T/
In thiseditionwe look at an old friendof the familyphysician:'influenza'
andthe'flu injection'.
Learning Objectives:
readersshouldbe ableto:
After readingthroughthe materialpresented,
.
.
.
.
.
.
.
.
Listthe components
of a virus
Understand
the nomenclature
for the differentlnfluenza
viruses
Explain
what haemagglutinin
andneuraminidase
areandwhattheydo
Knowthe indications
andcontraindications
for administering
the influenza
vaccine
Explainwhythe influenza
vaccineshouldor shouldnot be givento HlV-infected
persons
Recognise
the cost-effectiveness
ofthe influenzavaccine
Assimilate
evidence-based
conclusions
concerning
the prevention
andtreatmentof influenza
Understand
that the influenza
vaccinedoesnot cause'relapses'
in multiplesclerosis
patients.
Space
limitations
havemeantthatsomeof the materialcouldnot beincluded.
Thisincludes
the pathophysiologr
of influenza
andpathogenesis
aswellascomplications.
Thefascinating
historyof the discovery
of the shapeof
the virusand its particularproperties,aswell asongoingresearchinto new therapieswasalsonot included.
Theseaspects
areallwell-described
on severalinternetsitesandwellworth followingup.
Reporting of Influenza outbreaks
There is an appealfrom the NationalInstituteforVirologyto all MedicalPractitionersworking in clinicsand
hospitals
to report anysuspected
influenza
outbreakdirectlyto DrT G Besselaar
[email protected]
.
Dr Besselaar
canalsobe reachedat:
Telephone
Number:(01l) 3214269
(0| l) 8820596
FaxNumber:
PostalAddress: NationallnstituteforVirology
PrivateBagX4
Sandringham2l3l
Enjoythisedition's'Care
for Patients
andtheir Disorders'.
& tr^
- who wantsto know whether or not he should
Our patient,Johannes,
is a 3 | yearold man- H|V-positive
havea'flu injection'.Thestructureof this CPD exerciseis asfollows:
l. Backto basics
. Viruses
andtheircomponents
. lnfluenza
viruses
. Influenza
vaccines
. Recommendations
for winter200|
2. fohannes'sconcernsand questions
3. Evidence-basedconclusionsaboutinfluenzavaccinesandantiviral
agentsinthemanagementofinfluenza.
4. Questionsfor CPD pointsto be found on the flysheetin the envelope
@
T
i) Viruses and their components
Viruses are not visible under light microscopy. Our
knowledgeof their structure has been largelydependent
on electron microscopy and X-ray crystallography
techniques.
Virusesconsist of a nucleicacid-ribonucleic acid (RNA)
or deoxyribonucleicacid (DNA)- plus a protective coat
of protein which may incorporate lipid and/or carbohydrate
components. The nucleicacid may be single-or doublestranded,and may be segmentedinto two or more pieces.
Virusesdo not havetheir own mitochondriaor ribosomes.
s o c a n n o t s u r v i v e o r r e p r o d u c e i n d e p e n d e n t l y .T h e i r
parasitic existence is obligatory.
and 2 NA subtypesare common in humans,and they are
n a m e da c c o r d i n g l y : H
I N I , H I N 2 , H 2 N 2 ,H 3 N 2 a n d s o o n .
'flu'
HA attaches a
virus to the cell membrane of the
respiratory epithelialcell it is infecting.Neuraminidasehelps
penetrate the membrane allowing viral contents to enter
the cell'scytoplasm. lt also playsa role in inactivatingmucus
secretionsof endothelialcells so that the viral particles
cangain accessto them. The NA in the newly manufactured
viral particlesensurestheir expulsionfrom the cytoplasm
and cell membraneof the infectedcell.2
Table f: Nomenclature of influenzostroinC
TYPEI TOWN
r NUMBER,YEAR MAJOR
of ,
influenza
.of isolates,
where
first
isolated
of
i subtype
isolation (HA/NA)
.
I
Viral anatomyl
The CAPSIDdenotesthe proteinshellthatencloses
the nucleicacid.lt is built of structureunits.
STRUCTUREUNITS are the smallestfunctional
equivalent
buildingunitsof the capsid.
unitsseenon the
CAPSOMERS
are morphological
surface of particles and represent clusters of
structureunits.
nucleicacid
The capsidtotetherwith its enclosed
is calledthe NUCLEOCAPSID.
