1. Ida Jovanović Univerzitetska dečja klinika, Beograd
Prevencija infekcija respiratornim sincicijalnim virusom kod dece sa urođenim srčanim manama
Ida Jovanović
Univerzitetska dečja klinika, Beograd

2. Samo za stručnu javnost
Ovo predavanje je sponzorisano od strane kompanije AbbVie Biopharmaceuticals GmbH. Predstavništvo za Srbiju, Crnu Goru i Makedoniju

3. Respiratorni sincicijalni virus (RSV)
Čest patogen
Većina obolele dece je uzrasta do 2 godine
RSV je glavni uzročnik akutnih infekcija donjih respiratornih puteva kako u razvijenim zemljama tako i u zemljama u razvoju
Epidemije se uglavnom javljaju sezonski4 (na ovom podneblju od novembra do marta/aprila)
Respiratory syncytial virus (RSV):
RSV is a ubiquitous (existing or is everywhere) pathogen 1[Hall2005, 1a]
Most children are infected by age of 2 years 2[Glezen1986, 543f, 544a, table2]
RSV is a major cause of acute lower respiratory tract infections (LRTIs) in both developed and developing countries 3[Stensballe2003, S21d]
RSV mortality is higher in developing countries compared to developed countries 3[Stensballe2003, S21f]
Symptoms of primary RSV infection may include LRTIs (pneumonia, bronhciolitis, bronchitis) or upper respiratory tract illness. Reinfection can range from asymptomatic to severe. 1[Hall2005, 13c, 14d, 20a]
Outbreaks are seasonal in most of the world:
In temperate climates, on either side of the equator, peak outbreaks occur in the winter 4[Simoes2003, S14deg]
In equatorial countries, observed mainly during the rainy seasons 3[Stensballe2003, S21e]
References:
Hall CB, McCarthy CA. Respiratory Syncytial Virus. In: Principles and Practice of Infectious Diseases. 6th ed. Oxford, UK: Churchill Livingstone; 2005:1-49.
Glezen WP, Taber LH, Frank AL, et al. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child. 1986;140(6):
Stensballe LG, Devasundaram KJ, Simoes EAF. Respiratory syncytial virus epidemics: the ups and downs of a seasonal virus. Pediatr Infect Dis J. 2003;22(2 Suppl):S21-S32.
Simoes EAF, Carbonell-Estrany X. Impact of severe disease caused by respiratory syncytial virus in children living in developed countries. Pediatr Infect Dis J. 2003;22(2 Suppl):S13-S18.
1. Hall et al. Respiratory Syncytial Virus. In: Principles and Practice of Infectious Diseases. 6th ed.;2005:1.
2. Glezen et al. Am J Dis Child. 1986;140(6):543.
3. Stensballe et al. Pediatr Infect Dis J. 2003;22:S Simoes et al. Pediatr Infect Dis J. 2003;22:S13.
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4. Respiratorni sincicijalni virus (RSV) -epidemiologija-
RSV je najčešći uzročnik akutnih respiratornih infekcija
kod dece mlađe od 5 godina (podaci iz Belgije, 1998–2000.)
Adenovirus 7%
Chlamydia pneumoniae 0%
Mycoplasma pneumoniae 9%
Haemophilus influenzae 6%
Parainfluenza 2%
Influenza B 2%
Influenza A 3%
Streptococcus pneumoniae 8%
RSV 62%
RSV infection is the most common pathogen associated with acute respiratory infection in children < 5 years of age. 1[Simoes2003, S15figure 2]
The Belgian sentinel network laboratories identified pathogens on nose or throat swabs in children < 5 years of age who presented with acute respiratory tract illness and influenza-like illness. 1[Simoes2003, S15figure 2]
Among all the potential bacterial and viral infectious organisms in these children, RSV was responsible for almost two thirds of acute respiratory infections. 1[Simoes2003, S15figure 2]
Reference:
Simoes EA, Carbonell-Estrany X. Impact of severe disease caused by respiratory syncytial virus in children living in developed countries. Pediatr Infect Dis J. 2003;22(2 Suppl):S13-S18.
1. Simoes et al. Pediatr Infect Dis J. 2003;22:S13.
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5. Respiratorni sincicijalni virus (RSV) -epidemiologija-
RSV se prenosi:1,2
kapljičnim putem
direktnim kontaktom sa zaraženom osobom
preko prljavih ruku
preko kontaminiranih predmeta
RSV može da preživi 6–12 sati u spoljašnjoj sredini1
Bolničke infekcije predstavljaju glavni problem1
RSV is transmitted by droplets, large particles, and fomites. 1[Hall2000, 592b]
RSV may be spread by close contact and direct inoculation of large droplets from the secretions of an infected person, or indirect spread by touching infectious secretions in the environment. 2[Hall2005, 19d, 29c]
RSV can survive for 6–12 hours or more on hard, nonporous surfaces. 1[Hall2000, 592a]
Over 50% of medical personnel are infected with RSV when RSV is prevalent in the community. 1[Hall2000, 591b]
