Neumonia Adq. en La Comunidad 2013

Community-acquired pneumonia in children Fabio Cardinale a, ⁎, Anna Rita Cappiello a , Maria Felicia Mastrototaro a , Mariacristina Pignatelli a , Susanna Esposito b a Pediatric Unit, Division of Pulmonology, Allergy, and Immunology, AOU “Policlinico-Giovanni XXIII”, Bari, Italy b Pediatric Clinic 1, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy a b s t r a c t a r t i c l
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  Community-acquired pneumonia in children Fabio Cardinale a, ⁎ , Anna Rita Cappiello a , Maria Felicia Mastrototaro a ,Mariacristina Pignatelli a , Susanna Esposito b a Pediatric Unit, Division of Pulmonology, Allergy, and Immunology, AOU   “  Policlinico-Giovanni XXIII  ”  , Bari, Italy b Pediatric Clinic 1, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy a b s t r a c ta r t i c l e i n f o Available online xxxx Keywords: AntibioticsAntimicrobial treatmentCommunity-acquired pneumoniaPneumoniaRespiratory infection Community-acquiredpneumonia(CAP)remainsafrequentcauseofmorbidityandmortalityworldwideeveninindustrialisedcountries,anditsincidenceishighestamongchildrenaged b 5 years.Overthelasttwoyears,threeinternationalguidelineshavebeenupdatedwithnewevidenceconcerningtheincidence,aetiologyandmanage-mentofchildhoodCAP,buttherearestillsomemajorproblemsinstandardisation.Themainaimofthisreviewisto consider the available data concerning the aetiology, diagnosis, evaluation of severity, and treatment of paediatric CAP. Analysis of the literature shows that there are a number of unanswered questions concerningthe management of CAP, including its de 󿬁 nition, the absence of a paediatric CAP severity score, the dif  󿬁 culty of identifying its aetiology, the emergence of resistance of the most frequent respiratory pathogens to the mostwidely used anti-infectious agents, and the lack of information concerning the changes in CAP epidemiologyfollowingtheintroductionofvaccinesagainstrespiratorypathogens.Moreresearchisclearlyrequiredinvariousareas,andfurthereffortsareneededtoincreasevaccinationcoveragewiththealreadyavailablevaccinesinorderto reduce the occurrence of the disease.© 2013 Published by Elsevier Ireland Ltd. 1. Introduction Community-acquiredpneumonia(CAP)remainsafrequentcauseof morbidity and mortality worldwide, even in industrialised countries,and its incidence is highest among children aged  b 5 years [1]. It isestimated that CAP is responsible for one- 󿬁 fth of the deaths of youngchildren,withtwomillion deathsperyearinthedevelopingand devel-oped world: the incidence of CAP among children aged  b 5 years indeveloping countries is 0.29 per child-year, with a mortality rate of 1.3-2.6% and, in North America and Europe, its incidence in preschoolchildren is still approximately 36 per 1,000 child-years [2]. Extensiveinfantvaccinationswithpneumococcalconjugatevaccinesindevelopedcountries have signi 󿬁 cantly decreased the rates of hospital admissionsdue to childhood CAP (1,3,4), but concerns have been raised by theincrease in complicated CAP cases due to  Streptococcus pneumoniae serotypes 1, 3, 5 and 19A over the last few years [3,4]. Furthermore, anincrease in deaths due to Staphylococcal pneumonia has been reportedin North America, mainly following in 󿬂 uenza infection [5].During the last two years, three international guidelines have beenupdated with new evidence concerning the incidence, aetiology andmanagement of childhood CAP [1,6,7]. However, there are still somemajor problems in standardising the management of paediatric CAP,including the lack of a true diagnostic standard and the dif  󿬁 culty inidentifying the causative micro-organisms before selecting antibiotics.Thede 󿬁 nitionofCAPvarieswidelyworldwidedependingonwhetherchest radiography is used or not; furthermore, although chest radiogra-phy is still the main means of con 󿬁 rming a clinical suspicion of CAP ineveryday practice, its diagnostic accuracy is limited by signi 󿬁 cant intra-and inter-observer differences in interpreting plain chest radiographs[8]. Furthermore, as the recent international guidelines for the manage-mentofpaediatricCAPdonotrecommendroutineradiologicalinvestiga-tions in patients