T h e n u c l e o c a p s i dm a y b e i n v e s t e d i n a n
ENVELOPEwhich may contain materialof host
cell as well as viral origin.
TheVlRlONis the completeinfectivevirusparticle.
ii) Influenzo Viruses
lnffuenza viruses are members of the Orthomyxoviridoe
f a m i l y . T h e v i r u s i s a s i n g l e - s t r a n d e dR N A v i r u s w i t h
eight separate segments of ribonucleoprotein (RNP),
c l o s e l y a s s o c i a t e dw i t h a h e l i x - s h a p e dn u c l e o p r o t e i n
( N P ) . A , B a n d C i n f l u e n z at y p e s a r e b a s e do n v a r i a t i o n s
i n t h e n u c l e o p r o t e i n .T h e l i p o p r o t e i n e n v e l o p ei s l i n e d
o n i t s i n n e r s i d e b y a n a n t i g e n i cm a t r i x p r o t e i n ( M l ) .
InfluenzatypesA and B are responsiblefor epidemicsand
the occasionalpandemic in humans. Type C is rare. A
number of influenzaAvirusesare found in birds and animals.
Embeddedin the influenzaviral envelopeare two kinds of
protruding antigenic'spikes'.One is a glycoproteincalled
'haemagglutinin'
(HA). The other is'neuraminidase'(NA).
hemagglutinin
and nine neuraminidasesubtypes
So far l5
havebeen identifiedin typeA influenzavirions. Only 3 HA
t*A
B
New Caledonia,
Johannesburg :
20
5
ee
(HrNr)
,99
iii) I nfl u e nza va cci n es
Exposinga person to the HA and NA of different influenza
viruses reducesthe likelihoodof infectionand if infection
occurs - it reducesthe severityof the disease.The frequent
development of antigenicvariation of the influenzaviruses
-'antigenic drift' - is the basisof seasonalepidemics,and
the reasonfor incorporatingone or more new strainsin
each year's influenzavaccine. The vaccineis made from
highlypurified,egg-grownvirusesthat havebeen inactivated.
Two forms of inactivatedinfluenzaA,and one of influenzaB
virus are usuallycombined in the vaccine.
WHO CollaboratingCentres monitor the types and
subtypes of influenzaviruses circulating each season.The
components of the vaccine for the following season are
basedon these observations.A consultationis held in midmid-September
Februaryfor the Northern hemisphere,and
for the Southernhemisphereto recommendthe formulation
for the following year.sThis meansthat vaccinesare ayear
'behind'
in terms of the actualviruses,but becauseantigenic
drift results in only minor antigenicchangefrom year to
yeanthe vaccine remains highly effective.
An unpredictable'antigenic
shif is usuallydue to genetic
recombinationof differentsubtypesof influenzaA viruses
- usuallybetween humanand aviansub-types.The lastmajor
antigenicshift occurred in 1968when H3N2 (Hong Kong)
influenzasuddenlyappeared.A globalpandemiccould occur
if a'new' virus was efficientlytransmitted from person to
person.
of the l9l8 fluepidemic
Thismaybeanexplanation
people
died
worldwide.
in whichsome20million
system involved in maintaininghis CD4 count. You also
explain that becauseinfluenzavaccination can produce
high enough levels of protective antibodies,the impact
iv) Recornmendotionsfor winter 200/,5
on his CD4 count through being exposed to flu is likely
for the 2001 southern
The flu strainsrecommended
to be much lessthan if he did not havehis own antibodies.
hemisphere
influenza
season
are:
ln the CDC's Morbidity and MortalityWeekly Report of
l . A / N e w C a l e d o n i a / 2 0 / 9 9 - l i (kHe l N l ) [ A / N e w
l4 April 2000, it is stated:'Deterioration of CD4+ Tis suitableasa vaccinestrain]
Caledonia/2O/99
lymphocytecell counts or progressionof HIV disease
is
2. A,/Moscow/
l0/99-like(H3N2) lAlPanamal2007l99
hasnot been demonstrated among HIV-infectedpersons
recommended
asa suitablevaccinestrain]
following influenzavaccination.'5
(B) [EitherB{ohannesburg/5/ iii) You tell him that you cannot guaranteehe will not get
3. B/Sichuan1379l99-like
99 or BA/ictorial504l00
arerecommended
assuitable
sick this winter becausehe could be infected with a
vaccinestrains]
different kind of upper respiratory tract virus such as
respiratory syncitialvirus, or he could get a bacterial
Flu usuallyoccursfrom aboutMayuntil Septemberin
infection.