Nosocomial infection remains a major problem. 1[Hall2000, 590d]
<Click to reveal and read out loud.>
Hand-washing is the best way to prevent RSV transmission. 1,2[Hall2000, 594f; Hall2005, 29ac]
References:
Hall CB. Nosocomial respiratory syncytial virus infections: the "Cold War" has not ended. Clin Infect Dis. 2000;31(2):
Hall CB, McCarthy CA. Respiratory Syncytial Virus. In: Principles and Practice of Infectious Diseases. 6th ed. Oxford, UK: Churchill Livingstone; 2005:1-49.
Pranje ruku ja najbolji vid prevencije RSV infekcije1
1. Hall. Clin Infect Dis. 2000;31(2): Hall et al. Respiratory Syncytial Virus. In: Principles and Practice of Infectious Diseases. 6th ed.;2005:1.
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6. Kako RSV deluje na disajne puteve -patogeneza-
RSV se, nakon perioda inkubacije, umnožava u trepljastom epitelu disajnih puteva i razara ga1,2
Promene u disajnim putevima kod RSV infekcije
Edem submukoza
Nekroza i ljuštenje epitelnih ćelija
Following the incubation period, RSV replicates and begins to destroy the ciliated epithelial cells that line the airways. 1,2[Hall2001, 1917f; Hall2005, 9b]
This leads to: 1,2[Hall2001, 1917f, 1920a; Hall2005, 9b]
Submucosal edema
Necrosis and sloughing of epithelial cells
Increased secretion of mucus with mucus plugging
Obstruction of airflow in the small airways
References:
Hall CB. Respiratory syncytial virus and parainfluenza virus. New Engl J Med. 2001;344(25):
Hall CB, McCarthy CA. Respiratory Syncytial Virus. In: Principles and Practice of Infectious Diseases. 6th ed. Oxford, UK: Churchill Livingstone; 2005:1-49.
Povećana sekrecija mukusa i stvaranje mukusnih čepova
1. Hall. New Engl J Med. 2001;344(25):1917.
2. Hall et al. Respiratory Syncytial Virus. In: Principles and Practice of Infectious Diseases. 6th ed.;2005:1.
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7. RSV infekcija -komplikacije-
Otitis media
Traheo-bronhitis
Bronhiolitis
Pneumonia
RSV infekcije mogu dovesti do:1
akutnog zapaljenja srednjeg uha
traheobronhitisa
Teške RSV infekcije:1
bronhiolitis
pneumonija
Some RSV infections can lead to: 1[Hall2005, 13a]
Acute otitis media (infection of the middle ear)
Tracheobronchitis (inflammation of the trachea and bronchi)
Severe RSV illness is associated with: 1[Hall2005, 13ac]
Bronchiolitis (inflammation of the bronchioles)
Pneumonia (inflammation of the alveoli and surrounding tissues)
References:
Hall CB, McCarthy CA. Respiratory Syncytial Virus. In: Principles and Practice of Infectious Diseases. 6th ed. Oxford, UK: Churchill Livingstone; 2005:1-49.
1. Hall et al. Respiratory Syncytial Virus. In: Principles and Practice of Infectious Diseases. 6th ed.;2005:1.
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8. Teška RSV infekcija – bronhiolitis
Bronhiolitis - zapaljenje malih disajnih puteva:1,2
najčešća infekcija donjih disajnih puteva kod odojčadi
Simptomi i znaci:
kašalj
vizing
Tahi-dispnea
Kod dece, RSV je odgovoran za 50-90% hospitalizacija zbog bronhiolitisa.1,3
Within 1–3 days of symptom onset, RSV may spread to the lower respiratory tract and cause bronchiolitis, inflammation of the small airways. 1[Hall2001, 1917f]
Bronchiolitis is the most common lower respiratory infection in infants. 2[AAP2006, 1774a]
Obstruction and narrowing of the small airways, in turn, causes coughing, wheezing, and rapid breathing. 2[AAP2006, 1775c]
Among children, RSV is responsible for 50%–90% of hospitalization for bronchiolitis. 1,3[Hall2001, 1920c; Leader2003, S128f]
References:
Hall CB. Respiratory syncytial virus and parainfluenza virus. New Engl J Med. 2001;344(25):
American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006;118(4):
Leader S, Kohlhase K. Recent trends in severe respiratory syncytial virus (RSV) among US infants, 1997 to J Pediatr. 2003;143(5 Suppl):S127-S132.
1. Hall et al. Respiratory Syncytial Virus. In: Principles and Practice of Infectious Diseases. 6th ed.;2005:1. 2. American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Pediatrics. 2006;118(4): Leader et al. J Pediatr. 2003;143:S127.
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9. Rizične grupe Prevremeno rođena deca
novorođenčad i odojčad sa hroničnom bolesti pluća (CLD) tj. bronhopulmonalnom displazijom (BPD)
odojčad i deca sa urođenim srčanim manama (srčana insuficijencija, cijanogene srčane mane, umerena do teška plućna hipertenzija )
odojčad i deca sa imunodeficijencijom

