IL BURDEN DELL’INFLUENZA E L’IMPATTO DEL VACCINO SULL’ANZIANO

Stefania Maggi

CNR-Invecchiamento

Padova

DISCLOSURE

Grant di ricerca da:

• TAKEDA, MSD, GSK, PFIZER

Outline

• Il burden dell’Influenza: un problema complesso

• Il valore della vaccinazione: ben oltre la prevenzionedell’influenza

https://www.epicentro.iss.it/influenza/aggiornamenti

Casi di Influenza in Italia 2018-19

• Circa il 15% della popolazione

• Oltre 8 Milioni di casi sintomatici

• Ospedalizzazione e mortalità più frequenti nella popolazione anziana(oltre il 90% delle morti)

Copertura vaccinale in Italia: circa 50%

(target minimo 75%, target ottimale 95%)

Disabilità e influenza

Catastrophic Disability:Defined as a loss of independence in ≥3 basic activities of daily living2

• 14.6% of older adults hospitalized with influenza experience catastrophic disability3

• Dysregulated immune response is the ‘sleeping giant’ of chronic diseases. Flu wakes the giant, increasing the risk of catastrophic disability with:

– Stroke, heart failure

– Pneumonia4

– Ischemic heart disease

– hip fracture

1.McEthaney JE Front Immunol 2016; 7:41, 2.Ferrucci et al. JAMA1997; 277:728. 3.Andrewes MK. Canadian Immunization Conference 12/7/2016. 4.Barker Arch Int Med 1998; 158:645. 5.Falsev NEJM 2005; 352:1749 From Greember. ESWI Riga 2017,

Globally, most leading causes of death are non-communicable diseases1

1. WHO. The top 10 causes of death. 2018. https://www.who.int/en/news-room/fact-sheets/detail/the-top-10-causes-of-death [last accessed 29-Jul 2019].

Deaths (millions)0 2 4 6 8 10

Ischaemic heart disease

Stroke

COPD

Dementia

Lower respiratory

tract infections

1. WHO. The top 10 causes of death. 2018. https://www.who.int/en/news-room/fact-sheets/detail/the-top-10-causes-of-death [last accessed 29-Jul 2019]; 2. Fischer WA 2nd et al. Glob Heart 2014;9:325–36; 3. Corrales-Medina VF et al. PLoS Med 2011;8:e1001048;

4. Zhang Y et al. J Stroke Cerebrovasc Dis 2017;26:1807–16; 5. Lee KR et al. Neuroepidemiology 2017;48:103–10;

6. Froes F et al. Int J Chron Obstruct Pulmon Dis 2017;12:3457–68. 7. Chen VC et al. J Clin Psychiatry 2018;79:pii:16m11312.

Varicella/zoster4, Influenza5

Influenza2, Pneumococcus3, Varicella/zoster4

Influenza6, Pneumococcus6

Varicella/zoster7

VPDs associated wth triggering or exacerbation of

this condition

Deaths (millions)0 2 4 6 8 10

Ischaemic heart disease

Stroke

COPD

Dementia

Lower respiratory

tract infections

Globally, most leading causes of death are non-communicable diseases1

… but vaccine preventable diseases may play a role

Effetti dell’infezione del virus influenzale nella malattia cardiovascolare

StrokeInfarto del miocardio

L’infiammazione sistemica porta ad una rottura delle placche

aterosclerotiche

L’infezione virale può portare a miocardite o miopericarditi

Effetti direttiEsacerbazione di CVD pre-esistenti

Udell J. Expert Rev Cardiovasc Ther, 2015

Insufficienza cardiaca cronica

L’influenza può portare ad un’alterazione dell’omeostasi

Infarto Acuto del Miocardiodopo malattia influenzale (2009-2014)

● Studio caso-controllo in Canada (2009-2014) su 148,307 casi di influenza per valutare l’associazione tra malattia

influenzale confermata da laboratorio e ospedalizzazione per AMI in adulti (364 casi, età mediana: 77 a)

● INCIDENZA DI RICOVERO PER INFARTO ACUTO DEL MIOCARDIO:

6 VOLTE maggiore durante i 7 giorni successivi all’influenza

Kwong JC, et al. N Engl J Med. 2018;378(4):345-353

Kwong JC, Schwartz KL, Campitelli MA. N Engl J Med. 2018;378(26):2540-2541

Time-series: Association between influenza-like illness and hospitalization for heart failure. The ARIC Study

• ILI was temporally associated with increase in HF hospitalizations.

