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1.  Efficacy of Pneumococcal Nontypable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) in Young Latin American Children: A Double-Blind Randomized Controlled Trial 
PLoS Medicine  2014;11(6):e1001657.
In a double-blind randomized controlled trial, Xavier Saez-Llorens and colleagues examine the vaccine efficacy of PHiD-CV against community-acquired pneumonia in young children in Panama, Argentina, and Columbia.
Please see later in the article for the Editors' Summary
Background
The relationship between pneumococcal conjugate vaccine–induced antibody responses and protection against community-acquired pneumonia (CAP) and acute otitis media (AOM) is unclear. This study assessed the impact of the ten-valent pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on these end points. The primary objective was to demonstrate vaccine efficacy (VE) in a per-protocol analysis against likely bacterial CAP (B-CAP: radiologically confirmed CAP with alveolar consolidation/pleural effusion on chest X-ray, or non-alveolar infiltrates and C-reactive protein ≥ 40 µg/ml); other protocol-specified outcomes were also assessed.
Methods and Findings
This phase III double-blind randomized controlled study was conducted between 28 June 2007 and 28 July 2011 in Argentine, Panamanian, and Colombian populations with good access to health care. Approximately 24,000 infants received PHiD-CV or hepatitis control vaccine (hepatitis B for primary vaccination, hepatitis A at booster) at 2, 4, 6, and 15–18 mo of age. Interim analysis of the primary end point was planned when 535 first B-CAP episodes, occurring ≥2 wk after dose 3, were identified in the per-protocol cohort. After a mean follow-up of 23 mo (PHiD-CV, n = 10,295; control, n = 10,201), per-protocol VE was 22.0% (95% CI: 7.7, 34.2; one-sided p = 0.002) against B-CAP (conclusive for primary objective) and 25.7% (95% CI: 8.4%, 39.6%) against World Health Organization–defined consolidated CAP. Intent-to-treat VE was 18.2% (95% CI: 5.5%, 29.1%) against B-CAP and 23.4% (95% CI: 8.8%, 35.7%) against consolidated CAP. End-of-study per-protocol analyses were performed after a mean follow-up of 28–30 mo for CAP and invasive pneumococcal disease (IPD) (PHiD-CV, n = 10,211; control, n = 10,140) and AOM (n = 3,010 and 2,979, respectively). Per-protocol VE was 16.1% (95% CI: −1.1%, 30.4%; one-sided p = 0.032) against clinically confirmed AOM, 67.1% (95% CI: 17.0%, 86.9%) against vaccine serotype clinically confirmed AOM, 100% (95% CI: 74.3%, 100%) against vaccine serotype IPD, and 65.0% (95% CI: 11.1%, 86.2%) against any IPD. Results were consistent between intent-to-treat and per-protocol analyses. Serious adverse events were reported for 21.5% (95% CI: 20.7%, 22.2%) and 22.6% (95% CI: 21.9%, 23.4%) of PHiD-CV and control recipients, respectively. There were 19 deaths (n = 11,798; 0.16%) in the PHiD-CV group and 26 deaths (n = 11,799; 0.22%) in the control group. A significant study limitation was the lower than expected number of captured AOM cases.
Conclusions
Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice.
Trial registration
www.ClinicalTrials.gov NCT00466947
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pneumococcal diseases are illnesses caused by Streptococcus pneumoniae bacteria, pathogens (disease-causing organisms) that are transmitted through contact with infected respiratory secretions. S. pneumoniae causes mucosal diseases–infections of the lining of the body cavities that are connected to the outside world–such as community-acquired pneumonia (CAP; lung infection) and acute otitis media (AOM; middle-ear infection). It also causes invasive pneumococcal diseases (IPDs) such as septicemia and meningitis (infections of the bloodstream and the covering of the brain, respectively). Although pneumococcal diseases can sometimes be treated with antibiotics, CAP and IPDs are leading global causes of childhood deaths, particularly in developing countries. It is best therefore to avoid S. pneumoniae infections through vaccination. Vaccination primes the immune system to recognize and attack pathogens rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules that it recognizes as foreign (antigens). Because there are more than 90 S. pneumoniae variants (“serotypes”), each characterized by a different antigenic polysaccharide (complex sugar) coat, S. pneumoniae vaccines have to include antigens from multiple serotypes. For example, the PHiD-CV vaccine contains polysaccharides from ten S. pneumoniae serotypes.
