Community-acquired pneumonia in children

Constantine A. Sinaniotisa and Athanassios C. Sinaniotisb

Purpose of review This review highlights recent developments in the diagnosis, etiology, therapy, and prevention of community-acquired pneumonia in children. Recent findings Sensitive new diagnostic methods have increased the detection rate of the causative agent up to 94%. Streptococcus pneumoniae is the most prevalent bacterial pathogen in all ages. Polymerase chain reaction is a rapid and sensitive method for the detection of Chlamydia pneumoniae and Mycoplasma pneumoniae, which have gained greater importance in recent years. During the period covered by this review, two new agents causing pneumonia were extensively studied. Human metapneumonovirus detected in young children is a leading cause of respiratory disease during the first years of life. A novel coronavirus was identified as the causative agent of severe respiratory syndrome, a new respiratory illness that affects adults and children. One multicenter trial concluded that nonsevere pneumonia can be treated with a short course of oral amoxicillin and a multicenter international study showed that children with severe pneumonia have similar outcomes whether treated with oral amoxicillin or parenteral penicillin, but more data are needed to demonstrate the safety and efficacy of such regimens. Summary The continued evolution of bacterial resistance highlights the need for appropriate use of antibacterials. Improved diagnostic techniques will aid the treatment of children with community-acquired pneumonia. Aggressive vaccination with the pneumococcal conjugate vaccine and other available vaccines as well as the development of new vaccines will aid the prevention of respiratory disease in children. Keywords antibiotic resistance, community-acquired pneumonia, empyema, pneumococcal conjugate vaccine, pleural effusion, respiratory syncytial virus
Curr Opin Pulm Med 11:218 225. 2005 Lippincott Williams & Wilkins.
a

Abbreviations Hib hMPV PCR RSV SARS SARS-CoV WHO Haemophilus influenzae b human metapneumonovirus polymerase chain reaction respiratory syncytial virus severe acute respiratory syndrome SARS coronavirus World Health Organization

2005 Lippincott Williams & Wilkins. 1070-5287

Introduction
Community-acquired pneumonia remains a common and serious illness despite the availability of new and potent antibiotics and effective vaccines. It is, moreover, one of the main causes of death in young children, especially in developing countries, accounting for approximately 2 million deaths, 20% of all deaths in children [1]. Our understanding of community-acquired pneumonia is rapidly expanding and our ability to prevent and treat the disease has improved in recent years.

Etiology
The determination of the etiologic agent of pneumonia is a difficult diagnostic problem because appropriate specimens can rarely be obtained from the lower respiratory tract. There have been relatively few comprehensive studies of the bacterial and viral etiology of pneumonia [2]. This is explained by the fact that many bacteria and viruses can cause illness and many of them can be detected by methods available only in research laboratories. Depending on the number of tests used, evidence of a potential causative agent has been identified in 2485% of the cases [2,3]. In a recent prospective study [4] of 154 children aged 2 months17 years (median age 33 months) with radiographically confirmed lower respiratory infection evaluated with a battery of tests, a pathogen was identified in 79% of the children. Bacterial etiology was documented in 60% (Streptococcus pneumoniae in 73%), viruses in 45%, Mycoplasma pneumoniae in 14%, and Chlamydia pneumoniae in 9%. In 23% of the children a mixed bacterial/viral infection was identified [4]. The causative agent of pneumonia differs according to the age of the patient. In neonates group B Streptococcus and gram-negative bacteria are the most common pathogens. Pneumonia in infants 3 weeks3 months is most often bacterial; S. pneumoniae is the most common pathogen even in this young age group. Chlamydia trachomatis, Bordetella pertussis, Staphylococcus aureus, parainfluenza virus 3, and respiratory syncytial virus (RSV) are causative agents

Second Department of Pediatrics, University of Athens School of Medicine, and b Department of Allergy and Clinical Immunology, Laiko General Hospital, Athens, Greece Correspondence to C A Sinaniotis, MD, Second Department of Pediatrics, University of Athens School of Medicine, A & P Kyriakou Childrens Hospital, 11527 Athens, Greece Tel: +30 210 6726593; fax: +30 210 7216904; e-mail: konsinan@med.uoa.gr Current Opinion in Pulmonary Medicine 2005, 11:218 225