suspected of having uncomplicated CAP or CAP notrequiring hospitalisation [1,6,7], it is dif  󿬁 cult to establish the real inci-dence of childhood CAP.Intermsoftherapy,the 󿬁 rst-lineantimicrobialapproachvariesfromcountry to country, and there is no clear consensus concerning second-line treatment [1,6,7].The main aim of this review is to consider the available dataconcerningtheaetiology,diagnosis,evaluationofseverity,andtreat-ment of paediatric CAP. 2. Aetiology  Theuseofmolecularmethodstodetectmicrobialproductsinbiolog-ical  󿬂 uids has greatly improved our knowledge of CAP aetiology. Newrespiratory pathogens have been discovered over the last ten years,includinghumanmetapneumovirus,bocavirusandsomecoronaviruses[9], and new data concerning the importance of the different pneumo-coccal serotypes and the impact of the use of pneumococcal conjugate Early Human Development xxx (2013) xxx – xxx ⁎  Correspondingauthorat:PediatricUnit,DivisionofPulmonology,Allergy,andImmu-nology, AOU  “ Policlinico-Giovanni XXIII ” , 70126 Bari, Italy. E-mail address: (F. Cardinale). EHD-03832; No of Pages 4 0378-3782/$  –  see front matter © 2013 Published by Elsevier Ireland Ltd. Contents lists available at ScienceDirect Early Human Development  journal homepage: Please cite this article as: Cardinale F, et al, Community-acquired pneumonia in children, Early Hum Dev (2013), j.earlhumdev.2013.07.023  vaccines have been collected using polymerase chain reaction [3,4].However, determining the aetiology of CAP is still dif  󿬁 cult in routineclinical settings because appropriate lower respiratory tract specimenscanrarelybeobtainedfromchildren;theevaluationofupperrespiratorytract secretions is only useful for viruses and atypical bacteria becausetypicalbacteriaarepartofthenormal 󿬂 oracolonisingtheupperrespira-torytract[1];andthedetectionofbacterialantigensinurineisrelatedtothesame 󿬂 oraandcannotbeconsideredanaetiologicalmarkerofinfec-tion in children [2].TheaetiologyofCAPvariessigni 󿬁 cantlydependingontheageofthepatient.Respiratoryvirusesarethemostfrequentpathogensinchildrenaged between four months and  󿬁 ve years (with syncytial virus andrhinovirus the main viruses), and are responsible for approximately40%oftheCAPepisodesinhospitalisedchildren[1,10,11]. S.pneumoniae accounts for one-third of the cases of all ages, and  Mycoplasma pneumoniae  is the main pathogen in children aged 5-15 years [1 – 3,12]and also accounts for 30% of the cases in children aged 2-5 years [13].Untypeable  Haemophilus in  󿬂 uenzae ,  Staphylococcus aureus  and Chlamydiophyla pneumoniae  aremuchlessfrequentlyobserved,partlybecause of the lack of reliable diagnostic tests [1,2,6,7]. However, manystudies published over the last ten years have recorded mixedviral/bacterial infections in up to 45% of cases of childhood, with S. pneumoniae  being the most frequently involved bacteria [14,15].Dual viral infections have also been reported, with two or three virusesbeingdetectedin10-20% ofcases [11,16]. Someviruses(e.g.bocavirus)are detected more frequently than others in such multiple infections,but it is not clear what this means in clinical practice or whether viralinfection always precedes bacterial infection or not.Although some clinical and radiological pictures and laboratory 󿬁 ndings are more characteristics of particular etiological agents(e.g.  “ paroxysmal ”  cough in viral or atypical bacterial infections,necrotising pneumonia in infections due to  S. aureus  or  S. pneumoniae ,with the latter also inducing a signi 󿬁 cant increase), none is suf  󿬁 cientlysensitive or speci 󿬁 c to identify them de 󿬁 nitely. 