10. Razvoj pluća
Nezrela pluća1,
zrela pluća1,*
8 GN
Pseudoglandularni
36 GN – 3 godine
Alveolaran
16 GN
Kanalikularan
26–35 GN
Sacularan
Development of the lungs during gestation can be divided into different periods:
Pseudoglandular period (6 to 16 weeks): all major elements of the lung form, except those involved in gas exchange 1[Moore, 246e]
Canalicular period (16 to 26 weeks): terminal bronchioles give rise to respiratory bronchioles, which divide into alveolar ducts; some terminal saccules (primordial alveoli) develop 1[Moore, 246f]
Saccular period (26 weeks to birth): more terminal saccules develop and capillaries bulge into the developing alveoli 1[Moore, 246g]
Alveolar period (after birth): number of mature alveoli increases. About 95% of alveoli develop after birth. 1[Moore, 248c]
The images on the slide demonstrate that premature birth interrupts lung development.
<Click to reveal and read out loud.>
Although alveoli are present in some infants’ lungs as early as 32 weeks' gestational age (GA), they are not uniformly present until 36 weeks' GA. 2[Langston1984, 611c]
References:
Moore KL, Persaud TV. The respiratory system. In: The Developing Human: Clinically Oriented Embryology. 7 ed. Philadelphia PA: WB Saunders; 2003:
Langston C, Kida K, Reed M, et al. Human lung growth in late gestation and in the neonate. Am Rev Respir Dis. 1984;129(4):
Iako se kod nekih fetusa alveole razvijaju već u 32 GN, kod većine dece se razvijaju do 36 GN.
1. Moore et al. The respiratory system. In: The Developing Human: Clinically Oriented Embryology. 7th ed.;2003: Langston et al. Am Rev Respir Dis. 1984;129(4):607.
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11. Struktura i funkcija pluća su izmenjeni kod prematurusa
Slaba razvijenost pluća1
Debljina zida terminalnih disajnih puteva i alveola
Zapremina pluća (mL)
terminsko
novorođenče
34 GN
terminsko
novorođenče
34 GN
90 mL
171 mL
53%
18 μm
24 μm
zapremine pluća
terminskog
novorođenčeta
29% deblji
Pluća prematurusa su slabo razvijena, pri čemu je zapremina pluća manja, a debljina zidova terminalnih disajnih puteva i alveola veća u poređenju sa terminskom novorođenčadi.1
1. Langston C et al. Am Rev respir Dis. 1984; 129(4):
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12. Hronična bolest pluća(CLD)/ bronhopulmonalna displazija (BPD) -
Suportivno lečenje plućnih oboljenja doprinosi nastanku CLD/BPD:1
mehanička ventilacija
barotrauma
toksičnost kiseonika
CLD/BPD se ispoljava:1
hroničnom opstrukcijom disajnih puteva
tahidispneom
hiperreaktivnošću disajnih puteva
CLD/BPD značajno povećavaju rizik od nastanka infekcija respiratornog trakta kao što je infekcija RSV-om2
Effects of supportive therapies for pulmonary disorders contribute to the development of CLD/BPD: 1[Allen2003, 356a]
Mechanical ventilation
Barotrauma (physical damage to body tissues caused by a difference in pressure between an air space inside or beside the body and the surrounding gas or liquid)
(Mechanical ventilation can lead to barotrauma of the lungs. This can be due to either:absolute pressures used in order to ventilate non-compliant lungs. shearing forces, particularly associated with rapid changes in gas velocity. The resultant alveolar rupture can lead to pneumothorax, (PIE) and pneumomediastinum.
Oxygen toxicity
Chronic lung disease (CLD) and BPD manifest in: 1[Allen2003, 356a]
Chronic airflow obstruction
Increased work of breathing
Airway hyperreactivity
CLD and BPD may also result in increased risk for respiratory tract infections such as RSV. 2[Boyce2000, 867table1]
References:
Allen J, Zwerdling R, Ehrenkranz R, et al. Statement on the care of the child with chronic lung disease of infancy and childhood. Am J Respir Crit Care Med. 2003;168(3):
Boyce TG, Mellen BG, Mitchel EF, Jr., et al. Rates of hospitalization for respiratory syncytial virus infection among children in medicaid. J Pediatr. 2000;137(6):
Slika je preuzeta iz: Fowlie, McHaffie. BMJ. 2004; 329:
1. Allen et al. Am J Respir Crit Care Med. 2003;168(3): Boyce et al. J Pediatr. 2000;137(6):865.
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13. RSV infekcija -apnea-
Apnea je jedna od najčešćih akutnih komplikacija RSV infekcije:1-3
najugroženiji su:
prematurusi ≤ 32 GN
mlada odojčad
često zahteva primenu:
mehaničke ventilacije
kiseonika
Apnea (absence of breathing) is one of the most common acute complications, and may be the first sign of RSV infection: 1,2[Hall2005, 23c; Stedman's, 111a]
Those most at risk are:
Premature infants ≤ 32 weeks’ GA
Infants of young postnatal age
Associated with significantly higher use of: 3[Kneyber1998, 333b, 334c]
Mechanical ventilation
Supplemental oxygen
References:
Hall CB, McCarthy CA. Respiratory Syncytial Virus. In: Principles and Practice of Infectious Diseases. 6th ed. Oxford, UK: Churchill Livingstone; 2005:1-49.
Stedman TL. Stedman's Medical Dictionary. 27th ed. Philadelphia: Lippincott Williams & Wilkins;2000.
Kneyber MC, Brandenburg AH, de GR, et al. Risk factors for respiratory syncytial virus associated apnoea. Eur J Pediatr. 1998;157(4):
1. Hall et al. Respiratory Syncytial Virus. In: Principles and Practice of Infectious Diseases. 6th ed.;2005: Stedman. Stedman’s Medical Dictionary. 27th ed.; Kneyber. Eur J Pediatr. 1998;157(4):331.
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14. Patogeneza bronhoobstrukcije kod USM
USM sa:
velikim LD šantom
sa srčanom insuficijncijom
Cijanogene mane sa
povećanim protokom kroz
pluća

