Risk and prevention of pneumococcal diseases among patients in critical care setup

1. Current evidence and guidelines… Risk and prevention of pneumococcal diseases among patients in critical care setup

2. Table of contents • Review of S. pneumoniae and pneumococcal diseases • Chronic lung disease • Chronic renal disease • Immunosuppressed population • Impact of pneumococcal infections in patients with chronic lung disease • Vaccine recommendations for patients with chronic lung disease • Pneumococcal vaccination • Health economic benefits of pneumococcal vaccination

3. Review of S. pneumoniae and pneumococcal diseases

4. Review of S.pneumoniae and pneumococcal diseases (1/2) • Invasive Pneumococcal Disease (IPD) carries high risk of mortality (1) • S. pneumoniae is the leading cause of Community-acquired pneumonia (CAP) (2) • >90 serotypes of S. pneumoniae (3) • 8-10 cause two-thirds of serious infections in adults (4) • The infections caused by pneumococci include pneumococcal pneumonia, bacteremia and meningitis (5)

5. Review of S.pneumoniae and pneumococcal diseases (2/2) • Pneumococcal diseases are serious and associated with significant mortality(6) • 1 in every 20 adults who gets pneumococcal pneumoniadie. • 2 out of every 10 adults who get bacteremiadie. • 3 out of every 10 adults who get meningitisdie. (1) World Health Organization. Weekly Epidemiological Record. Pneumococcal vaccines No. 14, 2003, 78, 97-120. (2) Jokinen C, Heiskanen L, Juvonen H et al. Microbial etiology of community-acquired pneumonia in the adult population of 4 municipalities in eastern Finland. Clin Infect Dis. 2001 Apr 15;32(8):1141-54. (3) Fedson DS, Musher D. Pneumococcal polysaccharide vaccine. In: Plotkin A, Orenstein WA editors. Vaccines. 4th ed. Philadelphia, USA: WB Saunders Company; 2004. p. 529-88. (4) Pneumococcal. In: The green book chapter 25. Immunization against infectious disease. London, United Kingdom Department of Health; 2006. (5) Musher DM. Streptococcus pneumoniae. In: Mandell G, Bennett JE, Dolin R editors. Principles and practice of infectious disease. 4th ed. New-York, USA: Churchill Livingstone, Inc.; 1995. p. 1811-26. (6) CDC. Pneumococcal Polysaccharide Vaccine: What you need to know. [Online] 2007; [3 pages]. Available at: http://www.cdc.gov/vaccines/pubs/vis/downloads/vis-ppv.pdf

6. Meningitis, arthritis pleuritis etc. Invasive pneumococcal disease Bacteremic pneumococcal pneumonia Pneumococcal pneumonia Non-bacteremic pneumococcal pneumonia Invasive pneumococcal disease Overlap between pneumococcal pneumonia and invasive pneumococcal disease Adapted from Fedson DS. Pneumococcal vaccination for older adults—the first 20 years. Drugs Aging 15(suppl 1):21–30, 1999.

7. Factors predisposing to pneumococcal disease(1/2) • Age (7) • Chronic illnesses (7) • Functional or anatomical asplenia (7) • Immunodeficiency(7) • Environmental factors (5) (7) CDC. Recommendations of the ACIP. Prevention of pneumococcal disease. MMWR 1997; 46 (N° RR-8): 1-2 (5) Musher DM. In Mandell G, Bennett JE, Dolin R editors. Principles and practice of infectious disease. 4th ed. New York, USA: Churchill Livingstone, Inc.; 1995. p.1811-26

8. Factors predisposing to pneumococcal disease (2/2) Focus on Chronic illnesses RISK OF DECOMPENSATION OF THE UNDERLYING DISEASE AND INCREASED RISK OF SEVERE PNEUMOCOCCAL DISEASE Pulmonary disease Cardiovasculardisease Renal disease Diabetes Liver cirrhosis (7) CDC. Recommendations of the ACIP. Prevention of pneumococcal disease. MMWR 1997; 46 (N° RR-8): 1-24