3. Assessing severity  Many factors are associated with a complicated CAP course,including microbial load; the type and virulence of the pathogen,and its susceptibility to anti-infective drugs; and host susceptibilityto infections [1]. Individual susceptibility to CAP is also related tothe presence of comorbidities, pre-existing lung disease (such asbronchodysplasia, bronchiectasis or adenomatoid cystic malformations),previous vaccinations against respiratory pathogens, and genetic suscep-tibility to infections [1].This last may play an under-estimated role in the incidence andclinical course of CAP in patients of all ages. The risk of CAP is  󿬁 vetimes higher in adult patients discharged after being hospitalisedbecause of CAP than in those discharged with any other diagnosis [17]and, in primary care settings, it seems that subjects with CAP are alsomore likelyto have experienced previously recurrentupper respiratoryinfections [18]. Moreover, studies of adopted patients have shown thatthe risk of a fatal outcome is greatly conditioned by genetic factors[19], which seem to con 󿬁 rm their major role in determining individualsusceptibility [20]. Single nucleotide polymorphisms(SNPs)in manyof thegenesinvolvedininnateandadaptiveimmuneresponseshavebeenassociated with host susceptibility [21 – 26], and some of these geneshave also been associated with protection against [27] or susceptibilityto infectious diseases other than CAP [28].The international guidelines have suggested various criteria forassessing the severity of CAP in infants and older children [1,6,7]. Ingeneral, signs and symptoms suggesting a respiratory distress, such asage-adjusted tachypnea, SpO2 levels of less than 90-92% in room air,cyanosis, chest retractions, nasal  󿬂 aring or grunting, suggest a need forhospitalisation [1,6,7] but, unlike in the case of adults, there is novalidatedscoringsystemthatissensitiveandspeci 󿬁 cenoughtopredictwhich children have suf  󿬁 ciently severe CAP to warrant such a course[10]. The guidelines also point out that a child ’ s overall clinical appear-ance and behaviour may predict severity, and so any child with a “ toxic ” appearance(includingatemperatureof  N 39 °Candtachycardia,a capillary re 󿬁 ll time of   N 2 s, dehydration and respiratory distress)shouldbeadmittedtohospital[1,6,7].Furthercriteriaforhospitalisationinclude a younger age (i.e.  b 3-6 months), pre-existing comorbidities,suspected infection due to methicillin-resistant  S. aureus , feeding dif  󿬁 -culties, an inability to take oral medication because of vomiting, or thepossibilityofnon-compliancewithoraltreatmentbecauseofthefamilyenvironment [1].Some interesting perspectives have been opened up by the discov-ery of some new blood biomarkers of CAP severity in adults, includingnatriuretic peptide [29], mid-regional pro-adrenomedullin [30], and thetriggeringreceptorexpressedonmyeloidcells(TREM-1)[31].How-ever, there are still no data concerning the role of these biomarkers inpaediatric CAP. 4. Diagnosis Although the radiographic detection of in 󿬁 ltration is currently thegoldstandardforadiagnosisofCAP,expertsagreethatroutineimagingstudies are not essential to con 󿬁 rm the diagnosis in children, at least inthose who are well enough to be treated as outpatients and do notpresent recurrent episodes [1,6,7]. However, they are essential in themanagement of severe and/or recurrent CAP because, in addition tocon 󿬁 rming the diagnosis, they can also document the characteristicsoftheparenchymalin 󿬁 ltratesandthepresenceofcomplicationsrequir-ing speci 󿬁 c therapy [10].Computed tomography (CT) is usually reserved for patients withCAP complicated by parapneumonic effusions, necrotising pneumoniaor lung abscesses, especially when surgery needs to be considered [2].Chest radiographs are less sensitive in detecting lung abscessesthan CT scans, and fail in approximately 20% of cases [2]. Severe parapneumonic effusions and empyema (i.e. with more than half of the chest X-ray opaci 󿬁 ed) often require a CT scan before the placementof a chest tube, especially when loculated effusion is suspected [2]. Insuch cases, lung ultrasonography (LUS) may be an alternative as it hasthe advantage of avoiding radiation exposure, even though it is lessaccurate and gives rise to more inter-observer disagreement than CT[7]. A recent prospective multicentre study aimed at comparing theaccuracy of LUS, plain chest radiography andlow-doseCT in diagnosingadultCAPfoundasensitivityof93.4%(95%con 󿬁 denceinterval[CI]89.2 – 96.3%) and a speci 󿬁 city of 97.7% (95% CI 93.4 – 99.6%) [32].Aetiologically, a number of studies have shown that the signs andsymptoms of viral and bacterial CAP may be surprisingly similar, thatradiological characteristics cannot be used to distinguish differentaetiological