15. Lečenje bronhiolitisa
U Svetu postoji mnogo kntroverzi, konfuzije i nedostatak dokaza o efikasnosti pojedinih mera lečenja
Suportivne mere (uključujući i i.v. rehidraciju i primenu O2)
Bronhodilatatori
Adrenalin, inhalatorno
Kortikosteroidi
Ribavirin
Surfaktant, imunoglobulini, heliox (mešavina heliuma i kiseonika), vitamin A, interferon, eritropoetin
Mortalitet je <1%, ali je kod visokorizičnih pacijenata 3-5%.

16. Prevencija RSV: Palivizumab
Palivizumab je humanizovano IgG monoklonsko antitelo proizvedeno rekombinantnom DNK tehnologijom, usmereno se vezuje za epitop na A antigenom mestu F proteina RSV.
sastoji se od (95%) humanih i (5%) mišjih sekvenci

17. Pasivna imunoprofilaksa
Passive immunoprophylaxis describes the administration of antibodies from an external source, ie, antibodies, antisera, immune globulins, to provide temporary protection against an infectious pathogen. 1,2[Roitt13, 287b; Stedman's 1458a]
External antibodies have a half-life in the bloodstream, which is the time it takes for the concentration to decrease by 50%. 3[Rang-4, 101i]
<Click to reveal.>
Because of this, protection is short-term and antibodies must be administered at regular intervals to maintain a serum concentration sufficient to provide protection against infection by the pathogen.
References:
Delves PJ, Martin SJ, Burton DR, et al. Vaccines. In: Roitt's Essential Immunology. 11 ed. Malden, MA: Blackwell Publishing; 2006:
Stedman TL. Stedman's Medical Dictionary. 27th ed. Philadelphia: Lippincott Williams & Wilkins; 2000.
Rang H, Dale M. Absorption, distribution and fate of drugs. In: Pharmacology. 2nd ed. New York, NY: Churchill Livingstone Inc.; 1991:
Pasivna imunoprofilaksa obezbeđuje kratkotrajnu zaštitu od infektivnih agenasa1-3
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19. SynagisR
Preporučena doza Synagisa je 15 mg/kg, primenjena jednom mesečno tokom perioda povećanog rizika od pojave RSV infekcije.
Daje se 5 doza
“Vakcinacija” počinje u novembru, a završava se u martu