9. Chronic pulmonary diseases

10. Risk factors that lead to chronic inflammation • Genes • Hereditary deficiency of the protein Alpha1-antitrypsin (AAT) • Exposure to particles • Tobacco smoke • Occupational dusts and chemicals • Indoor air pollution from heating and cooking in poorly vented dwelling • Outdoor air pollution • Others • Lung growth and development • Oxidative stress • Gender • Age • Respiratory infections • Socioeconomic status • Nutrition • Co-morbidities (11) Buist S, Pauwels R, and al.Global Initiative for Chronic Obstructive Lung Disease report 2006. (12) American Lung Association. COPD. [Online], August 2006. Available from: URL: http://www.lungusa.org/site/pp.aspx?c=dvLUK9O0E&b=35020&pritmode=1

11. Chronic Obstructive Pulmonary Disease (COPD)A major health problem • According to the WHO: • 80 million have moderate to severe COPD • >3 million diedof COPDin 2005, ≈5% of all deaths globally • In 2002COPD was the 5th leading cause of death • Deaths from COPD are projected to increase by >30% in the next 10 years • COPD expected to be 4th leading cause of death worldwide by 2030 (9) World Health Organization. Chronic respiratory diseases. Burden. [Online]. 2007; [1 page]. Available from: URL: http://www.who.int/ respiratory/copd/burden/en/index.html

12. Infections have a role on exacerbations in COPD patients • Bacterial infection is a factor in 70 - 75% of exacerbations (15) • up to 60% caused by S.pneumoniae, H. influenzae or M. catarrhalis • The presence of an upper respiratory tract infection leads to:(17) • more severe exacerbation • longer symptom recovery time at exacerbation (15) Hunter M and King D. COPD: Management of acute exacerbations and chronic stable disease. American Family Physician 2001; Vol 6; number 4; 603-612 (16) Wongsurakiat P and Al. Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination. Chest 2004, 125(6): 2011-2020 (17) Jadwiga A. Wedzicha. Role of viruses in exacerbations of Chronic Obstructive Pulmonary Disease. Proc Am Thorac Soc. Vol 1., 2004, pp 115-120.

13. Impact of pneumococcal infections in patients with COPD

14. 233.4 71.2 Figure 4: Age-specific incidence of Invasive Pneumococcal Disease in healthy adults versus patients with Chronic lung disease. Adapted from Kyaw and al, 2005 Patients with chronic lung disease are at higher risk of invasive pneumococcal diseases especially in the elderly (22) Moe H Kyaw. The Influence of Chronic Illnesses on the Incidence of Invasive Pneumococcal Disease in Adults. JID 2005;192:377-86

15. Initiating factors: Smoking, Chronic bronchitis, Childhood respiratory disease… Inflammatory response Progression of COPD Alteredelastase- Anti-elastasebalance Increased elastolyticactivity COPD patients enter into a vicious circle Figure 5: Schematic diagram of the vicious circle hypothesis of the role of bacterial colonization in the progression of COPD. Adapted from Sanjay, 2000 (8) Salyers AA, Whitt DD. Streptococcus pneumoniae. In: Bacterial Pathogenesis: A Molecular Approach. 2nd ed. Washington, USA: ASM Press; 1994. p. 322-31. (23) Sanjay Sethi. Bacterial infection and the Pathogenesis of COPD. Chest 2000;117;286-291

16. Pneumococcal vaccination recommended for patients with COPD

17. Pneumococcal vaccine:Antigen composition • 23-valent pneumococcal vaccine contains purified capsular polysaccharides derived from 23 S. pneumoniae serotypes (3, 7) • Serotype coverage (3, 7) • 85-90% of serotypes responsible for all cases of IPD • Vaccine includes major serotypes that have developed antimicrobial resistance (90%) (3) Fedson DS, Musher D. In: Plotkin A, Orenstein WA editors. Vaccines. 4th ed. Philadelphia, USA: WB Saunders Company; 2004. p. 529-8 (7) CDC. Prevention of pneumococcal disease. Recommendations of the ACIP. MMWR 1997; 46 (N° RR-8): 1-2 (47) Wagner C. et al. Impact of pneumococcal vaccination on morbidity and mortality of geriatric patients: a case-controlled study. Gerontology 2003; 49:246-250.

