key: cord-1021747-d8q9lsck
authors: Musher, Daniel M; Abers, Michael S; Bartlett, John G
title: Evolving Understanding of the Causes of Pneumonia in Adults, With Special Attention to the Role of Pneumococcus
date: 2017-11-15
journal: Clin Infect Dis
DOI: 10.1093/cid/cix549
sha: 1c8c58a0e266b72842c08e90c476252327236116
doc_id: 1021747
cord_uid: d8q9lsck

Before 1945, Streptococcus pneumoniae caused more than 90% of cases of pneumonia in adults. After 1950, the proportion of pneumonia caused by pneumococcus began to decline. Pneumococcus has continued to decline; at present, this organism is identified in fewer than fewer10%–15% of cases. This proportion is higher in Europe, a finding likely related to differences in vaccination practices and smoking. Gram-negative bacilli, Staphylococcus aureus, Chlamydia, Mycoplasma, and Legionella are each identified in 2%–5% of patients with pneumonia who require hospitalization. Viruses are found in 25% of patients, up to one-third of these have bacterial coinfection. Recent studies fail to identify a causative organism in more than 50% of cases, which remains the most important challenge to understanding lower respiratory infection. Our findings have important implications for antibiotic stewardship and should be considered as new policies for empiric pneumonia management are developed.

Pneumonia, at first called "the special enemy of old age" [1] by Osler and later, by a more mature Osler, "the friend of the aged" [2] , has long been with humankind and shows little likelihood of going away. In the preantibiotic era, Streptococcus pneumoniae was the overwhelmingly predominant cause of pneumonia, but this is clearly no longer the case. Despite its prevalence and importance-pneumonia affects about 2% of all elderly persons each year [3] -and despite newly available techniques for diagnosis, at the present time and in the majority of cases, the causative organism(s) remain(s) uncertain.

How does such an evolution occur? For recognized or unrecognized reasons, there may be changes in the actual incidence of a disease. Rheumatic fever began to decline in the late 1920s, well before the introduction of antibiotics, and auxotrophic strains of Neisseria gonorrhoeae that made acute arthritis an everyday occurrence in public hospitals in the early 1980s have largely disappeared. Newly discovered organisms may cause disease, and new diagnostic techniques may increase recognition of already-identified diseases. Raised awareness of a condition may lead to more diagnostic testing and increased documentation.

Here, we document the declining role of S. pneumoniae and the increasing recognition of other pathogens in the etiology of community acquired pneumonia (CAP) in adults.

A PubMed search of the English-language literature through December 2015 was performed using the following search term: ( [ptyp] ). The references of included studies were also searched for candidate articles. We included studies that applied validated pneumococcal tests to ≥50% of patients. The following were considered evidence of pneumococcal infection: S. pneumoniae cultured from a sterile site or from a lower respiratory tract specimen (ie, not a nasopharyngeal specimen), including recovery after mouse intraperitoneal inoculation; pneumococcal antigen detection in urine; and polymerase chain reaction (PCR) testing of pleural fluid. Studies that focused on a specific population (eg, the elderly or immunocompromised) were excluded. See Supplementary Material for details. We identified 31 studies (21 120 patients) from the United States and Canada published between 1917 and 2015 and 37 studies (21 166 patients) from Europe. We included all publications that met our inclusion criteria (Table 1) .

In the preantibiotic era, S. pneumoniae caused approximately 90% of all cases of pneumonia [4, [72] [73] [74] (Figure 1A ). Streptococcus pyogenes, Klebsiella, Haemophilus influenzae, and Staphylococcus aureus were identified in the remaining cases; in fewer than 5%, no bacterial cause could be found. In the preantibiotic era, no antibiotic would have interfered with a bacteriologic diagnosis, and, compared to current practice, clinicians made greater efforts to obtain sputum samples for culture. Of course, pneumonia due to influenza virus had been recognized for quite some time [75] . Modern studies of patients who died in the 1918 influenza epidemic suggest that most of those deaths were, in fact, associated with secondary bacterial infection [76] . Outbreaks of pneumonia, thought to be viral and later identified as adenoviral [77] , occurred in young adults, especially in military settings where crowding and physical and mental exhaustion were prevalent.