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Community-acquired pneumonia Sinaniotis and Sinaniotis 219

of pneumonia in infants aged 3 weeks3 months [5]. Viruses are the predominant pathogens in the 4 months 4 years group. RSV is the most common cause of pneumonia in the younger children in this age group. Parainfluenza viruses, influenza virus, adenovirus, and rhinovirus are also common pathogens of pneumonia [5]. S. pneumoniae is the most common bacterial pathogen identified in children in this group [4,5,6]. Mycoplasma pneumoniae and C. pneumoniae are common causes of pneumonia in older children and adolescents, but contrary to what was previously thought, the incidence of pneumonia caused by these pathogens is high in children aged less than 5 years [7]. Mycoplasma pneumoniae is the main pathogen of pneumonia in children from ages 510 years. In Finland, M. pneumoniae was detected in 50% of cases of community-acquired pneumonia in children 5 years of age and older, and the incidence increased with age, being higher at the age of 10 years and older [7]. Predominance of this pathogen has also been documented in children of this age in other countries [8]. Coinfections with S. pneumoniae and C. pneumoniae have been documented in more than 30 and 15%, respectively, of cases of Mycoplasma infection [8]. Emerging evidence indicates that C. pneumoniae may be a significant cause of pneumonia among school-aged children and adolescents [7].

others [14]. These findings suggest that hMPV is a leading cause of respiratory tract infection in the first years of life with a spectrum similar to that of RSV. Severe acute respiratory syndrome (SARS) is a new infectious disease affecting the respiratory tract. The disease is caused by a novel coronavirus (SARS-CoV) and infections began in the Chinese province of Guangdong in 2002. SARS for reasons unknown preferentially affects adults and not children. Children appear to be less susceptible [15,16] and they have a more favorable prognosis. Unlike adult patients, no fatalities were reported among the pediatric SARS patients [15,16]. Although patients had clinically recovered from the initial illness, follow-up 6 months after the disease onset demonstrated exercise impairment and residual radiologic abnormalities [17]. Long-term follow-up of the patients is important to assess the clinical significance of these abnormalities [17]. Fever, cough, malaise, coryza, sputum production, headache, and myalgia are the presenting symptoms of the infection. Lymphopenia and elevated lactic dehydrogenase levels are common abnormalities [16]. Radiographic findings are not specific but high-resolution CT scan of the thorax is an early diagnostic aid [16]. A specific PCR assay for SARS-CoV is positive in less than 50% of the cases in children. Therapy is empiric, with methylprednisolone, and supportive. Some cases need assisted ventilation. At present it is unknown whether SARS may become a permanent respiratory pathogen.

Emerging pathogens
New and sensitive diagnostic tests such as polymerase chain reaction (PCR) have contributed in recent years to the identification of hitherto unknown pathogens that cause lower respiratory tract disease.
Human metapneumonovirus

Diagnosis
A diagnosis of pneumonia is often entertained on the basis of the initial presentation of symptoms and signs. The clinical presentation may be subtle; and radiographic and laboratory studies aid in the diagnosis and allow identification of the causative agent.
Clinical characteristics

In 2001 human metapneumonovirus (hMPV) was recognized as a common etiologic agent for lower respiratory infection in children [9,10,11]. The virus was documented in 720% of children with lower respiratory disease in whom no other etiologic agent was identified [9,10]. The mean age of hMPV-infected children was 11.6 months [9]. In one study hMPV infection was associated with bronchiolitis in 59% of the patients tested and pneumonia in 8%, croup in 18%, and exacerbation of asthma in 14% [9]. Mixed infections with hMPV and other respiratory viruses have been reported but the results are contradictory [11]. Clinical presentation of the infection with hMPV is similar to RSV disease and severe bronchiolitis and pneumonia are common among patients [9,11,12]. Asthma exacerbations have been reported in children with hMPV infection [13] but this association has not been documented by

Fever, headache, abdominal pain, dyspnea, cough, and crepitations are frequently found in children with pneumonia. Tachypnea has been suggested as the best sign that a child has pneumonia rather than an uncomplicated upper respiratory tract infection, but there is no widely accepted definition of what it is, especially in febrile children [18]. Cough, dyspnea, rhinorrhea, and abdominal pain, as well as fever, crepitations, and otitis media, are present in similar proportions of children with viral or bacterial pneumonia [6,19]. Wheeze occurs more frequently with viral infections but is also a common finding in Mycoplasma pneumonia. Therefore, children with viral or bacterial pneumonia cannot be distinguished by clinical signs only.

