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MCP 240309

REVIEW

CURRENT
OPINION Why is the rate of pneumococcal
pneumonia declining?
Carlos M. Luna, Laura Pulido, and Diego Burgos

Purpose of review
As Streptococcus pneumoniae was considered the etiological agent of nearly all the cases of pneumonia at
the beginning of the 20th century, and today is identified in fewer than 10–15% of cases, we analyze the
possible causes of such a decline.
Recent findings
Extensive use of early empiric antimicrobial therapy, discovery of previously unrecognized pathogens,
availability to newer diagnostic methods for the recognition of the pneumonia pathogens (PCR, urinary
antigens, monoclonal antibodies etc.) and of improved preventive measures, including vaccines, are some
of possible explanations of the declining role of S. pneumoniae in the cause of pneumonia.
Summary
The 14-valent and the 23-valent capsular polysaccharide pneumococcal vaccines were licensed in 1977
and 1983, respectively. The seven-valent protein-conjugated capsular polysaccharide vaccine, approved
for routine use in children starting at 2 months of age, was highly effective in preventing invasive
pneumococcal disease in children but also in adults because of the herd effect. In 2010, the 13-valent
protein-conjugated capsular polysaccharide vaccine replaced seven-valent protein-conjugated capsular
polysaccharide vaccine. With the use of conjugated vaccines, a decrease of the vaccine-type invasive
pneumococcal disease for all age groups was observed. Both the direct effect of the vaccine and the
so-called herd immunity are considered responsible for much of the decline.
Keywords
antimicrobial therapy, cause, community acquired pneumonia, Streptococcus pneumoniae, vaccine

INTRODUCTION last century was considered the etiological agent of

According to the Global Health Observatory, WHO’s
gateway to health-related statistics, lower respiratory
tract infections, a synonym of pneumonia, remained
ranked in the third place as the deadliest communi-
cable and, paired with chronic obstructive pulmo-
nearly all the cases of pneumonia. The incidence of
pneumococcal pneumonia has been reduced over the
last 100 years. After 1950, the proportion of pneu-
monia caused by pneumococcus began to decline. At
the present time, this organism is identified in fewer
&& &&

nary disease, respiratory diseases, causing 3.5 million than 10–15% of cases [4 ,5 ]. In Fig. 1, the incidence
deaths worldwide in 2015 [1]. Pneumonia incidence of S. pneumoniae as the pathogen of pneumonia dur-
&&

is higher in the low-income countries and interme-
diate-low-income countries. Among the population
its frequency and mortality increase together with
age, particularly after the age of 50 years.
Streptococcus pneumoniae, or pneumococcus, a
Gram-positive, facultative anaerobic member of
the genus Streptococcus, was isolated in saliva and
later connected with pneumonia in the 1880s [2]. By
1926, it was named Diplococcus pneumoniae, because
of its propensity to exist in pairs of cells in the Gram
stain and S. pneumoniae because of its trend to
formation of chains in liquid media [3].
Pneumococcus acquired its name due to its role
in this lung infection and during the first half of the
ing the last century is displayed [5 ,6–32]. This
reduction of the role of S. pneumoniae as a causative
microorganism of pneumonia should lead to a
Pulmonary Diseases Division, Department of Medicine, Hospital de
Clı́nicas, Universidad de Buenos Aires, Buenos Aires, Argentina
Correspondence to Carlos M. Luna, MD, Pulmonary Diseases Division,
Department of Medicine, Hospital de Clı́nicas, Universidad de Buenos
Aires, Arenales 2557, piso 1, dto A, Ciudad Autónoma de Buenos Aires,
Capital Federal, CP 1425 Buenos Aires, Argentina.
Tel: +54 9 11 5756 1535; fax: +54 11 5950 8929;
e-mail: dr.cm.luna@gmail.ar
Curr Opin Pulm Med 2018, 24:000–000
DOI:10.1097/MCP.0000000000000478