18. Several associations recommend pneumococcal vaccination: Summary (1/2) • IMA (Indian Medical Association) • ISN (Indian Society of Nephrology) • The ACIP (Advisory Committee on Immunization Practices) • AAFP (American Association of Family Physicians) • ACOG (American College of Obstetricians and Gynecologists) • ACP (American College of Physicians) • ATS (American Thoracic Society) • American Lung Association • National Heart Lung and Blood Institute • World Health Organization (WHO) • All recommend Routine administration of 23 valent polysaccharide vaccine to all ≥65 yrs, and younger at-risk individuals

19. Several associations recommend pneumococcal vaccination: Summary (2/2) • IAP (Indian Academy of Pediatrics) • AAP (American Academy of Pediatrics) • ACIP (Advisory Committee on Immunization Practices) • All recommend Routine administration of 23 valent polysaccharide vaccine to all at-risk children ≥2 yrs • Children 24-59 months of age, with a high risk of Pneumococcal infection can benefit more from a sequential schedule, i.e. children who have received 4 doses of Pneumococcal Conjugate Vaccine (7-valent PCV) should get a single dose of 23-valent PPV 6-8 weeks after the last dose of PCV

20. ACIP/ CDC recommends pneumococcal vaccination* Condition Timing All persons aged ≥65 yr Repeat in 5 yr Chronic lung disease Repeat in 5 yr (COPD, cystic fibrosis) Heart disease, Diabetes mellitus Repeat in 5 yr Nephrotic syndrome or renal failure Repeat in 5 yr Liver disease Repeat in 5 yr Splenectomy (functional or anatomic) 2 wk before, if possible; repeat in 5 yr Organ transplantation 2 wk before, if possible; repeat in 5 yr Immunosuppressive chemotherapy 2 wk before, if possible; repeat in 5 yr HIV infection Repeat in 5 yr Recurrent pneumococcal infections Repeat in 5 yr (7) CDC. Prevention of pneumococcal disease. Recommendations of the ACIP. MMWR 1997; 46 (N° RR-8): 1-24

21. Healthy elderly (over 65 years of age), particularly those living in institutions Patients with chronic organ failure, heart, lung, liver or kidney, diabetes mellitus, alcoholism Children ≥2 yrs at high risk for disease (splenectomised children and sickle-cell disease) Patients with immunodeficiencies particularly those with functional or anatomical asplenia Prevention of subsequent pneumococcal infection in patients recovering from proven or assumed pneumococcal pneumonia WHO recommends pneumococcal vaccination (1,26) (1) World Health Organization. Weekly Epidemiological Record. Pneumococcal vaccines.No. 14, 2003, 78, 97-120. (26) Immunization, Vaccines and Biologicals. Pneumococcal vaccines. [Online] 2003. Available from URL http://www.who.int/vaccines/en/pneumococcus.shtml

22. Several other associations recommend both pneumococcal and influenza vaccination • According to the American Thoracic Society(27) • Patients at risk for community-acquired pneumonia should be vaccinated with both pneumococcal and influenza vaccine. • Vaccines can be given simultaneously but at separate sites of injection • According to the American Lung Association, the National Heart Lung and Blood Institute: (12,28) • Pneumococcal and influenza vaccines should be given to patients with chronic pulmonary conditions and other high risk groups (12) American Lung Association. COPD. [Online], August 2006. Available from: URL: http://www.lungusa.org/site/pp.aspx?c=dvLUK9O0E&b=35020&pritmode=1 (27) American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia. 2001 (28) National Heart Lung and Blood Institute. COPD. Available at http://www.nhlbi.nih.gov/health/dci/Diseases/Copd/Copd_Treatments.html