Why Was This Study Done?
Although in most countries PHiD-CV has been licensed for protection against IPD and pneumococcal AOM, at the time of study, it was not known how well it protected against CAP and overall AOM, which are important public health problems. In this double-blind randomized controlled trial (the Clinical Otitis Media and Pneumonia Study; COMPAS), the researchers investigate the efficacy of PHiD-CV against CAP and AOM and assess other clinical end points, such as IPD, in Latin American infants. Double-blind randomized controlled trials compare the effects of interventions by assigning study participants to different interventions randomly and measuring predefined outcomes without the study participants or researchers knowing who has received which intervention until the trial is completed. Vaccine efficacy is the reduction in the incidence of a disease (the number of new cases that occur in a population in a given time) among trial participants who receive the vaccine compared to the incidence among participants who do not receive the vaccine.
What Did the Researchers Do and Find?
The researchers enrolled around 24,000 infants living in urban areas of Argentina, Panama, and Colombia. Half the infants were given PHiD-CV at 2, 4, and 6 months of age and a booster dose at age 15–18 months. The remaining infants were given a hepatitis control vaccine at the same intervals. The trial's primary end point was likely bacterial CAP (B-CAP) –radiologically confirmed CAP, with the airspaces (alveoli) in the lungs filled with liquid instead of gas (alveolar consolidation) or with non-alveolar infiltrates and raised blood levels of C-reactive protein (a marker of inflammation). In a planned interim analysis, which was undertaken after an average follow-up of 23 months, the vaccine efficacy in the per-protocol cohort (the group of participants who actually received their assigned intervention) was 22% against B-CAP. Intent-to-treat vaccine efficacy in the interim analysis (which considered all the trial participants regardless of whether they received their assigned intervention) was 18.2%. At the end of the study (average follow up 30 months), the vaccine efficacy against B-CAP was 18.2% and 16.7% in the per-protocol and intent-to-treat cohorts, respectively. Per-protocol vaccine efficacies against clinically confirmed AOM and vaccine serotype AOM were 16.1% and 67.1%, respectively. Against any IPD and against vaccine serotype IPD, the respective vaccine efficacies were 65% and 100%. Finally, about one-fifth of children who received PHiD-CV and a similar proportion who received the control vaccine experienced a serious adverse event (for example, gastroenteritis); 19 children who received PHiD-CV died compared to 26 children who received the control vaccine.
What Do These Findings Mean?
These findings indicate that in Latin America, a region with an intermediate burden of pneumococcal disease, PHiD-CV is efficacious against a broad range of pneumococcal diseases that often affect young children. The accuracy of these findings may be limited by the withdrawal of 14% of participants from the trial because of adverse media coverage and by the low number of reported cases of AOM. Moreover, because most study participants lived in urban areas, these findings may not be generalizable to rural settings. Despite these and other study limitations, these findings provide new information about the magnitude of the effect of PHiD-CV vaccination against CAP and AOM, two mucosal pneumococcal diseases of global public health importance.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001657.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination, including personal stories
Public Health England provides information on pneumococcal disease and on pneumococcal vaccines
The not-for-profit Immunization Action Coalition has information on pneumococcal disease, including personal stories
The GAVI Alliance provides information about pneumococcal disease and the importance of vaccination
MedlinePlus has links to further information about pneumococcal infections, including pneumonia and otitis media (in English and Spanish)
More information about COMPAS is available
The European Medicines Agency provides information about PHiD-CV (Synflorix)
doi:10.1371/journal.pmed.1001657
PMCID: PMC4043495  PMID: 24892763
2.  Measuring Coverage in MNCH: A Prospective Validation Study in Pakistan and Bangladesh on Measuring Correct Treatment of Childhood Pneumonia 
PLoS Medicine  2013;10(5):e1001422.
Background
Antibiotic treatment for pneumonia as measured by Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS) is a key indicator for tracking progress in achieving Millennium Development Goal 4. Concerns about the validity of this indicator led us to perform an evaluation in urban and rural settings in Pakistan and Bangladesh.