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Infectious diseases
KEY POINTS
 The incidence of pneumococcal pneumonia has been
falling over the last 100 years.
 After 1950, the proportion of pneumonia caused by
pneumococcus began to decline.
 Changes in the cause and improved diagnostic tests
could explain this change.
 The use of conjugate vaccine reduced the incidence of
pneumococcal disease.
reduction of the incidence of pneumonia, but this
phenomenon has not been observed. The cause of the
observed declining of the role of S. pneumoniae as the
etiological agent of community aquired pneumonia
(CAP) is not clear. There are different circumstances
who could explain why this reduction could be evolv-
ing and probably there are more than one explana-
tion of this phenomenon including extended use of
early empirical antimicrobial therapy, emergence of
previously unknown new pathogens, new more sen-
sitive and specific diagnostic methods improving the
recognition of previously known pathogens and bet-
ter preventive measures including influenza and
pneumococcal vaccines.
Consequently, the question of why the rate of
pneumococcal pneumonia is declining, remains
unanswered. In the following pages, we analyze
some of the possible answers.
CAUSE OF PNEUMONIA
S. pneumoniae was the overwhelmingly predomi-
nant cause of CAP accounting for more than 80% of
FIGURE 1. Evolution of the frequency of Streptococcus
pneumoniae as a cause of community-acquired pneumonia.
A comparison of this cause according to the data published
by different authors covering different periods of time,
namely: 1915–1944 [6–10], 1945–1974 [11–20],
1985–1994 [21–27] and 1995–2015 [5 ,28–32]. &&
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cases of community-acquired pneumonia in the era
before penicillin [33]. During the last years of
the 20th century, the incidence of S. pneumoniae
as the etiological agent of CAP was ranked first
in the world, both in outpatients and in those
admitted to the general ward or to the intensive
care units [34] (Table 1). Twenty years ago, we did
our own study to describe the epidemiology of CAP.
We had some doubts about whether it was correct
that the epidemiology of CAP was the same as that
observed elsewhere [28]. We found that in most of
the studies that analyzed the cause with a compre-
hensive and systematic methodology, S. pneumo-
niae was the main cause of CAP with a variable
incidence [19–21,24,27,35–38]. The final results
of our study confirmed that in our country the
causative organisms were the same as those
described in other parts of the world (Table 2)
[28]. On the other hand, the members of the
committee of CAP who elaborated the national
guidelines reviewed these previously mentioned
articles together with other comparable studies
[6,19,21,36 –38]. The conclusion was that there
were wide variations according to the different
authors, but it is also confirmed that S. pneumoniae
was at that time (1985–1995) by far, the most
common pathogenic microorganism, in all catego-
ries of the severity of the disease, and whatever the
site of care [35], Table 1. We focused on studies that
included at least one calendar year in which the
greatest efforts were made to know which were
the prevalent pathogens including bacteriological
examinations in respiratory secretions, blood cul-
tures and pleural fluid, search for viral antigens in
nasopharyngeal aspirates and serological studies in
acute and in the convalescence, trying to deter-
mine the presence of pathogens.
In this kind of studies, with the diagnostic tools
available at that time, even when the greatest efforts
were made to determine the cause, there was always
a large group of patients in whom it was not possible
to determine the cause due to the sensitivity of the
different methods and the presence in many cases of
antibiotic therapy before taking samples. The num-
ber of episodes of CAP without etiologic diagnosis
was the most common finding in all categories of
patients (outpatients, admitted to the general ward
and admitted to the ICU).
During the last 15–20 years, new diagnostic
tools to determine the cause of CAP, used both, at
the point of care and in the laboratory (PCR, urinary
antigen tests etc), became widely available. These
advances can enable an etiological diagnosis with
highly sensitive technology and provide the neces-
sary information in a fast and effective way; further-
more, it has excited physicians about the possibility
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Why is the rate of pneumococcal pneumonia declining? Luna et al.

Table 1. Cause of CAP, relative frequency of causative microorganisms considering the different sites of care in different
series in the 1990s
Outpatients (1), Admitted to the general Admitted to the ICU (3),
7 studies, from ward (2), 36 studies from 7 studies from Europe,
Europe and from Europe, United States, United States and
Latin America Oceania and Latin America Latin America
Pathogen % % %

Streptococcus pneumoniae 28.1 23.5 29.8

Haemophilus influenzae 7.0 4.4 7.6
Staphylococcus aureus 0.2 1.1 12.2
Aerobic Gram-negative bacteria 0.4 3.0 9.0
Pseudomonas aeruginosa 0.2 1.0 1.7
Mycoplasma pneumoniae 8.5 7.2 1.6
Chlamydophila pneumoniae 6.3 7.1 1.4
Chlamydophila psitacci 0.0 1.6 1.8
Coxiella burnetti 0.9 0.9 1.0
Legionella pneumophyla 0.9 5.0 6.7
All the viruses 17.3 10.1 2.4
Influenza 8.8 6.2 1.0
Other pathogens 0.7 2.1 9.2
Mycobacterium tuberculosis 0.2 1.0 1.7
Mixed 3.2 8.3 14.8
None 55.3 46.6 38.6

CAP, community aquired pneumonia.

