heart, and myoc a rd i tis, inflammation of the heart mu s cl e itself, have been associated with influenza. Although a certain amount of aches and muscular pains are com m on in influenza, some doctors have reported leg pains and muscle tenderness that may last up to five days in children. This muscular involvement for children has been rel a ted to infecti on by In f lu enza B virus. In f l a m m a tion of muscle fibers is known as myositis. Cases of en cephalitis, inflammation of the ti s sues of the brain, have also been reported. In children, a potentially severe complication of influenza is otitis media, an infection of the middle ear which, if not treated quickly, can lead to rupturing of the eardrum. The infection is caused by bacteria, and the tre a tment requires draining pus from the middle ear. The bacteria pass from the nasopharyngeal region (see Figure 7.4) into the eustachian tube. Since children have shorter eu s t achian tu be s , they tend to be more su s cepti ble to middle ear infecti on s . In ad d i ti on , because influ enza decreases the flow of mucus aw ay from the tu be , m ore bacteria are likely to be in the are a . One last con d i ti on to men ti on is Reye’s syndrom e , a previously men ti on ed con d i ti on that is more a com p l i c a ti on of the attem pt to con trol fever by taking aspirin produ cts. Although rare, it is an important complication in yo u n g children and adolescents. As many as 10 – 40 percent of those affected may die, and many survivors may suffer serious n ervous sys tem damage.

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Figure 7.4 Complications from influenza can even affect the ear. When mucous does not drain properly from the eustachian tubes, it can collect and cause an infection. This diagram of the interior region of the head shows some of the areas that can be affected by influenza, including the eustachian tube, the tonsils, and the nasopharynx (nasopharyngeal region).

The CDC suggests that, in an average year, complications from influenza may lead to approximately 20,000 deaths and over 100,000 hospital cases nationwide. Flu is the fifth leading cause of death of the elderly. HOW THE BODY DEALS WITH INFLUENZA We begin by studying the body’s defenses in general and then look in greater depth at how these defenses deal with invasion by viruses such as influenza. This first group of defenses is not selective and is designed to keep out any and all invaders and

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thus the members of this group are usually called nonspecific defenses. The first line of the body’s defense is the unbroken skin and the mucous membranes lining the respiratory, ga s trointestinal, and urogenital tracts (Figure 7.5). In additi on , t h ere are mech a n i c a l , cellu l a r, and bi och emical mechanisms that act along these su rface membranes. As has been discussed, influenza viruses kill some of the cells lining the t h roat and destroy or inactivate the cilia on their su rfaces. This damage to the cilia and to mucus produ cti on alon g the upper respiratory tract allows bacteria to invade the lower respiratory tract and cause pneumonia. An o t h er non s pecific re s ponse occ u rs when the skin or other cells are damaged or penetrated. This response is known as inflammation. The process fo ll ows a standard series of events, well known to most peop l e . This sequ en ce occurs no m a t ter what the cause or how frequ ent the inva s i on . Th e d a m a ged area becomes red (inflamed) and begins to feel warm to the to u ch . Soon the area is swo llen and begins to hurt. Within a few days the swelling, heat, and pain begin to su b s i de. Af ter a few more days one may be unaw a re of the previously damaged site . Most of these symptoms are the re sult of bl ood flow into the affected are a . In c re a s ed bl ood f l ow leads to the redness, heat, and swelling but also bri n gs t wo major types of wh i te bl ood cells (WBCs) to the are a , the neutrophils and the mon ocytes (Figure 7.6). Mon oc ytes have the ability to change their shape and increase their activi ty level wh en they move from the bl oodstream into the ti s sues. These modified mon oc ytes are known as macrophages, litera lly giant eating machines. These WBCs are i m portant for several re a s on s . Th ey begin to en g u l f , through the process of phagocytosis, pathogenic or ganisms or debri s from damaged cell s . Neutrophils are active for 24 to 48 hours and then die. Monocytes or macrophages may remain in the tissues for several weeks to aid in the repair ef fort s . Th ey may also release en z ymes that keep the inflammatory process going.

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Figure 7.5 Mucous membranes comprise the body’s first line of defense. They prevent foreign microorganisms from entering the body. They are considered a nonspecific defense because they keep out all types of invaders. The diagram above shows some of the locations of mucous membranes in the human body.

Unfortu n a tely, this may lead to further ti s sue damage and requ i re the use of a n ti - i n f l a m m a tory medicati ons su ch as aspirin. Ot h er ch emicals released by macroph a ges sti mu l a te m on oc ytes to convert into mac roph a ge s , t hus incre a s i n g t h eir nu m bers . Mac roph a ges also release a pro tein call ed interleukin-1, which signals the brain to increase the temperature in the region, causing a fever. The incre a s ed tem peratu re of ten increases the bl ood flow into the area. Inflammation is designed to eliminate the invader and repair the damaged cells or ti s sue. The WBCs move into the

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Figure 7.6 White blood cells are the body’s soldiers. They attack any foreign invaders and signal the body to pre p a re to fight the invading microorganisms, if they can not do the job entirely. This diagram shows how immune system mobilizes when it detects antigens in the body. The body has several choices. It can send T lymphocytes to attack the infected cell, ingest the antigen with a macrophage, or send a B lymphocyte to bind to the antigen.

damaged area. Neutrophils are followed several hours later by macrophages, wh i ch adhere to ed ges of the damaged tissue. From invasion to completed repairs usually takes eight to ten days. Viral invasion of cells causes the cells to produce a group of proteins known as interferons. This response is independent of, and thus nonspecific to, the type of virus that has invaded the cell. The production of these interferon proteins acts to inhibit the replication process of the viruses. The ability of the invaded cell to reprodu ce is inhibited , and a group of cells call ed natural k i l l e r (NK) cells are impacted . NK cells have the ability to recognize and lyse (break down) cells that have become infected with viruses. The NK cells release proteins that rupture the membranes of infected cells and then poison the cells with additional toxins that they produce. Researchers

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h ave not clearly identified the specific receptors that the NK cells are able to recognize. NK cells can act immediately and thus are effective early in the development of the viral infection. Their ability to destroy infected cells helps to limit the spread of the viral invasion. Ironically, most of the symptoms of the flu, such as headache, aching muscles, fever, and exhaustion, are caused by the release of the body’s defensive chemicals, particularly interferon. Recovery from a vi ral infecti on su ch as influenza takes s everal days and is attri but a ble mainly to a new class of protein molecules cre a ted specifically to destroy the vi ru s . Vi ru s e s , b acteri a , forei gn pro tei n s , or molecules from almost any source other than the body itself a re known as antigens ( Ag ) . Wh en cells of the immune sys tem recogn i ze these alien cells or molecules, they begin to mobi l i ze va rious ch emicals and cells against these specific antigens. This type of defense repre s ents a specific re s po n se because a unique Ag will cause producti on of m o l ecules specifically directed against that anti gen. A third type of WBC known as a lymphocyte is invo lved in the specific immune re s ponse. About one trill i on lymphocytes are invo lved, and they are divided into two major categories known as the B lymphocytes and the T lymphocytes. B lym ph oc ytes matu re mainly in the bone marrow, and when they recogn i ze anti gens, the B cells are mod i f i ed into shortlived cells that produce millions of copies of a single type of pro tein. The mod i f i ed cells are called plasma cells, and the pro tein produ ced is known as anti body (Ab) or i m mu n ogl obulin (Figure 7.7). The Ab has been produ ced to act against a specific anti gen . The joining of Ag - Ab re sults in the anti gen’s being tagged for de s tru cti on . The first mention of the action of the immune system cells was in Chapter 5. In order to recognize and react to specific antigens, both B and T cells have specific receptor glycoprotei n s embedded in their cell membranes. After recognition and con t act

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Figure 7.7a Plasma cells, like the one pictured here, produce antibodies which act against specific antigens. Plasma cells are m a t u re B lymphocytes and have special receptor glycoproteins that recognize specific antigens. When the plasma cell finds a cell containing an antigen (one that has been invaded by a virus) that matches its antibody, it will attempt to kill the cell.

with the foreign invader, a series of chemicals, usually proteins, are released to communicate this information to other parts of the immune system. Finally, action is taken. B cells are converted to plasma cells, which produce antibodies (Ab) specific to this foreign invader. Antibodies are released into the body fluids or

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humors. This type of specific immunity is sometimes referred to as humoral immunity or antibody-mediated immunity . There are five different types of antibodies or immunoglobulins (Ig) that are produced in response to recogniti on of a specific anti gen. The types are design a ted Ig A , IgD, Ig E , Ig G , and Ig M . The type of Ig produ ced depends on the target site in the body, gen etic va ri a bi l i ty of the host, type of a n ti gen invo lved, and wh ether or not this is the first ti m e that the anti gen has been recogn i zed by the host. IgG antibody is found in the sec reti ons of the lower re s p i ra tory tract, wh ereas IgA is the dominant form found in sec reti ons of the upper re s p i ratory tract. Both are invo lved in immu n i ty a gainst influ en z a . These circ u l a ting anti bodies are the pri m a ry pro tecti on against vi ral infecti ons or attach m en t to the host cell . From a functi onal standpoi n t , the most effective type of a n ti bodies are those that can bind to the hemagglutinin pro tein in the envelope of the influ enza virus. This prevents attach m ent and penetration of the virus. If antibodies are provided after an infection has already occurred, the nu m ber of i n fectious viral parti cles released f rom the cells is usu a lly redu ced . The major ben efit of vacc inati on is its priming effect on anti body devel opment. Without vacc i n a ti on , the immune sys tem must wait unti l cells have been infected and viruses are present in large enough nu m bers to be detected. By that time one is sick, and it will be three to five days before there are su f f i c i ent antibodies to slow the inva s i on . T lymphocytes are capable of regulating the enti re i m mune sys tem and its re s pon s e s . T cells can tu rn on or of f s ome or all parts of the sys tem. This regulati on is part of the body’s homeostatic controls. T cells interact with larger targets, su ch as cell su rface s . This type of i m mu n i ty is known as cell-mediated immunity (CMI) (Figure 7.8). Th ere are a number of subpopulations of T cells.“Helper” T cells are often mentioned in a discussion of acquired immunodef i c i en c y

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Figure 7.7b Macrophages attack foreign invaders. An asbestos fiber lodged in the lung tissue is surrounded by macrophages, which is stained pink in this photo. Iron complexes, stained blue, also surro u n d the asbestos fiber. The macrophages will attempt to engulf and break down the foreign body.

s y ndrome. Helper T cells are also call ed CD4 or T4 cells or lym ph oc yte s . Th ey serve as traffic police and cheerl e aders of the immune sys tem. Wh en anti gens (Ag) are recogn i zed and interleukin-1 (IL-1) is rel e a s ed by the mac rophages, helper

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Figure 7.8 Cell-mediated immunity involves T cells which can regulate the entire immune system. Once a helper T cell is activated, it can either mobilize macrophages to attack the invading object, or i n c rease the production of antigen specific killer T cells. Antigen specific killer T cells have special receptors that match receptors on the body of the invading virus. The diagram above describes this process.