In the late 1930s, a pneumonia that behaved differently from pneumococcal pneumonia was attributed to an "atypical agent" [78, 79] , subsequently called Eaton agent [80, 81] and eventually identified as Mycoplasma pneumoniae [82] . Recognized cases, [16] , an "aggressive" approach to diagnosis identified pneumococcus in 30% of cases.

Haemophilus influenzae was cultured from sputum in 29%. However, because only 1 patient was bacteremic, the authors stated that the "others can not critically be called Haemophilus pneumonia. " By 1979-1980 and 1990-1991, reports from Johns Hopkins Hospital implicated pneumococcus in 35% [21] and 15% [27] of cases, respectively.

In the 1970s attention was directed toward anaerobic flora of the mouth and upper respiratory tract as a potential cause of pneumonia. In 1898 Veillon implicated anaerobic bacteria in lung infection [87] ; their importance as the most common agents in lung abscess was subsequently emphasized by Smith [88] and confirmed by Cohen [89] . Further development of anaerobic bacteriology by Bartlett, Gorbach, and Finegold [90] , together with the use of transtracheal aspiration, showed the importance of these organisms as a cause of pneumonia, especially in patients whose lifestyle suggested aspiration and who presented with a subacute syndrome of respiratory infection characterized by putrid sputum, lung abscess, and/ or empyema.

Some adults who present with acute bacterial pneumonia were also shown to be infected by normal facultative or anaerobic organisms [90] [91] [92] [93] [94] [95] [96] [97] [98] . More recent reports on the etiology of pneumonia fail to mention these organisms, probably reflecting the failure to use transtracheal aspiration and/or anaerobic microbiology. Microscopic examination of good-quality sputum from patients with pneumonia may show large numbers of gram-positive cocci together with other organisms. Such findings suggest that so-called normal respiratory flora, including the Streptococcus anginosus group, Streptococcus mitis, and/or mixed respiratory flora, may cause a substantial proportion of cases of pneumonia when no recognized respiratory pathogen is identified.

An outbreak of pneumonia in 1977 [99] led to identification of Legionella [100] . Implication of Legionella in other outbreaks [101] was soon followed by recognition of this organism as a cause of sporadic pneumonia, both in hospitals [102] and in the community [103, 104] . The relation to water sources [105, 106] and the association with geographical locations [104] was also documented.

In 1983, Musher et al [107] showed that H. influenzae commonly caused pneumonia in older men, identifying 30 cases at a single hospital in a 2-year period. Haemophilus from 26 of these patients was nontypable; only 1 of these had associated bacteremia. Four patients had H. influenzae type b in their sputum, of whom 3 were bacteremic.

In 1986, Grayston et al identified Chlamydia pneumoniae as an important cause of pneumonia in university students [108, 109] . As with Mycoplasma, this organism was not found commonly in older adults with pneumonia, raising question about more recent studies that have used only serologic techniques to implicate it as a common cause of pneumonia in hospitalized adults.

During the 1980s, viral cultures of respiratory secretions increasingly documented a causative role for respiratory viruses in pneumonia. The potential importance of parainfluenza [14] and respiratory syncytial viruses [110] in adults was recognized; rhinovirus, coronavirus [111] , and human metapneumovirus [112] were added later. Thus, by the end of the 1980s, most microorganisms that are currently known to cause CAP had been identified. A landmark prospective study of CAP patients admitted to a private hospital, a university hospital, and a veterans' hospital in Pittsburgh in 1986-1987 [24] used classic bacteriologic techniques and identified pneumococcus in only 15% of cases, followed by Haemophilus in 11%. Serologic studies were positive for Mycoplasma or Chlamydia in 8%. Legionella was detected by antibody rise, immunofluorescence, and/or culture in 7%. Viruses were not sought. No cause was found in one-third of cases. The authors emphasized the decline of pneumococcus as a cause of pneumonia in the antibiotic era.

After 2000, new techniques greatly increased the ability to identify respiratory pathogens. Tests to detect antigens of S. pneumoniae and Legionella in urine reliably increased recognition of the role played by these agents [67, [113] [114] [115] [116] [117] . Detection of capsular polysaccharides [118] or other pneumococcal constituents such as DNA that encode lytA in sputum or nasal secretions [119] appeared to increase the diagnostic yield. However, these and other nonstandardized techniques may also lead to overdiagnosis [120] , and further validation is required before they can be used in diagnosis. There is, however, little question that the availability of PCR has revolutionized our understanding of the role of respiratory viruses in pneumonia in adults.

