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The 1918-1919 Influenza pandemicspread worldwide with remarkablespeed. Approximately 500 million peoplewere infected, and the death toll was be-tween 50 and 100 million worldwide.

It is hypothesized that a major causeof morbidity and mortality may not havebeen the viral pneumonitis, but the bacte-rial superinfection of the susceptible post-influenza lung. Here, we will review therole of bacterial coinfection in past influ-enza pandemics, and how it relates to thecurrent H1N1 strain of 2009-2010.

MORBIDITY AND MORTALITY:LESSONS FROM HISTORY

A number of scientific accounts elabo-rated on the role of bacterial superinfec-tion in the 1918-1919 influenza pandemic.In 1921, Opie et al.1 published an investi-gation of causes of respiratory diseases inmilitary personnel, investigating an epi-demic of influenza affecting 22.7% of morethan 50,000 personnel at Camp Pike, Ar-kansas, with an incidence of pneumonia of2.9% which was observed to follow oneweek after the influenza outbreak. Theexcess mortality, 466 deaths, was attributedto pneumonia: “In a civil hospital there isoften great difficulty in deciding, even inthe presence of an epidemic, if death frompneumonia is the result of influenza, but atCamp Pike the relation of the heighteneddeath rate to the epidemic has excluded allsave a trivial error in determining the rela-tion of fatal pneumonia to influenza.”

The group’s collection of microbiologi-cal and pathological data emphasizes thepervasive presence of Bacillus influenzae(Haemophilus influenzae) as well as pneumo-cocci, but makes mention of other Strepto-coccus species, Micrococcus catarrhalis(Moraxella catarrhalis) and even Bacillus coli(E. coli) as some of the most frequently foundpathogens. The isolation of H influenzae wasso frequent, in almost 80% of cases, that itwas thought to be “constantly present.” Pat-terns of bronchitis, bronchopneumonia, andlobar pneumonia were identified in autopsyinvestigation, and microscopic examinationof the lung described destruction of the epi-

Post-influenza Pneumonia:Everything Old Is New Again

Melina Irizarry-Acosta, MD, and Yoram A. Puius, MD, PhD

�thelium as “changes in the bronchial walls[that] destroy the defences against invasionby microorganisms.” The authors observedthat these findings were similar to previousepidemics, most notably a pandemic of1889-1890.

These themes recurred in a study pub-lished by Vaughan in the same year.2 Com-paring the 1918-19 pandemic with previ-ous outbreaks of influenza, he stated: “Thesecondary invaders of pathogenic impor-tance are the various forms of the strepto-coccus and pneumococcus, the meningo-coccus, the staphylococcus, and probablythe tubercle bacillus and the influenza ba-cillus. In the last epidemic as in that of thirtyyears previously, the chief complicationswere bronchitis and pneumonia..”

Also in 1921, McCallum describedthe pathology of post-influenza pneumo-nia3, making similar pathological and bac-teriological observations from cases seenin two military camps as well as at JohnsHopkins hospital. In contrast with otherscientists that regarded Bacillus influenzaeas a primary pathogen in the pandemic,he states that “[n]o direct information hasbeen gained as to the nature of the infec-tive agent which...causes the epidemic dis-ease influenza.”

The actual causes of influenza-relateddeaths have been under discussion amongthe scientific community. One importantaspect of the 1918-1919 pandemic, notalways seen in other pandemics, was the“W-shaped” death curve, in which influ-enza mainly targeted infants, young adults(ages 20-40) and the elderly.

A modern rationale for the high num-bers of young and otherwise healthy peopleamong the casualties is the “cytokine storm,”which leads to respiratory distress syndromethrough a hemorrhagic alveolitis. The patho-genic potential of the inflammatory responsemay have been more severe in pandemic com-pared to non-pandemic strains, which mayexplain the difference in mortality. Supportfor this theory has been found in animalmodels of infection with a reconstructed1918 virus, which demonstrated more se-vere lung pathology, higher mortality, and

greater activation of pro-inflammatory andcell-death pathways.4 An alternative hypoth-esis is simply that older patients had immu-nological memory to a related strain whichhad circulated in 1889, whereas the youngersegment of the population lacked these pro-tective antibodies5.

