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Pediatr Infect Dis J, 2000;19:3737 Vol. 19, No. 4Copyright 2000 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A.

Etiology and treatment of pneumoniaGEORGE H. MCCRACKEN JR., MD

Background. Lower respiratory tract infec-tions are a common cause of morbidity among children. Among these infections pneumonia isthe most serious illness and can be difficult todiagnose. The etiology of pneumonia is stillpartly unknown, primarily because of difficultyin obtaining adequate samples and lack of reli-able diagnostic methods.

Etiology of pneumonia. Streptococcus pneu-moniae is recognized as an important cause of pediatric pneumonia regardless of age in both

the inpatient and outpatient setting. In devel-oped countries S. pneumoniae probably accountsfor 25 to 30% of cases of pediatric community-acquired pneumonia. Viruses (mostly respira-tory syncytial virus) are responsible for 20% of cases, and Chlamydia pneumoniae and Myco- plasma pneumoniae occur commonly in olderchildren.

Future challenges. Despite the effectiveness of antimicrobial therapy, the emergence of resis-tant bacterial pathogens has resulted in in-creased interest in developing more effectivevaccines. If conjugate pneumococcal vaccines

prove effective at eradicating carriage of pneu-mococci in the nasopharynx, immunization maybe an important tool against the spread of pneu-mococcal disease. Future challenges include im-plementation of effective intervention strategies,production of simple diagnostic tools and devel-opment of effective vaccines.

INTRODUCTIONLower respiratory tract infections are a common

cause of mortality in developing countries 1, 2 and rep-resent a major source of morbidity among childrenworldwide. 3 Although the overall incidence of acuterespiratory infections is similar in developed and developing countries, there are marked differences in the

proportions of patients with specific infections. 4 Theincidence of pneumonia in the developing world is up to10 times higher than that in developed countries suchas the United States (Table 1). Because lower respira-tory tract infections can be associated with severemorbidity, such infections place an enormous burden,both economically and as a public health issue, on theentire health care system. 5

Factors such as the age of the patient, nutritionalstatus and underlying disease have a major impact onmortality, morbidity and microbial etiology associated

with lower respiratory tract infections.6

At present theepidemiologic pattern of pneumonia is also being al-tered by changes in patient characteristics, increasedimmunosuppression and changes in medical practice. 1

There is also an increasing level of resistance to anti-microbial agents by common pathogenic organismssuch as Streptococcus pneumoniae . For these reasonsknowledge of the etiologic agents in different patientpopulations is critical for both the development of vaccines and recommendations regarding treatment. 7

ETIOLOGY OF PNEUMONIA Identifying the etiologic agent(s) responsible for

pneumonia remains a challenge, primarily because of difficulty in obtaining adequate samples for cultureand in differentiating infection from colonization andlack of reliable diagnostic methods. 810 Although sev-eral factors such as age, underlying disease and envi-ronment have a substantial influence on the microbialetiology of pneumonia, 6 S. pneumoniae continues to bean important bacterial cause of pneumonia, especiallyin infants and young children. 11 More recently Chla-mydia pneumoniae and Mycoplasma pneumoniae havebeen recognized as pathogens responsible for mild tosevere lower respiratory tract infections, 11 particularlyin children older than 4 to 5 years. In younger patientspneumonia is mostly caused by respiratory viruses. 12

Bacteria that were previously considered nonpatho-genic for the respiratory tract such as nontypable Haemophilus influenzae and Moraxella catarrhalishave occasionally been implicated in lower respiratorytract infections. 11 Enterobacteriaceae and Staphylococ-cus aureus can cause pneumonia in immunocompro-mised patients. Legionella spp. can also cause sporadicas well as epidemic disease of the lower respiratorytract, although this organism is seen most frequentlyin adults rather than children.

From the Department of Pediatrics, The University of TexasSouthwestern Medical Center at Dallas, Dallas, TX.

Key words: Pneumonia, etiology, treatment, Streptococcus pneumoniae, Chlamydia pneumoniae, Mycoplasma pneumoniae , virus.

Address for reprints: George H. McCracken Jr., M.D., Depart-ment of Pediatrics, The University of Texas Southwestern Med-ical Center, Dallas, TX 75235-9063. Fax 214-648-2961; [email protected].