More recent studies in the United States, that were designed to select a convenience sample of patients or to include patients in a pharmaceutical study (but not a complete evaluation of successive admissions), detected pneumococcus in 10%-14% of adults hospitalized for CAP [121, 122] (Figure 1A ). During the same period, a greater proportion of cases have been attributed to pneumococcus in Europe than in the United States (Table 2) . Lim et al [123] reported an etiologic agent in 75% of cases, including pneumococcus in 48% and "atypical organisms, " principally Chlamydia and Mycoplasma, in 18%. Nearly one-third of pneumococcal diagnoses were made serologically by rises in antibody to various pneumococcal constituents or by counterimmunoelectrophoresis (CIE) to detect capsular polysaccharides in sputum. However, these serologic tests have not been validated, and CIE is regularly positive in sputum that does not contain pneumococci (D. Musher and C. Stager, unpublished) . If these serologic results are excluded, pneumococcus was found in 34% of cases. Diagnoses of Chlamydia and Mycoplasma were only made serologically. Interestingly, an earlier study by these same investigators [124] in which no special serologic techniques were used identified an etiologic agent in 54% of cases, with pneumococcus in 30%, Haemophilus in 8%, and "atypical organisms" in 1%. European investigators [125, 126] used only traditional microbiology and detection of pneumococcal cell wall antigen in urine to implicate S. pneumoniae in 37%-38% of cases of CAP. Our present study shows a marked decline in the frequency with which pneumococcus causes pneumonia in the United States/Canada but no such decline in Europe ( Figure 1B ). An important limitation of our findings is between-study heterogeneity in patient population, severity of illness, microbiologic tests performed, and the thoroughness of diagnostic testing. We attempted to minimize the latter 2 factors by including only studies that performed pneumococcal testing in a significant proportion of cases. For studies that provided sufficiently granular data, we calculated the frequency of pneumococcal pneumonia by limiting the denominator to only those patients who underwent such testing. Also, we chose a case definition of pneumococcal pneumonia that emphasizes validated microbiologic tests that have been in clinical practice for decades. While an in-depth qualitative analysis is beyond the scope of this article, we provide preliminary evidence to suggest differences between the United States/Canada and Europe with respect to the relative frequency of pneumococcus as a cause of pneumonia.

Factors that contribute to this difference might include the widespread use of pneumococcal polysaccharide vaccine [127] and the decreased rate of cigarette smoking among adults in the United States [128] . The nearly universal administration of pneumococcal conjugate vaccine to US children beginning in 2000 further explains the decline [3] . In Europe and other parts of the world where pneumococcal vaccines have been recommended for routine use for adults and where the incidence of cigarette smoking remains high, pneumococcus remains responsible for a higher proportion of cases of CAP ( Figure 1B) [40, 123, 126, [129] [130] [131] . Reliance on serologic techniques has probably led to overdiagnosis of Mycoplasma and Chlamydia [132] . As noted above, earlier studies that used culture for diagnosis suggested that these organisms only occasionally infect older adults. These findings have important implications for comparing results of CAP studies or following guidelines for management written on either side of the Atlantic.

An intensive investigation of the causes of pneumonia included all patients hospitalized for pneumonia at a Veterans Affairs (VA) medical center from July 5, 2011 to June 30, 2012 [33] . Blood culture, urine pneumococcal and Legionella antigen, PCR for 15 respiratory viruses (but not Mycoplasma or Chlamydia), and serum procalcitonin were each performed in more than 95% of cases. Sputum was studied in 70%. Of 259 patients admitted from the emergency department with CAP, 44 (17%) were thought to be uninfected, an observation with important implications for reconciling quality improvement measures that relate to promptness of antibiotic therapy. Of the remaining 215 patients (Table 3) , 29% had documented bacterial infection; S. pneumoniae was detected in only 9% of the 215 patients. PCR identified a respiratory virus in 23%. Bacterial and viral coinfection occurred in 6% of cases. Despite an intense search for an etiologic agent, the cause remained unknown in 55%.