23. Several other associations recommend pneumococcal vaccination • The Indian Medical Association recommends administration of pneumococcal vaccine in special circumstances such as: • Chronic Renal Disease • Immunodeficiency conditions • Congenital or acquired asplenia/ splenic dysfunction • HIV infection • Chronic cardiac and pulmonary disease • Cerebrospinal fluids leaks • Diabetes mellitus Indian Medical Association. http://www.imanational.com/PH0.htm 10-19-2006

24. Several other associations recommend both pneumococcal vaccination • IAP recommends Pneumococcal vaccination in all children with : • Sickle cell disease • Nephrotic syndrome on remission, especially those with a previous episode of peritonitis • Congenital or acquired asplenia/ splenic dysfunction • HIV infection • Chronic cardiac and pulmonary disease • Immunodeficiency conditions • Cerebrospinal fluids leaks • Diabetes mellitus • S. pneumoniae colonizes the throats of upto 91% children of 6 months to 5 years of age • 23-valent polysaccharide vaccine is capable of prevention of 85% of meningitis and bacteremia caused by pneumococcus • A single IM injection is recommended after the age of 2 years with revaccination every 3-5 years till the age of 10 years IAP Guidebook on Immunization

25. Several other associations recommend pneumococcal vaccination • Indian Society of Nephrology recommends 23 valent pneumococcal vaccination in patients with chronic renal disease • Single dose to be given IM or SC to all dialysis patients ≥2 yrs • Revaccination • 3 years after previous dose for children with chronic renal disease who will be ≤10 yrs at time of revaccination • Also recommended for other dialysis patients, provided 5 yrs have elapsed since first dose • Rationale • Chronic renal failure patients are prone for pneumonia • ≥75 % patients have an adequate response to the vaccine • In healthy person antibody titer remain elevated for 5 years and decrease to pre vaccination level after10 years. But in chronic renal failure patients, a rapid decline occurs in 6 months to 5 years after vaccination • Pneumococcal vaccine is well tolerated Indian J Nephrol 2005;15, Supplement 1: S72-S74

26. Pneumococcal vaccination

27. Patients with COPD respond to pneumococcal and influenza vaccination • PNEUMOCOCCAL POLYSACCHARIDE VACCINATION(31) • The immunogenicity of the pneumococcal polysaccharide vaccine in patients with bronchopulmonary disease equals that of healthy controls • INFLUENZA VACCINATION(32) • Following influenza vaccination, COPD patients experience a significant increase in HI (haemagglutinin) and NI (neuraminidase) antibody titres which is not significantly different from that of healthy controls. (31) Belgian consensus on pneumococcal vaccine. Acta Clin Belg. 1996;51-5:350-6 (32) Tadeusz Plusa, et al. Effect of influenza vaccinations on humoral response in patients with bronchial asthma or chronic obstructive pulmonary disease. International Congress eries, Options for the Control of Influenza V. Proceedings of the International Conference on Options for the Control of Influenza V. Volume 1263, June 2004, 563-567.

28. Immunocompetent, Person ≥ 65 years Coronary vascular disease Chronic pulmonary disease Anatomic asplenia Congestive heart failure Diabetes mellitus Adapted from Butler and al, 1993. Pneumococcal polysaccharide vaccine provides good efficacy in preventing pneumococcal infection in patients with chronic illnesses Figure: Reduction of invasive pneumococcal infections in the elderly and other at risk patients. Indirect cohort analysis for 2,837 patients over the age of 5. (33) Butler JC et al. Pneumococcal Polysaccharide vaccine efficacy. An evaluation of current recommendations. JAMA 1993;270