SouthAfrica.As flu antibodiestake one to two weeks iv) You make the point againthat his smoking dramatically
are that the
to develop,most recommendations
increaseshis chancesof a winter infection,and that you
shouldbegivenfrom mid-March
to mid-April.
vaccination
reallywould like him to try and stop smokingonce more.
It is importantto note, however,that there is no real
asmanyinfections QuestionTwo
cut-offdatefor vaccination,
especially
mayoccur latein the seasonaswell.
What information is availableabout influenzainfections in
HIV-infectedpeople?
for two years
hasknown that he is H|V-positive
Johannes
now. Lastyear he hada badwinter with severalweeksin
bed. He doesnot want a repeatof that this year. He was
evenill enoughto stop smoking,but unfoitunatelystarted
againa coupleof monthsafter gettingbetter."Too much
stress.Doc."
AnswerTwo6
i) The risk for cardiopulmonaryhospitalizationsamong
women with HIV infectionwas higher during influenza
seasonsthan in the peri-influenzaperiods in young and
middle-agedwomen enrolled in Tennessee'sMedicaid
program. In women with other high-riskconditionsfor
He wantsyou to tell him if he shouldhavethe'flu injection'.
influenzacomplications- includingchronic heart and lung
if
it
wont
mess
up
his
immune
system,
He wantsto know
diseases- the risk of hospitalizationfor those with HIVlowerhisCD4 count(whichishighat present)or precipitate
infection was higher.
AIDS. He wants to know if you can guaranteethat the ii) Influenzasymptoms may be prolonged,with an increased
immunisation
will preventhimfrom geftingsickthiswinter.
risk of complications,for HIV-infectedpersons
iii) Influenzavaccinationproducessubstantialantibody titers
in H|V-infectedpersons,such as Johannes,who have
Question One
What would you sayto Johannesl
minimalAlDS-relatedsymptomsand highCD4+ counts.
In patientswith advancedHIV diseaseand low CD4+
counts, influenza vaccine might not induce protective
antibody titers.
Answer One
i) You would recommend that he does have the
immunisation.You explain that becauseinfluenzacan
causeboth a seriousillnessand possiblecomplications,
vaccinationwill benefit himself(and many H|V-infected
patientslike him).[see later]
ii) You explain to him that it will not harm his'immune
system',but will protect him from havingto deal with
the onslaught of a flu infection. You explain that the
immunisationstimulatesthat part of his immune system
that makesantibodiesrather than the part of his immune
QuestionThree
What are the generalrecommendationsabout who should
receivean influenzaimmunisation?
AnswerThree
Thefollowinggroupsof peoplecanbe classified
ashighrisk
for influenzainfection:7
. Peopleover 65 years.[Note:This
is beingreconsidered
in the USAto includeanyoneover the ageof 50 years.]
.
.
.
Adultsandchildrenwith chronicdiseases
suchaschronic
lung/heart
disease,
diabetes,
chronicrenal(kidney)failure.
persons,i.e.those that havea
lmmunesuppressed
defectiveimmunesystem.
(Reye's
Childrenon longterm aspirintherapy.
syndrome)
Healthcareworkers.
Householdcontactsof high risk individuals
as stated
above,including
children.
Pregnantwomanwho are medicallyat highrisk should
be vaccinatedpreferablynot beforethe secondtrimester.
Question Six
ls a low CD4 counta contra-indication?
Answer Six
Generally
speaking,
no.The decisionis moredependent
on
the person'sclinicalcondition. When the CD4 is low
however,thevaccinemaynot be particularlyeffective.
