La patologia pneumococcica nell’adulto

Francesco BlasiDipartimento Fisiopatologia e Trapianti

Università degli Studi di Milano

Pharynx

Larynx

Nasopharynx

Eustachiantube

Nasal cavity

Trachea

Bronchitis

Lungs

Lower respiratory

tractinfections

Upper respiratory

tractinfections

Meningitis

SinusitisOtitis media

Pneumonia

Parapneumonicempyema

Bacteraemia/septicaemia

Invasivedisease

Colonisation

Pneumococcal bacteria cause disease when they spread beyond the nasopharynx

S. pneumoniae

“Pneumococcal paradise”

Streptococcus pneumoniae causes a spectrum of invasive and non-invasive disease

InvasivePneumococcalDisease

Vaccination drivers

SeverityDeaths

HospitalisationCosts

Volume of casesEconomic costs

Antibiotic use and resistance

Adapted from Melegaro et al. J Infection 2006, 52(1):37–48. Silfverdal et al. Vaccine 2009; 27: 1601–1608. WHO.The global burden of disease. 2008. O’Brien et al. Lancet 2009;374:893–902.

The impact of IPD in the EU

4.3 per 100.000 (2009)

The impact of InvasivePneumococcal Disease

7

Age is the first risk-factor: highest incidence and mortality rates of IPD at extremes of age

Incidence of IPD and associated mortality rates (USA, 2009)1

<1 1 2-4 5-17 18-34 35-49 50-64 ≥650

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1. Centers for Disease Control and Prevention. 2010. Active Bacterial Core Surveillance Report, Emerging Infections Program Network, Streptococcus pneumoniae, 2009. Available at: http://www.cdc.gov/abcs/reports-findings/surv-reports.html [accessed May 2012]

Cases Deaths

IPD incidence is increasing and will continue to risewith an increasing elderly population

• The population aged over 65 is increasing at twice the rate of the younger population, and cases of IPD are higher in this population 1

1. Stupka JE et al. Aging health, 2009; 5(6): 763-7742. Aguiar SI et al. Clina Microbiol Infect 2008; 14: 835–843

Number of isolates expressing serotypes included in conjugate vaccines causing invasive infection in adults in Portugal (2006–2008)

Isolates presenting both erythromycin resistance and penicillin non-susceptibility (EPNSP) are represented by closed black bars. Penicillin non-susceptible isolates (PNSP) are indicated by dark hatched bars. Erythromycin resistant isolates (ERSP) are indicated by light hatched bars. Isolates susceptible to both penicillin and erythromycin are represented by white open bars.

PPV23 serotypes continue to circulate despiteefforts to increase vaccination coverage

• After the initiation of PPV23 campaigns in England serotypes contained in the vaccine remained stable or increased in the elderly population2

1. Andrews NJ et al. Vaccine, 2012 article in press

Incidence of IPD by age for vaccine and non-vaccine serotypes from 1998/99 to 2009/10 2

Schito GC, et al. GIMMOC Vol. XV Q 4, 2011.

I sierotipi circolanti negliultra50enni in Italia

Also Co-morbidities are highly associated with Pneumococcal Disease

Age Underlying conditions Living conditions• Children <2

years • Adults ≥65

years

• Congenital or acquired immunodeficiency

• Sickle cell disease, asplenia, HIV• Chronic heart, lung (including asthma),

renal, or liver disease• Cancer• Cerebrospinal fluid leak• Diabetes• Chronic alcoholism or cigarette

smoking• Organ or hematopoietic cell

transplantation• Cochlear implants

• Childcare outside of the home ≥4 hours/week, and in the presence of ≥2 unrelated children

• Residence in a nursing home or other long-term care facility

Patients with chronic illnesses are a major target group for pneumococcal vaccination

1. Kyaw M et al. J Infect Dis. 2005;192(3):377-386.

Age-Specific Incidence of IPD in Healthy Adults (Aged ≥18 years) vs Adults With Chronic Illnesses, United States, 1999–2000

