Influenza

Question 1

Influenza: Basic Overview

Answer 1

Viral RESPIRATORY tract infection caused by influenza virus of
which there are several subtypes (influenza A, B, C and D) and
strains within types (type A: H1N1, H3N2, etc.)
Causes winter epidemics every year (~October – May) which
leads to clinical concern, but also has pandemic potential with
historical pandemic strains
Causes an acute bronchitis or viral pneumonia but can also
exacerbate chronic lung or cardiac conditions leading to
substantial morbidity and mortality

Influenza can cause serious and complicated disease in patients of all age groups.

Question 2

Influenza: Review of Basic Terminology
PANDEMIC
EPIDEMIC
SPORADIC
INFECTIOUS

Answer 2

PANDEMIC – disease that has spread over multiple countries or continents
EPIDEMIC – disease that affects large amount of people within a specific community, population or region
SPORADIC – disease that occurs infrequently/irregularly, with no discernible temporal or spatial pattern
INFECTIOUS – a disease likely to be transmitted to people, organisms etc. (does NOT infer person to person)

Really, what we mean by any infectious disease is just the disease you can acquire from your environment.
A contagious disease typically refers to that. It’s a candidate for human to human spread.

Question 3

Influenza: Epidemiology & Mortality

Answer 3

Influenza causes ~ 12,000 hospitalizations
and ~ 3500 deaths in Canada each year
* Influenza causes ~ 500,000 deaths annually
worldwide
* Burden of illness bimodal < 5 y.o and
> 75 years old but affects ALL ages
* More people die of influenza than ANY
OTHER vaccine-preventable illness
In Alberta:
* 1.1 million Alberta are immunized as of Jan
2022 (out of 4.371 million; ~25%)

Question 4

nfluenza: Basic Virology

Answer 4

Influenza virus is an RNA virus that causes respiratory
infection in humans. Only influenza A can also infect
pigs, birds (duck, geese, chickens), as well as cats, bats,
and dogs (e.g., H3N8), among other animals.
Sub-types of influenza virus occur due to
polymorphism in two key surface proteins:
* Haemagglutinin (H or HA) – vaccine target
* Neuraminidase (N or NA)
There are actually four types of influenza viruses
(influenza A, B, C and D):
* Influenza C – possible mild illness, nil threatening
* Influenza D – affects cattle, nil disease in humans

Influenza A virus (not B) circulates in animals as well – which primes it for dramatic genetic recombination

• So influenza is in Rna virus. That detail is important. Does anyone know why Rna viruses are a little bit trickier than DNA viruses.
• So Rna viruses have higher error rates in their Rna polymerase enzymes. So essentially they’re more likely to mutate year after year
• compared to DNA viruses. Of course DNA viruses can mutate as well. But Rna viruses do this with the greater turnover rate, and so this leads to a problem,

there are 2 important proteins to know on influenza,

hemagglutinin is the attachment protein that influezna uses to attach to your cells and enter them. And this is, of course, the vaccine target

NA - Which it used to escape your cell and infect other cells

Question 5

Influenza: Basic Virology – IAV vs. IBV

Answer 5

Influenza A
DISTINGUISHED BY H/N ANTIGEN TYPE
H1N1 H1N2 H3N2
PANDEMIC POTENTIAL
But also causes seasonal
(winter) epidemics

Influenza B
Victoria
Lineage
Yamagato
Lineage
Less harmful
Causes seasonal epidemics but nil pandemic potential since lack of animal reservoir

Bird subtypes (e.g., H5N1) occasionally cause sporadic “avian” flu which is not passed person to person

cause influenza B is so genetically similar. Year after year, with very small mutations, we actually refer to them in the lineages from which they were first described. So the 2 lineages we describe are the Victoria lineage and the Yamagato lineage of influenza. B. Year after year. They do mutate, but they’re so genetically similar that we just call them that lineage
- cause seasonal epidemics, and it does lead to a substantial amount of morbidity, especially in pediatrics. But it doesn’t have that same pandemic potential as influenza a

influenza. A however, does have that pandemic potential, and we actually refer to influenza, a strain specifically by their hemagglutinin, and in their neuramidase protein

Question 6

Influenza: Antigenic Drift & Shift

Answer 6

Type A & B Influenza virus\
Antigenic Drift
~Non-dramatic mutation of HA/NA
proteins as a consequence of reduced
proofreading activity of RNA polymerase