• A 5% increase in ILI was associated a 24% increase in HF hospitalizations rates

Kytömaa S, JAMA Cardiol 2019

- Retrospective cohort: 9,237 incident hip fractures Nursing Home (NH) residents, 2000 - 2009

Results:

ILI hospitalizations are associated with a 13% average increase in hip fracture hospitalization

Significant Temporal association

Influenza and Hip Fracture

McConeghy KW,. J Gerontol A Biol Sci Med Sci. 2017

Zullo AR. J Am Geriatr Ass 2018

Variation from 1 to 6 Hip Fracture/100 person-years in American NH, Cohort study ( Medicare) Result : < 15% variability explained by NH or residentcharacteristics

Could Flu be one of the causes?

Influenza Increases Disability

William H. Barker Arch Intern Med 1998 Gozalo PL JAGS 2013

Nearly 2 fold increase Disability rates with flu episodes

residents in 2351 Nursing home in the USA

influenza mortality was strongly associated with high (≥4 points) ADL decline

Influenza Mortality

ADL Decline (>3 points in the 0-28 ADL scale)

Outline

• Il burden dell’Influenza: un problema complesso

• Il valore della vaccinazione: ben oltre la prevenzionedell’influenza

IERI

Trivalente classico TIV

OGGI

QIV

ADIUVATO MF59 TIV

LAIV non in ITALIA

DOMANI

-Vaccino ad alto dosaggio [60 mg/ceppo]

USA dal 2009 TIV HD

Dal 2019 QIV HD

In fase di approvazione Europea

-Vaccino Ricombinante RIV QIV

già autorizzato USA

Sottomessa registrazione in Europa ottobre 2019

EVOLUZIONE DEI VACCINI ANTINFLUENZALI

• Attualmente utilizzato in US e Canada

• Procedura di registrazione avviata anche in Italia

• 60 mcg of HA per ceppo 4x quantità di antigene di HA in confronto ai vaccini tradizionali

(15mcg)

• Indicato per i soggetti dai 65 anni di età

• Novembre 2019 Approvazione FDA vaccino alto dosaggio formulazione quadrivalente con indicazione dai 65 anni di età

• Registrazione in corso in Europa già sottomessa a European Medicine Agency (EMA)

Vaccino antinfluenzale ad alto dosaggio- HIGH DOSE

Influenza vaccination reduces the incidence of ACS events in older adults with chronic disease

1. Sung LC et al. Vaccine 2014;32:3843

2. Chen CI et al. Medicine (Baltimore). 2016;95

Significantly fewer ACS first events in vaccinated vs

unvaccinated COPD patients in all seasons (P<0.001) with

clear dose effect

Significantly fewer ACS first events in vaccinated vs

unvaccinated CKD patients in all seasons (P<0.001) with clear

dose effect

0

0,2

0,4

0,6

0,8

1

1 vaccination 2-3 vaccinations ≥4 vaccinations

Relative risk of hospitalization with ACS in Chronic Kidney Disease (CKD) patients (n=4,406) 2

0

0,2

0,4

0,6

0,8

1

1 vaccination 2-3 vaccinations ≥4 vaccinations

Relative risk of hospitalization with Acute Coronary Syndrome (ACS) in COPD patients (n=7,722)1

Taiwan Longitudinal Health Insurance database 1996-2008

1.38 (0.44 – 4.32)

0.60 (0.41 – 0.87)

0.55 (0.30 – 0.98)

1.00 (0.54 – 1.85)

0.47 (0.29 – 0.77)

0.64 (0.48 – 0.86)

Study Events Total Events Total

Govaert 7 927 5 911

FLUVACS 32 145 54 147

FLUCAD 16 325 30 333

De Villiers 20 1620 20 1622

Phrommintikul 20 221 42 218

Total 95 3238 151 3231

2.93% 4.67%

Influenza Placebo/ MACE*: CV Death, MI, Stroke, HFVaccine Control UA, or Urgent Coronary Angioplasty

Absolute Risk Difference: 1.7%Number Needed to Treat: 58

0.2 0.5 1 2 5

Influenza Vaccine Better Placebo/Control Better

Udell JA, et al. JAMA. 2013;310(16):1711-1720.

Influenza Vaccination was Associated with a Lower Risk of Major CV Events in a Meta-Analysis of Small RCTs

RR (95% CI)

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* major adverse cardiovascular events

Danish nationwide study on Influenza vaccination and Heart Failure

To determine whether influenza vaccination is associated with improved long-term survival in patients with newly diagnosed HF.

To determine whether the frequency of vaccinations and the cumulative number of vaccinations is associated with improved long-term survival

Modin D et al. Circulation. 2019 Jan;139(5):575-586.

Exclusion:-569 < 18 years old-16 711 died 30 days

Final study population N= 134,048

Danish National Patient Registry

Data: study subjects

All first diagnosis of heart failure(ICD-10 I50, I130, I132)

1st Jan 2003– 1st June 2015N=151,328

Modin D et al. Circulation. 2019 Jan;139(5):575-586.