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Pediatric community-acquired pneumonia. A large number of studies have addressed the etiology of pneumonia in adults, but much less evidence is avail-able on the etiology of pneumonia in children. Recently,however, several large prospective studies have inves-tigated the cause of pediatric community-acquiredpneumonia (CAP) in European and North Americansettings using serology alone or serology combined withculture and PCR to define etiology. 12, 13

A population-based study of Finnish children ( 15years of age) with CAP found serologic evidence (using assays for antibody response to three pneumococcalantigens and for specific pneumococcal immunocom-plexes and conventional antibody tests) of a microbialetiology in 66% of pneumonia patients. 13 Evidence of bacterial infection was found in 51% of cases and viralinfection in 25% of cases. The most frequently found

bacterial causes were S. pneumoniae (28%) and M. pneumoniae (22%) (Fig. 1). The total number of Chla-mydia spp. infections was 14%, of which 68% werecaused by C. pneumoniae (10% overall). In addition,nontypable H. influenzae was identified in 6% and Moraxella catarrhalis in 3% of children. The mostcommon viral agent was respiratory syncytial virus(RSV), which accounted for 21% of cases. Other virusestogether accounted for only 4% of cases, among themadenovirus and parainfluenzae viruses.

Serologic evidence of more than one etiologic agentwas also found in 25% of patients; these consisted of mixed bacterial infection in 16%, mixed viral-bacterialinfection in 10% and mixed viral infection in 1% of cases. 13 The most frequent combinations were S. pneu-moniae with RSV or M. pneumoniae . In general theetiology of pneumonia varied according to age (Table2). Although there were no significant differences in S. pneumoniae etiology in younger and older children(range, 24 to 36%) as determined by antibody andimmune complexes, the occurrence of M. pneumoniaeand C. pneumoniae infections increased with age (51and 35% of cases, respectively, in children 10 years).In contrast viral infections, especially RSV infections,were most common in children 5 years of age. Alto-gether these results indicate that S. pneumoniae is acommon etiologic agent in CAP in children of all ages,and pneumococci are often associated with viral infec-tions (mostly in younger children) and mycoplasmal

and chlamydial infections (usually in older children).Similar results have been reported in the UnitedStates. 12 Using culture, PCR and serology, Wubbel etal. 12 identified etiologic agents in 43% of ambulatorypediatric patients (6 months to 16 years) with CAPpresenting to an emergency medical center in Texas.This study, which also compared antibiotic therapy,attributed bacterial infection to S. pneumoniae in 27%of patients, followed by M. pneumoniae in 7% and C. pneumoniae in 6%. Eleven percent of children hadserologic evidence indicating prior exposure to C. pneu-moniae . The percentage with acute or prior Chlamydiainfection increased with age (5% at 0 to 2 years and

43% at 9 years of age). In addition 20% of patientswere positive for viral disease (mostly RSV). Of thepatients with serologic evidence of acute pneumococcalinfection, 40% had coinfection with a virus, C. pneu-moniae or M. pneumoniae . The evidence of pneumococ-cal infection in 27% of patients in this study is nearlyidentical with the 28% of children reported in theFinnish study. Again, in accordance with the Finnishresults, Wubbel et al. 12 found that S. pneumoniae wasan important cause of CAP in children across all agegroups. Moreover despite different settings and popu-

F IG . 1. Specific etiology in pediatric community-acquiredpneumonia (adapted with permission). 12, 13

TABLE 1. Examples of annual incidence of pneumonia indeveloping and developed countries 4

Location Age ( yr) Annual Incidence per 100

Developed countryChapel Hill, NC 5 3.6Seattle, WA 5 3.0

Developing countriesBangkok, Thailand 5 7.0

Gadchiorli, India 5 13.0Gilgit, Pakistan 5 30.0Maragna, Kenya 5 18.0Haryana, India 1* 40.0

1 30.0Papua New Guinea 1 25.6

* Low birth weight. Normal birth weight.

TABLE 2. Etiology of pediatric community-acquiredpneumonia in Dallas, TX, and Helsinki, Finland, according

to age: percentage of children with specific etiology 12,13

Age (yr)

Etiologic Agent (%)

Streptococcus pneumoniae

Mycoplasma pneumoniae

Chlamydia pneumoniae Viral

Helsinki 13 04 24 4 1 37Dallas 12 33 6 3 28Helsinki 13 59 36 30 13 21Dallas 12 14 7 9 10Helsinki 13 10 16 31 51 35 4Dallas 12 29 14 14 0

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lations, both studies confirmed that the proportion of viral cases decreases and the proportion of Myco- plasma and/or Chlamydia infections increases in rela-tion to age. Serologic studies for diagnosis of pneumo-coccal infec tions are investigational . Thusinterpretation of results must be guarded with respectto determination of incidence rates of pneumococcaldiseases in children.

Two large prospective studies further defined theassociation between Mycoplasma and Chlamydia infec-tions in children with community-acquired pneumo-nia. 14, 15 In one multicenter study pretreatment cul-ture, PCR and serology was performed for C. pneumoniae and M. pneumoniae in patients (6 monthsto 16 years) presenting to geographically diverse cen-ters in the United States. 15 Evidence of infection wasidentified in 46% of patients by pretreatment culture orserology, with 15% of patients having C. pneumoniaeand 30% having M. pneumoniae infection. The trend

toward lower rates of infection with C. pneumoniae and M. pneumoniae in younger children was also observedin this study (Fig. 2). 15 In patients 5 years of age 15%of cases were associated with M. pneumoniae and 9%were associated with C. pneumoniae vs. 42 and 20%,respectively, in patients 5 years of age.