FOR EXAMPLE
H3N2 –> H3”b
Still “H3” but no longer as
recognizable by immune
system, change in
antigenic sit

Type A Virus ONLY (IAV) – animal reservoir*
Antigenic SHIFT
Dramatic change in HA/NA proteins
recombination never seen before in
humans – nil immunity
FOR EXAMPLE
H1N1 –> (H1N1)pdm09 virus
OR
Pig / Avian / Human triple reassortment

Avian H2N2 –> Human/Avian H3N2

Question 7

Influenza: Susceptibility to Future Strains

Answer 7

Building an immune library against various drift-mutants is likely our best protection against severe illness

Antigenic drift
mutants of H3N2
and H1N1

Question 8

Influenza: Route of Transmission

Answer 8

With HUMAN subtypes (e.g., H1N1, H1N2 and H3N2),
influenza is highly contagious (meaning the virus is
passed from person to person).
The leading theory on route of transmission is:
* Respiratory droplet (i.e., inhalation of virions in
moisture droplets from sneezing, coughing)
Suspected to occur less often is:
* Fomite spread (i.e., survives on inanimate objects
~24 hours) – considered less likely
Obviously – the details matter about the degree of
contact between individuals!

Remember: most the ROI for an infection probably ranges on a spectrum – think critically!

Question 9

Influenza: Pathophysiology

Answer 9

Influenza virus is inhaled via respiratory droplet
and binds to cells in the upper airway respiratory
epithelium via it’s haemagglutinin (HA) > to the
sialic acid glycoprotein (SA) – sometimes
colonizing the lower airway as well (not always).
Influenza uses its own RNA polymerase to
create mRNA using host substrates but uses host
ribosomes to synthesize proteins.

Importantly: active viral infection leaves patients
prone to secondary infection which can occur
with bacterial organisms OR even fungal
organisms (e.g., Aspergillosis).

Clinical illness caused by influenza is due mostly to the immune-response to the viral infection!

1Attach/Fusion
2 RNP Release
3 Transcription/Translation
4 Assembly/Packaging
5 Egress

Question 10

Influenza: Timeline of Infection

Answer 10

Inoculated w/ respiratory droplet or fomite

Asymptomatic
INCUBATION PERIOD
Day 7 of Sx (~Day 9)
SYMPTOMATIC PERIOD
Begins ~Day 2, worst about 2-3 days into illness, then recovers
over a 7–10-day period

ONTAGIOUS PERIOD
From ~1 day prior to onset of symptoms 
~5-days AFTER symptom onset
(possibly longer in children or immunocompromised)

For the most part, patients are contagious during the period where they are symptomatic

Illness generally lasts about a week. We say a week to 10 days, 7 days is the median. and generally about 2 to 3 days into your symptomatic period is the peak of your illness. So you get worse at day, 2 or 3 of illness, and then generally taper off thereafter

We’ve considered you contagious
practically, for as long as you’re ill, so as long as you’re symptomatic, you’re probably contagious.

Question 11

CASE EXAMPLE:
35F with known COPD presents to the emergency department
with fever, cough, pleuritic chest pain and myalgias. Patient has
been feeling unwell for about 5 days and the fever and cough
have been the worst today. She recalls seeing her nephew and
sick niece about 10 days ago. She is producing clear sputum.
T 38.1, HR 85, RR 15, BP 128/70 mmHg
WBC 12.1, other labs unremarkable. CrCl = 85.3 mL/min
CXR demonstrates bilateral patchy opacities perhaps R > L.
Q: MD asks you – what dose of ceftriaxone + azithromycin
should I use for this community-acquired pneumonia?

Which feature in this clinical history is the most compelling for the diagnosis of viral pneumonia?

Answer 11

What part in this history. There’s one single thing in this history that makes influenza much more likely than a bacterial organism.

if you get sick contacts with other people who are sick. That is the clue for viral pneumonia or viral illness. In general
there are bacterial illnesses that are contagious that are passed from person to person like tuberculosis. But bacterial pneumonia is not transmitted Person a person, and so viral pneumonia. The key giveaway in this case is sick contacts.