agents, and that non-microbiological laboratory tests (suchas total and differential white blood cell counts, serum C-reactiveprotein levels and the erythrocyte sedimentation rate) are often notuseful for decision making in individual cases [1,2,10]. Procalcitoninlevels currently seem to be the best marker for distinguishing bacterialfrom viral CAP and reducing the duration of antimicrobial therapy [33].Identifyingtheaetiology of paediatricCAP is alsoaproblemwhenmicrobiologicalmethodsareusedtodetectbacteria.Theriskof com-plications means that punctured lung puncture, bronchoalveolar la-vage and thoracoscopic lung biopsy should be reserved forcomplicated and life-threatening cases that do not respond to theo-retically adequate antibiotic therapy [1,2,6,7]. Blood cultures are posi-tive in 13 – 26.5% of children with complicated CAP, but in fewer than5% of those with mild or moderate disease [10]. Molecular methodscan increase the sensitivity of identifying bacterial pathogens in bloodsamples, but they are not routinely used in all laboratories [3]. Gramstaining and cultured expectorated sputum are widely used to identifythe bacteria responsible for adult CAP, but most children (particularlythose in the  󿬁 rst years of life) cannot provide adequate specimens for 2  F. Cardinale et al. / Early Human Development xxx (2013) xxx –  xxx Please cite this article as: Cardinale F, et al, Community-acquired pneumonia in children, Early Hum Dev (2013), j.earlhumdev.2013.07.023  testing. Furthermore, otherwise healthy younger children frequentlycarry nasopharyngeal bacteria that are the same as those that cancause CAP and so, when sputum is induced, contamination often leadsto unreliable results [10].In relation to atypical bacteria, culturing respiratory secretions inorder to identify  M. pneumoniae  is impractical in most laboratoriesbecause it requires speci 󿬁 c media and its slow growth means that ittakes too long to obtain information that is useful for therapeuticdecision making. The presence of cold-reacting antibodies against redblood cells in serum was once considered a reliable index of   M. pneumoniae  infection, but its accuracy has never been evaluated inchildren and so it is not currently recommended in paediatrics [10].Serological methods (mainly enzyme assays) can detect speci 󿬁 c IgMand IgG antibodies, and their sensitivity and speci 󿬁 city are good if twoserum samples are evaluated (one taken during the acute phase andone during convalescence) [10]; however, once again, although they areuseful for epidemiological studies, the  󿬁 ndings cannot be used to maketherapeutic decisions. Finally, PCR-based testing is theoretically verysensitive and speci 󿬁 c, but it is not readily available or practical, and isnot considered a standard means of identifying  M. pneumoniae  CAP [10].The diagnostic tests used to identify  Chlamydophila pneumoniae  areeven more limited because they are unreliable, and the performance of many of the serological assays is poor or inadequately validated [1,10].It used to be thought that identifying CAP-causing viruses in upperrespiratory secretions was more reliable because it was believed thattheycouldnotbecarriedbyhealthychildren.However,thisassumptionisnowwidelyquestionedbecauseithasbeenshownthatitisnottrueof some viruses; furthermore, viral/bacterial co-infections are frequent,andbacterialpathogensmayplayamoreimportantroleinconditioningclinical signs and symptoms, and patient outcomes [10].Inconclusion,identifyingtheaetiologyofpaediatricCAPisfrequentlynotpossible,particularlyinmildormoderatecases,andthismayleadtothe unnecessary prescription of antibiotics. 