Modified from [35].

of focusing treatment by reducing the need for

Table 2. Epidemiology of CAP in Argentina 20 years ago
Pathogen
Streptococcus pneumoniae
Haemophilus influenzae
Pseudomonas aeruginosa
Staphylococcus aureus
Moraxella catarrhalis
Other Gram-positive organisms
Other Gram-negative organisms
Mycoplasma pneumoniae
Chlamydia pneumoniae
Legionella pneumophila
Chlamydia psittaci
Coxiella burnetii
Mycobacterium tuberculosis
Fungi
Influenza A
Adenovirus
Respiratory syncytial virus
Parainfluenza virus
Measles
More than one pathogen
Aspirative
Unknown
CAP, community aquired pneumonia.
Data modified from [28].
empirical treatments with multiple drugs. However,
Number Percentage on the one hand, the early data show that these
techniques can have a false-positive rate, which
35 10.1
makes it difficult to interpret the results. On the
17 4.9 other hand, some studies show that the incidence of
8 2.3 S. pneumoniae is lower than before the middle of the
6 1.7 20th century, but also pneumococcus no longer
5 1.4 occupies the first place as a pathogenic agent of
9 2.6 CAP.
19 5.5 Those studies performed after 2010, looking at
19 5.5 the cause of CAP and with an intensive investigation
12 3.5 of the causes of pneumonia included all patients
4 1.2 hospitalized for pneumonia, and deserve further
1 0.3 attention. One study was performed at a Veterans
1 0.3 Affairs medical center from 5 July 2011 to 30
7 2.0 June 2012, using most of the classic and the modern
6 1.7 diagnostic techniques available, including blood
9 2.6 and respiratory specimen culture, urinary antigens
9 2.6 and PCR multiplex for 15 viruses [29]. In this study,
3 0.9 S. pneumoniae was detected in 9% of the 215
2 0.6
patients; PCR identified a virus in 23%, bacterial
1 0.3
and viral coinfection occurred in 6% of cases, but
significantly, even with this sophisticate technique
20 5.8
the cause remained unknown in 55%. The other is
4 1.2 &&
the CDC EPIC study [5 ] of (more than 2000
166 48.0
patients) which reported a lower proportion of
pneumococcal pneumonia (5%) and all bacterial
pneumonia (15%).

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Infectious diseases

WHAT IS THE ROLE OF ANTIBIOTICS IN Enterobacteriaceae extended-spectrum b-lactamase-