20. Indikacije za primenu Synagis-a, AAP 2009.
Deca <2 godine sa hroničnom bolesti pluća (CLD) na početku RSV sezone koja su zahtevala terapiju zbog osnovne bolesti unutar 6 meseci pre RSV sezone. II
Prematurusi<32 GN (sa ili bez CLD) i prematurusi GN ako su u riziku da dođu u kontakt sa infekcijom.
Prematurusi <35 GN sa kongenitalnom anomalijom disajnih puteva ili neuromuskularnim oboljenjem.
Deca <2 godine sa hemodinamski značajnom USM
Deca <2 godine koja su imunokompromitovana.
III
Deca <2 godine nakon hirurških intervencija koje zahtevaju primenu kardiopulmonalnog bypass-a.

21. Rezultati randomizovanih, placebom-kontrolisanih studija (Impact studija i Cardiac studija) sa više od 2700 bolesnika‚ ukazuju da se efekat Synagisa ogleda u smanjenju učestalosti i trajanju hospitalizacije zbog RSV infekcije.
Resch B, Michel-Behnke I. Respiratory syncytial virus infections in infants and children with congenital heart disease: update on the evidence of prevention with palivizumab. Curr Opin Cardiol 2013, 28:85–91

22. Prevencija RSV u našem okruženju
Sve zemlje u okruženju sprovode prevenciju infekcija RSV
U Hrvatskoj izmedju 350 i 400 dece godišnje primi Synagis
U Republici Srpskoj je se godišnje vakciniše 145 visoko rizičnih bolesnika

23. Situacija u Srbiji Synagis je u Srbiji registrovan 2009. godine
Na pozitivnoj B listi RFZO je od godine
Ampule od 50 mg i 100 mg Synagisa
Jedna ampula košta 500/800 eura
U Srbiji Institut za neonatoligiju poslednje 4 godine sprovodi prevenciju kod prevremeno rodjene dece, gestacijske starosti <28 GN.

24. Indikacije za primenu, RFZO 2011

25. Potrebe za prevencijom RSV kod dece sa USM
Na UDK se godišnje operiše 100 do 120 odojčadi sa USM
Prema preporukama AAP i indikacijama RFZO svi su kadidati za prevenciju infekcije RSV
Godišnja potreba je oko 500 do 600 doza Synagisa !!!

26. Na UDK se planira primena prevencije RSV kod dece koja su neposredno pred operaciju USM ili su sveže operisana od
Teških USM praćenih cijanozom i/ili srčanom isnuficijencijom
Planira se prevencija kod odojčadi koja se operišu u toku sezone RSV

27. Korist/cena
Modified Recommendations for Use of Palivizumab for Prevention of Respiratory Syncytial Virus Infections. Pediatrics 2009;124;
Harris KC, Anis AH, Crosby MC et al. Economic Evaluation of Palivizumab in Children With Congenital Heart Disease: A Canadian Perspective. Canadian Journal of Cardiology 27 (2011); 523.e11–523.e15
Resch B, Michel-Behnke I. Respiratory syncytial virus infections in infants and children with congenital heart disease: update on the evidence of prevention with palivizumab. Curr Opin Cardiol 2013, 28:85–91
Fitzgerald DA. Preventing RSV bronchiolitis in vulnerable infants: The role of palivizumab. Paediatric Respiratory Reviews 10 (2009) 143–147.
Bentley A, Filipovic I, Gooch K et al. A cost-effectiveness analysis of respiratory syncytial virus (RSV) prophylaxis in infants in the United Kingdom. Health Economics Review 2013;1-12.

28. Ekonomski aspekti primene Synagis-a
Većina studija je pokazala da troškovi primene profilakse prevazilaze njene pozitivne efekte (prevencija i smanjenje mortaliteta, broja hospitalizacija, dužine trajanja lečenja, itd.).
Korišćenje ove terapije je opravdano samo ako se primenjuje kod visokorizičnih pacijenata!