T cells produce a protein known as interleukin-2 (IL-2). IL-2 activa tes B cells to produce Ab specific to the Ag. It also activates other T cells called cytotoxic T cells which, together with NK cell s , attack infected cell s . The hel per T cells also activa te neutrophils and mac roph a ges and sti mu l a te release of WBCs from the bone marrow. This is on ly a small sample of what the hel per cells are invo lved in. It should be easy to s ee that any con d i ti ons that diminish the abi l i ty of the helper T cells to do their job have a major ef fect on the en ti re spectru m of i m mune respon s e s . The human immunodeficiency virus (HIV) targets the helper T cell.

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Figure 7.9 Helper T Cells have many roles. They activate other T cells, help to increase the number of T cells in the body, and aid in humoral immune response. Some of those functions are outlined in the diagram above.

Most people are aware of one type of cell-mediated immunity that invo lves rejection of transplanted organs. T cells produce a series of chemicals called cytokines or lymphokines. These cytokines bind to specific receptors on the targeted cells and can carry out a multitude of functions, depending on the type of cytokine. Some are involved in the inflammatory process, s ome direct ly de s troy targeted cells, and others serve as chemical messengers directing cellular traffic or promoting cellular growth and activity. One of the earliest cytokines to be discovered was interferon, mentioned earlier. This RCA sequ en ce (Recogn i ti on , Com mu n i c a ti on , Acti on ) , or some vers i on of it, con s titutes the most com m on i m mune re s pon s e . Thus, a strain of influ enza will cause i n fected individuals to produce Ab specific for that strain and set into moti on a cascade of ch emical messages that

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involve many segments of the body. Remember that Chapter 5 discussed diagnostic tests that can determine the pre s en ce of a n ti bod i e s . We have only scratched the surface of the intricate nature of the interactions involved in providing protection to the cells and the organism. There are numerous excellent texts and monographs that can provide an even deeper understanding of the immune system and its mechanisms. What is clear is that, in the case of infection by influenza viruses, a fully functioning immune system will allow the disease to run its course within a few days. Avoiding the disease and its symptoms requires a preemptive attack on your part —namely, vaccination. The f utu re awaits us. The next two chapters will examine those things that concern us and those that give us hope.

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8 What May the Future Bring? The Past and Future Concerns The great Spanish philosopher George Santayana reminded us that

“Those who cannot remem ber the past are condemned to repeat it.” With this thought in mind, we revisit the history of influenza in order to learn from it. THE EARLY YEARS An ton van Leeuwenhoek (Figure 8.1) discovered microor ganisms in the late 1600s with his simple micro s cope - l i ke devi ce . Discovery of these previ o u s ly unseen or ganisms led to speculati on that they might be the cause of disease. Du ring the 1700s, techniques were developed and refined that provided pro tection against some diseases by sti mulating an indivi du a l ’s immune sys tem. These tech n i ques, including vaccinati on s , were based on earl i er observati ons made by the Romans and also the Chinese that indivi duals who recover from some diseases do not con tract the same disease again. A virus was still thought of as a chemical poison or toxin through the 1700s, not a distinct structure. Much of our understanding was about to change as we moved into the mid-to-late 1800s. By the 1800s, all major trading routes and contacts had been established. Europe, Asia, and North America maintained continuous, although slow, contact through their shipping trade. Late in 1829, an epidemic of influenza s t a rted in As i a . By

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Figure 8.1 Using a simple magnifying device, Anton von Leeuwenhoek, pictured here, discovered microorganisms in the late 1600s. His “microscope” magnified up to 200 times, much more than previous magnifying devices. His discovery led to the hypothesis that microorganisms might be the cause of d i s e a s e .

Ja nu a ry of 1831 it had re ach ed In donesia. At the same ti m e , du ring the wi n ter of 1 8 30–1831, the disease appe a red in Russia and began to spre ad we s t w a rd . By November of 1831, it had re ach ed the Un i ted State s .

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The So ut h ern Hem i s ph ere was not free of the disease ei t h er. Fo ll owing a visit to New Zealand in 1826 by a British ship, a serious outbreak of the disease occurred. The native pop u l a ti on was highly su s cepti ble because they had had no previous con t act with the disease. A more severe epidem i c bro ke out at the end of 1838. It seem ed that everyone in the northern part of the island was affected. The elderly and those in poor health died in large nu m bers. Both New Zealand and Australia reported a large nu m ber of cases of f lu between 1852 and 1860. In the summer of 1889, a pandemic (worldwide epidemic) began in cen tral Asia. Foll owing a nu m ber of trade ro ute s , the disease spread north to Ru s s i a , east to China, and we s t to Eu rope. England was invaded by the disease during the first week of 1890. At the peak of the epidemic in 1891 and 1 8 9 2 , m ore than 4,000 peop l e , m o s t ly infants and the el derly, died in Lon don. It became known as the Ru s s i a n flu. It was the most devastating of all influ enza epidemics up to this point in recorded history. More than 250,000 people died in Eu rope, and two to three times that number d i ed worl dwi de . Even tu a lly the disease stru ck Nort h Am eri c a , p a rts of Af ri c a , and the major Pacific Ri m countries. In f lu enza remained in England with peaks in 1 8 9 5 , 1 9 0 0 , and 1908. The final on s l a u ght was part of the great pandemic of 1 9 18 –1 9 1 9 , k i lling more than 150,000 peop l e . THE GREAT PANDEMIC As noted in Ch a pter 1, the pandemic that caused more than t wenty mill i on deaths stru ck first in Spain and was call ed the Spanish Flu . Du ring World War I, the Spanish Flu affected mill i on s . However, even though the nu m bers of those dying f rom the flu seemed high, these nu m bers were overs h adowed by what was happening in the war zon e s . The war effort was h i n dered on both sides as more and more troops became too

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ill to fight. For a while the flu appe a red to be dormant in the Un i ted State s , however. Throughout Europe, the flu acquired a variety of names. In Germ a ny it was call ed Blitz Ka t a rrh, in England and Fra n ce , F l a n d ers gri ppe, and in Japan it was “ wre s t l er ’s fever.” The spring wave of flu was relatively mild in Spain, England, Japan, and China. Other regi ons of the world had few, if a ny cases. So uth America was missed completely. The flu had also been spre ad to the Eu ropean battlefields by more than 1.5 million American soldiers who cro s s ed the At l a n tic to help fight the war. Some died at sea from t h e d i s e a s e , while others carri ed the disease to the front lines and trenches. As the war came to a close, soldiers came home and brought with them a new, more viru l ent form of the disease. In the Un i ted States, on Ma rch 11, 1918, the company cook at Camp Funston (part of Fort Riley), Kansas, reported s i ck . Albert Gitchell had a fever, sore throa t , head ache, and muscular aches and pains. As his tem peratu re was being t a ken, a second soldier, Corporal Lee W. Dra ke reported to the same bu i l d i n g. His tem peratu re was 103°F, and his sym ptoms were nearly iden tical to Gitchell’s. By noon , 107 cases had been admitted to the hospital. (Figure 8.2) Within a week, 522 cases had been reported in Ca l i fornia, Florida, Virginia, Alabama, So uth Ca ro l i n a , and Geor gia. Pers ons aboa rd ships in East Coast harbors and prison ers in San Quentin Prison were also affected. The second wave of the flu was particularly lethal. As the virus passed through multiple human hosts, it changed from a relatively mild form to som ething horrible. It re ached China in July, Iran early in August, and France in mid-August. Wh en the second wave ended, between 22 and 40 million people were de ad worl dwi de . The actual nu m ber wi ll prob a bly never be known . In the Un i ted State s , 5 0 0 , 0 0 0 to 600,000 people died . The disease covered the gl obe in

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Figure 8.2 Influenza struck Camp Funston in 1918 and began a large epidemic that stretched across the United States. Medical personnel at Camp Funston set up an emergency hospital, shown above, to deal with the overwhelming number of flu patients. The virus mutated as it passed among people, and by the time the epidemic ended, over 500,000 people in the United States had died.

less than two mon t h s . How it traveled su ch great distances in su ch a short period of time is sti ll unknown. This disease was so widespread that even rem o te Eskimo villages were

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completely wiped out. Entrance to the United States probably occurred on August 28, 1918, just out s i de of Bo s ton. It has been su gge s ted that a sailor on a tra n s port ship in Bo s ton Ha rbor had sym ptoms of i n f lu en z a . By August 30, over 60 sailors were reported ill. F lu su f ferers descri bed feeling l i ke they “had been be a ten all over with a clu b.” Some of the sailors on this ship were transferred to Mi ch i gan and Illinois and became the starting point for the spre ad of the disease i n to the Mi dwe s t . Camp Deva n s , the army base out s i de Bo s ton , was a su pply and exchange point for soldiers going to and coming b ack from the war. A case of i n f lu enza was diagn o s ed at Camp Devans on Septem ber 12. By the end of O ctober, m ore than 17,000 cases had been reported at Devans. Ne a rly 800 men in the prime of their lives died. It was said that “dead bodies were stacked in the morgue like cordwood .” The disease moved down the East Coast, with death rates ranging from six to 15 percent of those affected. In crowded army camps as many as 24,000 soldiers died. By the third week of October, the disease had reached the West Coast and affected a ll of the major urban areas along the way. The civi l i a n popu l a ti on showed an infecti on rate of about 28 percent. O f ten , people attending open-air ra llies for the Liberty Loan drives or watching parades of retu rning soldiers were surrounded by sneezers and coughers. In Philadelphia, 200,000 people gathered at a rally to su pport the war effort. Within a few days, influenza covered the city. Six hundred thirty-five new cases of influenza were reported. The city closed theaters, schools, and churches and passed laws preventing outdoor group meetings. People were required to wear gauze masks when in public. (Figure 8.3) Unfortunately, the gauze was porous and did not stop the virus from escaping into the surroundings. The numbers of cases were staggering in the big cities: 851 New Yorkers died in a 24-hour period. In Boston, the number was 202 dead in a day,

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Figure 8.3 The flu spread quickly throughout the city of Philadelphia when over 200,000 people gathered for a war rally in 1918. Gauze masks, like those worn by the people in the picture above, were used to prevent spread of the disease but were ultimately unsuccessful because virus particles could still escape through the pores in the gauze.

while in Philadel ph i a , 289 died of the disease in one day. October 1918 was the deadliest month in American history. Philadelphia lost nearly 13,000 of its citizens. A total of nearly 195,000 American citizens died from influenza-related causes

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that October. The disease became so commonplace that young girls even sang a song as they played and jumped rope: I had a little bird Its name was Enza. I opened the window, And In-flu-enza

The disease conti nu ed to circle the gl obe. It was esti m a ted that more than 12 mill i on died in India. In some Pacific Islands, mort a l i ty figures re ach ed 20 percent of the total populati on . People living in areas of the world that had not previ o u s ly experi enced respiratory diseases of this type had no built-up immunity. Th ey were ex trem ely suscepti ble to the rava ges of the disease. The more suscepti ble the population, the high er the mort a l i ty ra te. The more den s ely packed the population, the h i gh er the mort a l i ty. It was therefore not unusual for urban are a s and overcrowded vi ll a ges to see a large nu m ber of deaths. The disease began a slow retreat in Novem ber 1918. Th i rty thousand people in San Francisco cel ebra ted the end of the war on Novem ber 11, by we a ring masks. On Novem ber 21, the siren s sounded telling people in San Francisco that it was safe to rem ove their masks. Thanksgiving Day took on new meaning for some in the United States. In Decem ber, 5,000 people in San Francisco came down with the flu. In San Di ego, a gen eral quarantine and the requ i red use of ga u ze masks occurred that Decem ber. (Figure 8.4) The citizens of San Di ego had their own little tune. Obey the laws And wear the gauze. Protect your jaws From septic paws.