REDUCING THE INCIDENCE OF
PNEUMOCOCCUS?
In the preantibiotic stage, S. pneumoniae was the
leader in the list of pneumonia causes [8]. Others
causative organisms involved in the preantibiotic
stage were Streptococcus pyogenes, Klebsiella pneumo-
niae, Staphylococcus aureus and Haemophilus influen-
zae with very small percentages compared with S.
pneumoniae and no bacterial cause in fewer than 5%
[6]. But nowadays, despite all the new diagnostic
techniques, it still represents a challenge to find all
&&
the pathogens involved [4 ].
In the early 20th century, a novel technique
called ‘antiserum therapy’ began to be applied to
patients with S. pneumoniae pneumonia, and by
1913, it was called antipneumococcal serum ther-
apy. If it was given in the early stage of disease, it was
able to reduce mortality from 25 to 7.5%. However,
this treatment was expensive and slow [39]. Use of
antibiotics as a treatment strategy for pneumonia
continued throughout the 1900s. In the thirties,
therapy of pneumonia with sulfonamides reduced
the mortality rate significantly. Although sulfapyr-
idine gained a lot of notoriety, this agent was
quickly set aside upon the discovery of the antibiotic
penicillin in the early 1940s [40]. With the intro-
duction of penicillin, the physicians reduced their
respect and fear for pneumonia (perhaps in excess),
and started to focus in strategies for prevention of S.
pneumoniae pneumonia by vaccination [41]. Like-
wise, antibiotics such as penicillin, acclaimed as the
‘knockout blow’ against the pneumococcus, are the
cause of selecting antibiotic-resistant mutants (it is
best to say: ‘the wrong use of antibiotics’) [42].
In reference to other pathogens of pneumonia,
during the mid-20th century, S. pyogenes was a com-
mon cause of severe pneumonia and caused epidemic
outbreaks [43]. Today, except for postinfluenza com-
plications, it is not considered a common cause of CAP
in adults; however, when this infection is present it is
usually reported to have a high mortality rate [44].
Previous antibiotic administration was significantly
associated with undetermined cause [21]; antimicro-
bial treatment before the collection of samples has
been associated specifically with the decrease of the
yields of conventional bacterial culture methods [45].
In recent years, concern has arisen regarding
some pathogens of CAP which require different
antibiotics than those used in the initial empiric
treatment recommended by the guidelines [46,47].
One of the explanations to this problem is the
irrational use of antibiotics that select the endoge-
nous flora and promote the emergence of resistant
pathogens, specifically Pseudomonas aeruginosa,
positive and methicillin-resistant S. aureus. Further-
more, the use of antibiotics for different reasons was
found to be related with the acquisition of CAP due to
P. aeruginosa. Pseudomonas pneumonia has been
described characteristically as a hospital-acquired
infection in patients with underlying medical disor-
ders. In the 1970s, some authors described few reports
of severe CAP produced by this microorganism in the
previously healthy without previous definite predis-
posing factors [48,49].
ROLE OF NEWER DIAGNOSTIC METHODS
During the last 20 years, some methods that were
previously unavailable, began to be routinely used,
which impacted on an early and accurate recogni-
&
tion of the cause of CAP [50 ,51]. The newer meth-
ods included the immunochromatographic urinary
antigen test for S. pneumoniae and for Legionella
pneumophila serotype I, and molecular methods,
including the PCR, available for the etiological diag-
nosis of several infectious diseases, including bacte-
rial and viral infections. Those methods may
threaten to revolutionize the diagnostic approach
and the therapeutic timing leading to the use of
directed treatment instead of the currently recom-
mended empirical treatment for the therapeutic
management of patients with CAP.
Through the use of PCR, the importance of the
viruses as CAP agents was shown (Table 1) to the
detriment perhaps of the bacterial agents [52], and a
&
not lesserser fact, the presence of coinfections [53 ].
However, there is a need to continue with further
research because the method can yield positive
results even after 2–5 weeks after an acute infection
and thus be a false-positive result. From this point of
view, it is highly probable that early recognition of
the pathogen, with sensitive and specific methods
that seek the cause in pulmonary infections in both
outpatients and hospitalized patients, may reveal
the presence of some of the previously recognized
pathogens and other microorganisms previously
not considered (including rhinovirus, bocavirus,
metapneumovirus), and thus make them appear
in statistics as pathogenic agents producing a detri-
ment of S. pneumoniae participation in pneumonia
cause. However, we must be careful because of these
and other nonstandardized techniques may also
lead to overdiagnosis [54], and further validation
is required before they can be used in diagnosis.
ROLE OF VACCINES
The first polyvalent pneumococcal vaccine licensed
was the 14-valent capsular polysaccharide vaccine

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Why is the rate of pneumococcal pneumonia declining? Luna et al.

FIGURE 2. Trends observed in invasive pneumococcal disease before (2000–2006) and after (2008–2009) the inclusion of
the seven-valent protein-conjugated capsular polysaccharide vaccine in the calendar in children in England and Wales. Two
age groups are displayed: children less than 2 years-old (who received the vaccine) and at least 65 years-old (not vaccinated).
The adjusted counts of invasive pneumococcal disease cases decreased overall in the two groups, more markedly for the invasive
pneumococcal disease due to vaccine type pneumococci, whereas the nonvaccine type increased, likely attributable to vaccine-
induced serotype replacement after introduction of the seven-valent protein-conjugated capsular polysaccharide vaccine.
Reproduced with permission [62].