Methods and Findings
Caregivers of 950 children under 5 y with pneumonia and 980 with “no pneumonia” were identified in urban and rural settings and allocated for DHS/MICS questions 2 or 4 wk later. Study physicians assigned a diagnosis of pneumonia as reference standard; the predictive ability of DHS/MICS questions and additional measurement tools to identify pneumonia versus non-pneumonia cases was evaluated.
Results at both sites showed suboptimal discriminative power, with no difference between 2- or 4-wk recall. Individual patterns of sensitivity and specificity varied substantially across study sites (sensitivity 66.9% and 45.5%, and specificity 68.8% and 69.5%, for DHS in Pakistan and Bangladesh, respectively). Prescribed antibiotics for pneumonia were correctly recalled by about two-thirds of caregivers using DHS questions, increasing to 72% and 82% in Pakistan and Bangladesh, respectively, using a drug chart and detailed enquiry.
Conclusions
Monitoring antibiotic treatment of pneumonia is essential for national and global programs. Current (DHS/MICS questions) and proposed new (video and pneumonia score) methods of identifying pneumonia based on maternal recall discriminate poorly between pneumonia and children with cough. Furthermore, these methods have a low yield to identify children who have true pneumonia. Reported antibiotic treatment rates among these children are therefore not a valid proxy indicator of pneumonia treatment rates. These results have important implications for program monitoring and suggest that data in its current format from DHS/MICS surveys should not be used for the purpose of monitoring antibiotic treatment rates in children with pneumonia at the present time.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pneumonia is a major cause of death in children younger than five years across the globe, with approximately 1.2 million children younger than five years dying from pneumonia every year. Pneumonia can be caused by bacteria, fungi, or viruses. It is possible to effectively treat bacterial pneumonia with appropriate antibiotics; however, only about 30% of children receive the antibiotic treatment they need. The Millennium Development Goals (MDGs) are eight international development goals that were established in 2000. The fourth goal (MDG 4) aims to reduce child mortality, specifically, to reduce the under-five mortality rate by two-thirds, between 1990 and 2015. Given that approximately 18% of all deaths in children under five are caused by pneumonia, providing universal coverage with effective treatments for pneumonia is an important part of MDG 4.
To ensure that MDG 4 targets are met, it is important to measure progress in providing effective treatments. For pneumonia, one of the key indicators for measuring progress is the proportion of children with pneumonia in a population who receive antibiotic treatment, also known as the antibiotic treatment rate. The antibiotic treatment rate is often measured using surveys, such as the Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS), which collect nationally representative data about populations and health in developing countries.
Why Was This Study Done?
Concerns have been raised about whether information collected from DHS and MICS is able to accurately identify cases of pneumonia. In a clinical setting, pneumonia is typically diagnosed based on a combination of physical symptoms, including coughing, rapid breathing, or difficulty breathing, and a chest X-ray. The surveys rely on information collected from interviews of mothers and primary caregivers using structured questions about whether the child has experienced physical symptoms in the past two weeks and whether these were chest-related. The DHS survey labels this condition as “symptoms of acute respiratory infection,” while the MICS survey uses the term “suspected pneumonia.” Thus, these surveys provide a proxy measure for pneumonia that is limited by the reliance on the recall of symptoms by the mother or caregiver. Here the researchers have evaluated the use of these surveys to discriminate physician-diagnosed pneumonia and to provide accurate recall of antibiotic treatment in urban and rural settings in Pakistan and Bangladesh.
What Did the Researchers Do and Find?
The researchers identified caregivers of 950 children under five years with pneumonia and 980 who had a cough or cold but did not have pneumonia from urban and rural settings in Pakistan and Bangladesh. Cases of pneumonia were identified based on a physician diagnosis using World Health Organization guidelines. They randomly assigned caregivers to be interviewed using DHS and MICS questions with either a two- or four-week recall period. They then assessed how well the DHS and MICS questions were able to accurately diagnose pneumonia and accurately recall antibiotic use. In addition, they asked caregivers to complete a pneumonia score questionnaire and showed them a video tool showing children with and without pneumonia, as well as a medication drug chart, to determine if these alternative measures improved the accuracy of pneumonia diagnosis or recall of antibiotic use. They found that both surveys, the pneumonia score, and the video tool had poor ability to discriminate between children with and without physician-diagnosed pneumonia, and there were no differences between using two- or four-week recall. The sensitivity (proportion of pneumonia cases that were correctly identified) ranged from 23% to 72%, and the specificity (the proportion of “no pneumonia” cases that were correctly identified) ranged from 53% to 83%, depending on the setting. They also observed that prescribed antibiotics for pneumonia were correctly recalled by about two-thirds of caregivers using DHS questions, and this increased to about three-quarters of caregivers when using a drug chart and detailed enquiry.