Other reports, however, describe themortality from primary pandemic influenzapneumonia as relatively uncommon.Brundage and Shanks6 discuss the accountsof fatalities in the US, UK and NewZealand. In all three regions the time ofdeath was highly variable, and that thosewith longer duration of illness were con-sidered to have secondary bacterial infec-tions. H. influenzae, pneumococci,hemolytic streptococci and on occasion, sta-phylococci were considered the main cul-prits. In 2008,7 they went on to suggest thatthe actual infections with influenza wereself- limited, but paving the way for lethalbacterial pneumonias, proposing the “se-quential infection” hypothesis.

Morens and coworkers8 reviewed avast amount of data from the 1918-1919pandemic which support the role of bacte-rial superinfections in the morbidity andmortality of pandemic influenza. Theyevaluated pathological, epidemiological,and microbiological reports published dur-ing the pandemic, encompassing a total of8398 postmortem examinations. Theythen went on to directly evaluate samplesobtained during autopsy from 58 influenzavictims during the 1918-19 pandemic.

Lung tissue blocks obtained from au-topsies performed during the pandemic,and preserved by the US military showedthat, in virtually all cases, there was com-pelling histological evidence of severe acutebacterial pneumonia, either as predomi-nant pathology or in conjunction with fea-tures now known to be associated with in-fluenza virus infection: desquamation ofrespiratory epithelium of tracheobronchialand bronchiolar tree; dilation of alveolarducts, hyaline membranes, evidence ofbronchial and/ or bronchiolar epithelialrepair. There were also changes consistentwith either pneumococcal or streptococcal

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pneumonia, and some had evidence of sta-phylococcal pneumonia, in the form ofmultiple small abscesses. In virtually all casesbacteria were seen in massive numbers.

Published articles from the pandemicperiod discuss postmortem examinationfindings as well as epidemiological data.Most agree that without secondary bacte-rial pneumonia most patients with influenzamay have indeed recovered. There is aprevalent description of desquamative tra-cheobronchitis and bronchiolitis as the pri-mary lesion of early severe influenza- asso-ciated pneumonia. This was associated witha sloughing of bronchiolar epithelial cellsto the basal layer, hyaline membrane for-mation in alveolar ducts and alveoli, andductal dilatation, as described by Opie etal.1 in 1921. A primary “panbronchitis”gave way to an aggressive invasion of bacte-ria throughout the denuded bronchial epi-thelium. In the most severe cases, zones ofvasculitis, capillary thrombosis and necro-sis surrounding the bronchiolar damagewere noted. Despite this, there was alsonoted a “histopathological asynchrony,”1

with early epithelial regeneration, capillaryrepair and occasional fibrosis even in themost fulminant cases. This may be a reasonwhy, despite the severe damage to the tra-cheobronchial tree that is generally ascribedto influenza-associated pneumonias, thereare few reports of chronic respiratory dam-age noted in survivors.

Blood cultures were positive in 70.3%of cases, mostly growing knownpneumopathogens such as Streptococcuspneumoniae and other streptococci. Thesewere also the primary pathogens reportedon cultures of pleural fluid and lung tissue.During the 1918-19 pandemic the inci-dence of Staphylococcus aureus was low, anda significant percentage of identified bac-teria were nonpneumopathogens such asviridans group streptococci, E. coli, Kleb-siella and H. influenzae, which were seenin coinfection with knownpneumopathogens. Bacillus (laterHaemophilus) influenzae was the primarycoinfector in early symptomatic influenzaand was associated with diffuse bronchitisand bronchiolitis. Outbreaks of meningo-coccal pneumonia were also documented.

An interesting alternative hypothesisfor the distribution of influenza-relateddeaths is provided by Starko. 9 She notesthat the doses in which aspirin was pre-scribed at the time are now known to be

toxic, and may have resulted in pulmonarytoxicity. Salicyclate overdose may have re-sulted in pulmonary edema, impairmentof mucociliary clearance and increase inprotein levels may have predisposed thesepatients to secondary pulmonary infections.

PROMINENT PATHOGENS:PNEUMOCOCCUS AND S. AUREUS

Two pathogens that deserve specialattention for their role in post-influenzapneumonia are Streptococcus pneumoniaand Staphylococcus aureus. These are par-ticularly noteworthy because they occurfrequently in the role of superinfectingpathogen, and their virulence often resultsin significant morbidity and mortality.