&
in 1977 [55 ]. The 23-valent capsular polysaccharide
vaccine, PSV23, replaced the 14-valent vaccine in
1983. The effectivity of this vaccine was approxi-
mately 60%, preventing particularly the incidence
of invasive pneumococcal disease (IPD) [56]. Seven
valent-protein-conjugated capsular polysaccharide
vaccine (PCV7) was approved for routine use in
children starting at 2 months of age and it proved
highly effective in preventing IPD and other pneu-
&
mococcal infections [55 ] not only in children but

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Infectious diseases
also in adults [57]. In 2010, the current 13-valent
protein-conjugated capsular polysaccharide vac-
cine, PCV13, replaced PCV7. With the introduction
in the national calendar of several countries of the
PCV7 (including the serotypes 4, 6B, 9V, 14,18C,
19F and 23F) in children in 2000 a drastic reduction
in invasive disease rates and in mortality has been
demonstrated [58]. Therefore, first the 10-valent,
and then the PCV13 including the serotypes 1, 3,
5, 6A, 7F and 19A were created. The efficiency of
these vaccines in children has been recognized in
several studies [59].
In addition to its role as a pathogen, S. pneumo-
niae is asymptomatically carried in the nasopharynx
by up to 50% of infants and up to 5% of adults [60].
It is accepted that colonization occurs before dis-
ease, and transmission is from child to child and
from children to adults [61]. Calculating the inci-
dence of vaccine type and nonvaccine type IPD in
England and Wales, Miller et al. [62] compared the
adjusted incidence of IPD observed in 2000–2006
(before of the inclusion of the PCV7 vaccine in the
calendar), with the incidence reported in 2009–
2010 (after the inclusion of the PCV7 in the calen-
dar). They observed a decrease of the vaccine-type
invasive disease for all age groups, whereas the non-
vaccine type disease did not show such decrease
(Fig. 2). Beside the substantial reduction in IPD
observed in the children under 2 years who were
vaccinated, there was also an indirect benefit in
other age groups (as in age 65 years) showing a
reduction in the incidence in unvaccinated patients
attributable to so-called herd immunity.
&
Rodrigo et al. [63 ] conducted a prospective
cohort study of adults admitted to hospital with
CAP in Nottingham, United Kingdom; they
observed a reduction in the number of adult patients
hospitalized for pneumococcal CAP over the 5-year
period of the study. The incidence of CAP due to
serotypes included in the PCV7 declined by 88%
[IRR 0.12, 95% confidence interval (CI) 0.08–0.20;
P < 0.001], and CAP due to the additional six sero-
types in PCV13 declined by 30% (IRR 0.70, 95% CI
0.51–0.96; P ¼ 0.024).
CONCLUSION
Despite improved diagnostic methods, more than
50% of CAPs end without an etiological diagnosis. S.
pneumoniae remains one of its main causative organ-
isms, and although incidence, prevalence and mor-
tality of pneumonia remains high in children and
adults worldwide, it was found in only 10–15% of
the causes of CAP.
This finding could be related to the coexistence
of multiple factors, such as vaccination against
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S. pneumoniae, its inclusion in the national calendars
to populations at risk and the herd effect that it
generates, the increased incidence of emerging
pathogens and the dissemination and use of current
treatment guidelines.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
C.L. was member of the advisory board of AstraZeneca,
Bayer, Cempra, OM Pharma and Pfizer. C.L. was also
speaker in scientific meetings or courses financed by OM
Pharma, Pfizer and Merck. The remaining authors have
no conflicts of interest.
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. The top 10 causes of death. Geneva: World Health Organization, 2013.
Available from: http://www.who.int/mediacentre/factsheets/fs310/en/in-
dex.html.
2. Murray J. The captain of the men of death. In: Marrie TJ, editor. The history of