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Radiographic findings

Microbiologic investigations

A chest radiograph is generally regarded as the gold standard for confirming the presence of pneumonia but routine use of a chest radiograph for every child with mild uncomplicated acute lower respiratory infection is not appropriate. One large study of the value of chest radiography in ambulatory children with acute lower respiratory infection, aged 2 months5 years, concluded that chest radiography did not affect the clinical outcome of the children [20]. A chest radiograph is advisable, however, in a child younger that 5 years with a fever of unknown origin [18]. Chest radiographs do not discriminate between bacterial, atypical, and viral pneumonia. Lobar consolidation has been associated with pneumococcal infection and interstitial infiltrates with viral infections. Both lobar consolidation and interstitial infiltrates, however, have been identified in all types of infection, viral, bacterial, or mixed. Virkki et al. [19] studied 254 consecutive children hospitalized with community-acquired pneumonia. A potential causative agent was identified in 85% of them. Bacterial infection was documented in 71% of 137 children with alveolar infiltrates, while half of the 77 patients with solely interstitial infiltrates had evidence of bacterial infection, suggesting that alveolar pneumonia, especially with lobar infiltrates, is mostly seen in bacterial pneumonia but interstitial infiltrates are seen in both viral and bacterial pneumonias. Follow-up chest radiography in asymptomatic children with prior radiologic evidence of pneumonia is not helpful and should only be performed after lobar collapse, round pneumonia, or for persisting symptoms [18,21]. The leukocyte count, total neutrophil count, C-reactive protein, and erythrocyte sedimentation rate are not helpful in distinguishing viral from bacterial pneumonia. Several prospective studies have shown that these acute-phase reactants have a low sensitivity and specificity between bacterial and viral infection and no combination of these markers is sufficiently sensitive and specific to be used in clinical practice [22]. Procalcitonin has been evaluated as a potentially useful marker for distinguishing between viral and bacterial infections and for the early detection of invasive infections. Procalcitonin offers better specificity than C-reactive protein for differentiating between viral and bacterial cause of fever with similar sensitivity [23,24,25] and high values indicate the presence of bacterial infection [2426]. Other studies concluded, however, that measurement of serum procalcitonin is of little value in differentiating between bacterial and viral pneumonia in children [27].

In most children with community-acquired pneumonia, identification of the causative organism is not critical, but in hospitalized children with severe or complicated pneumonia it may be important, and microbiologic investigation should be performed. Blood cultures are rarely positive in pneumonia. In a recent study of children aged 224 months with pneumonia [28], the prevalence of bacteremia was 1.6%, suggesting that the widespread use of the heptavalent conjugate pneumococcal vaccine may further decrease the prevalence of bacteremia in pneumonia [29]. Therefore blood cultures are not recommended as routine studies for outpatients but may help direct treatment in inpatients with more severe form of pneumonia [18]. Sputum Gram stain and culture should be considered in older children and adolescents with severe disease [18,30]. When pleural effusion is present it should be aspirated and sent for microscopic examination and culture [18,30,31]. Antigen detection of bacteria in serum lacks specificity and sensitivity to be of diagnostic value and it is not recommended. Rapid antigen tests such as immunofluorescence assay and solid-phase immunoassay are available for RSV; parainfluenza 1, 2, and 3; influenza A and B; and adenovirus. Nasopharyngeal aspirates from children under the age of 18 months should be sent for viral antigen detection or PCR assay. The best test for rhinovirus is PCR assay [5]. Serologic testing for IgM or at least quadrupling of serum IgG between the acute phase and convalescence for children with suspected Chlamydia pneumonia and Mycoplasma pneumonia is a satisfactory test but has limited clinical value to the physician who needs interpretation quickly for decision making. Cold agglutinins are often used as an acute test for diagnosis of M. pneumoniae but there are false-positive results with viral diseases and the positive predictive value of the test is 70% [32]. PCR assay may be helpful for rapid diagnosis of C. pneumoniae and M. pneumoniae. Pulse oximetry should be obtained in all patients in whom pneumonia is suspected. Measurement of oxygen saturation should be useful to support the diagnosis of pneumonia and influence management decisions as how to treat the patient, such as in the hospital or outpatient [34].

Management
The treatment of pneumonia is always empirical, as it is extremely rare that the causative organism is identified before antibiotics are selected. Empiric therapy should be based on knowing the most likely pathogen in each community, as the relative frequency varies from one region to another, but also the risk for resistant organisms

Community-acquired pneumonia Sinaniotis and Sinaniotis 221

and the age of the child. Recent serologic studies have confirmed that S. pneumoniae is an important causative agent for community-acquired pneumonia of all ages. M. pneumoniae is common from the age of 5 years onwards and C. pneumoniae is common from the age of 10 years onwards [5,30,31]. Because it is difficult to distinguish between bacterial, viral, and mixed infections, most children with communityacquired pneumonia are treated with antibiotics. Treatment decisions regarding selection of antibiotic should be based on the age of the child and epidemiologic factors and sometimes the results of chest radiography [5,18]. Infants between 3 weeks and 3 months of age in whom pneumonia is suspected are best treated as inpatients, particularly if they are febrile and have a toxic appearance [18,30,31]. The most likely causes of pneumonia in this age group are C. trachomatis, which causes afebrile, subacute interstitial pneumonia, and RSV. B. pertussis and S. aureus are nowadays less common causes of pneumonia [5]. Afebrile patients are treated as outpatients with oral erythromycin or with intravenous erythromycin if they are hospitalized. Patients with lobar or lobular infiltrates or pleural effusion alone or in combination should be treated with cefotaxime or ampicillin [5].
Preschool-aged children (6 months 5 years)