In their review of historical culturedata of specimens from the 1918-1919pandemic, Morens et al.8 S. pneumoniaewas generally the single most commonly iso-lated organism, appearing in 1235/5266positive lung tissue cultures (23.5%), 509/1887 positive blood cultures (27.0%), and263/1245 pleural fluid cultures (21.1%).Brundage and Shanks7 cited much of thesame data, and argued that the mediantime to death of 7-11 days in military popu-lations correlated with pneumococcal bac-terial superinfection. Klugman et al.10 gen-erated a startling graph showing that thedistribution of days of illness before deathfrom influenza-related pneumonia during

the 1918-1919 pandemic precisely repro-duced that of untreated pneumococcalpneumonia in the 1920s and 1930s, lead-ing to their conclusion that “similar timesto death provide additional evidence thatthe in?uenza-related pneumonia deathsduring the 1918 influenza pandemic werelargely due to the pneumococcus.”

In 1949, after the influenza virus hadalready been identified as the etiologicagent of the disease, Maxwell et al.11 alsonoted the particular role of pneumococ-cus in coinfection. They studied cases ofknown bacterial pneumonia from 1946-7, spanning a time when influenza A wasprevalent in the community, as well as dur-ing a time described as an “interpepidemicperiod.” They found that “there was a si-multaneous infection with pneumococciand influenza virus in about one-half of thehuman cases of lobar pneumonia studiedduring an influenza epidemic,” suggestingthat “bacterial pneumonia is in some wayrelated to recent or concurrent infectionwith influenza virus.”

Studies of later epidemics highlightthe pneumococcus as well: patients con-firmed to have epidemic influenza inStockholm12 (1969-70, 1971-72) showedbacteriologic and/or serologic evidence ofpneumococcal infection in 12/116 pa-tients (10%) in 1969-1970, and 37/176patients (21%) in 1971-72.

A makeshift emergency hospital at Camp Funston, Kansas, caring for soldiers sickened by the1918 flu, as mentioned by Opie et al.1 (Credit: The National Museum of Health and

Medicine, Armed Forces Institute of Pathology, Washington, D.C. Image number NCP 1603)

206MEDICINE & HEALTH/RHODE ISLAND

However, since the seasonality ofpneumococcal infection mirrors that ofseasonal influenza, it has been unclearwhether the correlation between influenzacirculation and invasive pneumococcaldisease has been causal. The most recentstudy of this association, using data in theUnited States from 1995-2006, found thatin?uenza circulation was associated with11%–14% of pneumococcal pneumoniaduring periods of elevated in?uenza cir-culation, with rates of 5%–6% overall.13

Vaccination of children with aheptavalent protein–polysaccharide con-jugate and adults with a 23-valent polysac-charide vaccine has led to a decline in in-vasive disease. Pediatric vaccination seemsto be associated with a decreased incidencein viral pneumonia due to influenza A, aswell as other viral etiologies such as RSV,parainfluenza, and adenovirus, presum-ably through a “synergism between viraland pneumococcal infection.” 14

The role of S. aureus had not histori-cally been as significant. Morens et al.8 alsoidentified S. aureus in autopsy cultures from1918-1919, in 427/5266 (8.1%) of posi-tive cultures of lung tissue, and 68/1887(3.6%) of positive blood cultures, and 59/1245 (4.7%) of pleural fluid cultures.During the Hong Kong influenza epidemicof 1968-1969, the bacterial etiology ofpneumonia admissions to Grady Memo-rial Hospital shifted: 25.9% of allpneumonias included S. aureus, comparedto 10.2% from the previous year14, al-though the actual rate of true influenza-S.aureus coinfection was not documented.

However, beginning in 2003, S.aureus, most notably community-acquiredmethicillin-resistant S. aureus (CA-MRSA),had been noted to be a significant cause ofinfluenza-associated bacterial pneumonia asreported in a small case series15, with a casefatality rate of 4/15 (26.7%), generally inpeople without comorbidities. A larger se-ries of cases from the 2006-2007 influenzaseason16, 17 confirmed that S. aureus pneu-monia occurred in younger patients with-out comorbidities, the strains involved werepredominantly CA-MRSA (28 out of 31S. aureus isolates), and documented influ-enza virus coinfection was associated with aworse outcome. Worse outcomes of CA-MRSA-influenza coinfection have also beenseen in the pediatric population.18