pneumonia. Community-acquired pneumonia. New York: Kluwer Academic/
Plenum Publishers; 2001.
3. Winslow C, Broadhurst J. The families and genera of the bacteria: final
report of the Committee of the Society of American Bacteriologists on
Characterization and Classification of Bacterial Types. J Bacteriol 1920;
5:191–229.
4. Musher DM, Abers MS, Bartlett JB. Evolving understanding of the causes of
pneumonia in adults, with special attention to the role of pneumococcus. Clin
&&
Infect Dis 2017; 65:1736–1744.
Review article analyzing the role of the different pneumonia pathogenic micro-
organisms during the last 70 years, focusing specially on Streptococcus pneu-
moniae.
5. Jain S, Self WH, Wunderink RG, et al. Community-acquired pneumonia
requiring hospitalization among U.S. adults. N Engl J Med 2015; 373:
&&
415–427.
One of the newer and more extensive studies looking at the cause of community-
acquired pneumonia that enrolled 2488 of 3634 eligible adults, 2320 with
radiographic evidence of pneumonia.
6. Avery OT, Chickering HT, Cole R, Dochez AR. Acute lobar pneumonia:pre-
vention and serum treatment. In: Monographs of the Rockefeller Institute for
Medical Research; 1917.
7. Bullowa JGM. The management of the pneumonias: for physicians and
medical students. New York: Oxford University Press; 1937.
8. Cecil RL, Larsen NP. Clinical and bacteriologic study of one thousand cases
of lobar pneumonia. JAMA 1922; 79:343–349.
9. Cecil RL, Lawrence EA. Pneumonia in private practice: a study of 911
patients. JAMA 1938; 111:1989–1994.
10. Sutliff WD, Finland M. The significance of the newly classified types of
pneumococci in disease: types IV to XX inclusive. JAMA 1933; 101:
1289–1295.
11. Dorff GJ, Rytel MW, Farmer SG, Scanlon G. Etiologies and characteristic
features of pneumonias in a municipal hospital. Am J Med Sci 1973;
266:349–358.
12. Fekety FR Jr, Caldwell J, Gump D, et al. Bacteria, viruses, and mycoplasmas in
acute pneumonia in adults. Am Rev Respir Dis 1971; 104:499–507.
13. Fiala M. A study of the combined role of viruses, mycoplasmas and bacteria in
adult pneumonia. Am J Med Sci 1959; 257:44–51.
14. Miller J, Sande MA, Gwaltney JM Jr, Hendley JO. Diagnosis of pneumococcal
pneumonia by antigen detection in sputum. J Clin Microbiol 1978; 7:
459–462.
Volume 24  Number 00  Month 2018
CE: Swati; MCP/240309; Total nos of Pages: 7;
MCP 240309
Why is the rate of pneumococcal pneumonia declining? Luna et al.
15. Moore MA, Merson MH, Charache P, Shepard RH. The characteristics and
mortality of outpatient-acquired pneumonia. Johns Hopkins Med J 1977;
140:9–14.
16. Oseasohn R, Skipper BE, Tempest B. Pneumonia in a Navajo community: a
two year experience. Am Rev Respir Dis 1978; 117:1003–1009.
17. Boerner DF, Zwadyk P. The value of sputum Gram’s stain in community-
acquired pneumonia. JAMA 1982; 239:642–645.
18. Ebright JR, Rytel MW. Bacterial pneumonia in the elderly. J Am Geriatr Soc
1980; 28:220–223.
19. Jokinen C, Heiskanen L, Juvonen H, et al. Incidence of community-acquired
pneumonia in the population of four municipalities in eastern Finland. Am J
Epidemiol 1993; 137:977–988.
20. Woodhead MA, MacFarlane JT, McCracken JS, et al. Prospective study of the
aetiology and outcome of pneumonia in the community. Lancet 1987;
i:671–674.
21. Fang GD, Fine M, Orloff J, et al. New and emerging etiologies for community
acquired pneumonia with implications for therapy: a prospective multicenter
study of 359 cases. Medicine (Baltimore) 1990; 69:307–316.
22. MacFarlane JT, Colville A, Guion A, et al. Prospective study of aetiology and
outcome of adult lower-respiratory tract in the community. Lancet 1993;
341:511–514.
23. Ortqvist A, Hedlund J, Grillner L, et al. Aetiology, outcome and prognostic
factors in community-acquired pneumonia requiring hospitalization. Eur Re-
spir J 1990; 3:1105–1113.
24. Bates JH, Campbell D, Barron AL, et al. Microbial etiology of acute pneumonia
in hospitalized patients. Chest 1992; 101:1005–1012.
25. Fine MJ, Stone RA, Singer D, et al. Processes and outcomes of care for