Children 5 15 years

Mycoplasma pneumoniae is the main pathogen causing pneumonia in children aged 515 years, C. pneumoniae being less common [5]. S. pneumoniae remains a significant pathogen in school-aged children [5]. Macrolides are the first choice in this age group because of the increased prevalence of Mycoplasma and because they are effective against pneumococci sensitive to penicillin. Outpatients with pneumonia are treated with erythromycin or clarithromycin or azithromycin [18,30,31]. Hospitalized patients are treated with intravenous erythromycin or intravenous azithromycin, and if there is strong evidence of a bacterial infection ampicillin, cefuroxime, or cefotaxime is added.

Antibiotic resistance
The emergence of strains of S. pneumoniae that are resistant to penicillin is of great concern. Antimicrobial resistance is increasing globally, although patterns and degree of resistance vary by geographic region [33,35,36]. The highest prevalence of S. pneumoniae resistance is most often observed among children younger than 2 years of age compared with children older than 2 years, but despite resistance, children respond to conventional therapy [33]. Results of the Alexander project show that amoxicillin (95.1%) and amoxicillin/clavulanate (95.597.9%) were the only oral nonfluoroquinolone agents active against more than 90% of S. pneumoniae [36]. Susceptible to penicillin organisms are those with a minimal inhibitory concentration of 0.06 mg/mL or less, intermediate at 0.11.0 mg/mL, and resistant at 2 mg/mL or more [35]. Treatment of pneumococcal pneumonia, in otherwise normal children, caused by penicillin-resistant strains, with high-dose amoxicillin or second-generation (cefuroxime) or third-generation (cefotaxime) cephalosporins is effective [5,30]. For patients in whom pneumonococcal infection with high-level penicillin resistance is suspected, as in nosocomial pneumonia or in critically ill patients, it is advisable to use in the initial empiric treatment agents such as clindamycin, vancomycin, or the oxalidone, linezolid [37].

Viruses are the predominant pathogen in preschool-aged children (6 months5 years), RSV being the most common cause of pneumonia followed by parainfluenza and influenza viruses and adenovirus and rhinovirus. hMPV is also responsible for pneumonia in this age group [9,10]. S. pneumoniae is the most common [5,6] bacterial pathogen in preschool children. Haemophilus influenzae, a common cause of pneumonia in the past, is very rare nowadays in areas with wide vaccine coverage. In children who present symptoms of viral infection such as pharyngitis, rhinorrhea, and diarrhea, especially during an epidemic, and who have a mild disease, withholding treatment seems appropriate if a close follow-up of the patient is ensured [6]. When bacterial pneumonia is suspected because S. pneumoniae is the most common cause of pneumonia in this age group, the patient should be treated with amoxicillin in high dose, if resistance to it is anticipated. Other alternatives are amoxicillin/clavulanate and second-generation cephalosporins. Macrolides such as erythromycin or clarithromycin may be used when Mycoplasma infection is suspected. Patients who require hospital admission are treated with ampicillin or cefuroxime or cefotaxime intravenously [5,18,30,31].

Route of administration
Most children with community-acquired pneumonia can be treated as outpatients with oral antibiotics [18,30] with the exception of the patient who cannot absorb oral antibiotics because of vomiting or who otherwise is averse to a first dose of oral medication [30]. Initiating treatment with a single parenteral dose of ceftriaxone in these children has been shown to be effective [38]. The intravenous route is reserved to treat severe pneumonia in hospitalized patients, but a switch from intravenous administration to oral antibiotics should be considered