The mask law was not pop u l a r. Men cut holes in the mask to smoke ciga rs and ciga ret te s . Wom en dra ped the

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mask like a veil. Failure to obey the law could result in a $100 fine and 30 days in jail. However, the law was ra rely enforced. It has been su gge s ted many times that du ring the time of the second wave of the flu ep i demic in the Un i ted S t a te s , more people died in Am erica from the flu than in combat in all of the wars of this century. The postwar ye a rs were rel a tively qu i et from a flu s t a n d poi n t . Regi onal ep i demics con ti nu ed to flare up, but t h ere was no worl dwi de pandem i c . Re s e a rch on vi ru s e s con ti nu ed to expand and become more soph i s ti c a ted . By the 1930s, re s e a rch ers were looking for an animal host in which to test the disease. In 1932, the structu re of the virus was seen with an el ectron micro s cope . Th ree Engl i s h scientists used throat materials taken from patients, during the ep i demic of 1 9 32 –1933 in Engl a n d , to try to infect labora tory animals. The usual labora tory animals of ra bbi t s , mice, and guinea pigs were not affected. Only ferrets showed the sym ptoms of i n f lu en z a . By 1940, ch i ck em bryos had become the standard ex peri m ental animals. In 1935, Wen dell Meredith Stanley showed that vi ruses con s i s ted of pro tein and nu cl eic acid and could be cryst a ll i zed . Historical accounts from the 1930s to present d ay are covered in Ch a pter 1. FUTURE CONCERNS S teph en Spen der, an early twen ti eth cen tu ry poet , on ce suggested that “History is the ship carrying living memories into the future.” Few are alive today to provide those living memories of the time when influenza was a major regulator of the global pop u l a tion. Our look to the futu re wi ll con clu de by identifying some concerns regarding influenza. A separate chapter will examine hopes for the future. It must also be understood that concerns about influenza are part of a larger, more general concern about the emergence of deadly infectious diseases of all types.

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Figure 8.4 Other cities, such as San Francisco and San Diego, California, also required citizens to wear masks. Here, Red Cross workers are sewing gauze masks for distribution. However, some people refused to wear the masks, cut holes in them for cigarettes, or wore them like veils instead of masks. In addition, the masks were ineffective because the gauze was porous and the virus could pass through the tiny holes.

The State of Minnesota has recently propo s ed the developm ent of a new Pu blic Health Laboratory Facility. As part of its justi f i c a ti on, it has enu m erated a nu m ber of em er ging

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health con cerns that wi ll increase the demand for futu re l a bora tory servi ce s . That list of con cerns is shown here ; it clearly demonstra tes our com m on health con cerns. • Increased international travel, making it easier for diseases like tuberculosis or pandemic influenza to spread from one part of the world to another. • The globalization of our food supply, potentially exposing us to new foodborne illnesses from other parts of the world. • Human encroachment on wilderness areas, which i n c reases human ex posu re to animal species that may harbor new or unusual threats —like hantavirus or the West Nile virus. • An increase in the number of disease-causing microbes that won’t respond to antibiotic treatment. • Growing con cern abo ut the pre s ence in our drinking w a ter of pharmaceuticals and other com m ercial ch emicals, m a ny of wh i ch are capable of disrupti n g the endocrine sys tem or otherwise affecting human health. • The very real threat of a bioterrorism attack, invo lving po tentially deadly agents like anthrax, smallpox, or plague. — Minnesota Department of Health, “Proposed Public Health Lab Facility,” February 5, 2002.

It should be clear that our gre a test con cern is the possibi l i ty of a n o t h er pandemic of the magnitu de of the Gre a t Pa n demic of 1918. With our incre a s ed mobi l i ty by land, sea, and air, the entire world could be invo lved in less than a week. The American College of Physicians has identified several recom m en d a ti ons to con s i der in preparing for the

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possibility of the next influ enza pandemic. These five recommendati ons indicate that pandemic preparedness requ i re s the fo llowing:2 1) Rapidly recognize new virus strains. 2) Establish an adequate surveillance network to detect new strains and assess their effects on populations. 3) Identify the origination of new strains from the animal population. 4) Define the target groups for vaccination. 5) Clarify the role of antiviral drugs.

Ma ny of these recom m en d a ti ons are being actively p u rsu ed . The World Health Orga n i z a ti on has iden ti f i ed a gl obal agenda for pandemic planning and its influ en z a su rveill a n ce net work. However, Dr. Robert Web s ter, Di rector of the World Health Orga n i z a ti on Co ll a bora ting Cen ter on the Eco l ogy of In f lu enza Vi ruses in Lower Animals and Bi rd s , c i tes a nu m ber of defects and crises assoc i a ted wi t h these progra m s . D r. Web s ter is con cern ed that there wi ll be inadequate com munication between labora tories working on the eco l ogy of i n f lu enza vi ruses in animals and the su rvei ll a n ce net work for human influ en z a . The 1997 bi rd flu incident in Hong Kong showed the po ten tial for p a n demic infecti on by tra n s m i s s i on from lower animals to hu m a n s . In April of 2002, the Agri c u l tu re , F i s h eries and Con s ervation Department of Hong Kong indicated that they would begin carrying out dual preventative measures to counteract the possible spread of influenza viruses from chickens to humans. They are depopulating chicken farms in some areas 2. Gross, Peter. “Preparing for the Next Influenza Pa n demic: A Reemerging In fecti on .” Annals of In ternal Med i ci n e, 124 (1996): 682-685.

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and using a vaccine in other areas. All chicken farms in Hong Kong are under constant monitoring. Dr. Liu Kwei-kin, deputy Director of the Department, stated that: We will implement the fo ll owing three measu res at farm level: to amend licensing con d i ti ons so as to introdu ce bi o s ec u ri ty measu res and raise hygiene level on farms; to con tinue active mon i toring of the health of ch i ckens to en su re that on ly ch i ckens that pass our test can be sold at market; to close any farm con cerned on ce there is an outbreak.3

Chickens are not the only animals that can carry influenza viruses. Birds of various types are responsible for transmitting viruses to other animals. Wa terfowl do not develop the flu, yet they carry nearly all the known types of influenza viruses. Animals come into contact with the viruses through the fecal materials of the birds. Until the outbreak of flu in Hong Kong in 1997, it was felt that humans could not get the viruses directly from birds. The most common means of transmission f rom animals to humans was, and is, by way of p i gs . As the populations of chickens and pigs has increased through commercial farming, the chances for viral transmission and reassortment within different species have increased. Dr. Web s ter’s second major con cern is the lack of recom m en d a ti ons for stockpiling anti - i n f lu enza drugs to deal with a pandemic. Th ere con tinue to be insu f f i c i ent su pp l i e s of f lu vaccine worl dwide. The Centers for Disease Con tro l and Preventi on esti m a tes it would take abo ut 22 weeks to develop and manu f actu re a new vaccine. If the cause of the f lu pandemic is a viral strain alre ady known, the time might be reduced to 12 weeks. G et ting the flu vaccine to the public and overcoming public apathy rega rding the severity of the probl em are two other con cerns. 3. http://www. i n fo. gov.hk/gi a / general/200204/06/0406176.htm

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The final group of con cerns to be noted here invo lve s a n tiviral drugs for use against influ en z a . Th ere are curren t ly no new antiviral influ enza drugs that are being con s i dered. D ru gs that had been in devel opm ent have ei t h er been c a ncelled or have failed in Phase III trials and been removed from further testing.4 The future of the newest drugs, Tamiflu and Relenza, continues to be debated by the drug companies. F i n a lly, viral mut a tion has led to re s i s t a n ce to amantadine and is an escalating con cern. Although concerns are many, they are being identified, and systematic attempts are being made to find answers to these problems. In the last chapter, we looked to our hopes for the future. These include new genetic information about various strains of influenza that will provide opportunities for new treatm ents and therapies, worl dwide su rveill a n ce net works, and new types and forms of vaccines.

4. See gl o s s a ry for an ex p l a n a ti on of the three phases of clinical trials.

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9 The Future: Hopes and Dreams We have come a long way in trying to find ways to treat and cure diseases.

Early attempts to kill microbes were based on uncritical human observations and ranged from the use of moldy bread to whisky, vinegar mixed with egg whites, or gunpowder. Treating materials with heat resulted in developments such as pasteurization, while spraying the operating room with phenol provided an early means of disinfection. Discovery and development of antibiotic chemicals and antibacterial or antimicrobial drugs in the 1930s led to a growing new pharmaceutical industry toward the end of World War II. Ki lling bacteria, h owever, has tu rned out to be a lot easier than destroying viruses. Viruses are intracellular parasites that use the resources of the host cell to make more viruses. Finding or developing drugs that will destroy or inactivate the viruses without harming the host is a major challenge. Some new antiviral drugs have been developed; however, current research and development for new antivirals is agonizingly slow. Just when s c i en tists think they have finally figured out this latest viral wrinkle, the virus mutates. Where will the future lead us as we attempt to find new treatments for influenza? INCREDIBLE EDIBLES We can all remember being told at some point in our lives: “You are what you eat!” Maybe it was a biology teacher or perhaps a frustrated parent talking to an adolescent who was eating non s top. Within a few ye a rs we may be able to put a new spin on that idea. We now have the tech n o l ogy to

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Figure 9.1 Genetic engineering is the scientific process of altering DNA to enhance desired traits or remove undesirable ones. For example, certain plants can be engineered to contain natural pesticides, so that they are not as vulnerable to insects. Or they may contain enhanced growth horm o n e s to boost crop production. In the biomedical field, corn plants, like the ones pictured here, have been engineered to secrete human antibodies.

genetically engineer plant crops, such as corn, to secrete human antibodies. (Figure 9.1) After a number of unsuccessful attempts, we now have “plantibodies” that are being used to treat nonHodgkins lymphoma in test animals. Soybeans are being grown with plantibodies against the herpes simplex 2 virus. Epicyte , a bi o tech com p a ny in San Diego, will be starting