Two subsequent studies (Table 3 ) yielded similar results. The Centers for Disease Control and Prevention's EPIC study [34] of more than 2000 patients at 8 medical centers reported an even lower proportion of pneumococcal pneumonia (5% vs 9%) and all bacterial pneumonia (15% vs 29%) than Musher et al [33] . Routine use of PCR for Mycoplasma and Chlamydia confirmed [132] that these organisms are very uncommon causes of CAP leading to hospitalization of adults, suggesting that serologic tests have contributed to marked overdiagnosis. Two more recent studies identified Mycoplasma as a cause of pneumonia in 6% of cases; however, 1 included 50% [133] and the other [134] included 25% of patients with a PORT (Patient Outcomes Research Team) score of ≤2. Such patients are generally not hospitalized and would not have been included in the VA study or the EPIC study. Using a serotype-specific enzyme-linked immunosorbent assay (ELISA) on urine [135] , a Dutch pneumococcal vaccine trial [136] identified pneumococcus in 16% of CAP in the control (nonvaccinated) group, consistent with the higher incidence of pneumococcus in Europe, although lower than some of the other European studies cited above [40, 123, 126] . The finding in these 3 studies [33, 34, 136] of Legionella, Pseudomonas, or S. aureus as a cause of 1%, ≤3%, or ≤5% of pneumonias, respectively, has important implications for the selection of empiric antibiotics used to treat CAP.

Perhaps the most important observation in these 3 studies was the failure to identify a cause for pneumonia in more than 50% of cases. The VA study [33] attempted to use clinical scenarios with support from laboratory and radiologic studies to distinguish bacterial from nonbacterial (largely viral) pneumonia. The investigators defined a likely bacterial pneumonia as 3 or more of the following: hyperacute presentation; septic shock; white blood cell count >15 000 or <6000 with increased band forms; dense segmental or lobar consolidation; absence of upper respiratory symptoms; biphasic illness with upper respiratory symptoms followed by a sudden deterioration; or an elevated procalcitonin level. Likely nonbacterial pneumonia had none of these findings plus 2 or more of the following: exposure to sick contact(s); upper respiratory symptoms; patchy infiltrates; and a low serum procalcitonin level. About 58% of patients with no identifiable cause stratified to likely bacterial disease and 15% to likely viral disease; 27% could not be categorized. The authors hypothesized that so-called normal respiratory flora play a prominent etiologic role in patients whose syndrome suggested likely bacterial pneumonia and in whom all other tests failed to reveal a recognized pathogen.

A serotype-specific urinary ELISA increases the diagnostic yield for pneumococcus by 15%-20% [135] . Unfortunately, the available test only detects strains in the 13-valent conjugate pneumococcal vaccine, many of which have greatly declined in incidence [137] . Therefore, a new set of antigens needs to be studied and the method validated before it will provide useful information in the future.

Albrich et al [138] used a quantitative PCR on nasopharyngeal swabs to detect pneumococcal lytA in human immunodeficiency virus (HIV)-infected South African patients with pneumonia. Patients who met criteria for pneumococcal infection had 1000-fold greater counts than patients without nonpneumococcal CAP and 100 000-fold greater counts than HIV-infected controls without CAP. To our knowledge, this work has not been validated in a study from a developed country. A quantitative, multiplex PCR detects 40 pneumococcal serotypes [139] but has yet to be studied as a diagnostic tool for CAP.

A recent study from the United Kingdom identified an etiologic agent by quantitative PCR in 87% of CAP patients, including S. pneumoniae in 36%, H. influenzae in 40%, Moraxella in 14%, S. aureus in 10%, Klebsiella in 4%, Pseudomonas in 3%, and Mycoplasma or Legionella in <2% each [140] . This technique appears to be either overly sensitive or nonspecific since 2 or more bacterial pathogens were found in 32% of cases and Moraxella was found in 14%. A respiratory virus was detected in 30% of cases but alone (without a bacterial respiratory pathogen) in only 6%.

