La gestione del bambino con sospetta polmonite Nicola Principi

DIAGNOSI DI CAP Sospetto diagnostico -> VALUTAZIONE CLINICA (ipofonesi plessica, modificazioni del FVT, alterazioni del MV, polipnea) Certezza diagnostica -> RADIOGRAFIA DEL TORACE (presenza di infiltrati alveolari o interstiziali con o senza versamento pleurico)

FREQUENZA RESPIRATORIA E PRESENZA DI CAP NEL BAMBINO Età Frequenza respiratoria/min < 2 mesi > 60 2 – 12 mesi > 50 > 12 mesi > 40 I dati in Tabella risultano avere una sensibilità del 74% e una specificità del 67% per la diagnosi di CAP

E’ sempre necessario eseguire la radiografia del torace per porre diagnosi di CAP? NO nei casi di lieve o media gravità con sintomatologia clinica ben espressa SI nei casi dubbi, per evitare inutili trattamenti antibiotici SI nei casi gravi, per definire la situazione di partenza dell’episodio SI nei casi inseriti in protocolli di ricerca per definire i rapporti esistenti tra le variabili in studio e i tipi di alterazione polmonare

Esposito S et al., Pediatr Infect Dis 2012

ETIOLOGY OF CAP IN FINNISH HOSPITALIZED CHILDREN AGE (Years) N° VIRAL ETIOLOGY BACTERIAL ETIOLOGY MIXED ETIOLOGY ALL* <2 108 80 47 34 93 2-5 84 58 56 33 81 >5 62 37 19 76 TOTAL 254 53 30 85 *Total with detected etiology. Results expressed as percentages of patients. Adapted from Juven et al. Pediatr Infect Dis J. 2000

Episodes of Rx-confirmed CAP with viruses in children aged 13-36 months (Esposito S et al., Influenza & Other Resp Viruses 2013) 2007-08 2008-09 2009-10 Total episodes VIRUS No. (%) * Coinf. No.(%)^ (%)* Coinf. No.(%)^ RSV 35 (41.1) 16 58 (38.6) 21 30 (30.3) 10 123 (36.8) 47 Rhinovirus 26 (30.5) 15 44 (29.3) 24 (24.2) 7 94 (28.1) 43 Bocavirus 12 (14.1) 9 15 (10.0) 11 12 (12.1) 6 39 (11.6) Influenza 4 (4.7) 1 16 (10.6) 10 (10.1) 39 (11.6) 8 Metapneumo. 12 (14.1) 5 13(8.6) 4 6 (6.1) 31 (9.2) Coronavirus 3 (3.5) 2 7 (5.8) 3 5 (5.0) 15 (4.5) Parainfluenza (1-4) 0 (0) 4 (2.6) 10 (3.0) Adenovirus 1 (1.1) 2 (2.0) 7 (2.1) Episodes with viruses 68/85 (80.0) 20/68 (29.4) 122/150 (81.3) 36/122 (29.5) 78/99 (78.8) 14/78 (17.9) 268/334 (80.2) 70/268 (26.1) % among the total number of CAP investigated; ^ % of the total number of infections in which the single virus was identified

Principal Bacteria Causing Childhood Pneumonia (Community-Acquired Apart From the Age Group Birth-1 Month), by Age Bacterial etiology varied by age while group b Ster. Staph auerous and gram negatives are common in the first month of life while pneumococcus is common in all age groups and mycoplasma pneumonia considered to be common in older age group Esposito S, Cohen R, Domingo JD, Pecurariu OF, Greenberg D, Heininger U, Knuf M, Lutsar I, Principi N, Rodrigues F, Sharland M, Spoulou V, Syrogiannopoulos GA, Usonis V, Vergison A, Schaad UB. Pediatr Infect Dis J. 2012 Jun;31(6):e78-85. doi:

PNEUMOCOCCAL SEROTYPES IN CHILDREN WITH CAP AGED <5 YRS BEFORE THE USE OF PCV-13 (Esposito S et al., Pediatr Infect Dis 2012 ) COVERAGE PCV-7 : 28% PCV-10: 36% PCV-13: 74%

PNEUMOCOCCAL SEROTYPES IN PEDIATRIC CAP (Resti M et al PNEUMOCOCCAL SEROTYPES IN PEDIATRIC CAP (Resti M et al. Clin Infect Dis 2010)

CAP AND ATYPICAL BACTERIA IN 418 CHILDREN Principi et al. Clin Infect Dis 2001 %

BACTERIAL vs VIRAL PNEUMONIA Virkki et al. Thorax 2002 N=215 Bacterial Viral % % Alveolar infiltrates 71 29 Interstitial infiltrates 48 52 WBC >15 x 109/l 63 37 ESR > 30 mm/h 64 36 CRP > 40 mg/l 70 30 CRP > 80 mg/l 75 25

ADVANTAGES AND LIMITS OF PROCALCITONIN IN CLINICAL PRACTICE From Gendrel D et al. Pediatr Infect Dis J 1999