Question 12

Influenza: The Key To Recognize a Viral Infection

Answer 12

viral inf

HISTORY OF SICK CONTACTS
i.e., exposed to someone with known
illness/symptoms (often even known
virus) recently in the last 1-2 weeks

bacterial
NIL SICK CONTACTS
BUT can be
SIMULTANEOUSLY SICK
i.e., group of people become sick on the
same day (e.g., after eating at a restaurant)

The clinical history of sick contacts is the most important history question for recognizing a virus!

Question 13

Influenza: Common Clinical Presentations

Answer 13

CONSTITUTIONAL FEATURES of INFECTION:
* FEVER (classically high in true influenza)
* Myalgias (commonly prominent in influenza)
* Malaise, fatigue, headache
UPPER AIRWAY (UAW) Disease:
* Nasal congestion
* Pharyngitis (sore throat)
LOWER AIRWAY DISEASE:
* Cough (commonly non-productive, but can be
productive)

Variability in the likelihood of UAW or lower airway disease may depend on the strain (i.e., IAV > lower disease).

Question 14

Influenza: Complete Assessment for Influenza

Answer 14

SYMPTOMS AND SIGNS OF INFLUENZA:
* Fever (classically high fever)
* Cough (typically dry, but can be productive)
* Myalgias
* Headaches
* Sore throat/pharyngitis
* Rhinorrhea/nasal congestion
* Gastrointestinal distress (some strains more than others)
KEY POINT IN HISTORY: SICK CONTACTS
* Unlike bacterial infections – viral infections (particularly respiratory viruses)
have histories of exposure to others who are known to be infected –
this alone might clue into the dx
BLOODWORK: mild leukocytosis, if any. Elevated acute phase reactants
DIAGNOSTIC IMAGING:
* CXR imaging if PNA – typically bilateral patchy opacities/interstitial
pattern (as opposed to lobar infiltrate)

No ONE feature of an illness is pathognomonic. Assess ALL features and produce a GESTALT judgement!

Question 15

Influenza: Influenza, COVID, or Something Else?

Answer 15

Common Cold
* Perhaps predominant URTI symptoms, like rhinorrhea,
sneezing, congestion, sore throat
Influenza
* Classically fever, myalgias and cough
COVID-19
* Initially cough, shortness of breath – but now evolving into a
URTI syndrome
The KEY LEARNING POINT:
* Recognize features of illness that are concerning for severe
illness requiring referral
* Recognize features that are bacterial vs. viral – to limit the
prescribing of antibiotics!

Influenza MIGHT be associated (depending on the strain) more with fever, myalgias and cough.

Question 16

Features Indicative of Bacterial Infection
Features Indicative of Viral Infection

Answer 16

Features Indicative of Bacterial Infection
* Nil sick contacts
* Double sickening
* Rapid acute onset (1-2 days ago)
* Severe illness (relative, not a rule)
* +/- Purulent sputum
* Very high leukocytosis (~>15)
* Lobar infiltrate on CXR

Features Indicative of Viral Infection
* Sick contacts
* Less severe or delayed onset >2-3 days
* +/- Clear sputum or non-productive
* Minor leukocytosis

- Double sickening KNOW FOR EXAM
	○ somebody can have a viral pneumonia like Influenza or Covid, but then be secondarily infected with a bacterial pneumonia
	○ somebody who is having influenza or coronavirus infection
	looks like they're at their peak of illness actually starts to improve. But then suddenly it becomes much worse. That's somebody who is undergoing the phenotype of somebody who might be secondarily infected with the bacterial pneumonia.

The other types of features that are classic for bacterial pneumonia, and not for viral pneumonia, are very rapid, acute on set of illness, like one to 2 days ak. They go to sleep totally fine, and they wake up with a very severe illness that’s more classically bacterial.

Question 17

Influenza: Complications & Secondary Infections

Answer 17

RESPIRATORY:
* ARDS (usually pandemic strain but can
be any IAV)
* Secondary bacterial PNA (classically
Staphylococcus necrotizing pneumonia,
but can be simply Streptococcal)
* Secondary FUNGAL PNA (i.e., invasive
pulmonary aspergillosis or variants)
* Exacerbation of chronic lung disease

CNS:
* Febrile seizures (pediatrics)
* Reye Syndrome - aspirin
* RARE others (encephalitis)
* Guillain-Barre Syndrome?
CARDIAC:
* Exacerbation of chronic heart failure
* Viral myocarditis/pericarditis
PREGNANCY:
* Increased obstetrical/maternal complications
* Increased infant prenatal fatality
* Increased risk of prematurity, lower birth weight

The most common cause of death from influenza is ARDS and secondary bacterial pneumonia.