222 Infectious diseases

when fever has abated and the patient can tolerate oral medication and is otherwise improving [30]. In a recent study treatment of severe pneumonia in hospitalized patients, oral amoxicillin was found to be equivalent to treatment with injectable penicillin [39]. The trial involved 1702 children, 359 months of age, with severe pneumonia according to World Health Organization (WHO)-defined criteria [40]. Patients were randomly allocated to receive oral amoxicillin in a dose of 45 mg/kg per day in three doses or parenteral penicillin G 200 000 IU/kg per day in four doses. Treatment failure was 19% in each group at 48 hours. Twelve children (0.7%) died within 14 days of enrollment. More deaths occurred in the penicillin group. Of these deaths, nine were associated with treatment failure. The study was well designed and monitored, but there are some drawbacks such as the probable inclusion in the study of infants with unrecognized HIV infection, something that may have contributed to early deaths. Also, the dose of amoxicillin of 45 mg/kg per day probably was not adequate treatment for penicillin-resistant pneumococci, which may have resulted in treatment failure. Nevertheless, the study showed that in some children with severe pneumonia, exclusively oral therapy is effective and safe. More data are needed to identify the appropriate candidates for such therapy. Two recent multicenter studies [41,42] examined whether a 3-day course of oral amoxicillin was as effective as a 5-day course for treatment for nonsevere pneumonia in young children. Both studies were well designed, doubleblind, randomized, and placebo controlled. The first study in Pakistan [41] involved 2000 children aged 259 months with nonsevere pneumonia according to the WHO algorithm [40]. Results showed that oral amoxicillin given for 3 days at a dose of 45 mg per kilogram body weight per day was equally as effective as treatment for 5 days in children with nonsevere pneumonia. Treatment failed in 20% in both groups and the most important risk factor for treatment failure was noncompliance. The second study [42] in India used the same dosing and treatment protocol and involved 2188 children aged 259 months. The dose of amoxicillin was 3154 mg per kilogram of body weight per day. The clinical cure rates with 3 days and 5 days of treatment were 89.5 and 89.9%, respectively. Treatment failure was associated with infection with RSV and noncompliance. The results of both studies emphasize the need for more randomized controlled trials in different settings to determine the effectiveness of oral treatment of pneumonia in children as well as the optimum dose of the antibiotic to be used and the duration of treatment.

Pleural effusion and empyema

Pleural effusions develop in at least 40% of patients with bacterial pneumonias admitted to hospital, and up to 60% of the effusions progress to empyema [18]. During the past decade increasing rates of complicated pleural effusion associated with community-acquired pneumonia were reported. Two recent reports [43,44] documented an increase of complicated effusion from 19932001 and then a decline concomitant with the introduction of the pneumococcal conjugate vaccine [44]. Whereas S. pneumoniae was the predominant organism, S. aureus emerged as a cause of complicated pleural effusion and empyema [43]. In one report S. aureus increased from 6% in 19962000 to 30% in 2001 and in another study from 18 to 60% between 19992002 [43,44]. The management of empyemas remains controversial. Among the current treatments video-assisted thoracic surgery has been suggested as the best method because of decreased length of stay in hospital [43].

Prevention
Widespread use of vaccines against pertussis, measles, H. influenza, and influenza in selected cases has resulted in preventing many cases of pneumonia in children. The impact of the conjugate H. influenzae type b vaccine (Hib) in preventing pneumonia is not known. A recent study documented a vaccine effectiveness of the Hib vaccine of 31% in infants with radiologically confirmed pneumonia, showing the potential benefit of Hib immunization in the prevention of community-acquired pneumonia [45]. The seven-valent polysaccharide pneumococcal conjugate vaccine that was incorporated in the vaccination schedule for infants and children in the United States in 2000 produces immunity for the seven most common disease-producing serotypes of S. pneumoniae in children. The vaccine proved to be highly effective (97%) in preventing invasive disease in normal children, especially children under 2 years of age [46]. In this group of children the rate of disease was 69% lower 1 year after licensure than the baseline rate. The rate of disease caused by vaccine and vaccine-related serotypes declined by 78 and 50%, respectively [46]. Disease rates also fell in adults, suggesting herd immunity from the use of the vaccine [46,47]. Although the vaccine is less effective in preventing pneumonia [47], it has been shown that the immunization of children younger than 2 years is associated with a 10-fold greater reduction in pneumonia than previously reported in culture-confirmed invasive disease in children less than 2 years old [48].

Community-acquired pneumonia Sinaniotis and Sinaniotis 223

The most dramatic effect has been documented in cases of pneumonia with a positive radiograph, an overall reduction of 17%. This effect was more evident in children less than 1 year old: there was a 32.3% reduction in children older than 2 years [47]. A recent review in Cochrane Database of Systematic Reviews on the effect of the pneumococcal conjugate vaccine in reducing radiologically confirmed pneumonia concluded that there were uncertainties about definition of this outcome and suggested data from more trials should be evaluated [49].
Influenza

Conclusion
Pneumonia remains a serious illness in children and continues to challenge in diagnosis, treatment, and prevention. New rapid and sensitive techniques such as PCR detect most of the respiratory pathogens and make evaluation of the epidemiology of pneumonia more accurate. Treatment of pneumonia is mostly empirical and this results in overuse of antibiotics, which is an important factor in the increase of bacterial resistance. The use of pneumococcal conjugate vaccine resulted in a decline in invasive pneumococcal disease and to a lesser extent in pneumonia. Another benefit of vaccination is the decrease in antibiotic-resistant strains, suggesting that vaccination will aid the prevention of respiratory disease and the development of bacterial resistance.