CA-MRSA pneumonia is oftencharacterized by high fever, hypotension,

rapid progression, and a requirement forventilator support, often with multilobarinfiltrates or cavitation.19 Since it has nowbeen firmly established as a major etio-logical agent of post-influenza pneumo-nia, it is worth considering empirictherapy for MRSA in any patient with asevere pneumonia fitting this presenta-tion.20 Vancomycin has long been con-sidered the drug of choice for MRSApneumonia; however, several recent ret-rospective studies and pharmacologicadvantages of linezolid – greater pen-etration into the lung, the ability to shutdown production of toxins such as thePanton-Valentine Leukocidin — supportthe empiric use of linezolid.19

THE CURRENT H1N1 PANDEMICThe role of superinfection in the cur-

rent H1N1 pandemic (2009-2010) hasbeen extensively studied. The pathologyof H1N1 influenza infection has overallbeen similar to that of prior pandemics,21,22

with findings including diffuse alveolardamage, pulmonary hemorrhage, andnecrotizing bronchiolitis. These results arethought to be due to some combinationof direct damage from the virus and thehost inflammatory response.

Of interest is the lower fraction ofcases in which bacterial superinfectionhave been evident on pathology: Therewas no clear evidence of bacterial infec-tion in a series of 5 confirmed H1N1 fa-talities from Mexico21, and only 3 of 21patients had bacteria seen on histologyin a series from Brazil.22 However, anti-biotics were given to many of these pa-tients, possibly decreasing the amount ofbacteria detectable on histochemistryalone compared to prior eras.

Other efforts to determine the rela-tive contributions of viral pneumonitisand bacterial superinfection included astudy of the immunomodulatory effectof H1N1 on the host23. Unsurprisingly,pro-inflammatory cytokines were el-evated in the serum of infected patients,

much with other strains of influenza.However, when peripheral blood mono-nuclear cells from H1N1-infected pa-tients were stimulated with S.pneumoniae, they produced decreasedamounts of TNFα and IFNγ, suggestinga defective cytokine response which maypredispose to superinfection.

The use of molecular methods as anadjunct to traditional culture techniquesadds another dimension to the estimationof the epidemiology of superinfection.On one hand, it can be argued that it en-hances the sensitivity of culture techniques,which is especially important when theroutine use of broad-spectrum antibioticsmay cause false-negative results, both inculture and in lung pathology. On theother hand, the high sensitivity may re-sult in colonizing organisms in low colonycounts (e.g. as in chronic bronchitis) be-ing counted as true pathogens.

With this caveat in mind, the mostpublicized study of bacterial coinfectionin H1N1 found that, by a combinationof PCR and immunohistochemistry, acoinfecting organism could be identifiedin 22/74 fatal cases24. The distribution oforganisms was comparable to that ob-served in prior influenza superinfections:S. pneumoniae (45%), S. pyogenes (27%),S. aureus (32%), Streptococcus mitis (9%),H. influenza (5%), and multiple organ-isms (18%). (So far, the literature con-tains only one published report of a de-finitive coinfection with H1N1 and CA-MRSA.) The editorial note in the studyconcludes that “[t]he findings in this re-port indicate that, as during previous in-fluenza pandemics, bacterial pneumoniais contributing to deaths associated withpandemic H1N1” but cautions that “theresults cannot be used to assess the preva-lence of bacterial pneumonia among pa-tients who have died from pandemicH1N1.” A series of 36 pediatric deathsalso showed significant coinfections withS. aureus, S. pneumoniae, and other Strep-tococcus species25.

A molecular study of 199 cases ofH1N1 in Argentina allowed for the iden-tification of coinfecting bacteria and virusesby PCR of nasopharyngeal swabs26. Thisstudy provided the best estimate of super-infection so far, detecting at least one addi-tional potential pathogen in 152/199(76%) of cases. Clinical outcomes seen inthis molecular survey suggested that

The pathology ofH1N1 influenza

infection has overallbeen similar to thatof prior pandemics.

207VOLUME 93 NO. 7 JULY 2010

coinfection with S. pneumoniae (62 cases)was associated with a worse prognosis. Ad-ditional bacteria identified included H.influenzae (104 cases), methicillin-sensitiveS. aureus (35), and MRSA (6), as well as asmaller number of cases of Klebsiellapneumoniae, Acinetobacter baumannii, andSerratia marcescens. These methods alsoallowed for the identification of coinfectingrespiratory syncytial viruses (12 cases), rhi-noviruses (5), and coronaviruses (3), add-ing an entire additional dimension to thepossible causes of superinfection.