Using similar diagnostic techniques (culture, PCRand serology), C. pneumoniae was documented in 28%and M. pneumoniae in 27% of patients (3 to 12 years of age). 14 Serologic confirmation of infection was observedin 23 and 53% of patients with documented C. pneu-moniae and M. pneumoniae infection, respectively.Consistent with the findings of other studies, younger

children had fewer infections caused by C. pneumoniaeand M. pneumoniae .Etiology of acute lower respiratory tract infec-

tion in hospitalized children. To investigate the

etiology of acute lower respiratory tract infection inchildren (mean, 1.75 years of age) requiring hospital-ization, Nohynek et al. 7 used both conventional micro-biologic methods and a range of serologic methods(bacterial antibody assays and detection of viral andbacterial antigens and nucleic acid). The study estab-lished an etiologic diagnosis in 70% of cases. Twenty-five percent of episodes were found to be associatedwith a bacterial agent and 25% with a viral agent; in20% of episodes a mixed infection was diagnosed. Among the bacterial agents nontypable H. influenzaeand S. pneumoniae were the most common organisms(17 and 16% of all patients, respectively). Moraxellacatarrhalis was found in 7% and M. pneumoniae in 9%of the cases. Of the viral agents RSV was encounteredin 28% of patients. The remaining viral agents wereadenovirus, influenzae A or B and parainfluenzaetype 1.

Although this study involved only hospitalized pa-

tients, the findings support the notion that bacterialetiologies of pneumonia increase with age, whereas viral diseases decrease (Fig. 3). 7 For example S. pneu-moniae was seen in all ages and M. pneumoniae in allages except infants, although the proportional roles of both of these etiologic agents increased with age. Withregard to viruses RSV and adenovirus were morecommon in infants and young children.

MANAGEMENT OF PNEUMONIA

For the management of pneumonia, it is importantto define the likely etiology and grade the severity of the infection. 1 Ideally treatment should be directedagainst the identified pathogen, but this is impracticalin pediatric patients. 2 In the past, however, there havebeen only fragmentary data on culture, serology andPCR results in pediatric pneumonia in relation toclinical course and antimicrobial therapy. 12 More re-cently three studies, which defined the etiology of CAPin children, also compared the efficacy of newer mac-rolides vs. conventional therapy using some or all of

F IG . 2. Role of M. pneumoniae and C. pneumoniae in pediatriccommunity-acquired pneumococcal pneumonia according to age(adapted with permission). 14, 15

F IG . 3. Specific etiology in pediatric pneumonia requiring hos-pitalization (adapted with permission). 7

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these diagnostic methods. 12, 14, 15 Taken in aggregatethe evidence from these comparative studies indicatesthat treatment with traditional antimicrobials, such asamoxicillin alone or amoxicillin/clavulanate or erythro-mycin, or with newer macrolides, including azithromy-cin and clarithromycin, produce satisfactory rates of clinical cure and are similarly effective for the treat-ment of CAP in children.

Treatment of antimicrobial-resistant pneumo-nia. Despite progress in the management of pneumo-nia in children, the emergence of multidrug-resistantpathogens continues to pose challenges for the clini-cian. In particular drug-resistant S. pneumoniae is agrowing concern because of the importance of thispathogen in infections of the respiratory tract in in-fants and children. 16 Recently the effects of increasedantimicrobial resistance on the management of pediat-ric pneumonia were assessed in a US-based, multi-center, retrospective study that compared the treat-

ment and outcome of patients with pneumoniaattributed to penicillin-susceptible or -nonsusceptible S. pneumoniae .17 Of the 257 isolates obtained in thisstudy, 9% were penicillin-intermediate and 6% wereresistant to penicillin. 17 In addition 3% were interme-diate to ceftriaxone and 2% were resistant to ceftriax-one. The types of antimicrobial regimens were highly variable in this retrospective analysis; however, 80% of patients treated as outpatients and 48% of inpatientsreceived a parenteral second or third generation ceph-alosporin followed by a course of an oral antimicrobialagent. Overall the clinical presentation and outcome of therapy did not differ significantly between patientswith penicillin-susceptible vs. those with nonsuscep-tible isolates of S. pneumoniae . However, it is likelythat a majority of patients from whom pneumococciwere recovered from blood or pleural fluid culturesreceived initial treatment with intravenous antibiotics.This route would result in excellent eradication of eventhe most resistant pneumococcus, whereas oral antibi-otic therapy may not be as effective.