IPD risk increases in patientswith co-morbidities

ODIN study: distribution of IPD patients according to the presence of ≥1 co-morbidity 2010 to 2011

1. Polverino et al. ECCMID poster presentation, 2012

Data from an interim analysis. Study was a prospective, active, hospital-based surveillance of all culture-confirmed IPD inadults ≥18 years, performed in 7 Spanish hospitals (August 2010-June 2011)

*includes presence of immunosuppression, HIV infection/AIDS, other immunodeficiencies, cancer or chronic renal disease

*

14

IPD and risk of death is higherin patients with co-morbidities

• Patients with certain conditions are associated with an increased risk of contracting, and dying from IPD1

• In a recent Swedish study, IPD case records were reviewed to determine the prevalence of IPD among patients with selected diagnoses1

1. Backhaus E et al. ISPPD poster 2012.

Predisposing factor Relative Risk to get IPD (95% CI)

Case-fatality ratio (%) Relative Risk of death (95% CI)

COPD 3.52 (3.12–3.98) 12 1.29 (0.94–1.78)

Asthma 0.57 (0.48–0.68) 3 0.27 (0.10–1.71)*

Myeloma 154.37 (132.51–179.84) 18 1.89 (1.28–2.78)**

Solid tumor 1.26 (1.07–1.48) 32 3.66 (2.82–4.73)**

Rheumatoid Arthritis 4.91 (3.93–6.14) 10 1.01 (0.52 –1.97)

Haemodialysis 22.56 (14.15–35.98) 29 3.01 (1.43–6.34)**

HIV 16.30 (9.53 – 27.87) 8 0.78 (0.12–5.13)

Asplenia 14.08 (10.38–19.10) 12 1.24 (0.54–2.84)

*Significantly lower relative risk (RR) to die respectively to get IPD among asthma patients. The risk to die remained significantly lower after correcting for age, sex and co-morbidity**Significantly higher RR to get IPD or to die within 30 days from culture, respectively, for a patient with this risk factor compared to all patients without this risk factor

Pathophysiological interactions between influenza and bacterial respiratory pathogens

Pathophysiological interactions between influenza and bacterial respiratory pathogens

Antibiotico-resistenza degli pneumococchi circolantiSu un totale di 105 S. pneumoniae compresi in uno studio microbiologico in Italia, l’incidenza di ceppi pneumococcici che veicolano uno o più tratti di resistenza è pari al 65,7% (1)

1. Schito GC, et al. GIMMOC Vol. XV Q 4, 2011. 2. EARSS 2010

Resistenza di S. pneumoniae ai macrolidi in EU (2)

Most non-susceptible isolates belong to few serogroups, especially serogroups 1, 19, 7 and 3

Country CAP Incidence (per 1000/population/year)Outpatient Inpatient

Finland1 11.6

Italy2,3 1.7 0,8 (under 65)

Spain4 1.62

Spain5 1.6 (male); 0.9 (female) 0.9Spain6 4.2 (male); 2.9 (female)

England7 0,9 (under 65)Germany8 8.7 (over 18)

Over 64

Italy2,3 3.3 4,8Spain4,6 5.2 (male); 2 (female) 11.2 (male); 4.3

(female)England7 2.63 - 3.55Portugal8 9,8

Over 75

Spain5 8.7 (male); 3.0 (female)

Spain6 5.2 (male); 2.8 (female) 11.2 (male); 4.3 (female)

England7 6.8 – 8.8

1) Jokinen C et al. Am J Epidemiol. 1993;137(9):977-988.2) Viegi G et al. Respir Med. 2006;100(1):46-55.3) Rossi, PG et al Int J Tuberc Lung Dis 2004; 8:528; 4) Almirall J et al. Eur Respir J. 2000;15(4):757-763.5) Gutierrez f et al J infect 2006; 53:166-174

6)Ochoa-Gondar et al BMC Public Health 2008; 8: 222 7( Trotter CL et al. Emerg Infect Dis. 2008;14(5):727-733.8) Schnoor M et al. J Infect. 2007;55(3):233-239.9) Froes F et al Rev Port Pneumol 2003; 187 10) Ewig S, et al. Thorax. 2009;169:910-914.