What Do These Findings Mean?
The findings of this study suggest that the current use of questions from DHS and MICS based on mother or caregiver recall are not sufficient for accurately identifying pneumonia and antibiotic use in children. Because these surveys have poor ability to identify children who have true pneumonia, reported antibiotic treatment rates for children with pneumonia based on data from these surveys may not be accurate, and these surveys should not be used to monitor treatment rates. These findings should be interpreted cautiously, given the relatively high rate of loss to follow-up and delayed follow-up in some of the children and because some of the settings in this study may not be similar to other low-income settings.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001422.
More information is available on the United Nations goal to reduce child mortality (MDG 4)
The World Health Organization provides information on pneumonia, its impact on children, and the global action plan for prevention and control of pneumonia
More information is available on Demographic and Health Surveys and Multiple Indicator Cluster Surveys
KidsHealth, a resource maintained by the Nemours Foundation (a not-for-profit organization for children's health) provides information for parents on pneumonia (in English and Spanish)
MedlinePlus provides links to additional information on pneumonia (in English and Spanish)
doi:10.1371/journal.pmed.1001422
PMCID: PMC3646205  PMID: 23667339
3.  Cardiac Complications in Patients with Community-Acquired Pneumonia: A Systematic Review and Meta-Analysis of Observational Studies 
PLoS Medicine  2011;8(6):e1001048.
Vicente Corrales-Medina and colleagues report estimates of the risk of cardiac complications among patients with community-acquired pneumonia from a systematic review and meta-analysis.
Background
Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality. CAP can trigger acute cardiac events. We sought to determine the incidence of major cardiac complications in CAP patients to characterize the magnitude of this problem.
Methods and Findings
Two investigators searched MEDLINE, Scopus, and EMBASE for observational studies of immunocompetent adults with clinical and radiological evidence of CAP that reported any of the following: overall cardiac complications, incident heart failure, acute coronary syndromes (ACS), or incident cardiac arrhythmias occurring within 30 days of CAP diagnosis. At a minimum, studies had to establish enrolment procedures and inclusion and exclusion criteria, enrol their patients sequentially, and report the incidence of cardiac complications as a function of their entire cohorts. Studies with focus on nosocomial or health care–associated pneumonia were not included. Review of 2,176 citations yielded 25 articles that met eligibility and minimum quality criteria. Seventeen articles (68%) reported cohorts of CAP inpatients. In this group, the pooled incidence rates for overall cardiac complications (six cohorts, 2,119 patients), incident heart failure (eights cohorts, 4,215 patients), acute coronary syndromes (six cohorts, 2,657 patients), and incident cardiac arrhythmias (six cohorts, 2,596 patients), were 17.7% (confidence interval [CI] 13.9–22.2), 14.1% (9.3–20.6), 5.3% (3.2–8.6), and 4.7% (2.4–8.9), respectively. One article reported cardiac complications in CAP outpatients, four in low-risk (not severely ill) inpatients, and three in high-risk inpatients. The incidences for all outcomes except overall cardiac complications were lower in the two former groups and higher in the latter. One additional study reported on CAP outpatients and low-risk inpatients without discriminating between these groups. Twelve studies (48%) asserted the evaluation of cardiac complications in their methods but only six (24%) provided a definition for them. Only three studies, all examining ACS, carried out risk factor analysis for these events. No study analyzed the association between cardiac complications and other medical complications or their impact on other CAP outcomes.