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clinical trials of antibody production against herpes simplex 2 using corn kernels. Tobacco plants are producing plantibodies to prevent tooth dec ay. Proper eating for bet ter health take s on a whole new meaning. While there is no current ed i ble vaccine for influ enza, potatoes are being used as vaccine vehicles for a diabetes vaccine that has been su ccessful in mice . In April 2002, researchers in California identified genes in tomatoes that would enable the tomatoes to be used for production of antibodies against diseases such as cholera. Given the aversion of children and adults to needles, new delivery systems using plants and vegetables would encourage many more people to become vaccinated. Dr. Hoong-Yeet Yeang of the Rubber Research Institute of Malaysia announced in February 2001 that he had succeeded in producing anti bodies against bacteria in the sap of the rubber tree. He also has produced human serum albumin in his rubber trees. This serum albumin is a vital fluid given to patients who are fed intravenously in intensive care units. THE PATCH Another type of needl e - f ree vaccine under devel opment is the transcut a n eous patch. Dr. De - chu Tang (Figure 9.2), a research er at the Univers i ty of Alabama, has devel oped a needl efree vaccine for influenza that can be swabbed on the skin and covered temporarily with an adhesive patch. Eventually, the vaccine could be incorpora ted direct ly into the patch. Trials of the patch are awaiting approval from the Food and Drug Administration (FDA). Five to ten years of development would fo ll ow su ccessful field te s ti n g. Ma rk R. Prausnitz, engineering professor at the Georgia Institute of Technology and his colleagues have developed a tiny patch with 400 needles that poke beneath the upper layers of the skin but above the nerve endings. Figures 9.3 and 9.4 show the overall size of the patch and a magnified view of the needle array. The skin is

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Figure 9.2 Dr. De-chu Tang of the University of Alabama, pictured here, is developing a needle-free version of the influenza vaccine. This new vaccine would be applied to the fingertip in liquid form. The skin contains a large number of immune cells and administering the vaccine this way would potentially boost the immune response.

filled with immune cells that provide a useful environment for stimulating the immune sys tem. This improved immune response is another powerful stimulus to developm ent of this method of vacc i n a ti on. The abi l i ty of the pati ent to selfadminister the patch and to obtain the vaccine over the counter at the local pharmacy would increase appeal and efficiency. THE “HYPOSPRAY” Those who remember the various Star Trek series will recall that the doctors were able to give patients shots directly into the skin using a painless spraygun called a hypospray. Liquid jet injections have been used for a number of years, particularly

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Figure 9.3 Mark Prausnitz and his team at the Georgia Institute of Technology have also developed an alternative influenza vaccine. A tiny patch containing 400 microscopic needles would deliver the vaccine below the skin. This picture shows the size of the patch relative to the patient’s finger.

by the armed services, with so-called “guns” that are still often painful. A new system being tested uses helium to push tiny amounts of powdered vaccine into the skin without pain. Developed by a company called PowderJect, this system may be very effective for vaccines because it delivers to the outer layer of the skin. (Figures 9.5 and 9.6) Currently, the company is testing a vaccine against hepatitis B, and the results have shown the vaccine to be both safe and to provide a high degree of immunologic protection. The influenza vaccine is one of those

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Figure 9.4 A magnified view of the vaccine patch shows the m i c roscopic needles that would deliver the vaccine underneath the skin. This patch raises the possibility of over- t h e - c o u n t e r availability and patient self-administration, making the flu vaccine more accessible to the public.

that will be te s ted with this sys tem . The Powder Ject com p a ny is also working on a DNA-based influenza vaccine that may provide protection against antigenic drift. NASAL SPRAYS — NOW In July 2002, the FDA was supposed to announce whether it had approved the use of a new nasal vaccine called FluMist™. However, on July 11, the FDA requested further information and clarification about the vaccine but did not request more

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Figure 9.5 This picture diagrams the inside of a PowderJect system. The PowderJect “gun” works by using helium gas to push a dry, powdered version of the vaccine at a very high speed through the skin. Scientists hope that the PowderJect system will eventually be a less painful, more efficient way to administer the influenza vaccine.

patient testing. If approved, FluMist would become the first vaccine of any kind to be delivered as a nasal spray. (Figure 9.7) Patient trials have found the vaccine to be highly effective, especially for children. This type of vaccine would offer doctors another tool in their arsenal and might help to make up for shortages of the flu vaccine that have occurred in recent years. The original re s e a rch that culminated in the development of Flu Mist started over 40 ye a rs ago. Scientists at the University of Mi ch i gan were re s e a rching new flu vaccines in the wake of the 1958 pandemic that killed about 70,000 Americans. In 1967, Dr. John Maassab developed a live , “cold-ad a pted” i n f lu enza vi rus that on ly grew at the coo l er tem pera tu res found in the nasal passage s . This characteri s ti c of the virus could prevent infecti on of the lower respiratory tract, such as the lungs, where the disease normally progresses.

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Figure 9.6 In the picture above, a nurse administers the influenza vaccine via the PowderJect System to a patient. The PowderJect vaccine does not have to be delivered to a large muscle group such as the upper arm or thigh, as does the traditional influenza vaccine.

The vi rus was mod i f i ed so that it could sti ll sti mu l a te an immune re s ponse without causing illness. In the 1970s and 1980s, the Na tional In s titutes of Health (NIH) took over development of the vaccine and spon s ored the pati ent trials to test the safety, effectiveness, and dosage requ i rements of the vacc i n e . In 1995, a priva te com p a ny licensed the vaccine f rom the university and funded the large clinical trials . Th e studies invo lved approx i m a tely 24,000 pati ents and were found to provide protection for more than 90 percent of the patients. The vaccine was also ef fective in preventing f lu - related ear infections. Another advantage of this type of

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Figure 9.7 Scientists are working on an inhaled version of the influenza vaccine. This vaccine would be delivered via a nasal spray, similar to the one the woman pictured above is using. Test studies have shown it to be very eff e c t i v e , especially with children. The virus used in the vaccine had to be altered so that it would grow in at the cooler temperatures found in the nasal passage.

vaccine is that it stimu l a tes a broader range of antibody producti on . Being ad m i n i s tered at the site of the infection s ti mu l a tes loc a l , hu m oral (bl ood - b a s ed ) , and cellu l a r immunity re s ponses.

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The Future: Hopes and Dreams 105 NASAL SPRAYS — LATER An o t h er nasal spray influ enza vaccine curren t ly en ro lling su bj ects into Phase II Clinical Trials has the brand name “FluINsu re ™ .” Results of the su ccessful Phase I Clinical Trials were presented to the 2002 World Vaccine Conference held in Montreal, Quebec, on April 17, 2002. There are some significant differences between FluINsure and FluMist. First, FluMist uses a live vi rus preparation, while Flu I N su re is a subunit vaccine that contains no live viruses. FluINsure is a proteinbased nasal vaccine that is not infectious and thus cannot be transmitted from person-to-person. There are also no interactions with wild type viruses that might be present in the nasal passages of the patient. The preparation of influenza proteins used in the FluINsu re vaccine includes the hemagglutinin protein that has been shown to be important in determining future pandemic strains. There are, according to the company developing FluINsure (ID Biochemical), significant differences in the immune re s ponse that is el i c i ted . According to the com p a ny, these differen ces su ggest that Flu I N su re may be superior to FluMist. Only time will tell whether FluINsure is approved for use and if it outperforms FluMist. LEARNING TO PREDICT FUTURE INFLUENZA OUTBREAKS An ex tremely useful bit of i n formati on abo ut influ en z a would be to know ahead of time what type of In f lu enza A virus has the gre a test po tential for causing the next major pandemic. Professors Wa l ter Fitch and Robin Bush at the Un iversity of Ca l i fornia, Irvine, believe they may have identified how viral protein mut a tions lead to new influ en z a s tra i n s . Working with the CDC , the re s e a rchers stu d i ed the ch a n ges that occ u rred in a com m on form of i n f lu enza from 1986 to 1997. The group con s tru cted a “f a m i ly tree” of influ enza viruses based on this past informati on . Th en, they te s ted their abi l i ty to correctly predict how the virus would

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mut a te and ch a n ge . The su ccess ra te was nearly 82 percent, nine correct in 11 predicti ons. F i tch’s group d i s covered that mutations occurring in particular parts of a specific envelope protein were the best predictors of new flu strains. The protein in question is the hemagglut inin protein. Future strains of influenza were most likely to appear when there were several amino acid changes in particular regions of the protein. For new epidemics and pandemics to occur, there needs to be a large, susceptible population. Each time a new variation occurs in the influenza virus, the population no longer has an effective immunity against the flu. New mutations of the virus are required if epidemics or pandemics are to occur. Being able to predict in advance the new strains that will develop would greatly aid development of all types of influenza vaccines. In September 2001, separate studies published in Science magazine reported that re s e a rch ers had found the genetic causes of t wo of the most de adly influenza viruses: the virus that caused the 1918 Spanish Flu Pa n demic and the 1997 Hong Kong stra i n . This inform a ti on can be used to distinguish qu i ck ly bet ween de adly and rel a tively harm l e s s viruses. A team of re s e a rchers from the Au s tralian Na ti onal Un iversity created a com p uter program that could analy ze gen e s . Th ey discovered that the genes from the 1918 pandemic came from two different sources and then combi n ed to form a su pervirulent strain of the flu. For the first time, scientists found that influenza genes could be spliced or recom bined in this way. Re s e a rch ers are firm ly convi n ced that the strain of influ enza virus re s pon s i ble for the 1918 pandemic origi n a ted in pigs. We know that the Hong Kong virus began in chickens and was shown to be the first time that a virus could move d i rectly from chickens and infect hu m a n s . Over one mill i on ch i ckens were kill ed in Hong Kong in what appe a rs to h ave been a su ccessful attempt to prevent another ep i demic. (Figure 9.8) In June 2002, Protein Sciences Corporation ( P S C )

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Figure 9.8 A widespread epidemic in Hong Kong in 1997 was linked to a strain that had originally infected chickens. Humans contracted the virus by eating infected chickens or having direct contact with the infected animals. In the photo above, workers kill chickens to prevent spreading the avian flu.

a n n o u n ced that it had signed an agreem ent to produ ce and distri bute a paten ted swine flu vaccine intern a ti onally. Th e vaccine is a hem a gglutinin vaccine produ ced thro u gh recom binant (gene splicing) tech n o l ogy. In 1997, PSC was aw a rded the con tract to produ ce a human vaccine in re s ponse to the Hong Kong episode . It has worked well in all

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te s t s . PSC also has devel oped recom binant hemagglutinin and recom binant neu raminidase vaccines for human use. These vaccines have proceeded thro u gh Phase II Cl i n i c a l trials. Phase III clinical trials will probably begin before the end of the ye a r. ADDITIONAL ITEMS OF INTEREST In June 2002, Eu ropean aut h orities approved the use of Tamiflu for the treatment of influenza in adults and children and the prevention of the flu in ado l e s cents and children. Ta m i f lu has been ava i l a ble in the Un i ted States since 1999, wh en the FDA approved it. It is effective wh en used within the first two days of symptoms and shortens the length of the illness. It wi ll be ava i l a ble for the 2002 – 2003 flu season . New laboratory studies are helping to cl a rify the re a s on s why those who take Ta m i f lu are less likely to develop severe com p l i c a ti ons, su ch as pneu m on i a . A recent breakthrough in the control and spread of infectious diseases, including influenza, was announced in March of 2002 by the Environmental Protection Agency (EPA). Alistagen Corporation, a biotechnology com p a ny based in New York Ci ty, received approval to market a new a n ti m i c robial su rf ace coa ting. Ca lled Ca l iwel™, this nontoxic, n a tu ral mineral-based material has been shown to be 99.9 percent effective against more than 20 microbes that cause disease, i n cluding influ en z a . The list inclu des bo t h bacterial and viral causes. The active ingredient is an encapsu l a ted form of c a l c ium hyd rox i de . Most airborne microbe s a re de s troyed soon after con t act with the coa ted su rf ace. Origi n a lly, Ca l iwel was developed with the thought of being used in hospitals, nu rsing hom e s , and dayc a re centers. It can be applied to any hard su rf ace , including floors and walls. It comes in a va riety of co l ors , kills bacteria, fungi, molds, and viruses within minutes and prevents growth on these su rf aces for six ye a rs .