In conclusion, principal trends in determining etiologic agents in pneumonia include the following: a marked but unexplained decline in the prevalence of pneumococcal disease; continued recognition of pneumococcus as the most commonly identified bacterial pathogen, especially in critically ill patients; a greater frequency of pneumococcus in Europe compared to the United States; a greatly increased role for respiratory viruses; detection of Mycoplasma and Legionella in a far smaller proportion of cases than had been reported in 1990-2010; and, perhaps most importantly, failure to establish an etiologic diagnosis in more than 50% patients. The principal challenges for the future appear to be to create a balance between overly sensitive and sufficiently sensitive diagnostic techniques, to identify an etiologic agent in the one-half of cases that now go undiagnosed, and to investigate the role of so-called normal respiratory flora in causing pneumonia. All these factors need to be considered as guidelines for management of community acquired pneumonia are formulated.

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

The Principles and Practice of Medicine: Designed for the Use of Practitioners and Students of Medicine

The Principles and Practice of Medicine: Designed for the Use of Practitioners and Students of Medicine

hospitalizations for pneumonia after a decade of pneumococcal vaccination

Acute lobar pneumonia: prevention and serum treatment. Monographs of the Rockefeller Institute for Medical Research

Clinical and bacteriologic study of one thousand cases of lobar pneumonia

The significance of the newly classified types of pneumococci in disease: types IV to XX inclusive

The Management of the Pneumonias: For Physicians and Medical Students

Pneumonia in private practice: a study of 911 patients

A study of pneumonia in San Francisco

A further study of pneumonia in San Francisco

The Acute Bacterial Diseases

Bacterial colonization and clinical superinfection of the respiratory tract complicating antibiotic treatment of pneumonia

A study of the combined role of viruses, mycoplasmas and bacteria in adult pneumonia

Bacteria, viruses, and mycoplasmas in acute pneumonia in adults

Etiologies and characteristic features of pneumonias in a municipal hospital

The characteristics and mortality of outpatient-acquired pneumonia

Pneumonia in a Navajo community: a twoyear experience

Diagnosis of pneumococcal pneumonia by antigen detection in sputum

Bacterial pneumonia in the elderly

The value of the sputum gram's stain in community-acquired pneumonia

Management of pneumonia in the prospective payment era. A need for more clinician and support service interaction

Community-acquired pneumonia requiring hospitalization. Is it different in the elderly?

Diagnosis of community-acquired pneumonia: experience at a community hospital

New and emerging etiologies for community-acquired pneumonia with implications for therapy. A prospective multicenter study of 359 cases

Predicting death in patients hospitalized for community-acquired pneumonia

Microbial etiology of acute pneumonia in hospitalized patients

Community-acquired pneumonia: impact of immune status

Incidence of community-acquired pneumonia requiring hospitalization. Results of a population-based active surveillance study in Ohio. The Community-based Pneumonia Incidence Study Group

Processes and outcomes of care for patients with community-acquired pneumonia: results from the Pneumonia Patient Outcomes Research Team (PORT) cohort study

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

Quantitative PCR assay using sputum samples for rapid diagnosis of pneumococcal pneumonia in adult emergency department patients

A comparative study of community-acquired pneumonia patients admitted to the ward and the ICU

Can an etiologic agent be identified in adults who are hospitalized for community-acquired pneumonia: results of a one-year study

CDC EPIC Study Team. Communityacquired pneumonia requiring hospitalization among U.S. adults

A year's review of bacterial pneumonia at the central hospital of

Prospective epidemiologic survey of patients with community-acquired pneumonia requiring hospitalization in Switzerland

Enhancing the etiologic diagnosis of community-acquired pneumonia in adults using the urinary antigen assay

The routine use of urinary pneumococcal antigen test in hospitalised patients with community acquired pneumonia has limited impact for adjustment of antibiotic treatment

Definite, probable, and possible bacterial aetiologies of community-acquired pneumonia at different CRB-65 scores

Etiology of community-acquired pneumonia: increased microbiological yield with new diagnostic methods

Etiologic study of patients with community-acquired pneumonia

Incidence of community-acquired pneumonia and Chlamydia pneumoniae infection: a prospective multicentre study

Diagnosis of pneumococcal pneumonia by polymerase chain reaction (PCR) in whole blood: a prospective clinical study

Epidemiology of community-acquired pneumonia in adults: a population-based study

Epidemiology of community-acquired pneumonia in adult patients at the dawn of the 21st century: a prospective study on the Mediterranean coast of Spain