Conclusions
Major cardiac complications occur in a substantial proportion of patients with CAP. Physicians and patients need to appreciate the significance of this association for timely recognition and management of these events. Strategies aimed at preventing pneumonia (i.e., influenza and pneumococcal vaccination) in high-risk populations need to be optimized. Further research is needed to understand the mechanisms underlying this association, measure the impact of cardiac complications on other CAP outcomes, identify those patients with CAP at high risk of developing cardiac complications, and design strategies to prevent their occurrence in this population.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Community-acquired pneumonia (CAP), that is, pneumonia infections contracted outside of hospital or health care settings, is a common condition and can be fatal, particularly to older people. For example, every year, an estimated 5–6 million people contract this form of pneumonia in the US, leading to 1.1 million people being admitted to hospitals and causing 60,000 deaths—the most frequent cause of infectious disease-related mortality. In the US for example, more than half of older patients who present to the hospital with CAP have preexisting chronic cardiac conditions—an important fact given that acute infections, such as CAP, can affect the cardiovascular system in various ways and precipitate acute cardiac events, such as heart failure, heart attacks, and cardiac arrhythmias.
Why Was This Study Done?
Although it is bio-medically plausible that a considerable proportion of patients with CAP have cardiac complications, systematic data on the scale of this potential problem are lacking—a concerning omission given the important implications for health policy-making and direct patient care. Therefore, in this study, the researchers conducted a systematic review to examine the published literature on cardiac complications in patients with CAP in order to characterize the nature and significance of this association, and to identify areas that require further research and investigation.
What Did the Researchers Do and Find?
The researchers searched MEDLINE, Scopus, and EMBASE for all relevant articles published in English, French, or Spanish languages until June 2010. The researchers used strict criteria to select appropriate articles (such as radiographic evidence of CAP) and only selected studies that had outcomes of the incidence of cardiac complications, such as incident (new or worsening) heart failure, acute coronary syndromes (acute myocardial infarction or unstable angina), and incident cardiac arrhythmias within 30 days of diagnosis of CAP.
Using these methods, the researchers identified 2,176 articles for review and selected 25 eligible papers for their analysis. Seventeen articles (68%) reported cohorts of CAP inpatients. In this group, the pooled incidence rates of overall cardiac complications (six cohorts, 2,119 patients), incident heart failure (eight cohorts, 4,215 patients), acute coronary syndromes (six cohorts, 2,657 patients), and incident cardiac arrhythmias (six cohorts, 2,596 patients), were 17.7%, 14.1%, 5.3%, and 4.7% respectively. Only three studies, (all of acute coronary syndromes) did risk factor analysis for these events. Possible risk factors identified included older age, preexisting congestive heart failure, severity of pneumonia, and the use of insulin by glucose sliding scales in hospitalized patients. No study analyzed the association between cardiac complications and other medical complications (such as acute renal failure, respiratory failure, shock, etc.) or their impact on other outcomes, such as death, in patients with CAP.
What Do These Findings Mean?
Although limited to a mostly descriptive analysis, these findings clearly show that major cardiac complications occur in a significant proportion of patients with CAP, especially in those admitted to hospital. These findings have important clinical and public health implications. Clinicians should be more aware of the significance of the association between CAP and cardiac complications to better inform, treat, and manage patients. Physicians and health officials need to increase efforts to optimize the rates of influenza and pneumococcal vaccination among older people and those with chronic cardiac conditions to reduce the incidence of CAP in these high-risk populations. There needs to be more consideration given to the potential impact of cardiac complications on mortality and costs associated with CAP. Finally, these findings highlight the need for prospective, well-designed, and adequately powered studies of cardiac complications in patients with CAP. More research attention should be given to this important area in order to improve the outcomes for patients with CAP and to decrease the consequent burden on health care systems through recognition of risk, prevention, and intervention on acute cardiac complications.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001048.
Information can be found on Wikipedia on community-acquired pneumonia (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The US Centers for Disease Control provide patient information on community-acquired pneumonia
The American Heart Association provides information on heart failure, acute coronary syndromes, and arrhythmias
doi:10.1371/journal.pmed.1001048
PMCID: PMC3125176  PMID: 21738449
4.  Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this analysis was to determine the effectiveness of the influenza vaccination and the pneumococcal vaccination in patients with chronic obstructive pulmonary disease (COPD) in reducing the incidence of influenza-related illness or pneumococcal pneumonia.