Increasing incidence from age 50 years11

Mortality very high

Outpatients (1–2%)11

Higher in hospitalized patients (10–20%)11

Highest in patients admitted to the ICU (up to 50%)11

11) Welte T. Thorax 2010..

Pneumonia – Incidence and Mortality

A Considerable Proportion of Patients with CAP Require Hospitalization

CountryHospitalization Rate of CAP

Patients

Finland1 42%

Italy2 31.8%

Spain3 61.4%

UK4 22–42%

US5 27%

1. Jokinen C, et al. Am J Epidemiol. 1993;137:977–988.2. Viegi G, et al. Respir Med. 2006;100:46–55.3. Almirall J, et al. Eur Respir J. 2000;15:757–763. 4. British Thoracic Society Standards of Care Committee. Thorax. 2001;56 (suppl 4):IV1-IV64.5. Nelson JC, et al. Vaccine. 2008;26:4947–4954.

Significant direct costs associated with community acquired pneumonia (CAP)

• Hospitalisation costs1

– US• $4 million per 100’000 individuals

– Europe• $0.4-1.3 million per 100’000 individuals• 90% of total costs

1. Lode HM, Respiratory Medicine (2007) 101, 1864-18732. Niederman et al. Clinical therapeutics Vol. 20, N°. 4, 1998

Total direct treatment costs of CAP are largely due to the cost of hospitalisations and the elderly account for a disproportionate share of costs2

Socioeconomic impact of pneumonia in EU is relevant

Pneumonia. In: European lung white book. 2 edn. Sheffield, UK: European Respiratory Society/European Lung Foundation. 2003:55e65.http://www.european-lung-foundation.org/index.php?id=155

Europe, pneumonia costs ~€ 10.1 billion annuallyinpatient care accounting for € 5.7 billionoutpatient care accounting for € 0.5 billiondrugs accounting for € 0.2 billionIndirect costs of lost work days amount to € 3.6 billion

0 50 100 150

Austria 1998

Greece 1997

Luxemburg 1997

Italy 1995

Germany 1997

Spain 1995

Belgium 1994

France 1996

Netherlands 1997

Denmark 1996

Portugal 1998

Finland 1996

Sweden 1996

Ireland 1996

UK 1997

FemaleMale

PNEUMONIA DEATH RATES IN EUROPE

Rate / 100,000(Source www.who.int/whosis/)

CAP in the ElderlyEwig S et al. Thorax 2009; 64: 1092-9

CAP incidence is increasing and will continue to risewith an increasing elderly population

• The population aged over 65 is increasing at twice the rate of the younger population1

• Incidence of pneumonia in the older population is four times that of younger populations1

• The incidence of CAP in Europe varies by country, age and gender. incidence increases sharply with age1

• Mortality amongst hospitalized CAP patients: 520%2

1. Stupka JE et al. Aging health, 2009; 5(6): 763-7742. Welte T et al. Thorax, 2012; 67: 71–793. Rudolph D et al. Antimicrobial Agents and Chemo, 2011; 55(10): 4915–4917

2000 3,03

2001 2,83

2002 3,26

2003 3,46

2004 3,27

2005 3,83

2006 3,55

2007 4,10

2008 4,14

2009 4,72

2000-2004 3,17

2005-2009 4,07

2000-2009 3,63

10,84

10,22

11,73

12,59

12,17

14,29

13,08

15,12

15,30

16,46

11,53

14,87

13,26

18,64

17,25

19,73

21,54

20,88

24,50

22,27

25,41

25,94

27,25

19,66

25,13

22,60

Ano/período Global 65+ 75+

Internamento/1000h/ano

Admissions CAP/ 1000 inhabitants2000-2009 28,4%

Froes F, Diniz A, Mesquita M, Serrado M, Nunes B. Hospital admissions of adults with community-acquired pneumoniain Portugal between 2000 and 2009. Eur Respir J erj02167-2011