The contribution of influenza to the total cases of viral pneumonia varies year to year [2,50], and by age, but averages 8%. A recent study using PCR showed that the clinical burden of influenza A pneumonia was much more common than it was previously thought and was comparable to that of RSV pneumonia [51,52]. Pneumonia caused by S. aureus and S. pneumoniae has been associated with preceding influenza infection [51]. This association is based on observations of simultaneous epidemics of influenza and pneumonia and on serologic evidence of previous influenza infection among patients with bacterial pneumonia [51]. Prevention of pneumococcal pneumonia may be a potential benefit of influenza vaccination [54]. The live attenuated cold-adapted intranasal influenza vaccine has a high efficacy against influenza, is well tolerated, and has the advantage that it requires no injection. These properties raise the possibility of incorporating the vaccine in the immunization schedule for children.
Respiratory syncytial virus

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1 Williams BG, Gouws E, Boschi-Dinto C, et al. Estimates of worldwide distribution of child deaths from acute respiratory infections. Lancet Infect Dis 2002; 2:25 32. Henrickson KJ. Viral pneumonia in children. Semin Respir Infect Dis 1998; 9:217 233. Sinaniotis CA. Viral pneumoniae in children: incidence and aetiology. Paediatr Respir Rev 2004;5(suppl A):S197 S200.

2 3 4

Michelow IC, Olsen K, Lozano J, et al. Epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children. Pediatrics 2004; 113:701 707. Interesting prospective study confirms the importance of S. pneumoniae and the frequent occurrence of bacterial/viral coinfections in community-acquired pneumonia.

5 6 7

McIntosh K. Community-acquired pneumonia. N Engl J Med 2002; 346:429 437. Lichenstein R, Suggs AH, Campbell J. Pediatric pneumonia. Emerg Med Clin North Am 2003; 21:437 451.

Respiratory syncytial virus is the main cause of hospitalization in the first year of life for bronchiolitis and pneumonia [2,55] in infants and young children. Premature babies born at 3035 weeks of gestation and infants with congenital anomalies, especially congenital heart disease, are at significantly greater risk for complications [5658]. Ribavirin is the only antiviral therapy available against RSV but trials of ribavirin therapy lack sufficient power to provide reliable estimates of the effects [59]. Passive immunization with humanized monoclonal antibody (palivizumab, Synagis, MedImmune, Inc., Gaithersburg, MD) offers the prospect of preventing hospitalization in infants at high risk for severe RSV infection [54,57], but because of the high costs of therapy the use of palivizumab is restricted to infants who fulfil certain criteria established by advisory bodies [60]. Vaccination in future may reduce morbidity. Progress is currently being made in developing vaccines, but it may be some time before these become available.

Korppi M, Heiskanen-Kosma T, Kleenola M. Incidence of community-acquired pneumonia in children caused by Mycoplasma pneumoniae: serological results of a prospective, population-based study in primary health care. Respirology 2004; 9:109 114. This study showed that M. pneumoniae is a common cause of community-acquired pneumonia in children and coinfection with S. pneumoniae and C. pneumoniae is common.

Tsolia MN, Psarras S, Bossios A, et al. Etiology of community-acquired pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections. Clin Infect Dis 2004; 39:681 686. Prospective study of the etiology of community-acquired pneumonia in schoolaged children showed (contrary to what was thought) a high prevalence of viral and mixed viral bacterial infections. 8 9

Williams JV, Harris PA, Tollefson SJ, et al. Human metapneumonovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med 2004; 350:443 450. Retrospective study of previously virus-negative sera from children with acute lower respiratory tract illness identified hMPV in 20%. 10 Van den Hoogen BG, Osterhaus DME, Fouchier RAM. Clinical impact and diagnosis of human metapneumonovirus infection. Pediatr Infect Dis J 2004; 23:S25 S32.

11 Mejias A, Chavez-Bueno S, Ramilo O. Human metapneumonovirus: a not so new virus. Pediatr Infect Dis J 2004; 23:1 10. Comprehensive review of the topic. 12 Esper FBD, Weibel C, Martinello RA, Kahn KS. Human metapneumonovirus in the United States: clinical manifestations associated with the newly emerging respiratory infection in children. Pediatrics 2003; 111:1407 1410.