6,5 y, S.pneumoniae, widespread interstitial Bacterial Versus Viral Pneumonia Virkki R et al Thorax, 2002 6,5 y, S.pneumoniae, widespread interstitial 1,9 y, S.pneumoniae, alveolar changes 2.8 y, Rhinovirus, alveolar changes 0.3 y, parainfluenzae and HHV6, alveolar changes

QUICKVUE INFLUENZA TEST EFFICIENCY OF RAPID DIAGNOSTIC TESTS FOR INFLUENZA VIRUSES IN OFFICE PRACTICE TEST DIRECTIGEN FLU A+B Z STAT FLU QUICKVUE INFLUENZA TEST FLU OIA COMPANY BECTON DICKINSON ZYME TX, INC. QUIDEL BIOSTAR SENSITIVITY (%) 67 (T) 62 73 (N) SPECIFICITY 92 99 95-99 79.5 T= Throat Swab; N= Nasal Swab Benjamin J. Contemp Pediatr 2000

TEST MICROBIOLOGICI PER LA DIAGNOSI EZIOLOGICA DI CAP VANTAGGI LIMITI Tampone nasofaringeo Facile esecuzione Non correla con i dati polmonari se non per virus e batteri atipici Coltura dell´espettorato Buona sensibilitá Non attendibile nel bambino piccolo Emocoltura Bassa sensibilitá Puntura polmonare Facile esecuzione, buona sensibilitá Media invasivitá Puntura cricoidea Alta invasivitá BAL

NASOPHARYNGEAL COLONIZATION (%) IN PNEUMONIA VS HEALTHY CHILDREN From Nohynek et al. Pediatr Infect Dis J 1995

RISULTATI DEL TEST RAPIDO BINAX NOW Popolazione Tot. con Binax NOW positivo (%) Binax NOW pos e colonizzaz. NF (%) Binax NOW pos e assenza di colonizzaz. NF (%) Casi con IPD 5/5 (100,0)* 2/2 (100,0)* 3/3 (100,0)* Casi senza IPD 29/150 (19,3) 16/28 (57,1)° 13/122 (10,7) Controlli 35/200 (17,5) 26/53 (49,1)° 9/147 (6,1) *p<0,05 vs casi senza IPD e controlli °p<0,0001 vs casi senza IPD e controlli senza colonizzaz. NF Esposito S et al. Pediatr Infect Dis J 2004

DIAGNOSTIC TESTS FOR M. PNEUMONIAE AND C. PNEUMONIAE TEST SPECIMEN COMMENTS CULTURE Throat or NP swab, Requires tissue culture; not sputum, bronchial routinely available; requires washing, tissue several days of incubation PCR Throat or NP swab, No FDA-approved kits; available sputum, bronchial from research laboratories; washing, tissue potential for rapid diagnosis SEROLOGY Serum Paired acute-convalescent sera preferred; IgM may take up to 4-6 weeks to appear (therefore retrospective)

HOW TO TREAT PEDIATRIC CAP The choice of empirical antibiotic treatment for paediatric CAP should be based on diagnostic algorithms that begin with age of the patient, and then consider epidemiological and clinical factors (with particular attention on severity of the disease), vaccination status, PK/PD characteristics and finally the results of laboratory tests and chest radiography Esposito S et al., Pediatr Infect Dis J 2012

CHILDREN IN THE FIRST MONTH OF AGE The traditionally used combination of ampicillin and one of the aminoglycosides (mainly gentamicin) remains the treatment of choice As an alternative, a broad spectrum parenteral cephalosporin can be used In cases when Listeria monocytogenes or Enterococcus sp. or anaerobes are considered, ampicillin should be included in the regimen In critically ill patients, staphylococcal pneumonia should be considered and, in these circumstances, anti- staphylococcal penicillin or, in areas where methicillin- resistant strains of S. aureus have appeared, an active non beta-lactam agent (such as clindamycin or vancomycin) should then be added to the regimen

CHILDREN AGED 1 MONTH UP TO 3 MONTHS S. pneumoniae is the most important aetiological agents of CAP in this age group throughout the world A -lactam antibiotic is recommended As in the case of neonates, in critically ill patients anti- staphylococcal antibiotic can be used Chlamydia trachomatis and Bordetella pertussis should be considered especially in presence of little or no fever and severe cough. In such cases, macrolides are the drugs of choice

TERAPIA DELLA CAP NEL LATTANTE DI 1-3 MESI (LIVELLO DI PROVA: 6; FORZA DELLA RACCOMANDAZIONE: B) ASSENZA DI FEBBRE, TOSSE IMPORTANTE, INFILTRATO INTERSTIZIALE PRESENZA DI FEBBRE, CONSOLIDAMENTO LOBARE VEROSIMILMENTE CHLAMYDIA TRACHOMATIS E BORDETELLA PERTUSSIS VEROSIMILMENTE STREPTOCOCCUS PNEUMONIAE; RARAM. Hib E STAPHYLOCOCCUS AUREUS ERITROMICINA O CLARITROMICINA PER 14 GIORNI O AZITROMICINA PER 3 GIORNI AMOXICILLINA ORALE O, NEI CASI PIU’ GRAVI, CEFOTAXIMA O CEFUROXIMA O CEFTRIAXONE EV PER 10 GIORNI