Impact of rapid urine antigen tests to determine the etiology of community-acquired pneumonia in adults

Assessment of analysis of urinary pneumococcal antigen by immunochromatography for etiologic diagnosis of community-acquired pneumonia in adults

Communityacquired pneumonia: aetiologic changes in a limited geographic area. An 11-year prospective study

Risk factors and outcome of community-acquired pneumonia due to gram-negative bacilli

Microbial aetiology of community-acquired pneumonia and its relation to severity

Current and potential usefulness of pneumococcal urinary antigen detection in hospitalized patients with community-acquired pneumonia to guide antimicrobial therapy

Poblational Study of Pneumonia (PSoP) Group. Etiology of community-acquired pneumonia in a population-based study: link between etiology and patients characteristics, process-of-care, clinical evolution and outcomes

Communityacquired pneumonia during the first post-pandemic influenza season: a prospective, multicentre cohort study

Mortality risk and etiologic spectrum of community-acquired pneumonia in hospitalized adult patients

Aetiology and risk factors of community-acquired pneumonia in hospitalized patients in Norway

Pneumococcal capsular antigen detection and pneumococcal serology in patients with community acquired pneumonia

Aetiology of community-acquired pneumonia: a prospective study among adults requiring admission to hospital

Clinical features predicting failure of pathogen identification in patients with community acquired pneumonia

Predicting pneumococcal community-acquired pneumonia in the emergency department: evaluation of clinical parameters

The incidence of legionella pneumonia: a 1-year prospective study in a large community hospital

Dalhoff K; Competence Network for Community-Acquired Pneumonia Study Group. Outcome of community-acquired pneumonia: influence of age, residence status and antimicrobial treatment

Community-acquired pneumonia. importance of initial noninvasive bacteriologic and radiographic investigations

Etiological diagnosis of pneumonia in military conscripts by combined use of bacterial culture and serological methods

Aetiological diagnosis of community acquired pneumonia: utility of rapid microbiological methods with respect to disease severity

Microbial pathogens of adult community-acquired pneumonia in Southern Estonia

Causes of pneumonia presenting to a district general hospital

Serotype prevalence in adults hospitalised with pneumococcal non-invasive community-acquired pneumonia

Etiology of community-acquired pneumonia. Evaluation by transtracheal aspiration, blood culture, or serology

Evaluation of PCR as rapid microbiological method in diagnosis of pneumococcal pneumonia

Incidence of community-acquired pneumonia caused by Chlamydia pneumoniae in Italian patients

Community-acquired pneumonia in adults: a multicentric observational AIPO study

Clinical and bacteriological study of 2000 typed cases of lobar pneumonia

Acute pulmonary infections, Delamar Lectures

Pneumonia with special reference to pneumococcus lobar pneumonia

Rivers TM, Horsfall FL, Jr. Viral and Rickettsial Diseases of Man

Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness

Recovery of new agent from patients with acute respiratory illness

An acute infection of the respiratory tract with atypical pneumonia. A disease entity probably caused by a filterable virus

Pneumococcal and "virus" pneumonia

Eaton agent pneumonia

Serological and epidemiological studies on primary atypical pneumonia and related acute upper respiratory disease

Respiratory disease in volunteers infected with Eaton agent: a preliminary report

The role of viruses, mycoplasmas and bacteria in acute pneumonia in civilian adults

Mycoplasma pneumoniae pneumonia in an urban area. Five years of surveillance

Clinical patterns of undifferentiated and other acute respiratory diseases in Army recruits

Pneumococcal pneumonia

Recherches sur quelques microbes strictement anaerobies et leur role en pathologie

Fusospirochetal disease of the lungs, its bacteriology, pathology and experimental reproduction

The bacteriology of abscess of the lung and methods for its study

The bacteriology of aspiration pneumonia

Anaerobic bacterial infections of the lung and pleural space

Transtracheal aspiration in the evaluation of patients with pneumonia

Etiologic diagnosis of lower respiratory tract infections

Percutaneous transtracheal aspiration in the diagnosis of anaerobic pulmonary infection