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13 Jartti T, Van den Hoogen B, Garofalo RP, et al. Metapneumonovirus and acute wheezing in children. Lancet 2002; 360:1393 1394. 14 Rawlinson WD, Walliuzzaman Z, Carter IW, et al. Asthma exacerbations in children associated with rhinovirus but not human metapneumonovirus infection. J Infect Dis 2003; 187:1314 1318. 15 Hon KL, Leung CW, Cheng W, et al. Clinical presentations and outcome of severe acute respiratory syndrome in children. Lancet 2003; 361:1701 1703. 16 Leung CW, Kwan YW, Ko PW, et al. Severe acute respiratory syndrome among children. Pediatrics 2004; 113:e535 e543. Interesting study of SARS in children. 17 Li AM, Chan CHY, Chan DFY. Long-term sequelae of SARS in children. Pae diatr Respir Rev 2004; 5:296 299. Results of a short follow-up of patients with SARS. 18 BTS. BTS Guidelines for the management of community-acquired pneumonia in childhood. Thorax 2002; 57:S1 S24. 19 Virkki R, Juven T, Rikalainen H, et al. Differentiation of bacterial and viral pneumonia in children. Thorax 2002; 57:438 441. 20 Swingler GH, Zwarenstein M. Chest radiograph in acute respiratory infections in children. Cochrane Database Syst Rev 2000;(2):CD00 1268. 21 Wacogne I, Negrine RJS. Are follow up chest X-ray examinations helpful in the management of children recovering from pneumonia? Arch Dis Child 2003; 88:457 458. 22 Korrpi M. Non-specific host response markers in the differentiation between pneumococcal and vital pneumonia: what is the most accurate combination? Pediatr Int 2004; 46:545 550. This interesting study concluded that early markers of infection have very limited value in differentiating bacterial from viral pneumonia.

36 Jacobs MR, Felmingham D, Appelbaum PC, et al. The Alexander Project 1998-2000: susceptibility to pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents. J Antimicrob Chemother 2003; 52:229 246. 37 Kaplan SL, Deville JG, Yogev R, et al. Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children. Pediatr Infect Dis J 2003; 22:677 685. 38 Chumpa A, Bachur RG, Harper MB. Bacteremia associated pneumococcal pneumonia and the benefit of initial parenteral antimicrobial therapy. Pediatr Infect Dis J 1999; 18:1081 1085. 39 Addo-Yobo E, Chisaka N, Hassan M, et al. Oral amoxicillin versus injectable penicillin for severe pneumonia in children aged 3 to 59 months: a randomised multicentre equivalency study. Lancet 2004; 364:1141 1148. In this large multicenter international study in developing countries, oral amoxicillin and parenteral penicillin were equally effective in treating severe pneumonia.

40 World Health Organization. Technical basis for the WHO recommendations on the management of pneumonia at first-level facilities. WHO/ ARI/ 91-2. Geneva: World Health Organization; 1991. 41 Pakistan Multicentre Amoxicillin Short Course Therapy Pneumonia Study Group (MASCOT). Clinical efficacy of 3 days versus 5 days of oral amoxicillin for treatment of childhood pneumonia: a multicentre double-blind study. Lancet 2002; 360:835 841.

42 ISCAP Study Group. Three day versus five day treatment with amoxicillin for non-severe pneumonia in young children: a multicentre randomised controlled trial. BMJ 2004; 328:791 796. Large multicenter double-blind study documented the efficacy of 3-day oral treatment of pneumonia. 43 Buckingham SC, King MD, Miller ML. Incidence and etiologies of complicated parapneumonic effusions in children, 1996 to 2001. Pediatr Infect Dis J 2003; 22:499 504.

23 Van Rossum AMC, Wulkan RW, Ondesluys-Murphy AM. Procalcitonin as an early marker of infection in neonates and children. Lancet Infect Dis 2004; 4:620 630. Interesting and comprehensive review of the topic. 24 Lopez AF, Cubells L, Carcia JJG, et al. Procalcitonin in pediatric emergency departments for the early diagnosis of invasive bacterial infections in febrile infants: results of a multicenter study and utility of a rapid qualitative test for this marker. Pediatr Infect Dis J 2003; 22:895 903. 25 Prat C, Dominguez J, Rodrigo C, et al. Procalcitonin, C-reactive protein and leukocyte count in children with lower respiratory tract infection. Pediatr Infect Dis J 2003; 22:963 967.

44 Schultz KD, Fan LL, Pinsky J, et al. The changing face of pleural empyema in children: epidemiology and management. Pediatrics 2004; 113:1735 1740. Interesting epidemiologic study of empyema over a 10-year period (1993 2002). 45 de Andrade AL, de Andrade JG, Martelli CM, et al. Effectiveness of Haemophilus influenzae b conjugate vaccine on childhood pneumonia: a case-control study in Brazil. Int J Epidemiol 2004; 33:173 181.