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While viruses su ch as the influ enza viruses will con ti nu e to repre s ent a constant public health ch a ll enge and con cern, it should be clear that human ingenu i ty and cre a tivity are up to the ch a ll en ge . In this type of b a t t l e , the wi n n er has l i ttle time to gloat, s i n ce the losers are finding new ways to c i rc u mvent the previous defenses. Th ere is no ending to this drama, but there is a great ch a ll enge that awaits those wh o a re re ady to take it on .

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Glossary A d s o r p t i on — To stick to a surface; sometimes used synonymously with

attachment when talking about viruses. AIDS — Acquired immunodeficiency syndrome; caused by a virus and charac-

terized by loss of or diminished immune system function; death may result from diseases such as pneumonia that would ordinarily have been taken care of by a healthy immune system. Antibiotics — Substances usually produced by microbes or fungi that can

destroy or inhibit the growth and reproduction of other microorganisms. Antibody — Protein produced by a plasma cell (modified B lymphocyte) in

response to the presence and recognition of an antigen; major fighter for the immune system. Antibody-mediated immunity —See humoral immunity. Antigen — A molecule, group of molecules, or part of a cell that is recognized

by the host immune cells as being n o n - self or forei gn ; s ti mulates producti on of antibodies (antibody generating). Antiviral — Drugs designed to destroy or prevent the replication of viruses

which result in decreased severity or shortened time of disease process. Asian Flu — Name usually associated with 1957 pandemic that killed over

one million people. B cells or B lymphocytes — White blood cells derived from and matured in

bone marrow; when stimu l a ted they develop into plasma cells, which produce antibodies. Capsid — Protein outer covering of a virus particle. Capsomeres — Individual protein subunits that make up the capsid. Cell-mediated or cellular immunity (CMI) — T lym ph oc yte and other

immune sys tem cells that seek out and attem pt to de s troy invaders directly, in contrast to soluble protein antibodies that often tag or identify invaders for other cells to destroy. Clinical trials — Rigorous scien tific evaluati on of a procedu re, devi ce, or

drug(s) used for prevention, diagnosis, or treatment of a disease; usually three Phases (Phases I, II, III) required for approval by the FDA (Food and Drug Administration). Phase I: Evaluation of clinical pharmacology, involves volunteers; testing for safety. Phase II: Performed in a small group of patients; testing for dosage and overall desired clinical effect.

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Phase III: L a r ge , com p a ra tive study using pati ents to establish a clear clinical ben efit; con trol groups using placebos or comparisons to establ i s h ed or current procedures. Cytokines —General term for chemical substances produced by a variety of

cells; lymphokines are one example; effects vary with cell type produced and affected; high con centrati ons may be toxic; interferon is one type. Cytotoxic T cells — A su bpop u l a tion of the T lymphocyte s ; will find and

de s troy cells that have been mod i f i ed by infecti on with bacteri a , f u n gi , or viruses or by some cancer- producing factor; also known as kill er T cells. Drift or genetic drift —A gradual change in the structure of one of the pro-

teins in the envelope of the virus, usually the hemagglutinin protein; these genetic changes occur because of the lack of error checking that occurs with RNA viruses when they are copying their genome; will lead to new subtypes that require new vaccine preparations. Endocytosis — The general term for taking other cells, particles, or molecules

into the cell; the cell must use energy to accomplish this task; when a cell becomes irritated or stimulated by contact with its membrane, it may engulf the stimulant or irritant; some viruses enter cells in this manner. Envelope — Outermost portion of some viruses; may consist of a portion of

the animal cell’s membranes and contain unique proteins and lipids. Enzyme — Protein that serves as an organic catalyst; speeds up the rate of a

biochemical re acti on but is not consumed or used up in that re acti on ; all biochemical reactions within living systems are controlled or regulated by enzymes. Epidemic —A dramatic increase in the number of individuals showing the

symptoms of a disease within a specified area and during a specified time period; in the Un i ted State s , statistics to determine a true epidemic are co llected and maintained by the CDC. Genome —Sum total of all the genetic information in a cell or virus. Helper T cells — A su b group of T lym ph ocytes that are the main regulators

of immune sys tem respon s e s ; i nvo lved in many functions including activation of antibody production and activation of cytotoxic T cells. Hemagglutinin —Protein that is found as part of the outer envelope of the

influenza virus; required for attachment and penetration of the virus into the cell; rod-shaped spike; named for its ability to cause agglutination or clumping of red blood cells.

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Haemophilus influenzae—Bacterium found in the respiratory tract ori gi n a lly

thought to be responsible for the flu; causes secondary infections of the respiratory tract, including pneumonia. HIV — Human immunodeficiency virus; the virus responsible for AIDS. Hong Kong flu —Common name for the strain of Influenza Type A virus that

killed nearly 750,00 people in 1968; another Hong Kong flu emerged in 1997 with six deaths; millions of chickens feared to be the cause of the disease were slaughtered. Humoral immunity — Refers to circulating parts of the immune sys tem,

soluble proteins in the gamma globulin fragment of the plasma of the blood, namely, the antibodies. Inflammation — A series of responses consisting of redness, increased heat in

the area, swelling, and pain; this is followed by repair of the inflamed area; part of the nonspecific defenses of the body. Influenza — Com m only called the flu; a serious viral disease; infects the

respiratory tract; can lead to severe and deadly complications. Interferon —A family of proteins that acts nonselectively in response to the

presence of viruses in a cell; serves as an early warning sytem. Intracellular — Within a cell. -itis — This ending on a word refers to inflammation; the first part of the

word tells what is inflamed. Lymphocytes — One of the five t ypes of white blood cel ls produced by

hu m a n s ; d ivi ded into B and T lym ph oc ytes that are both essen tial to proper immune function. Lymphokines —Cytokines produced by lymphocytes; help to regulate action

of immune system. Macrophage — A modified version of the monocyte, one of the five types of

white blood cells in humans; a large cell that seeks out and engulfs foreign particles and cells through phagocytosis; literally a large eater. M u t a t i on— Change in the gen etic information of a cell or virus (either

DNA or RNA in some viruses); changes in genetic information usu a lly lead to new pro teins, a l tered pro teins, or loss of pro teins. Natural killer (NK) cells — Lymphocytes that kill infected cells and tumor

cells; they attack without receiving specific chemical messages from the T cells; important in antiviral defenses.

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Neuraminidase — Protein that is part of the outer envelope of the influenza

virus; serves as an enzyme and is responsible for newly formed viruses escaping the host cells; aids in spread of the virus. Neutrophil — One of the five types of white blood cells in humans; these are

the most numerous, making up about 60 percent of the total white blood cells under normal circumstances; highly phagocytic. Nucleocapsids —Viruses that have only a capsid (coat) and genetic material. Pandemic — Worldwide epidemic; widespread disease in humans; results

when person-to-person contact occurs among individuals who have the virus but no current immune protection against it (these types of individuals are sometimes called immunologically naïve). Parasite — An or ganism or vi ral parti cle that invades and lives within another

cell or or ganism (call ed the host) using the resources of that cell ; the parasite ben efits from the rel a ti onship but the host is harm ed or may be killed. Pathogenic — An organism or entity capable of causing disease. Pericarditis — Inflammation of the pericardium, the membrane sac that

encloses the heart. Phagocytosis — A type of active tra n s port invo lving the en ti re cell ; t h e

gen eral term for the cell ’s using en er gy to bring cell s , p a rti cl e s , or molecules into itself is active transport, and the acti on taken by the cell is called endoc yto s i s . The cell su rrounds and then engulfs its prey; the prey is then encl o s ed in a mem branous stru ctu re that will fuse with lys o s omes and digest the prey; its molecules will then diffuse into the cell for reuse. Plasma cells —Cells produ ced from B lym ph oc ytes that have been sti mulated

by a specific antigen; they produce millions of copies of a single protein antibody specific for the antigen. Preclinical —S tudies of dru gs or vaccines that are carri ed out in ti s sue or cell

cultures of animals; this phase occurs before clinical trials involving humans. Reassortment — In the context of this book, it refers to a rearrangement of

genes in two different and distinct influenza strains that leads to production of a new or novel influenza strain. R e c e p t o r-mediated endocytosis — The act of a cell taking in other cells,

particles, or molecules after they have attach ed themselves to specific protein receptor molecules in the host cell’s membrane; the influenza virus enters its host in this way.

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Replicate — To make an ex act copy; the process of du p l i c a ting or reproducing

as in viral replication. Sentinel Physicians — Pa rt of the WHO (World Health Orga n i z a ti on) gl obal

flu surveillance network; approximately 260 U.S. physicians who report to the CDC weekly, indicating numbers of patients seen by the physicians by age group, with or without flu-like symptoms. Serology — Study of serum. Seropositive — Individual possessing antibodies specific to a particular strain

of virus or bacteria. Serum — The clear light yellow-orange fluid left when the formed elements

and the clotting factors of the blood are removed is the serum; the entire liquid portion of the blood is called the plasma and contains the formed el em ents (red blood cells, white blood cells, and platelets); it also contains a number of soluble proteins, including the antibodies and the clotting factors. Shift or genetic shift —Extension of genetic drift; these accumulated changes

may lead to new subtypes of influenza in animals such as ducks, chickens, or pigs that may be transmitted to humans; this new strain may be the result of reassortment of currently circulating influenza strains or of direct contact between the lower animals and humans; often these new strains lead to epidemics or pandemics. Spanish Flu — Common name given to the pandemic of 1918–1920; respon-

sible for more than 20 million deaths. Subtype — Am ong the In f lu enza Type A vi ru s e s , t h ere are curren t ly 15

subtypes or variations within that broader category. Subunit vaccines —A vaccine that uses on ly one or more of the parts of

a disease-causing organism or virus to stimulate an immune reaction. Surveillance — A continuous and organized collection and analysis of data

regarding all aspects of influenza; the information is then sent to national and regional public health professionals, who use it to provide an up-todate prevention and control program. T cell or T lymphocyte — A subpopulation of lymphocytes; they are involved

in cell-mediated immunity and are well known in transplant rejection situations; they release a number of different kinds of cytokines; there are four different types of T cells: helper T cells, suppressor T cells, cytotoxic T cells, and delayed hypersensitivity T cells.