Question 18

Acute Respiratory Distress Syndrome (ARDS) – Mortality at ANY Age Group

Answer 18

PATH: An exaggerated, dramatic and inappropriate IMMUNE
response to a pulmonary insult (i.e., viral infection, bacterial,
trauma, foreign body aspiration, other) that leads to inability of
the lung to participate in gas exchange
PROBLEM:
* Therefore, we can try to ventilate these patients – but pushing
air in DOES NOT WORK
ATTEMPTED TREATMENTS:
* Mechanical ventilation (might assist in milder ARDS) and
pharmacologic lung paralysis
* Proning (recruiting different lung segments)
* Eventually this fails
* Extracorporeal membrane oxygenation/ECMO/ECLS
* “Dialysis for the lungs” – performs gas exchange –
requires major CVICU procedure and is life-threatening

Patients of ALL AGES can get ARDS – carries a mortality rate of ~50%, survivors can have chronic lung disease.

Question 19

Influenza: When To Refer

Answer 19

Most of the recommendations on when to a refer an
adult or pediatric patient with suspected influenza is
common sense…
BOTTOM LINE: if you suspect evolution into a BACTERIAL
ILLNESS or ARDS – OR difficulty breathing – patients
should be referred to the emergency/urgent care setting.
* All patients < 2 years old with influenza
* Shortness of breath/tachypnea
* Signs of hypoxia (cyanosis, altered level of
consciousness, difficult to rouse)
* Seizure activity
* Double sickening (indicative of ?bacterial infection)

Viral illness followed by apparent IMPROVEMENT > then SUDDEN CLINICAL WORSENING = double sickening

Question 20

Influenza: Molecular Testing & Diagnostics

Answer 20

Rapid Antigen Testing – i.e., immunoassay w/
nasopharyngeal or nasal swab
* Less sensitive – i.e., if “negative” doesn’t rule out!!
* Specific – i.e., if “positive” – almost certainly positive
* Results in 10-15 minutes
* Depending on assay, can be expensive or covered

Molecular Testing – i.e., PCR (polymerase
chain reaction) looking for viral RNA
* Much more sensitive – if “negative” = NEGATIVE
* Specific as well – but more costly and turnaround time
is delayed (can be 24-72 hours) depending on capacity
* Can be done with any specimen, sputum, BAL, NP swab
(in hospital done with RPP from NP specimen)
This should make you think – why would we ever do a rapid antigen test?! (resources limited)

in the hospital setting. We always do molecular testing in the outpatient setting. There’s no really commercially available test outside of public health offices. And even then they’ll probably do molecular tests, not rapid antition tests.

rapid antigen tests which are usually immunoassays. They’re looking for circulating antibodies to influenza or coronavirus
Rapid antigen tests would rely on you being actively sick. And so they’re less sensitive. So, generally speaking, a less sensitive test
doesn’t rule out disease, but might be useful in the community setting. - you’re really hoping to find out that. Yes, they’re positive for a disease

then things like molecular tests like Pcr testing. So we’re actually looking for genetic material.
what we do in the hospital setting. We don’t do rapid tests for anybody. We do molecular tests for absolutely everybody, because their sensitivity is very high. So if they’re negative, we’re really confident you don’t have influenza or covid
even if you had influenza weeks ago, and you just have dead virus in your nose. For example, we’ll find it anyways, because it can still pick up dead genetic material.