Vaccination for other GroupsT
Anyonewho wantsto protectthemselves
from the risk of
gettinginfluenzacanbe vaccinated.These
include:
l. One of the most readilyfreelyavailable
sourcesof evidence-based
medicineon the world wide web is the
'TherapeuticsInitiative',Universityof BritishColumbia
. Peoplewho provideessentialcommunityservices
. Peoplein the workforce,sinceextensiveabsenteeism
Vancouveq
Canada.
Theiremphasis
ison'evidence-based
dueto influenza
resultsin hugeeconomiclosses.Small
drug therapy'.(wwwti.ubc.ca)
businesses
are particularly
vulnerable
asthey mayhave
to closedown for a period.
Prevention andTreatment of InfluenzaA and 88
. Schoolchildrenand students,especiallyresidingin
dormitories.
Conclusions.'
. Sportspersons
and athletesas they could be prone to
Prevention: Vaccination
in cohort studiesloweredrates
viral myocarditisif they do not recoverfully before
hospitalization,
of
serious
morbidityand mortalityin
exercising
again.
patients
preventive
over
60.
Amantadine
is a second-line
. Travellerstravellingfrom one hemisphereto another
agent.
maybe at riskandshouldbe vaccinated
at least2 week
Treatment Antiviraltreatmentat the onsetof symptoms
beforedeparture.As the appropriatevaccinemaynot
showsthat amantadinereducesfever by one day and
be readilyavailable,
amantadine
canbe prescribedif the
oseltamivir
andzanamivirreducedurationof flu symptoms
patientfallsin the highrisk category.
by 0.8- 0.9 day.
Note: The lattertwo drugsareneuraminidase
inhibitors
Question Four
yet
andare not
available
in SouthAfrica.
What is the cost-effectivenessof vaccinatingpeople?
Answer Four
Studiesin SouthAfrica haveshownthat influenzavaccination
couldsavethe medicalaid industrymore than R53 million
(assumingan 80% efficacyof the vaccine). In the work
environment
the costbenefitratiowasfoundto be upto 5:1.7
2 The CochraneCollaborativeReviewsare widely known
for their highlyfocusedapproachusingrandomised
controlledclinical
trials.Not surprisingly
several
systematic
reviewshavebeenundertakenwhich involveinfluenza.
Question Five
Who shouldprobablynot be givenInfluenza
vaccination?
Vaccinesfor preventinginfluenzain healthyadultse
(Lastamendedon 2 | June| 999)
Reviewers' conclusions: Influenzavaccinesare
effectivein reducingserologicallyconfirmedcasesof
influenzaA.However,theyare not aseffectivein reducing
c a s e so f c l i n i c a li n f l u e n z a .T h e u s e o f W H O
r e c o m m e n d e vda c c i n e sa p p e a r st o e n h a n c et h e i r
effectiveness
in practice.
Answer FiveT
. Childrenunder6 monthsold
. Individuals
with allergiesto (chicken)eggs
. Anyonewith an allergyto neomycin,
or thimerosol(a
preservativepresentin contact lens solutionsand flu
vaccines)
Amantadine and rimantadine for preventing
and treating influenzaA in adultsr0
(Lastamendedon | 9 February| 999)
Reviewers'conclusions:Amantadine
andrimantadine
havecomparableeffectiveness
in the preventionand
and multiplesclerosis.The
involvingvariousvaccinations
vaccinationhistoryof MSpatientswho hadrelapsedbetween
foundno
1993and 1997wasfollowedup.The researchers
andtetanus,hepatitisB or
association
betweenMSrelapses
|3
influenzavaccinations.
treatment of influenzaA in healthyadults,although
rimantadineinducesfewer adverseeffectsthan
amantadine.
in SouthAfrica.)
(Note:Rimantadine
is not yet available
Neuraminidase inhibitors for preventing and
References:
treating influenza in healthy adultsrl
(Lastamendedon 05 June| 999)
Departmentof Medical
of VirusArchitecture.
Inhibitors l. StannardLf'1,Principles
Reviewers' conclusions:Neuraminidase
|
995.
http:/iwrywv.uct.ac,zaldePts/
of
CapeTown,
Microbiology,
University
of
prevention
treatment
the
and
(Nls) are effectivefor
mmi/stannard/virarch.html
causes
influenza.OverallNls aresafe,akhoughoseltamivir
http://
FluViruses.
N,WebsterRG.Disarming
2.