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Transcription — Part of protein synthesis process in which information in the

DNA molecule is converted into a messenger RNA (mRNA). Type — Wh en used in reference to influenza virus, it is one of three broad

categories or classes; there is Influenza Type A, Type B, and Type C. Vaccine —A substance, organism, viral particle, or group of molecules that,

when injected or put into the body by other means, causes the immune system to provide an immune response to that specific agent; supplied antigens that stimulate production of antibodies. Virion — A complete virus particle consisting of capsid and genome. Virology — The study of viruses. Virus — A submicroscopic, infectious particle consisting of a protein covering

called the capsid, which encloses genetic information and the genome; t h ere may be an ad d i ti onal outer envel ope ; vi ruses are intracellular para s i tes.

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Bibliography CHAPTER 1

ASM News, 59, no. 8 (1993): 402. Picture of Beijerinck and notes Brock, Thomas. Milestones in Microbiology. (Upper Saddle River, NJ: Prentice-Hall, 1961). BSCS, Videodiscovery, NIH Curriculum Supplement Series, National Institute of Allergy and Infectious Diseases, Emerging and Re-emerging Infectious Diseases. (Bethesda, MD: NIH Publication, October 1999). Burnett, Sir MacFarlane and David O. White. Natural History of Infectious Disease, 4th ed. (London: Cambridge University Press, 1972). Haimann, Barbara. Disease: Identification, Prevention, and Control. (St. Louis: Mosby-Year Book Inc., 1994). Kolata, Gina. Flu: The Story of the Great Influenza Pandemic of 1918 and the Search for the Virus That Caused It. (New York: Farrar, Straus & Giroux Publishers, 1999). Madigan, M.T., Martinko, J.M., and J. Parker. Brock Biology of Microorganisms. 8th ed. (Upper Saddle River, NJ: Prentice Hall, 1997). 943, Fig 23.17 Marks, Geoffrey and William K. Beatty. Epidemics. (New York: Charles Scribner’s Sons, 1976). McCullough, David. John Adams. (New York: Simon & Schuster, 2001). McNeil, William H. Plagues and Peoples. (Garden City, NY: Doubleday, 1976). Mims, Cedric A. The Pathogenesis of Infectious Disease. (San Diego, CA: Academic Press, 1977). Morison, Samuel Eliot. The Oxford History of the American People. (New York: Oxford University Press, 1965). “The Hong Kong Incident,” Science 151, no. 7 (Feb 23, 1998). Voyles, Bruce A. The Biology of Viruses. (St. Louis: Mosby-Year Book, Inc., 1993). Wark, Lori. The Flu:The Hunt for a Killer in Disguise. http://www.discovery.com/exp/epidemic/flu/flu.html.

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Picture of Camp Funston http://www.ukans.edu/heritage/graphics/towns/funston.jpg Picture of makeshift emergency ward at Camp Funston http://www2.okstate.edu/ww1hist/fnsthosp.html Influenza’s reach over time – time line of events http://www.msnbc.com/news/130842.asp?cp=1=1 Martin, B.E. and J. Risser, The History of Influenza. http://www.goshen.edu/bio/BIOL206/BIOL206LabProject/Influenza/ brookejodi/HOME.HTM http://classics.mit.edu/Hippocrates/epidemics.html General information http://www.pbs.org/wgbh/amex/influenza/ Table showing death rates http://www.pbs.org/wgbh/amex/influenza/maps/index.html Picture of man in a gauze mask http://www.spartacus.schoolnet.co.uk/FWWinfluenzia.htm Richardson, Renee. The Brainerd Daily Dispatch (web posted 2/22/99) 1918 spanish flu epidemic struck with devastating quickness. http://celebrate2000.brainerddispatch.com/stories/022299/his_flu.shtml San Diego pictures http://www.sandiegohistory.org/stranger/flu.htm

CHAPTER 2

Electron micrographs of influenza virus http://www.uct.ac.za/depts/mmi/stannard/fluvirus.html Diagram of structure of HA http://www.uct.ac.za/depts/mmi/jmoodie/influen2.html Public Health Laboratory Service Bulletin http://www.phls.co.uk/facts/influenza/VaccineComp2002.htm Diagrams showing structure and organization of influenza viruses http://www-ermm.cbcu.cam.ac.uk/01002460h.htm

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CHAPTER 3

Alcamo, I.E. Fundamentals of Microbiology, 6th ed. (Sudbury, MA: Jones and Bartlett Publishers, 2001). Goto, Hideo and Yoshihiro Kawaoka. “A novel mechanism for the acquisition of virulence by a human influenza A virus.” Proceedings of the National Academy of Sciences, USA 95 (1998):10224–10228. Laver, W. Graeme, Norbert Bischofberger, and Robert G. Webster. “Disarming Flu Viruses.” Scientific American, 280, no. 1 (January 1999): 78–87. Lewis, Ricki, “Electron microscopy reveals protein translocation channel.” BioPhotonics News (Jan.– Feb. 1997). Madigan, Michael T., John M. Martinko, and Jack Parker. Brock: Biology of Microorganisms, 8th ed. (Upper Saddle River, NJ: Prentice Hall, 1997). Purves, William K., Sadava, David, Orians, Gondanlt, and H. Craig Heller. Life: The Science of Biology, 6th ed. (Sunderland, MA: W.H. Freeman and Co., 2001) Tortora, Gerard J., Berdell R. Funke, and Christine L. Case. Microbiology: An Introduction, 6th ed. (Menlo Park, CA: Benjamin Cummings Publishing Co., 1998). Voyles, Bruce A. The Biology of Viruses. (St. Louis, MO: Mosby-Year Book, 1993). Wagner, Edward K. and Martinez, J. Hewlett. Basic Virology. (Malden, MA: Blackwell Science, Inc., 1999). CHAPTER 4

American Lung Association http://lungusa.org/diseases/c&f02/cftable1.html http://lungusa.org/diseases/c&f02/cftable2.html National Reye’s Syndrome Foundation http://www.reyessyndrome.org/ Reye’s Syndrome Hub http://www.knowdeep.org/reye Public Health Laboratory Service http://www.phls.co.uk

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CHAPTER 5

Alcamo, I.E. Fundamentals of Microbiology, 6th ed. (Sudbury, MA: Jones and Bartlett Publishers, 2001). Diagnostic Virology Laboratory Newsletter, Texas Children’s Hospital, Houston, Texas. http://www.bcm.tmc.edu/pedi/infect/dvl/nws10_2001.htm Finegold, Sydney M. and William J. Martin. Diagnostic Microbiology, 6th ed. (St. Louis, MO: C.V. Mosby, 1982). Howard Hughes Medical Institute, Information on Immune System. http://www.hhmi.org/biointeractive/animations/tcell/tcell_print.htm Howard Hughes Medical Institute Virtual Laboratory. http://www.hhmi.org/biointeractive/vlabs/index.htm E.W. Koneman, S.D. Allen, V.R. Dowell, Jr., and Herbert M. Sommers. Color Atlas and Textbook of Diagnostic Microbiology, 2nd ed. (Philadelphia: J.B. Lippincott Company, 1983). Laboratory Diagnostic Procedures for Influenza, National Center for Infectious Diseases. http://www.cdc.gov/ncidod/diseases/ MEDLINE Plus, Medical Encyclopedia. http://www.nlm.nih.gov/medlineplus/ency/ CHAPTER 6

Centers for Disease Control and Prevention, “Prevention and Control of Influenza, Recommendations of the Advisory Committee on Immunization Practices.” Morbidity and Mortality Weekly Report, 51, no. RR-3 (April 12, 2002). U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention. “Addressing Emerging Infectious Disease Threats: A Prevention Strategy for the United States” (Atlanta, Georgia, 1994). U.S. Department of Health and Human Services, National Institute of Allergy and Infectious Diseases. “Understanding Vaccines.” NIH Publication No. 98-4219 (January 1998).

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Focus on the Flu http://www.niaid.nih.gov/newsroom/focuson/flu00/default.htm WHO Information Fact Sheet No. 211, February 1999. http://www.who.int/ CHAPTER 7

National Institutes of Health, National Institute of Allergy and Infectious Diseases. “Understanding Vaccines.” U.S. Department of Health and Human Services, NIH Publication No. 98-4219 (January 1998). National Institutes of Health, National Institute of Allergy and Infectious Diseases. “Understanding Autoimmune Diseases.” U.S. Department of Health and Human Services, NIH Publication No. 98-4273 (May 1998). Schindler, Lydia Woods. “Understanding the Immune System.” U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, NIH Publication No. 90-529, revised (March 1990). National Institutes of Health, National Institute of General Medical Sciences. “Medicines By Design: The Biological Revolution in Pharmacology.” NIH Publication No. 93-474 (September 1993). CHAPTER 8

Gillette, B. “Pork Production is Linked to the Risk of Epidemics and Infections.” E-Magazine (May-June 2000). http://www.organicconsumers.org/toxic/porkfilth.cfm Gross, Peter A. “Preparing for the Next Influenza Pandemic: A Reemerging Infection.” Annals of Internal Medicine, American College of Physicians 124 (1996): 682-685. Johnson, David A. “Proposed Public Health Lab Facility.” Minnesota Department of Health, February 5, 2002. http://www.health.state.mn.us/facts/labfacility.html Press Release, What’s New. “Measures to control chicken flu in Pak Sha, Saturday, April 6, 2002.” http://www.afcd.gov.hk/news/text/epress/pr281.htm Vaccine Bulletin 156 June 2002, Clinical Update. http://www.vaccinebulletin.com/156/clin156.html

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CHAPTER 9

Ainsworth, Claire. “Antibodies Could be Grown in Fields.” New Scientist, (October 3, 2001). http://www.newscientist.com/news/news.jsp?id=ns99991373 Bush, Robin M., Catherine A. Bender, Kata Subbarao, Nancy J. Cox, and Walter M. Fitch. “Predicting the Evolution of Human Influenza A,” Science, 286: 194-1925 (1999) Product information news about Caliwel http://www.caliwel.com/ Coghlan, Andy. “Tree of Life.” New Scientist, (February 9, 2001). http://www.newscientist.com/news/news.jsp?id=ns9999407 FluINsure Nasal Vaccine http://www.idbiomedical.com/vaccines_flu_info.html Gibbs, W. Wayt. “Plantibodies.” Scientific American, (November 1997): 44. (Shows picture of corn field) Hoffert, Stephen P. “Transcutaneous Methods Get Under the Skin.” The Scientist, 12[16]:0 (August 17, 1998). (Shows electron micrograph of needle array) The Jordan Report 2000: Accelerated Development of Vaccines (excerpt on Influenza) http://www.niaid.nih.gov/newsroom/focuson/flu00/jordanflu.htm Graeme, Laver and Elspeth Garman, “The Origin and Control of Pandemic Influenza.”Science, 293 (September 7, 2001): 1776–1777. Masato Hatta, Peng Gao, Peter Halfmann, and Yoshihiro Kawaoka. “Molecular Basis for High Virulence of Hong Kong H5N1 Influenza Viruses.” Science, 293 (September 7, 2001): 1840. PowderJect (picture of “hypospray”) http://www.powderject.com Roche Receives Approval in Europe for Tamiflu http://www.biospace.com/b2/news_rxtarget.cfm?rxtargetid=120 Smaglik, Paul. “Needle-Free Vaccines: Success of Edible Vaccine May Depen d on Picking Right Fruit.” The Scientist, 12[16]:0 (August 17, 1998).