Given the prominent role of bacterialsuperinfection in morbidity and mortality,the fraction of critically ill H1N1 patientswith evidence of bacterial pneumonia islower than might be expected. Surveys ofcritically ill patients with H1N1 inCanada27, Mexico28, and Spain29 docu-mented a relatively low rates of detectionof bacterial pneumonia after ICU admis-sion, respectively 24.4%, 8%, and 3%. Bac-terial pneumonia was not noted to be asso-ciated with a poorer outcome, but overallthe use of empiric antibiotics was very high.Nosocomial pneumonia has also been notedin these studies28, and should be consid-ered for any hospitalized patient not im-proving on appropriate therapy.

IMPLICATIONS FOR MANAGEMENTThe practical application of these

data to the current H1N1 pandemic ul-timately comes down to a few clinicalquestions: which H1N1 patients havepost-influenza pneumonia, how shouldthey be managed, and how do we pre-vent or prepare for it?

A textbook description of post-influ-enza bacterial pneumonia is as follows:“The patients (most often older adults orthose with chronic pulmonary, cardiac,and metabolic or other disease) have aclassic influenza illness followed by a pe-riod of improvement that lasts usually 4to 14 days. Recrudescence of fever is as-sociated with symptoms and signs of bac-terial pneumonia such as cough, sputumproduction, and an area of consolidationdetected on physical examination andchest radiograph.”30

Specifically pertaining to H1N1,Wright et al.31 also suggest that second-ary bacterial pneumonia is more likely tobe characterized by a secondary fever af-ter a period of defervescence, a positivesputum Gram stain and/or culture, in-

creased white blood cell count, and a lateronset of respiratory compromise.

There are, however, difficulties withapplying these generalizations, especiallyin the setting of the current H1N1 pan-demic:

• Cases of infection and death appearto be concentrated in younger pa-tients. Older age may reduce thelikelihood of H1N1 infection, pos-sibly due to exposure to related vi-ruses earlier in life32.

• No data are available to confirm thetiming of bacterial infection de-scribed above, and bacteria are of-ten cultured on first presentationwith H1N1.

• Chest radiography findings inH1N influenza may be unilateralor bilateral, may include consolida-tions or ground glass opacities33, andthis cannot reliably exclude bacte-rial pneumonia

Cunha raises issues as to whetherantibiotics should be withheld in H1N1patients unlikely to be superinfected,since it may be rarer than previouslythought34, 35. He then goes on to pro-pose that patients without lobar or seg-mental infiltrates on chest radiographymay not need antibiotics36.

So, who is to be treated for bacterialsuperinfection? It is, perhaps, a tautologyto state that a patient who meets criteriafor diagnosis of community-acquiredpneumonia20 or healthcare-associatedpneumonia37 should be treated as such.

Patients who are not ill enough tobe hospitalized may be considered fororal antibiotic therapy (see Cilley andSilverblatt, in this issue). Superinfectionwith atypical organisms such as Myco-plasma, Chlamdyophila, and Legionellaspecies is rare and need not be a focus ofthe regimen, although tetracyclines,macrolides, or fluoroquinolones maycover them incidentally.

Patients ill enough to be hospitalizedmay be considered for broader-spectrumantibiotics, and risk-stratified for resistantorganisms. The high prevalence of CA-MRSA in influenza cases, coupled with thehigh morbidity and mortality, make it es-sential that critically ill patients receivetherapy to cover MRSA, such as linezolid

or vancomycin.Of course, the optimal method of

managing post-H1N1 bacterial pneumo-nia is prevention. Thus, vaccination againstboth influenza and S. pneumoniae are es-sential components of preventive healthcare, as are all age-appropriate vaccinations.

REFERENCES1. Opie EL, Blake FG,et al. Epidemic Respiratory

Disease. The Pneumonias and Other Infections ofthe Respiratory Tract Accompanying Influenza andMeasles. St. Louis: C.V. Mosby Company; 1921.