Results (Median follow-up about 3.7 years, mean age: 73 years)

Vaccination parameters and age were entered as time-varying covariates in a time-dependent Cox regressions model adjusted for all variables displayed in Table 1 with the addition of inclusion year.

Modin D et al. Circulation. 2019 Jan;139(5):575-586.

Results: Causation

Vaccination parameters and age were entered as time-varying covariates in a time-dependent Cox regressions model adjusted for all variables displayed in Table 1 with the addition of inclusion year.

Modin D et al. Circulation. 2019 Jan;139(5):575-586.

Possibile meccanismo cardioprotettivo della vaccinazione antinfluenzale

Bhatt et al. JACC Heart Fail. 2017 Mar;5(3):194-203

23

● Prevenire l’infezione evita

un’alterazione dell’omeostasi

● La risposta immunitaria a seguito

della vaccinazione può di per sé

avere un effetto benefico:

● Gli anticorpi indotti dalla

vaccinazione potrebbero

promuovere la stabilizzazione

della placca attraverso

l'attivazione del recettore della

bradichinina 2

Vaccinazione antinfluenzale come intervento per la prevenzione dell'infarto miocardico

MacIntyre CR, et al. Heart 2016, 102(24):1953

● La vaccinazione antinfluenzale offre potenzialmente rendimenti maggiori rispetto alla maggior parte degli altri interventi in prevenzione secondaria dell'infarto del miocardio:

● Le stime sull'efficacia dei vaccini anti influenzali nella prevenzione dell'infarto miocardico si mantengono in un intervallo di efficacia simile rispetto alla normale misura di terapia coronarica di routine come lo smettere di fumare o l’uso delle statine o della terapia ipertensiva

Intervento Efficacia (%)

Smettere di fumare 32–43

Statine 19–30

Farmaci anti ipertensivi 17–25

Vaccino anti influenzale 15–45

Influenza and Hip Fracture

Impact of flu vaccine on hip fracture ( Cohort study) (n=4344)2001 and 2013

Increase risk was 1.26 (1.1-1.51) ONLY in Unvaccinated Cohort 2 weeks following a week with high infection burden

Daily fracture rates were significantly higher in winter (1.1 fractures/day) compared to summer, fall, and spring.

Fraenkel M,. Osteopor Int . 2017

1. Doherty TM et al. Eur Geriatr Med 2018;9:289–300; 2. Preaud E et al. BMC Public Health 2014;14:[Epub]; 3. Bonanni P et al. J Mark Access Health Policy 2015;3:[Epub]; 4. Kwong JC et al. Clin Infect Dis 2009;49:750–756

Economic benefits from vaccinations

• Generally, economic evaluations of vaccinations in older adults show a favourable cost-

effectiveness ratio and cost is lower than for other preventive actions1

• Influenza vaccination coverage of 75% among individuals >65 years in Europe would

result in €153–219 million saved in healthcare cost1,2

BUT ALSO

• Intangible economic benefits due to:– attenuated severity of disease3

– reduction in complications (influenza and pneumococcal vaccinations may reduce the incidence of MI by up to 50%) and comorbidities1,3

– decreased polypharmacy and antibiotics use4

CO-MORBIDITIES Influenza

more likely & sooner

more severe

lung injury, bacteremia, acute stress etc.

(and unknown)

etc. (and unknown), frustrated homeostasis,

immune dysregulation, chronic inflammation

immediate step loss

accelerated chronic decline

failure (life-threatening)

dysfunction (symptomatic)

death

Influenza

Influenza

Influenza

Age

Sys

tem

s F

un

cti

on

(Re

sp

ira

tory

, C

ard

iova

sc

ula

r,

etc

.)

adolescence geriatrics

Modified from Quinton LJ et al. Physiol Rev. 2018;98(3):1417-1464.

...................To Summarize

Self-amplifying cycle between Influenza and comorbidities leading to decline in physiological function

Infections in Elderly Adults

Traditional

parameters

Geriatric

parameters

• Clinical features

• Changes in laboratory

values

• Clinical response

• Microbiological response

• Cause-specific mortality

Physical and Cognitive

functions

Complications

Health care aspects

Does the patient return to the same level of physical function?

Did the cognitive function of the patient change during and after the infection?

Has depression become clinically apparent and has it affected the recovery of function?

Physical &

Cognitive

functions

What are the infectious and not infectious complications?

Do they differ from those seen in the younger patients with the same infection?Complications

Is the length of hospitalization and the cost care higher for older than for younger patients with the same infectious disease?

Is the discharge to a place other than home required?

Healthcare

aspects

Geriatric Parameters