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%