A prospective study conducted in South Africa fur-ther defined the optimal therapy and clinical responsein penicillin-resistant bacteremic pneumococcal infec-tions in children. 18 Approximately three-fourths of the

children in this study had pneumococcal pneumonia.Patients were treated with a number of different dailyantimicrobial regimens, including oral beta-lactamtherapy or intravenous penicillin G (100 000 units/kg),ampicillin (100 mg/kg), amoxicillin (40 to 60 mg/kg),cefuroxime, cefotaxime or ceftriaxone (all 80 to 100mg/kg), or vancomycin (40 mg/kg). After 48 h of therapy64% of penicillin-susceptible infections showed im-provement compared with 60% of penicillin-resistantinfections. By Day 7 of therapy 93% of children withpenicillin-susceptible pneumococcal pneumonia

treated with ampicillin or an equivalent beta-lactamhad improved compared with 88% with resistant infec-tions.

Role of vaccines in prevention of pneumonia.In spite of the effectiveness of standard antimicrobialtherapy, effective vaccination against pneumococcalinfections is desirable not only because of the continuedemergence of antibiotic-resistant strains but also be-cause prevention of pneumococcal disease is the ulti-mate goal. 19 The existing capsular polysaccharide vac-cine is neither immunogenic nor protective in young children, 19 and it is not recommended for use in thoseyounger than 2 years. 20 Given the immunogenic natureof S. pneumoniae proteins, however, these moleculesare currently being investigated as potential vaccinecandidates. 19, 20 If conjugate pneumococcal vaccinesalso prove to eradicate carriage, immunization may bean important weapon against the spread of pneumo-coccal infection. 21 Nevertheless such vaccines will rep-

resent only a partial solution to the management of pediatric pneumonia because of the complex and variedetiology of the disease.

To date, clinical trials of first generation pneumococ-cal conjugate vaccines have shown that covalent cou-pling of pneumococcal capsular polysaccharides to pro-tein carriers improves the immunogenicity of thepolysaccharides. 19 Most recently the efficacy of a pneu-mococcal conjugate vaccine was assessed in a large,randomized, double blinded, controlled clinical trial ina multiethnic pediatric population in Northern Califor-nia. 22 Primary immunization occurred at 2, 4 and 6months of life follwed by a booster dose at 12 months.

Preliminary results indicate that the vaccine is effec-tive in reducing the incidence of pneumonia caused by S. pneumoniae with capsular serotypes covered by the vaccine (4, 6B, 9V, 14, 18C, 19F, 23F).

CONCLUSIONThe causes of acute lower respiratory tract infec-

tions, including pneumonia, are still incompletely de-fined, primarily because of the difficulty in obtaining adequate samples for testing and the lack of reliablediagnostic methods. 8, 10 This is an important shortcom-ing, because knowledge of etiologic agents in differentpatient populations and settings is crucial for both thedevelopment of vaccines and recommendations regard-ing treatment. 7 In recent years, however, newer diag-nostic methods, such as serology and PCR testing, havecomplemented the use of blood and pleural fluid cul-tures to assess the etiology of pneumonia. In the futureimmunization with conjugate pneumococcal vaccinesmay become an important means of reducing the inci-dence of pneumococcal infections in children. Althoughmuch progress has been made in defining the etiologyand treatment strategies for pediatric pneumonia, re-search is still needed to determine the spectrum of

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organisms involved and to delineate the pathogenesisof infection. The challenge for the future is to evaluateand implement effective intervention strategies, pro-duce simple and inexpensive diagnostic tools and de- velop vaccines that will be effective in the targetpopulations.

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Bull WHO 1978;56:48198.4. Pechere JC, ed. Community-acquired pneumonia in children.

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8. Isaacs D. Problems in determining the etiology of community-acquired childhood pneumonia. Pediatr Infect Dis J 1989;8:1438.

9. Lode H, Schaberg T, Raffenberg M, Mauch H. Diagnosticproblems in lower respiratory tract infections. J AntimicrobChemother 1993;32(Suppl A):2937.

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17. Tan TQ, Mason EO Jr, Barson WJ, et al. Clinical character-istics and outcome of children with pneumonia attributable topenicillin-susceptible and penicillin-nonsusceptible Strepto-coccus pneumoniae. Pediatrics 1998;102:136975.

18. Friedland IR. Comparison of the response to antimicrobialtherapy of penicillin-resistant and penicillin-susceptiblepneumococcal disease. Pediatr Infect Dis J 1995;14:88590.

19. Kayhty H, Eskola J. New vaccines for the prevention of pneumococcal infections. Emerg Infect Dis 1996;2:28998.

20. Briles DE, Tart RC, Swiatlo E, et al. Pneumococcal diversity:considerations for new vaccine strategies with emphasis onpneumococcal surface protein A (PspA). Clin Microbiol Rev1998;11:64557.

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