patient Outcomes Research Team (PORT) (Cohort Study). Arch Intern Med
1999; 159:970–980.
26. Marston BJ, Plouffe JF, File TM, et al. Incidence of community acquired
pneumonia requiring hospitalization: results of a population-based active
srveillance study in Ohio. Arch Intern Med 1997; 157:1709–1718.
27. Mundy LM, Auwartee PG, Oldach D, et al. Community acquired pneumonia:
impact of immune status. Am J Respir Crit Care Med 1995; 152:1309–1315.
28. Luna CM, Famiglietti A, Absi R, et al. Community-acquired pneumonia:
etiology, epidemiology and outcome at a teaching hospital in Argentina.
Chest 2000; 118:1344–1354.
29. Musher DM, Roig IL, Cazares G, et al. Can an etiologic agent be identified in
adults who are hospitalized for community-acquired pneumonia: results of a
one-year study. J Infect 2013; 67:11–18.
30. Park DR, Sherbin VL, Goodman MS, et al., Harborview CAP Study Group. The
etiology of community-acquired pneumonia at an urban public hospital:
influence of human immunodeficiency virus infection and initial severity of
illness. J Infect Dis 2001; 184:268–277.
31. Restrepo MI, Mortensen EM, Velez JA, et al. A comparative study of com-
munity-acquired pneumonia patients admitted to the ward and the ICU. Chest
2008; 133:610–617.
32. Yang S, Lin S, Khalil A, et al. Quantitative PCR assay using sputum samples
for rapid diagnosis of pneumococcal pneumonia in adult emergency depart-
ment patients. J Clin Microbiol 2005; 43:3221–3226.
33. Bullowa JGM. The reliability of sputum typing and its relation to serum therapy.
JAMA 1935; 105:1512–1518.
34. Niederman MS, Bass JB, Campbell GD, et al. Guidelines for the initial
management of adults with community-acquired pneumonia: diagnosis, as-
sessment of severity, and initial antimicrobial therapy. Am Rev Respir Dis
1993; 148:1418–1426.
35. Luna CM, Calmaggi A, Caberlotto O, et al. Community acquired pneumonia.
Clinical practice guideline designed by an intersocieties committee. Medicina
(B Aires) 2003; 63:319–343.
36. Blanquer J, Blanquer R, Borrás R, et al. Aetiology of community acquired
pneumonia in Valencia, Spain: a multicenter prospective study. Thorax 1991;
46:508–511.
37. Chan CHS, Cohen M, Bing J. A prospective study of community-acquired
pneumonia in Hong-Kong. Chest 1992; 101:442–446.
38. Marrie TJ, Durant H, Yates L. Community-acquired pneumonia requiring
hospitalization: a 5-year prospective study. Rev Infect Dis 1989; 11:
586–599.
39. Haddon J. The natural history and treatment of pneumonia. Br Med J 1902;
2:1932.
40. Luna CM, Efron E, Schiavi E, et al., Grupo Argentino de estudio de la NAC.
Community acquired pneumonia, clinical practice guideline for Argentina.
Medicina (B Aires) 1997; 57:343–355.
41. Peterson L. Penicillins for treatment of pneumococcal pneumonia: does in
vitro resistance really matter? Clin Infect Dis 2006; 42:224–233.
42. Podolsky SH. Pneumonia before antibiotics: therapeutic evolution and eva-
luation in twentieth-century America. In: Project MUSE, 2006. Baltimore: The
Johns Hopkins University Press; 2006.
1070-5287 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
43. Keefer CS, Rantz LA, Rammelkamp CH. Hemolytic Streptococcal pneumonia
and empyema: a study of 55 cases with special reference to treatment. Trans
Am Clin Climatol Assoc 1940; 56:31–56.
44. Barnham M, Weightman N, Anderson A, et al. Review of 17 cases of
pneumonia caused by Streptococcus pyogenes. Eur J Clin Microbiol Infect
Dis 1999; 18:506–509.
45. Korsgaard J, Møller JK, Kilian M. Antibiotic treatment and the diagnosis of
Streptococcus pneumoniae in lower respiratory tract infections in adults. Int J
Infect Dis 2005; 9:274–279.
46. Spellberg B, Guidos R, Gilbert D, et al. The epidemic of antibiotic-resistant
infections: a call to action for the medical community from the Infectious
Diseases Society of America. Clin Infect Dis 2008; 46:155–164.
47. Viasus D, Garcia-Vidal C, Carratalà J. Advances in antibiotic therapy for
community-acquired pneumonia. Curr Opin Pulm Med 2013; 19:209–215.