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Smaglik, Paul. “Needle-Free Vaccines on the Horizon.” The Scientist, 12[16]:1 (August 17, 1998). (Shows picture of Georgia Tech patch) Smaglik, Paul. “Needle-Free Vaccines: Mucosal Tissues Offer Tempting Targets.” The Scientist, 12[16]:4 (August 17, 1998) (Shows picture of nasal flu vaccine, FluMist) Skin Patch Flu Vaccine Trials Awaiting FDA Approval http://unisci.com/stories/20004/1023001.htm http://www.cosmiverse.com/science102403.html Swine Flu Vaccine http://www.proteinsciences.com Webster, Robert G. “A Molecular Whodunit.” Science, 293 (September 7, 2001): 1773-1775. World Vaccine Conference http://www.pharma-rd.net/WVC_Mont2002 ADDITIONAL REFERENCES CONSULTED

Scott, John D. and Tony Pawson. “Cell Communication: The Inside Story.” Scientific American, 282, no. 6 (June 2000): 72–79. Ingber, Donald E. “The Architecture of Life.” Scientific American, Vol. 278, no. 1 (January 1998): 49– 57. Weiner, David B. and Ronald C. Kennedy. “Genetic Vaccines.” Scientific American, 281, no. 1 (July 1999): 50– 57. Nesse, Randolph M. and George C. Williams. “Evolution and Origins of Diseases.” Scientific American, 279, no. 5 (November 1998): 86–93. Gottfried, Sandra S. Human Biology. (St Louis, MO: Mosby-Year Book, 1994). Jaroff, Leon. “Stop That Germ.” Time Magazine, 131, no. 21 (May 23, 1998): 56– 64.

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Index Acetaminophen, 39 Active immunity, 61 Aerosols, 52-53, 55, 64-65 Africa, flu in, 84 Airplanes, 52-53 Alistagen Corp., 108 Allergies, 58, 61 Alveoli, 67 Am a n t adine (Sym m etrel), 41, 55-56, 95 American College of Physicians, 92-93 American Lung Association, 58 Animals, and spread of flu, 93-94, 106-107 Antibiotics, 41, 42, 44, 69, 92, 96 Antibodies, 48-51, 61, 75, 76-77, 879, 80, 96-98 Antigen detection tests, 50-51 Antigenic draft, 101 Antigens, 75, 77, 78, 79 Antihistamines, 40 Antisense, 29 Antiviral drugs, 40-41, 42, 44, 55-56, 95, 96 Asia, flu in, 11, 13, 22, 8283, 84, 93, 94, 106-107 Asian Flu, 11 Aspirin, 39, 60, 70, 73 Assembly, 28 Atrial fibrillation, 70 Attachment/adsorption, 24, 26, 29-30 Australia, flu in, 84 Bacterial pn eu m on i a , 68-69 Bed rest, 39 Beijerinck, Martinus, 10, 14 Birds, and spread of flu, 92-94, 106-107 Blitz Katarrh, 85

B lymphocytes, 75-76 Boston, flu in, 897 Brain complications, 70 Bronchioles, 67 Budding, 28, 33-34 Bush, Robin, 105-106 Ca l i forn i a , flu in, 87, 89-90 Caliwel, 108 Camp Devans, 87 Camp Funston, 85 Caps, 30, 32 Capsid, 15 Capsomeres, 15 Cell-mediated immunity, 77-80 Cells, and virus, 14-16 Center for Virus Reference and Research, 62-63 Centers for Disease Control and Prevention, 58, 94 Chemotherapy, 60 Chickens and cells for tissue culture, 48 and eggs, 48, 61, 90 and Hong Kong flu, 13, 22, 93, 106-108 and spre ad of flu, 93-94 Children complications in, 39, 60, 70 vaccine for, 60, 62 China, 82 flu in, 11, 13, 22, 84, 85, 93, 94, 106-107 Cholera, 98 Ch ronic conditions, 58, 60 Cilia, 67, 69, 72 Circulatory failure, 69 Coated vesicle, 26 Cold symptoms, 38

Collection techniques, for diagnosis, 45-48 Colonies, flu in, 8-10 Complications, 64-71 and antiviral drugs, 108 and Reye’s syndrome, 39, 60, 70 Contagion period, 55 Co n t a gium vivum fluidum, 10 COPD (chronic obstructive pulmon a ry disease), 69 Coughing and spread of flu, 5253, 55, 64-65 as symptom, 36, 66 Crusaders, 8 Cytokines, 80 Cytotoxic T cells, 79 Deaths, 102 from Great Influenza Pandemic, 11, 84, 85, 86-89, 90 from Hong Kong flu, 11, 13 from Russian flu, 84 yearly, 71 Decongestants, 40 Defenses against influenza, 71-81 Diabetes vaccine, 98 Diagnosis, 44-51 types of tests for, 44-48 Diseases, microorganisms as cause of, 82 DNA, in virus, 15, 26, 2 8 -29 Doctor visits, for flu, 40-43 Door handles, cleaning of, 54, 55 Drake, Lee W., 85 Drinking water, toxin in, 92

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Ear, 70 Elderly, 58, 64, 71 ELISA (enzyme-linked immunosorbent assay/ EAI test), 51 Encephalitis, 70 Endoplasmic reticulum, 33 Endosome, 26 England, flu in, 10, 84, 85 Envelope, 15, 16, 18 Enveloped virus, 15, 16 Environmental Protection Agency, 108 Epicyte, 97-98 Eskimos, and flu, 86-87 Europe, flu in, 8-9, 10, 11, 83, 84-85 Fatigue, 36, 66, 75 Fever, 36, 66, 73, 75 Fibrinogen, 50 Fitch, Walter, 105-106 Flanders grippe, 85 Fluids, for treatment, 39 Flu-like symptoms, 37-39 FluINsure, 105 FluMist, 101-105 Food and Drug Administration, 58, 98, 101103, 109 Foods and global supply, 92 and plantibodies, 9698 as vaccines, 98 Foot-and-mouth disease, 10 Formed elements, in blood, 50 France, flu in, 85 Frosch, P., 10 Future, 90-95, 96-109 Gastroenteritis, 38 Genetic drift, 21 Genetic shift, 21

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Genomes, 15, 18, 19, 21-23 Germany, flu in, 85 Gitchell, Albert, 85 Global Agenda for the Management and Control of an Influenza Pandemic, 63, 93 Glycoproteins, 15, 16, 30, 33, 75 Golgi apparatus, 33 Goodpasture, Ernest W., 48 Great Influenza Pandemic, 11, 84-90, 106 Guillain-Barre syndrome, 62 Haemophilus influenzae, 69 HAI (hemagglutinininhibition test), 50 Hands, washing of, 55 Headache, 36, 66, 75 Heart complications, 69-70 Helper T cells, 77-80 Hemagglutinin (HA), 16, 17, 18, 19, 21, 30, 33 Hepatitis B vaccine, 100 Herpes simplex 2 virus, 97-98 Hippocrates, 8 HIV (human immunodeficiency virus), 26, 60, 79 Hong Kong, and spread of virus from chickens to humans, 93-94 Hong Kong flu, 11, 13, 22, 93-94, 106-108 Hospital cases, 71 Host cells, 16 Hu m oral immu n i ty, 75-77 ID Biochemical, 105 IgA antibody, 77

IgG antibody, 77 Immune response, 75-81 Immune system, 82 comprom i s ed, 60, 67-69 and immune re s ponse, 75-81 and vaccination, 61 Immunity, 30, 75-80 Immunofluorescence test, 50-51 Immunoglobulin, 75, 77 India, flu in, 89 Indonesia, flu in, 83 Inflammation, 72-74 Influenza virus, 16-23 and genomes, 18, 19, 21-22 in microscope, 10 and naming viral stra i n s , 18 and new vaccine components, 18, 22-23 replication of, 29-35 spread of, 52-53, 55, 64-65 structure of, 16-17, 41 Type A, 16, 18, 29, 23, 29, 32, 34, 41, 4445, 55-56, 67, 105 Type B, 16-17, 18, 22, 29, 41, 45, 56, 67, 70 Type C, 17, 29, 67 and use of term, 8 Interferon, 74-75, 80 Interleukin-1, 73, 78 Interleukin-2, 79 Iran, flu in, 85 Italy, flu in, 8 Japan, flu in, 11, 85 Jefferson, Thomas, 9-10 Kidney cells, for tissue culture, 48 Kwei-kin, Liu, 94

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Leeuwenhoek, Anton van, 82 Leg pains, 70 Leukemia, 60 Light sensitivity, 66 Livy, 8 Loeffler, Friedrich, 10 Lymphocytes, 75-81 Lymphokines, 80 Lysosomes, 26 Maassab, John, 102 Macrophages, 72-73, 74, 78, 79 Madison, James, 9 Matrix protein, 16, 17 Maturation, 28 Medications for flu and future, 95, 96, 108 and outbreak of pandemic, 94 over-the-counter, 39-40 prescri pti on , 40-42, 44, 55-56, 95, 96, 108 Microorganisms, 82 Microscope, 90 Middle Ages, flu in, 8 Monocytes, 72-73 Mouth, covering of, 55 mRNA, 28, 29, 30, 32, 33 Mucous membranes, 72 Mucus, and complications, 67, 69, 72 Muscle aches and pain, 36, 66, 70, 75 Myocarditis, 70 Myositis, 70 Nasal sprays, as vaccine, 101-105 Nasal swabs or washes, 46-47 Nasopharyngeal washes, 47-48 National Institutes of Health, 58, 103