29. 1 0.95 0.90 0.85 1 0.80 0.95 Log rank = 3.85 P = 0.049 0.75 0.90 0.70 0.85 0.80 Log rank = 6.68 P= .0097 0.75 0.70 Pneumococcal polysaccharide vaccine is effective in preventing community-acquired pneumonia (CAP) in COPD patients 76% efficacy in patients <65 years old 48% efficacy in patients with severe COPD Cumulative proportion of patients without pneumonia Cumulative proportion of patients without pneumonia • Figure : Cumulative proportion of patients <65 years • without pneumonia during the follow up period. • 3 cases for vaccinated persons • 16 cases for unvaccinated persons • Figure : Cumulative proportion of patient with severe COPD • without pneumonia during the follow up period. • 12 cases for 132 vaccinated persons • 20 cases on 114 unvaccinated persons Adapted from Alfageme, 2006 Adapted from Alfageme, 2006 Pneumococcal Polysaccharide vaccine is even more effective in patients under 65 with severe COPD: 91% efficacy (34) Alfageme I, Vazquez R, Reyes N et al. Clinical efficacyof anti-pneumococcal vaccination in patients with COPD. Thorax 2006;61;189-195

30. Chronic renal disease

31. Chronic Kidney Disease Carries a Big Risk for Pneumococcal Disease • Pneumonia remains a major cause of morbidity and mortality in patients with renal disease • Rates of pneumonia during the first year of hemodialysis have increased gradually from 24.8 admissions/100 patient-years at risk in 1991 to 30.6 admissions/100 patient-years at risk in 2001.1 • S pneumoniae is responsible for up to 53% of reported pneumonia cases in dialysis patients.34 • Mortality rates after pneumonia in dialysis patients: up to 14- to 16-fold greater mortality compared with the general population The Use of Vaccines in Adult Patients With Renal DiseaseAm J Kidney Dis 46:997-1011.

32. The Value of Pneumococcal Vaccination in Chronic Kidney Disease • Infectious disease is the second most common cause of death in late-stage chronic kidney disease (CKD/ ESRD) patients • Centers with vaccination protocols have demonstrated reduced infection rates and resultant decreased morbidity and mortality • It could be extrapolated from this that widespread vaccination would reduce the total cost of ESRD patient care, and potentially improve patient well-being • Vaccination appears to be underutilized in CKD patients, and it is a readily available intervention to improve outcomes Kausz A; Pahari D Semin Dial 2004 Jan-Feb;17(1):9-11

33. Benefits of pneumococcal vaccination: pharmaco-economic perspective

34. Cumulative 2-year net cost-saving associated with pneumococcal vaccination: US$294 per vaccinee • In every scenario, vaccination was found to be a cost-saving strategy Pneumococcal vaccination of elderly with chronic lung disease is cost-saving • Methodology • Retrospective cohort study in US & multivariate model - Cost-effectiveness ratio per Quality-Adjusted Life-Year gained • N = 1,898 with chronic lung disease diagnosis • 2 years • Vaccination with a polysaccharide23-valent vaccine • Direct medical costs (37) Nichol K L. and al. The health and economic benefits associated with pneumococcal vaccination of elderly persons with chronic lung disease, Arch Intern Med 1999; 159:2437-2442.

35. Pneumococcal polysaccharide vaccination is safe • There are no contraindications to pneumococcal vaccination (except a severe reaction to a previous dose)(3) • The most frequently reported adverse events are fever, and local reaction at the injection site.(42) • Severe systemic reactions are very rare(42) (3) Fedson and Musher. In: Vaccines, 4th ed. 2004 (42) Sanofi Pasteur, Pneumo 23 product prescribing information. June 2005

36. Pneumo23™Composition and presentation • Each 0.5 ml dose contains 25 µg of each of the 23 pneumococcal capsular polysaccharide types Isotonic saline Phenol preservative • is presented as a sterile solution in a single-dose pre-filled syringe or multidose vial. • can be administered intramuscularly or subcutaneously (42) Sanofi Pasteur, Pneumo 23 product prescribing information. June 2005

37. CONCLUSION • Patients with Chronic Lung Diseases as well as Chronic Kidney Diseases are at increased risk for pneumococcal and influenza infections • Influenza and pneumococcal infections can be effectively prevented using available vaccines • Vaccines are cost-effective, safe, and efficacious

38. Thank You!