46 Whitney CG, Farley MM, Hadler J, et al. Decline of invasive pneunococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003; 348:1737 1746.

26 Toikka P, Iriala K, Juven T, et al. Serum procalcitonin, C-reactive protein and interleukin-6 for distinguishing bacterial and viral pneumonia in children. Pediatr Infect Dis 2000; 19:598 602. 27 Korppi M, Remes S, Heiskanen-Kosma T. Serum procalcitonin concentrations in bacterial pneumonia in children: a negative result in primary healthcare settings. Pediatr Pulmonol 2003; 35:56 61. 28 Shah SS, Alpern ER, Zwerling L, et al. Risk of bacteremia in young children with pneumonia treated as outpatients. Arch Pediatr Adolesc Med 2003; 157:389 392. 29 Lin PL, Michaels MG, Janosky J, et al. Incidence of invasive pneumococcal disease in children 3 to 36 months of age at tertiary care pediatric center 2 years after licensure of the pneumococcal conjugate vaccine. Pediatrics 2003; 111:896 899. 30 Cincinnati Childrens Hospital Medical Center. Evidence-based clinical practice guideline of community-acquired pneumonia in children 60 days to 17 years of age. Cincinnati, OH: Cincinnati Childrens Hospital Medical Center; 2000. pp. 1 11. 31 Jadavji T, Law B, Lebel MH, et al . A practical guide for the diagnosis and treatment of pediatric pneumonia. Can Med Assoc J 1997; 156:S703 S711. 32 Waites KB. New concepts of Mycoplasma pneumoniae infections in children. Pediatr Pulmonol 2003; 36:267 278. 33 Kaplan S. Review of antibiotic resistance, antibiotic treatment and prevention of pneumococcal pneumonia. Paediatr Respir Rev 2004;5(suppl A): S153 S158. Interesting review of the topic. 34 Maneker AJ, Emory MP, Krug SE. Contribution of routine pulse oxymetry to evaluation and management of patients with respiratory illness in a pediatric emergency department. Ann Emerg Med 1995; 25:36 40. 35 Jacobs MR. Worldwide trends in antimicrobial resistance among common respiratory tract pathogens in children. Pediatr Infect Dis J 2003; 22:S109 S119.

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50 Henrickson KJ, Hoover S, Kehl KS, et al. National disease burden of respiratory viruses detected in children by polymerase chain reaction. Pediatr Infect Dis J 2004; 23:S11 S18. 51 OBrien KL, Walters MI, Selliman J, et al. Severe pneumococcal pneumonia in previously healthy children: the role of preceding influenza infection. Clin Infect Dis 2000; 30:784 789. 52 Laundy M, Ajayi-Obe E, Hawrami K, et al. Influenza A community-acquired pneumonia in East London infants and young children. Pediatr Infect Dis J 2003; 22:S223 S227. 53 Wise RP, Iskander J, Pratt RD, et al . Postlicensure safety surveillance for 7-valent pneumococcal conjugate vaccine. JAMA 2004; 292:1702 1710. 54 Klig JE, Chen L. Lower respiratory infections in pediatrics. Curr Opin Pediatr 2003; 15:121 126. 55 Ogra PL. Respiratory syncytial virus: the virus, the disease and the immune response. Paediatr Respir Rev 2004;5(suppl A):S119 S126. Very interesting review of the topic.

56 Willson DF, Landrigen CP, Horn SD, Smout RJ. Complications in infants hospitalised for bronchiolitis or respiratory syncytial virus pneumonia. J Pediatr 2003; 143(suppl):S142 S149.

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57 Fingueras-Aloy J, Carbonell-Estany X, Quero J. Case-control study of the risk factors linked to respiratory syncytial virus infection requiring hospitalisation in premature infants born at a gestational age of 33-35 weeks in Spain. Pediatr Infect Dis J 2004; 23:815 820. 58 Horn SD, Smout RJ. Effect of prematurity on respiratory syncytial virus, hospital resource use and outcomes. J Pediatr 2003;(suppl):S133 S141. 59 Randolph AG, Wang EEL. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract. Cochrane Database Syst Rev 2000; (2):CD000181.

60 Law BJ, Langley JM, Allen U, et al. The Pediatric Investigators Collaborative Network On Infections in Canada study of predictors of hospitalisation for respiratory syncytial virus infection for infants born at 33 through 35 completed weeks of gestation. Pediatr Infect Dis J 2004; 23:806 814. This epidemiologic study of infants 33 35 weeks of gestation identified risk factors for hospitalisation for RSV infection and candidates for palivizumab prophylaxis.