Natural killer cells, 74-75, 79 Negative-stranded RNA, 29, 30 Neuraminidase, 16, 17, 18, 19, 21, 33, 34, 41, 50 Neutrophils, 72, 74, 79 Newborn infants, 54, 58 New England, flu in, 8 New York, flu in, 87 New Zealand, flu in, 84 Non-Hod gkins lym phoma, 97 Nonspecific defenses, 7175 Norwalk virus, 37 Nucleic acid, 15 Nucleocapsids, 15, 18, 34 O rt h omyxovi rus group, 29 Oseltamivir (Tamiflu), 41, 56, 95, 108 Otitis media, 70 Outbreaks, 8-13, 82-90 in American colonies, 8-10 in 1800s, 82-83, 84 in Europe, 8, 9-10, 11, 84-86 in 1500s, 8 and first accounts, 8-9 and Great Influenza Pandemic, 11, 8590, 106 in Middle Ages, 8 in 1900s, 11-13, 14, 22, 84-90, 93, 94, 102, 106-107 prediction of future, 106-108 and preparations for future, 91-93 in 1700s, 9-10 in 1600s, 8-9 and surveillance efforts, 62-63

in U.S., 8-10, 11-12, 83, 85, 87-90, 102 Over-the-counter drugs, 39-40 Pacific Rim, flu in, 84, 89 Pasteur, Louis, 14 Patch, as vaccine, 98-99 PB2 gene, 21-22 Peking, China, flu in, 11 Penetration, 26, 30, 32 Pericarditis, 70 Personal hygiene, 55 Phagocytosis, 72 Philadelphia, flu in, 87-88 Phospholipids, 15 Pigs and Great Influenza Pandemic Virus, 106 and spread of flu to humans from, 94, 106-107 and swine flu, 11-12, 106-107 Plantibodies, 96-98 Plasma, 50, 75, 76 Platelets, 50 Pn eu m on i a , 58, 67-69, 72, 108 Po lym erase chain reaction (PCR) technique, 51 Positive-stranded RNA, 28 PowderJect, 99-101 Prausnitz, Mark R., 98 Pregnant women, vaccine for, 60 Prescri ption dru gs , 39, 4 042 44, 55-56, 95, 96, 108 Prevention, 52-63 and antimicrobial surface coating, 108 and prescription drugs, 40-41, 42, 44, 55-56, 95, 96 See also Vaccination

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Protein Sciences Corporation, 106-108 Prothrombin, 50 Public gatherings, 61 Public Health Laboratory Facility, 91-92 Radiation treatments, 60 Rapid diagnostic tests, 44-45, 50 Rapoport, Thomas, 33 RCA sequence, 49-50, 75-81 Receptor-mediated endocytosis, 26, 30 Recovery, 75 Red blood cells, 50 Reed, Walter, 10 Replicase, 28-29 Replication of virus, 2429, 96 in influenza virus, 29-35 and interferon, 74-75 Respiratory complications, 67-69, 72 Respiratory droplets, and spread of flu, 52-53, 55, 64-65 Respiratory infections, 62 Retroviruses, 29 Reverse transcriptase, 29 Reye’s syndrom e , 39, 60, 68 Rhesus monkey cells, for tissue culture, 48 Ribonucleoproteins, 18 Ri m a n t adine (Flumadine), 41, 56 RNA, in virus, 15, 18, 21, 26, 28-29 RNA polymerase, 28-29, 30 Rome, 82 flu in, 8, 10 Rotavirus, 37 Rubber trees, 98

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Russia, flu in, 83, 84 Russian flu, 84 Samples, for diagnosis, 46-48 San Diego, flu in, 89-90 San Francisco, flu in, 89 San Sebastian, Spain, flu in, 11 Santayana, George, 82 Sense, 28 Serologic tests, 48-51 Seropositive, 50 Serum, 50 Shivering, 36, 66 Sialic acid, 30, 34 Singapore, flu in, 11 Skin, 67, 72 Sneezing, and spread of flu, 52-53, 55, 64-65 South Carolina, flu in, 9 Southern Hemisphere flu in, 84 and vaccine, 60 Spain, flu in, 11, 84, 85, 106 Spanish Flu, 11, 84, 106 Specific defenses, 75 Spikes, 15, 16 Splicing process, 33 ssRNA viruses, 28 Stanley, Wendell Meredith, 90 Staphylococcus aureus, 69 Stomach flu, 37-38 Strep throat symptoms, 38-39 Streptococcus pneumoniae, 69 Students, vaccine for, 61 Subtype A/(H1N2), 22 Superinfection, 69 Surface coating, antimicrobial, 108 Swine flu, 11-12, 106-107 Symptoms of flu, 42-43, 44, 65-67

and body’s chemicals, 75 and contagion, 55 and incubati on peri od, 65 Synthesis, 26, 28-29 Tang, De-chu, 98 Telephones, cleaning of, 54, 55 Three-day fever, 11 Throat swabs, 46 T lymphocytes, 75, 76-80 Tobacco mosaic disease, 10 Toxic shock syndrome, 69 Transcription, 29 Transcutaneous patch, as vaccine, 98-99 Transplanted organs, 80 Travel and spread of disease, 92 and vaccination, 60 Treatment, 36-44 and drugs, 39-42, 44, 95 and identification of sickness as influenza, 36-39, 44. See also Diagnosis and symptoms, 36-37, 39-40, 42-43, 44 Tropics, and vaccine, 60 Turkey, flu in, 8 Tylenol, 39 Uncoating, 26 United States, flu in, 8-10, 11-12, 83, 102 in colonies, 8-10 first account of flu in, 8-9 and Great Influenza Pandemic, 11, 86, 87-90

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Vaccination, 56, 58-62, 81 allergies to, 58, 61 and antibodies, 77 and antiviral drugs, 55-56, 108 DNA-based, 101 history of, 82 and Hong Kong flu, 106-108 and liquid jet injections, 99-101 and naming viral strains, 18 and nasal sprays, 101105 needle-free, 96-105 and new components for,18, 22-23 and outbreak of pandemic, 94 people not recommended for, 58, 61-62 people recommended for, 58, 60-61 and predicting new strains, 105-108 and recombinant hemagglutinin and recombinant neuraminidase, 108

side effects of, 62 and surveillance efforts, 63 as suspension of inactivated influenza viruses, 61 and swine flu, 106107 and transcutaneous patch, 98-99 for 2002-2003 season, 22-23 for season, 23 and viral genomes, 19 Viral gastroenteritis, 38 Viral isolation, for diagnosis, 48 Viral pneumonia, 68 Vi ral stra i n s , naming, 18 Virginia, flu in, 8 Virion, 28 Virus as chemical poison or toxin, 82 definition of, 14-15 growth of, 16 history of research on, 10, 14, 90 as intracellular parasite, 16, 24, 96

and origin of term, 14 structu re of, 15-16, 90 See also Influenza virus; Replication of virus Washington, George, 9 Webster, Robert, 93, 94 West Coast, flu in, 87, 89-90 White blood cells, 50, 72-81 Wilderness areas, human encroachment on, 92 Woodruff, Alice M., 48 World Health Organization, 22-23, 48, 62-63, 93 World War I, and Great Influenza Pandemic, 11, 85-90 Wrestler’s fever, 85 Yeang, Hoong-Yeet, 98 Yellow fever, 10 Zanamivir (Relenza), 41, 95 ZstatFlu, 50

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Picture Credits 9: 12: 17: 19: 25: 27: 31: 35: 37: 46: 47: 49: 53: 57: 59: 65: 66: 68:

© Lesly A. Robertson for the Kluyver Lab © Bettmann/Corbis Courtesy CDC © Cambridge University Press Lambda Science Artwork © 2002 Southwest Biotechnology and I n f o rmation Center. Used with permission. Lambda Science Artwork Courtesy CDC Courtesy UTMB, Department of Microbiology and Immunology Lambda Science Artwork Lambda Science Artwork Lambda Science Artwork © Bettmann/Corbis © Corbis AP/Wide World photos Courtesy McGraw-Hill © Lester V. Bergman/Corbis Lambda Science Artwork

71: Lambda Science Artwork 73: Lambda Science Artwork 74: © 2002 Southwest Biotechnology and I n f o rmation Center. Used with permission. 76: Courtesy CDC 78: Courtesy CDC 79: Lambda Science Artwork 83: © Bettmann/Corbis 86: Courtesy AFIP’s National Museum of Health and Medicine 88: © Bettmann/Corbis 91: © Bettmann/Corbis 97: © Stock Photos/Corbis 99: Courtesy of Dr. Tang 100: Courtesy of Georgia Tech 101: Courtesy of Georgia Tech 102: Courtesy of PowerJect 103: Courtesy of PowerJect 107: AP/Wide World photos

Cover: © Howard Sochurek/Corbis

Tylenol is a registered trademark of the Tylenol Company, Raritan, NJ; Relenza is a registered trademark of Glaxo Group Limited, Middlesex, UK; Tamiflu is a registered trademark of Hoffmann-La Roche Inc., Nutley, NJ; Symmetrel is a registered trademark of Endo Pharmaceuticals Inc., Chadds Ford, PA; Flumadine is a registered trademark of Hoffmann-La Roche Inc., Nutley, NJ; Directigen is a registered trademark of Becton, Dickinson and Company, Franklin Lakes, NJ; FLU OIA is a registered trademark of Biota,Melbourne, Australia; ZstatFlu is a registered trademark of ZymeTx, Inc., Oklahoma City, OK; Quick-Vue is a registered trademark of the Quidel Corporation, San Diego, CA; Dacron is a registered trademark of E. I. du Pont de Nemours and Company, Wilmington, DE; Q-Tips is a registered trademark of Chesebrough-Pond’s Inc., Wilmington, DE; FluMist is a trademark of Aviron Corp., Mountain View, CA; FluInsure is a trademark of ID Biomedical Corp., Burnaby, British Columbia, Canada; Caliwel is a trademark of Alistagen Corp., New York, New York.

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About the Author Dr. Don Emmeluth spent most of his teaching career in upstate New York. He is an avid hiker and golfer, and both endeavors have provided him with ample opportunities to view the forests and grasslands of the countryside. In 1999, Dr. Emmeluth retired from the State University of New York system and moved to the warmer climate of Savannah, Georgia. He became a member of the Biology Department of Armstrong Atlantic State University in Savannah. He continues to hike after golf balls on the various courses in and around Savannah and the Hilton Head, South Carolina areas. At AASU, Dr. Emmeluth teaches BIOL 1107, Principles of Biology and a BioEthics module that is part of the Ethics course on campus. He developed and maintains the Biology Department website. Dr. Emmeluth has published several journal articles and is the co-author of a high school biology textbook. His most recent article appeared in the Febru a ry 2002 issue of The Am erican Biol o gy Te a ch er on the topic of Bioinformatics. He has served as President of the National Association of Biology Teachers. During his career, Dr. Emmeluth has received a number of honors and awards, including the Chancellor’s Award for Ex cellence in Teaching and the Two-Year College Biology Teaching Award from NABT.

About the Editor The late I. Edward Alcamo was a Distinguished Teaching Professor of Microbiology at the State Un iversity of New York at Farmingdale. Al c a m o stu d i ed biology at Iona Co ll ege in New York and earned his M.S. and Ph.D. degrees in microbi o l ogy at St. John’s Un ivers i ty, also in New York . He taught at Fa rm i n gdale for over 30 years. In 2000, Alcamo won the Ca rski Award for Di s ti n g u i s h ed Te aching in Microbi o l ogy, the highest honor for microbi o l ogy teachers in the Un i ted States. He was a member of the American Society for Mi c robiology, the Na ti onal Associati on of Biology Teach ers, and the Am erican Medical Wri ters As s oc i a ti on . Alcamo aut h ored nu m erous books on the su bj ects of microbi o l ogy, AIDS, and DNA tech n o l ogy as well as the awardwinning tex tbook Fundamentals of Mi crobiology, now in its sixth ed i ti on.

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