2. Vaughan WT. Influenza: An EpidemiologicStudy. Baltimore, MD: Amer J Hygiene; 1921.

3. McCallum WG. Pathological Anatomy of Pneu-monia Associated with Influenza.The JohnsHopkins Press; 1921.

4. Kobasa D, Jones SM, et al. Nature 2007;445:319-23.5. Ahmed R, Oldstone MB, Palese P. Nat Immunol

2007;8:1188-93.6. Brundage JF, Shanks GD. J Infect Dis

2007;196:1717-8; author reply 8-9.7. Brundage JF, Shanks GD.. Emerg Infect Dis

2008;14:1193-9.8. Morens DM, Taubenberger JK, Fauci AS. J Infect

Dis 2008;198:962-70.9. Starko KM. Clin Infect Dis 2009;49:1405-10.10. Klugman KP, Astley CM, Lipsitch M. Emerg In-

fect Dis 2009;15:346-7.11. Maxwell ES, Ward TG, Van Metre TE, Jr. J Clin

Invest 1949;28:307-18.12. Jarstrand C, Tunevall G. Scand J Infect Dis

1975;7:243-7.13. Walter ND, Taylor TH, et al. Clin Infect Dis

2010;50:175-83.14. Schwarzmann SW, Adler JL, et al. Arch Intern Med

1971;127:1037-41.15. Hageman JC, Uyeki TM, et al. Emerg Infect Dis

2006;12:894-9.16. Severe methicillin-resistant Staphylococcus aureus

community-acquired pneumonia associated withinfluenza—Louisiana and Georgia, December2006-January 2007. MMWR Morb Mortal WklyRep 2007;56:325-9.

17. Kallen AJ, Brunkard J, et al. Ann Emerg Med2009;53:358-65.

18. Reed C, Kallen AJ, et al. Pediatr Infect Dis J2009;28:572-6.

19. Hidron AI, Low CE, et al. Lancet Infect Dis2009;9:384-92.

20. Mandell LA, Wunderink RG, et al. InfectiousDiseases Society of America/American ThoracicSociety consensus guidelines on the managementof community-acquired pneumonia in adults.Clin Infect Dis 2007;44 Suppl 2:S27-72.

21. Soto-Abraham MV, Soriano-Rosas J, et al. NEJM2009;361:2001-3.

22. Mauad T, Hajjar LA, et al. Am J Respir Crit CareMed 2010;181:72-9.

23. Giamarellos-Bourboulis EJ, Raftogiannis M, etal. PLoS One 2009;4:e8393.

24. Bacterial coinfections in lung tissue specimens fromfatal cases of 2009 pandemic influenza A (H1N1)- United States, May-August 2009. MMWR MorbMortal Wkly Rep 2009;58:1071-4.

25. Surveillance for pediatric deaths associated with2009 pandemic influenza A (H1N1) virus infec-tion - United States, April-August 2009. MMWRMorb Mortal Wkly Rep 2009;58:941-7.

211VOLUME 93 NO. 7 JULY 2010

Community-Acquired Pneumonia In ChildrenPenelope H. Dennehy, MD

�Community-acquired pneumoniaCommunity-acquired pneumoniaCommunity-acquired pneumoniaCommunity-acquired pneumoniaCommunity-acquired pneumonia(CAP) is one of the most common infec-tions encountered in pediatrics, with anannual incidence of approximately 40cases per 1000 children in NorthAmerica.1 Despite its frequency, CAP inchildren remains difficult to diagnose,evaluate, and manage because manypathogens may be responsible, co-infec-tions occur frequently, clinical featuresmay vary widely, and laboratory testingto support the diagnosis is limited.

ETIOLOGY OF COMMUNITY-ACQUIRED PNEUMONIA

Many pathogens cause pneumonia inchildren, including bacteria, viruses, andfungi. Because culture of lung parenchymaor pleural fluid requires an invasive proce-dure, most studies in children have reliedon indirect methods such as rapid viral test-ing or polymerase chain reaction assay(PCR) on upper respiratory tract secretions,serology, and/or blood culture to identifythe infecting pathogen. Studies that includean intensive search for etiology in hospital-ized children with pneumonia identified alikely cause in up to 85% of cases, but anetiologic diagnosis is made in a muchsmaller proportion of outpatient cases. Dueto a reluctance to perform invasive diag-nostic procedures on young children, theepidemiology of CAP in children remainspoorly defined.

The most common etiologies of pneu-monia vary with the age of the patient (Table1). In neonates, group B streptococcus andgram-negative enteric bacteria are the mostcommon bacterial pathogens and are gen-erally acquired through vertical trans-mission.2 Viral pneumonia with cytome-galovirus and herpes simplex virus shouldbe considered even without a suspiciousmaternal history. Chlamydia trachomatis in-fection, once a common cause of infectionin infants, has become much less commonthrough prenatal screening and treatmentof maternal infection.