Question 21

Influenza: Antiviral Pharmacology Available

Approved,
Marketed in
Canada

Approved,
NOT Marketed
in Canada

Answer 21

Approved,
Marketed in
Canada
OSELTAMIVIR (Tamiflu)
Neuraminidase inhibitor
ZANAMIVIR (Relenza)
Neuraminidase inhibitor
PERAMIVIR (Rapivab)
Neuraminidase inhibitor

Approved,
NOT Marketed
in Canada
AMANTADINE/RIMANTIDINE
M2 Ion Channel Inhibitors
BALOXAVIR MARBOXIL (Xofluza)
Endonuclease inhibitor
RINTATOLIMOD (IN TRIALS)
Unknown Mechanism

Question 22

Influenza: Antiviral Pharmacology – Mechanisms of Action

Answer 22

Antiviral activity and symptom improvement may be from pleiotropic effects of these agents.

generally speaking. These mechanisms, even the Cochrane Review authors and the systematic reviews that study these drugs. Don’t believe that these mechanisms of action are actually relevant based on the way they work, and there’s a lot of suspicion that there might be pleiotripic effects of these drugs that make them work the way they do

slide 26

Question 23

Influenza: Antiviral Pharmacology – Neuraminidase Inhibitors

Answer 23

Oseltamivir and zanamivir are both schedule I
(prescription only) agents available and
marketed in Canada for influenza virus
treatment and prophylaxis.
Both are administered TWICE daily (for
treatment) and then once daily when used if
indicated for chemoprophylaxis but are very
well tolerated (GI disturbance if any adverse
effect).
HOWEVER:
* NAIs are well tolerated, but are they
actually effective? What would our goals
of care be?

Just because treatments are well tolerated DOES NOT mean they should be given “just in case”!

see table slide 27

Question 24

Influenza: Evidence for Neuraminidase Inhibitors… Is It Worth It?

Answer 24

Patients requiring hospitalization
NIL RCTs: Large 2014 SR of observational studies during 2009 (H1N1)pdm09
Mortality: ?decreased mortality if NAIs used; adults > children (OR 0.75; 95% CI 0.64-0.87), irrespective of timing of administration with
illness. Not replicated with subsequent SR.
Severe Outcomes: ICU/Death – increase in
propensity of severe outcomes, pre-admit NAI
use reduced severe outcomes (OR 0.51; 95% CI
0.29-0.89)

Patients NOT requiring
hospitalization
++RCTs, 2 metaanalyses/SR of RCTs
TTAS: Oseltamivir/zanamivir reduce TTAS by ~15-
25 hours in adults and pediatrics, maybe less in
older adult (>65 population); more effect seen
when given within 12-24 hours of illness
Development of PNA: ~maybe a 1% ARR
Hospitalization: Conflicting data

Do patients who were GOING to do very poorly – do BETTER if treated early with NAIs?

If not at substantial risk of complication – benefit is questionable for NAIs in influenza.

what I would ask you to remember, bolded and highlighted here from a severe outcome perspective, is that what did seem more compelling across multiple systematic reviews is that when patients came to the hospital already on neuron in a day Inhibitors it looked like they ended up having less severe outcomes.

Question 25

Influenza: Antiviral Pharmacology – Baloxavir Marboxil

Answer 25

Baloxavir Marboxil is an oral capsule medication that has an
indication for patients (12 years and older) at high risk of serious or
complicated influenza infections if given within 48 hours (similar to
NAIs). It is currently NOT marketed in Canada.
The common dose given is 40 mg PO x1 dose – or 80 mg if
between >80 kg in weight.
But would we ever prefer baloxavir to our NA inhibitors?
* Very well tolerated (similar to NAIs), unknown in pregnancy
* Single dose is reasonably preferable – but what about efficacy?
* Randomized, double-blind, placebo AND oseltamivir controlled
RCTs done (phase III) demonstrate similar efficacy to
oseltamivir (maybe slightly earlier symptom resolution).

Unfortunately, although promising – the type of benefit obtained is very limited and probably similar to NAIs.

Question 26

Influenza: Antiviral Resistance… Is That A Thing?

Answer 26

Antiviral drug resistance is certainly possible and a phenomenon
that is better characterized with other viruses (e.g., HIV). Although
it is possible for viruses to develop drug resistance, this is rarely a
clinical concern for the following reason:
* Clinical failure of influenza antivirals is nearly impossible to
observe/detect (i.e. ?1-less of day of symptoms, how can you
tell if that didn’t happen? – or perhaps reduced mortality, but
patients develop ARDS and other causes)
Even if epidemic strains of influenza were suspected of being
antiviral resistant, viral genotyping to confirm this on an
individual level would be delayed, and treatment may be
complete by the time of receipt. Instead – the CDC monitors for
resistance patterns every year, but susceptibilit

BOTTOM LINE: The limited baseline benefit of antivirals makes consideration of resistance difficult.