LaverWG,Bischofberger
s@ificantnausea.
|
99laver:html
|
999lO
|
99issue/0
www.sciam.com/
antigenof
(Note: Nls act againstthe neuraminidase
| ,html
http://wwwuct.ac.zaldeptsimmi/jmoodie/welcome
3. KeenA.Influenza.
A
influenzavirions. They are usedfor both Influenza
u | 0.asp
4. http://wwwworldwidevaccines.com/public/diseas/infl
andRimantadine
B infections.Amantadine
andlnfluenza
l-38. http://www.cdc.gov/mmwr/
5. MMWR April 14,2000 / 49(RR03);
A
infections.)
against
Influenza
effective
are only
Homoeopathic Oscillococcinum for preventing
and treating influenza and influenza-like
syndromesl2
(Lastamendedon 07 September1999)
B a c k g r o u n d : O s c i l l o c o c c i n u mi s a P a t e n t e d ,
medicine.The rationalefor its use in
homoeopathic
principleof
influenza
comesfrom the homoeopathic
'let likebe curedby like'.The medicineis manufactured
from wild duckheartand liver;a well-knownreservoir
for influenza
viruses.
probably
Reviewers'conclusions:Oscillococcinum
patients
presenting
reducesthe durationof illnessin
the data
with influenzasymptoms.Thoughpromising,
are not strong enough to make a general
for first-line
to useOscillococcinum
recommendation
treatment of influenzaand influenza-likesyndrome.
Furtherresearchiswarrantedbut requiredsamplesizes
are large. Current evidencedoes not suPPorta
preventativeeffect of homeopathyin influenzaand
influenza-like
syndromes.
Andfinallya word for peoplewith multiplesclerosis
Patients
who wonder abouthavingan influenzavaccination:
The February1,200l,issueof the New England
Journalof
study
Medicinereports on a controlledepidemiologic
Lhtm
preview/mmwrhtml/rr4903a
l-29
6, MIYWR1999;48
[No.RR-4]:
7. htto://www.flu.co.za./medical.htm
8. TherapeuticsLetter:issue38, November/ December2000.http//
www.ti,ubc.ca,/pages/lette138,htm
TO.Vaccines
for preventing
9, DemicheliV RivettiD, Deek JJ,Jefferson
Librory,4,
influenzain healthyadults(CochraneReview).In:Ihe Cochrane
2000. Oxford: Update Software.(http://www.cochrane.org/cochrane/
| 269.htm)
revabstr/abOO
andrimantadine
DemicheliV
DeekJJ,RivettiD.Amantadine
lO. leffersonTO,
for preventingandtreatinginfluenzaA in adults(CochraneReview),ln:
The CochroneLibrary,4,2000. Oxford: Update Software.(httP://
| | 69.htm)
www.cochrane,orgicochrane/revabstr/abOO
-l
inhibitors
for
| | . Jefferson Demicheli
V Deek J,RivettiD. Neuraminidase
preventingand treatinginfluenzain healthyaduhs(CochraneReview).
ln: The CochroneLibrory,4,2000. Oxford: Update Software.(httP://
| 265.htm)
wranru.cochrane,org/cochrane/revabstr/abOO
and
for preventing
Oscillococcinum
12.VickersAJ,SmithC. Homoeopathic
In:
syndromes(CochraneReview).
and influenza-like
treatinginfluenza
The CochroneLibrory,4,2000. Oxford: Update Software.(http://
| 957,htm)
wvwv,cochrane.orglcochrane/revabstr/abOO
andthe riskof relapsein multiplesclerosis,
C.Vaccinations
| 3. Confavreux
| /0344/
N EJM 344:3 | 9-326, 200| . http://www.nejm.com/content/200
0005/03| 9,asp
For a reviewof viral structureand some extraordinaryelectomicrographic
http://wwwuct,ac.za"/depts/mmi/
pictures:StannardLM.VirusUhra-Structure,
stannard/linda,html
...andguwrotoiltL
hq
Practice
S,A,Family
to Read!
The0nlyOneYoiiIEED
/,
,@e @oaadue, le Wetsbn
totntgnttr frare'.'
.gct Inoobe/
Jointhe SouthAfricanAcademyof FamilyPnctice/ PrimaryGare
GallPenryEryceon 011-8075605
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