The most common cause of bacterialpneumonia in children older than 3 weeksis Streptococcus pneumoniae. Before thepneumococcal vaccine was introduced in2000, Streptococcus pneumoniae accountedfor 13 % to 28% of pediatric CAP.3 Post-licensure epidemiologic studies show thatall-cause pneumonia hospitalizations in chil-dren under age 2 in the United States havedecreased by 39%, providing further evi-dence of the role of pneumococcus as amajor cause of childhood CAP.1, 4, 5

Group A streptococcus, Staphylococ-cus aureus, Haemophilus influenzae type b,and Moraxella catarrhalis are less commonbacterial causes of pneumonia. The organ-isms Mycoplasma pneumoniae andChlamydophila pneumoniae (formallyChlamydia pneumoniae) commonly causeCAP in school-age children and adoles-

cents, although they may infect preschool-age children more commonly than gener-ally recognized. In one study, the age ofpatients with atypical infection ranged from9 months to 13 years, with 47% of infec-tions occurring in those aged younger than5 years.6 Bordetella pertussis should be con-sidered in young or unimmunized childrenwith paroxysmal cough, whoop, posttussiveemesis, or apnea. Tuberculosis should alsobe considered if the patient has suggestiveclinical signs, has recently been to an en-demic area, or has had contact with an in-dividual with active tuberculosis.

Most cases of CAP in preschool-agechildren are caused by viruses, includingrespiratory syncytial virus (RSV), aden-ovirus, parainfluenza 1, 2 and 3, influenzaA and B, human metapneumovirus, andrhinoviruses. Preceding viral illness isthought to play a part in the pathogenesisof bacterial pneumonia. A study byAmpofo and colleagues recently showeda strong temporal association between con-firmed viral respiratory illness with RSV,influenza, and human metapneumovirusand invasive pneumococcal disease over sixwinter seasons.7 Although their data donot prove causation, rates of invasive pneu-mococcal disease rose in close associationwith the diagnosis of respiratory viral ill-nesses each winter season.

Mixed infections may occur in 30%to 50% of children with CAP, including

26. Palacios G, Hornig M, et al. PLoS One2009;4:e8540.

27. Kumar A, Zarychanski R, et al. Critically ill pa-tients with 2009 influenza A(H1N1) infectionin Canada. JAMA 2009;302:1872-9.

28. Gomez-Gomez A, Magana-Aquino M, et al. EmergInfect Dis 2010;16:27-34.

29. Rello J, Rodriguez A, et al. Crit Care2009;13:R148.

30. Treanor JJ. Chapter 165: Influenza Viruses, Includ-ing Avian Influenza and Swine Influenza. In: MandellGL, Bennett JE, Dolin R, eds. Mandell, Douglas,and Bennett’s Principles and Practice of InfectiousDiseases. 7 ed: Churchill Livingstone; 2009.

31. Wright PF, Kirkland KB, Modlin JF. NEJM2009;361:e112.

32. Fisman DN, Savage R, et al. NEJM 2009;361:2000-1.33. Agarwal PP, Cinti S, Kazerooni EA. AJR Am J

Roentgenol 2009;193:1488-93.34. Cunha BA. S Int J Antimicrob Agents 2009.

35. Cunha BA. J Clin Virol 2009.36. Cunha B, Syed U, Strollo S. J Chemother

2009;21:584-9.37. Guidelines for the management of adults with

hospital-acquired, ventilator-associated, andhealthcare-associated pneumonia. Am J Respir CritCare Med 2005;171:388-416.

Melina Irizarry-Acosta, MD, is a fel-low in the Division of Infectious Diseases,Roger Williams Medical Center/BostonUniversity School of Medicine.

Yoram A. Puius, MD, PhD, is an at-tending physician in the Division of Infec-tious Diseases, Roger Williams MedicalCenter, and an Assistant Professor at theBoston University School of Medicine.

Disclosure of FinancialInterests of authors and/orsignificant others

Melina Irizarry-Acosta, MD. No fi-nancial interests to disclose.

Yoram A. Puius, MD. Consultant:Excelimmune, Inc. (Woburn, MA) forunrelated research

CORRESPONDENCEYoram A. Puius, MD, PhDDivision of Infectious DiseasesRoger Williams Medical Center825 Chalkstone AvenueProvidence, RI 02908Phone: (401) 456-2437E-mail: ypuius@rwmc.org