5. Therapy  Intheabsenceofreliablemarkerscapableofdistinguishingviralandbacterial CAP or CAP caused by common and atypical bacteria, treat-ment remains largely empirical. However, the distinction seems to besomewhat arti 󿬁 cial as 25-60% of childhood CAP cases have a mixedaetiology. Some guidelines suggest that antimicrobial therapy shouldnot be routinely started in preschool-aged children with CAP becauseviralpathogensmayberesponsibleinsomecases[1,7],althoughanother guideline states that all children with a clear clinical diagnosis of CAPshould receive antibiotics because bacterial and viral pneumonia cannotbe reliably distinguished [6].Different antibiotics should be used for mild/moderate and severe/complicated CAP. Other factors to bear in mind are the patient's age,the presumed aetiology of the disease, the prevalence of antimicrobialresistance, and pneumococcal vaccination status.Duringthe 󿬁 rstfourweeksoflife,thetraditionallyusedcombinationofampicillin(oramoxicillin)andaminoglycosides(mainlygentamicin)remains the treatment of choice, with a broad spectrum parenteralcephalosporin as apotential alternative [1]. In patients aged 1-3 months, S.pneumoniae isthemainbacterialcauseofCAP,anda β -lactamantibioticistheproposed 󿬁 rst-linetreatment. Chlamydiatrachomatis and Bordetella pertussis  should be considered, especially in the presence of little or nofever and severe cough when macrolides should be proposed [1].In children aged between four months and  󿬁 ve years, the mainbacterialcausativeagentofCAPisstill S.pneumoniae ,butatypicalbacte-ria(particularly M.pneumoniae )mayplayasigni 󿬁 cantrole,especiallyinchildren aged  N 2 years. The proposed drugs are penicillin G or anaminopenicillin, of which the most widely used is amoxicillin. Clinicalfailuresandchildrenwhoarenotfullyimmunisedagainst S.pneumoniae and/or  󿬂 uenzae typebcouldbetreatedwithamoxicillin-clavulanateor third-generation cephalosporins. Second-generation cephalosporinscanbeproposedinareaswithalowprevalenceof  S.pneumoniae penicil-lin resistance. In cases of severe CAP or suspected atypical bacteria,consideration can be given to combined therapy with a  β -lactamase-resistant drug plus a macrolide [1].The main cause of CAP in children and adolescents aged 5-18 yearsis  M. pneumoniae , although  S. pneumoniae  still plays a signi 󿬁 cantaetiological role, particularly in more severe cases [1]. Macrolides arethe  󿬁 rst-line drugs in mild and moderate cases, whereas combined  β -lactamandmacrolidetherapycanbeconsideredinmoreseverecases[1].Inallagegroups,ananti-staphylococcalantibioticshouldbeconsid-eredincriticallyillpatients[1].Astheyarenotapprovedfortheregulartreatment of children and can lead to the selection of resistant strains,quinolones should only be used in selected cases if there are no othereffectivealternatives(e.g.macrolide-resistant M.pneumonia einfectionswith persistent symptoms), or in children with immunoglobulin E-mediated allergy to ß-lactams [1].The recommended duration of antimicrobial therapy is 7-10 daysfor mild/moderate CAP, but longer (e.g.  ≥ 14 days) in cases of severeand/or complicated CAP [1]. 6. Conclusions Although CAP is one of the most frequent paediatric infectiousdiseases, the  󿬁 ndings of this review indicate that there are a numberof unanswered questions concerning its management, including thede 󿬁 nitionofCAP,thelackofapaediatricCAPseverityscore,thedif  󿬁 cultyof identifying the aetiology of the disease, the resistance of the most fre-quent respiratory pathogens to the most widely used anti-infectiousagents,andthelackofinformationconcerningthechangesinCAPepide-miologyfollowingtheintroductionofvaccinesagainstrespiratorypatho-gens.Moreresearchisclearlyrequiredinvariousareas,andfurthereffortsare needed to increase vaccination coverage. Con 󿬂 ict of Interest The authors have no con 󿬂 ict of interest to declare. Role of the funding source This review was supported in part by a grant from the ItalianMinistry of Health (Bando Giovani Ricercatori 2009). 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Respirology 2011;16:321 – 5.[32] Reißig A,CopettiR,Mathis G,MempelC,Schuler A,ZechnerP, etal.Lungultrasoundin the diagnosis and follow-up of community-acquired pneumonia. A prospectivemulticentre diagnostic accuracy study. Chest 2012;142:965 – 72.[33] EspositoS,TagliabueC,PicciolliI,SeminoM,SabatiniC,ConsoloS,etal.Procalcitoninmeasurements for guiding antibiotic treatment in pediatric pneumonia. Respir Med2011;105:1939 – 45.4  F. Cardinale et al. / Early Human Development xxx (2013) xxx –  xxx Please cite this article as: Cardinale F, et al, Community-acquired pneumonia in children, Early Hum Dev (2013), j.earlhumdev.2013.07.023


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