ANTIBIOTIC THERAPY OF CAP OF INFANTS AND CHILDREN > 4 MONTHS OF AGE STREPTOCOCCUS PNEUMONIAE AND ATYPICAL BACTERIA ARE THE MOST FREQUENT CAUSE OF CAP IN CHILDREN > 4 MONTHS OF AGE DIFFERENTIATION OF PNEUMOCOCCAL FROM ATYPICAL BACTERIA CASES IS VERY DIFFICULT ANTIBIOTIC THERAPY MUST COVER ALL THE MOST FREQUENT ETIOLOGIES

TERAPIA SUGGERITA NEL BAMBINO CON CAP (4 mesi – 5 anni) AMOXICILLINA ORALE (80-90 mg/kg/die in 3 dosi) Se la terapia sembra fallire dopo 48-72 ore, aggiungere: ERITROMICINA ORALE (30-40 mg/kg/die in 3-4 dosi) O CLARITROMICINA (15 mg/kg/die in 2 dosi) O AZITROMICINA (10 mg/kg/die in 1 dose) NEI CASI GRAVI USARE DA SUBITO UN BETA-LATTAMICO BETA-LATTAMASI RESISTENTE (ES. CEFALOSPORINA EV) IN ASSOCIAZIONE A UN MACROLIDE PER OS O EV Durata usuale della terapia: 10-14 giorni LIVELLO DI PROVA: 6; FORZA DELLA RACCOMANDAZIONE: B

Role of pneumococcal penicillin resistance on CAP outcome (From Cardoso MRA et al., Arch Dis Child 2008)

From ECDC, 2013

TERAPIA SUGGERITA NEL BAMBINO CON CAP (6-18 anni) ERITROMICINA ORALE (30-40 mg/kg/die in 3-4 dosi) O CLARITROMICINA (15 mg/kg/die in 2 dosi) O AZITROMICINA (10 mg/kg/die in 1 dose) Se la terapia sembra fallire dopo 48-72 ore, aggiungere: AMOXICILLINA ORALE (80-90 mg/kg/die in 3 dosi) NEI CASI GRAVI USARE DA SUBITO UN BETA-LATTAMICO BETA-LATTAMASI RESISTENTE (ES. CEFALOSPORINA EV) IN ASSOCIAZIONE A UN MACROLIDE PER OS O EV Durata usuale della terapia: 10-14 giorni LIVELLO DI PROVA: 6; FORZA DELLA RACCOMANDAZIONE: B

Terapia con Vancomicina delle polmoniti da in pediatria Nei soggetti pluritrattati e nelle aree geografiche ove la resistenza di Streptococcus pneumoniae e Staphylococcus aureus è >20%, la vancomicina è considerata il farmaco di scelta Il dosaggio consigliato da molti anni è 40 mg/kg/die in 3-4 dosi Recenti ricerche indicano un aumento del rischio di fallimento per aumento delle MIC Un riferimento considerato ottimale per la previsione dell’efficacia della terapia è il trough level, vale a dire la concentrazione immediatamente precedente la dose successiva Il trough level deve rimanere quante più volte possibile sopra 10 mg/L per avere efficacia ed evitare l’insorgere di eventi avversi

Through serum levels of glycopeptides according to initial dosage (25, 40 or 50 mg/kg/die) (From Ito H et al., J Infect Chemother 2013)

New drugs for the treatment of pneumococcal infections with interesting preliminary results (From Esposito S & Principi N. Expert Opinion Pharmacotherapy 2013) Drug Main finding Linezolid It seemed to be effective in 77.5-90.0% of children with pneumococcal bacteremia or pneumonia; few data concerning its effect on pneumococcal penicillin-resistant strains Ceftobiprole It inhibited 95% of S. pneumoniae strains, including penicillin non-susceptible strains (those with a MIC ≥4 µg/mL) and highly resistant ceftriaxone strains (those with a MIC ≥8 µg/mL) Ceftaroline It had greater in vitro activity (MIC=0.5 µg/mL) than penicillin, cefotaxime or ceftriaxone (MIC=8 for all the comparators)

Antibiotic (Ab) exposure by treatment group and CAP severity (From Esposito S et al., Respir Med 2011)

Chest Radiography Repeated chest radiographs should be obtained in children who fail to demonstrate clinical improvement and in those who have progressive symptoms or clinical deterioration within 48–72 hours after initiation of antibiotic therapy (strong recommendation; moderate-quality evidence) Routine daily chest radiography is not recommended in children with pneumonia complicated by parapneumonic effusion after chest tube placement or after videoassisted thoracoscopic surgery (VATS), if they remain clinically stable (strong recommendation; low-quality evidence) Follow-up chest radiographs should be obtained in patients with complicated pneumonia with worsening respiratory distress or clinical instability, or in those with persistent fever that is not responding to therapy over 48-72 hours (strong recommendation; low-quality evidence)) IDSA guidelines; CID 2011. Kindly proded by Prof. Greenberg