CAP Hospitalization Rate/1000 inhabitantsin Portugal (2000-2009)

CAP Adult Hospitalization (2000-2009):CAP hospitalization / 1.000 inhabitants

Welte. Internist 2005;260:93

Pathogens in CAP (using Bartlett criteria): Data from the German CAPNETZ

Pneumococcal vs.non-pneumococcal CAP

• Pneumococcal CAP is associated with a more severe disease course than non-pneumococcal CAP.1

• Significantly more pneumococcal CAP patients required:1

– hospitalization– mechanically ventilation – oxygen insufflation

CURB scores on admission

Pneumococcal CAP Non-pneumococcal CAP

Clinical course

Outcome

1. Pletz MW et al. Pneumologie, 2012; 66: 470–475

Hospital Mortality 2006Mortality during course of hospital stay

Hazard-Ratio for different CRB-65-Classes in 2006

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

20%

22%

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29

Hospital Stay (days)

HR

CRB-65=0CRB-65=1CRB-65=2CRB-65=3CRB-65=4

La Polmonite Pneumococcica BatteriemicaLo pneumococco è l’agente eziologico più frequentemente in causa nei pazienti CAP ricoverati in terapia intensiva (2)

Emocolture positive si ritrovano fino al 20-30% dei casi di polmonite pneumococcica (3)

Il case fatality rate per batteriemia pneumococcica può raggiungere il 15-20% negli adulti e il 30-40% nei pazienti anziani, nonostante una terapia antibiotica appropriata e la terapia intensiva (1)

2. Chiou CC. Severe Pneumococcal pneumonia: new strategies for management. Curr Opin Crit Care 2006; 12: 470-476.3. Spindler C. Prognostic score systems and community acquired bacteraemic pneumococcal pneumonia. Eur Respir J 2006; 28: 816-823.WHO weekly epidemiological record, no. 42, 17 October 2008. http://www.who.int/wer/2008/wer8342.pdf.

S. pneumoniae either triggers pneumoniaor pneumonia followed by bacteraemia and sepsis

Serotype 19S. pneumoniae

Day 1 Day 2 Day 3 Day 4

A

B

Serotype 2/3S.

pneumoniae

Day 1 Day 2 Day 4

Henken S, Welte T AAC 2010;54(8):3155-60

Overall CAP incidence is also higherin patients with certain conditions

• The higher the number of underlying diseases, the higher was the risk of CAP1

1. Schnoor M et al. Epidemiol Infect, 2007;135:1389–1397

Predisposing factor Odds ratio to get CAP (95% CI) P value

Chronic Pulmonary Disease 3.9 (3.1–4.9) <0.001

Chronic Heart Disease 3.2 (2.6–4.1) <0.001

Chronic Liver Disease 2.1 (1.2–4.0) <0.05

Chronic Renal Disease 1.7 (1.1–2.8) <0.05

Ever Smoked 1.2 (1.1–1.5) <0.01

“Despite multiple studies conducted during > 30 years, the efficacy and effectiveness of PPV in children and adults remain poorly defined and the subject of controversy.”

“There is a need for more efficacious conjugate vaccine covering the majority of pneumococcal serotypes that cause serious diseases in older children and adults worldwide and that are responsible for resistance to commonly used antimicrobial drugs”

“WHO supports the ongoing efforts to develop such products”

WHO position paper on 23-valent pneumococcal polysaccharide vaccine, 2008

PPV-23 WHO Position Paper

Current situation amongst European adults:

Burden of pneumococcal disease increases at the extremes of age, with older patients (aged 50 onwards) having a higher incidence and mortality from pneumococcal disease

IPDs occur more frequently and have a greater mortality in patients with certain chronic illnesses and other co-morbidities

Some serotypes are more virulent than others

CAP will increase with an aging population and will continue to represent a significant clinical and economic burden

Current situation

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