48. Govan J, Reis-Levy E, Bader L, et al. Pseudomonas pneumonia with bacter-
emia. Med J Aust 1977; 1:627–628.
49. Iannini PB, Claffey T, Quintiliani R. Bacteremic pseudomonas pneumonia.
JAMA 1974; 230:558–561.
50. Botelho-Nevers E, Grattard F, Viallon A, et al. Prospective evaluation of RT-
& PCR on sputum versus culture, urinary antigens and serology for Legion-
naire’s disease diagnosis. J Infect Chemother 2016; 73:123–128.
The results of this study determined that PCR on noninvasive respiratory speci-
mens is reliable and may contribute to better identify cases of Legionnaire’s
disease.
51. Yoshii Y, Shimizu K, Morozumi M, et al. Identification of pathogens by
comprehensive real-time PCR versus conventional methods in community-
acquired pneumonia in Japanese adults. Infect Dis (Lond) 2016;
48:782–788.
52. Jartti T, Lehtinen P, Vuorinen T, et al. Persistence of rhinovirus and enterovirus
RNA after acute respiratory illness in children. J Med Virol 2004; 72:
695–699.
53. Wunderink RG, Waterer G. Advances in the causes and management of
& community acquired pneumonia in adults. BMJ 2017; 358:j2471.
Review on recent advances, including computed tomography and MRI studies in
the clinical diagnosis of pneumonia and changes on the perspective of the cause of
pneumonia.
54. Musher DM, Mediwala R, Phan HM, et al. Nonspecificity of assaying for IgG
antibody to pneumolysin in circulating immune complexes as a means to
diagnose pneumococcal pneumonia. Clin Infect Dis 2001; 32:534–538.
55. Daniels CC, Rogers PD, Shelton CM. A review of pneumococcal vaccines:
& current polysaccharide vaccine recommendations and future protein anti-
gens. J Pediatr Pharmacol Ther 2016; 21:27–35.
The review describes development of currently available pneumococcal vaccines,
summarizes current pneumococcal vaccine recommendations in children and
adults and describes new potential vaccine antigens in the pipeline.
56. Palma I, Mosquera R, Demier C, et al. Impact of bacteremia in a cohort
of patients with pneumococcal pneumonia. J Bras Pneumol 2012; 38:
422–430.
57. Norton NB, Stanek RJ, Mufson MA. Routine pneumococcal vaccination of
children provokes new patterns of serotypes causing invasive pneumococcal
disease in adults and children. Am J Med Sci 2013; 345:112–120.
58. Ben-Shimol S, Greenberg D, Givon-Lavi N, et al. Early impact of sequential
introduction of 7-valent and 13-valent pneumococcal conjugate vaccine on
IPD in Israeli children <5 years: an active prospective nationwide surveillance.
Vaccine 2014; 32:3452–3459.
59. Moore CE, Paul J, Foster D, et al., Oxford Invasive Pneumococcal Surveillance
Group. Reduction of invasive pneumococcal disease 3 years after the
introduction of the 13-valent conjugate vaccine in the Oxfordshire Region
of England. J Infect Dis 2014; 210:1001–1011.
60. Le Polain De Waroux O, Flasche S, Prieto-Merino D, et al. The efficacy and
duration of protection of pneumococcal conjugate vaccines against naso-
pharyngeal carriage: a meta-regression model. Pediatr Infect Dis J 2015;
34:858–864.
61. Almeida ST, Nunes S, Santos Paulo AC, et al. Low prevalence of pneumo-
coccal carriage and high serotype and genotype diversity among adults over
60 years of age living in Portugal. PLoS One 2014; 9:e90974.
62. Miller E, Andrews MJ, Waight PA, et al. Herd immunity and serotype replace-
ment 4 years after 7-valent pneumococcal conjugate vaccination in England
and Wales: an observational cohort study. Lancet Infect Dis 2011;
11:760–768.
63. Rodrigo C, Bewick T, Sheppard C, et al. Impact of infant 13-valent pneu-
& mococcal conjugate vaccine on serotypes in adult pneumonia. Eur Respir J
2015; 45:1632–1641.
A 5-year prospective cohort study of adults hospitalized with CAP. Incidence of
adult pneumococcal pneumonia declined indicating early herd protection effects
from 13-valent protein-conjugated capsular polysaccharide vaccine infant vacci-
nation on adult nonbacteremic disease.
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