Question 27

Influenza: The Problem With Recognizing Influenza

Answer 27

Despite the opportunity to provide some small treatment
with small benefit in those who are not hospitalized – the
problem remains that most patients present DELAYED to
medical care – such that they are beyond 48 hours from
their onset of illness.
Further: other viruses and illnesses commonly mimic the
presentation of influenza – and recognition can be delayed,
which also removes many patients from the “early” group (<
48 hours). The time it takes influenza testing to return can
delay treatment – depending on the assay used.
THEREFORE:
* Keen attention should be paid to recognizing a VIRAL
illness in the winter with questions RE: local outbreaks
to expedite recognition and provide treatment IF it is
warranted (perhaps BEFORE testing results)

Delayed presentation or delayed recognition might reduce the added benefit of antiviral pharmacotherapy.

Question 28

Influenza: The Decision to Treat

Answer 28

Caught BEFORE 48 hours of illness onset

Immunocompetent and no risk factors for severe disease and 5-64 years of age

Giving neuraminidase inhibitors might have zero patient benefit

Caught AFTER 48 hours of illness onset
Hospitalized? Severe illness or IMC status? Circulating in close quarters?

Giving neuraminidase inhibitors might be reasonable

So patients that are immunocompromised
risk factors for severe disease, or in that very young or very old population, and in patients who are hospitalized with severe illness, we might consider giving them their amenities inhibitors as well. If you catch anyone after 48 h, the only reason we’d be giving also time of year is in those patients that are hospitalized
just because we want to see if we can reduce their severe outcomes and offer something

Question 29

Influenza: Supportive Care & Treatment

Answer 29

Non-Pharmacologic Approaches
* Rest and relaxation (avoidance of strenuous
activity which could exacerbate respiratory
illness if progressive pneumonia)
* Cold compresses on forehead (for fever)
* Maintenance of fluid and food intake
(especially in the elderly, reduced PO intake
could be related to development of AKI or
electrolyte disturbances which can require
admission)

Supportive Pharmacologic Approaches
* Acetaminophen / ibuprofen reasonable
for fever and muscle aches although
remember to consider these when
assessing for fever
* Nausea vomiting if a component as
general viral illness symptom can be
assisted with OTC anti-nauseants

Peak illness typically occurs 2-3 days into symptoms, although may be delayed if immunocompromised.

Question 30

Prevention of Influenza

Answer 30

Vaccination is the primary strategy for
preventing morbidity and mortality associated
with influenza (& SARS-CoV-2) infection
Appropriate infection control measures should
also be taken when influenza (or SARS-CoV-2) is
in circulation:
 Frequent hand-washing
 Conceal/cover cough; throw away any used tissues
 Avoid infected/uninfected individuals (social
distancing)
Masks (especially for SARS-CoV-2)

Common sense should be applied to preventative measures. Stay away from infected individuals!

Question 31

Oseltamivir for Prevention of Influenza: Welliver et al. JAMA 2001

Answer 31

Design: Randomized, double-blind, placebo-controlled study
@ 76 centers in NA/Europe in 1998-1999
Patients: N = 955 household contacts of influenza cases (415
were contacts of lab-confirmed influenza cases), all >12 y.o
Intervention/Comparator: Either 75 mg PO daily oseltamivir
(n = 493) OR placebo (n = 462) within 48 hours of their
contacts symptoms, cases did not receive antiviral treatment
Outcomes: Clinical influenza (sx) confirmed by lab as
influenza
Results: 0.8% (4/493) developed clinical influenza in
oseltamivir group versus 7.4% (34/462) in placebo group
(overall efficacy ~89%; 95% CI 71-96%, p < 0.001). Side
effects in ~10%

We know that vaccination may PREVENT influenza cases, but it is common for patients to develop clinical illness despite vaccination
(although attenuated). Especially in the older adult or immunocompromised population where development of immune response is reduced – we may consider providing antiviral prophylaxis to prevent clinical influenza.
BOTTOM LINE:
* It appears that oseltamivir prophylaxis when given to high-risk individuals prevents the development of symptomatic influenza (~80%
effective) when exposed to close contacts

Regardless of vaccination: in high-risk scenarios (I.e., group homes) – oseltamivir proph may be justified.