Transtracheal aspiration in pulmonary infection

The diagnostic value of sputum culture in acute pneumonia

Anaerobic bacterial infections of the lung

Diagnostic accuracy of transtracheal aspiration bacteriologic studies

Legionnaires' disease: description of an epidemic of pneumonia

Legionnaires' disease: isolation of a bacterium and demonstration of its role in other respiratory disease

Legionnaires' disease in Nottingham

Isolation of Pittsburgh pneumonia agent from nebulizers used in respiratory therapy

Pneumonia due to the Pittsburgh pneumonia agent: new clinical perspective with a review of the literature

Legionnaires' disease: new clinical perspective from a prospective pneumonia study

Hot water systems as sources of Legionella pneumophila in hospital and nonhospital plumbing fixtures

Ubiquitousness of Legionella pneumophila in the water supply of a hospital with endemic Legionnaires' disease

Pneumonia and acute febrile tracheobronchitis due to Haemophilus influenzae

A new Chlamydia psittaci strain, TWAR, isolated in acute respiratory tract infections

Pneumonia associated with the TWAR strain of Chlamydia

Respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults

Respiratory viral infections in immunocompetent and immunocompromised persons

Human metapneumovirus as a cause of community-acquired respiratory illness

Evaluation of the immunochromatographic Binax NOW assay for detection of Streptococcus pneumoniae urinary antigen in a prospective study of community-acquired pneumonia in Spain

Contribution of a urinary antigen assay (Binax NOW) to the early diagnosis of pneumococcal pneumonia

Rapid diagnosis of pneumococcal pneumonia among HIV-infected adults with urine antigen detection

A 3-year prospective study of a urinary antigen-detection test for Streptococcus pneumoniae in community-acquired pneumonia: utility and clinical impact on the reported etiology

Systematic review and meta-analysis of a urine-based pneumococcal antigen test for diagnosis of community-acquired pneumonia caused by Streptococcus pneumoniae

Development of a sensitive, multiplexed immunoassay using xMAP beads for detection of serotype-specific Streptococcus pneumoniae antigen in urine samples

Comparison of sputum and nasopharyngeal aspirate samples and of the PCR gene targets lytA and Spn9802 for quantitative PCR for rapid detection of pneumococcal pneumonia

Nonspecificity of assaying for IgG antibody to pneumolysin in circulating immune complexes as a means to diagnose pneumococcal pneumonia

Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia

Distribution of 13-valent pneumococcal conjugate vaccine Streptococcus pneumoniae serotypes in US adults aged ≥50 years with community-acquired pneumonia

Study of community acquired pneumonia aetiology (SCAPA) in adults admitted to hospital: implications for management guidelines

Prospective study of aetiology and outcome of adult lower-respiratory-tract infections in the community

Clinical impact of combined viral and bacterial infection in patients with community-acquired pneumonia

Efficacy of corticosteroids in community-acquired pneumonia: a randomized double-blinded clinical trial

Vaccines for preventing pneumococcal infection in adults

Current cigarette smoking among adults-United States

The role of Streptococcus pneumoniae in community-acquired pneumonia among adults in Europe: a meta-analysis

Diagnostic accuracy of a serotype-specific antigen test in community-acquired pneumonia

Lower respiratory tract virus findings in mechanically ventilated patients with severe community-acquired pneumonia

Community-acquired pneumonia

SOLITAIRE-ORAL Pneumonia Team. Efficacy and safety of oral solithromycin versus oral moxifloxacin for treatment of community-acquired bacterial pneumonia: a global, double-blind, multicentre, randomised, active-controlled, non-inferiority trial (SOLITAIRE-ORAL)

SOLITAIRE-IV: a randomized, double-blind, multicenter study comparing the efficacy and safety of intravenous-to-oral solithromycin to intravenous-to-oral moxifloxacin for treatment of community-acquired bacterial pneumonia

South-West Pneumococcus Study Group. Diagnosis of invasive pneumococcal infection by serotype-specific urinary antigen detection

Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults

Intervals between PCV13 and PPSV23 vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP)

Use of a rapid test of pneumococcal colonization density to diagnose pneumococcal pneumonia

The relevance of a novel quantitative assay to detect up to 40 major Streptococcus pneumoniae serotypes directly in clinical nasopharyngeal and blood specimens

Comprehensive molecular testing for respiratory pathogens in community-acquired pneumonia