Clinical Need: Condition and Target Population
Influenza Disease
Influenza is a global threat. It is believed that the risk of a pandemic of influenza still exists. Three pandemics occurred in the 20th century which resulted in millions of deaths worldwide. The fourth pandemic of H1N1 influenza occurred in 2009 and affected countries in all continents.
Rates of serious illness due to influenza viruses are high among older people and patients with chronic conditions such as COPD. The influenza viruses spread from person to person through sneezing and coughing. Infected persons can transfer the virus even a day before their symptoms start. The incubation period is 1 to 4 days with a mean of 2 days. Symptoms of influenza infection include fever, shivering, dry cough, headache, runny or stuffy nose, muscle ache, and sore throat. Other symptoms such as nausea, vomiting, and diarrhea can occur.
Complications of influenza infection include viral pneumonia, secondary bacterial pneumonia, and other secondary bacterial infections such as bronchitis, sinusitis, and otitis media. In viral pneumonia, patients develop acute fever and dyspnea, and may further show signs and symptoms of hypoxia. The organisms involved in bacterial pneumonia are commonly identified as Staphylococcus aureus and Hemophilus influenza. The incidence of secondary bacterial pneumonia is most common in the elderly and those with underlying conditions such as congestive heart disease and chronic bronchitis.
Healthy people usually recover within one week but in very young or very old people and those with underlying medical conditions such as COPD, heart disease, diabetes, and cancer, influenza is associated with higher risks and may lead to hospitalization and in some cases death. The cause of hospitalization or death in many cases is viral pneumonia or secondary bacterial pneumonia. Influenza infection can lead to the exacerbation of COPD or an underlying heart disease.
Streptococcal Pneumonia
Streptococcus pneumoniae, also known as pneumococcus, is an encapsulated Gram-positive bacterium that often colonizes in the nasopharynx of healthy children and adults. Pneumococcus can be transmitted from person to person during close contact. The bacteria can cause illnesses such as otitis media and sinusitis, and may become more aggressive and affect other areas of the body such as the lungs, brain, joints, and blood stream. More severe infections caused by pneumococcus are pneumonia, bacterial sepsis, meningitis, peritonitis, arthritis, osteomyelitis, and in rare cases, endocarditis and pericarditis.
People with impaired immune systems are susceptible to pneumococcal infection. Young children, elderly people, patients with underlying medical conditions including chronic lung or heart disease, human immunodeficiency virus (HIV) infection, sickle cell disease, and people who have undergone a splenectomy are at a higher risk for acquiring pneumococcal pneumonia.
Technology
Influenza and Pneumococcal Vaccines
Trivalent Influenza Vaccines in Canada
In Canada, 5 trivalent influenza vaccines are currently authorized for use by injection. Four of these are formulated for intramuscular use and the fifth product (Intanza®) is formulated for intradermal use.
The 4 vaccines for intramuscular use are:
Fluviral (GlaxoSmithKline), split virus, inactivated vaccine, for use in adults and children ≥ 6 months;
Vaxigrip (Sanofi Pasteur), split virus inactivated vaccine, for use in adults and children ≥ 6 months;
Agriflu (Novartis), surface antigen inactivated vaccine, for use in adults and children ≥ 6 months; and
Influvac (Abbott), surface antigen inactivated vaccine, for use in persons ≥ 18 years of age.
FluMist is a live attenuated virus in the form of an intranasal spray for persons aged 2 to 59 years. Immunization with current available influenza vaccines is not recommended for infants less than 6 months of age.
Pneumococcal Vaccine
Pneumococcal polysaccharide vaccines were developed more than 50 years ago and have progressed from 2-valent vaccines to the current 23-valent vaccines to prevent diseases caused by 23 of the most common serotypes of S pneumoniae. Canada-wide estimates suggest that approximately 90% of cases of pneumococcal bacteremia and meningitis are caused by these 23 serotypes. Health Canada has issued licenses for 2 types of 23-valent vaccines to be injected intramuscularly or subcutaneously:
Pneumovax 23® (Merck & Co Inc. Whitehouse Station, NJ, USA), and
Pneumo 23® (Sanofi Pasteur SA, Lion, France) for persons 2 years of age and older.
Other types of pneumococcal vaccines licensed in Canada are for pediatric use. Pneumococcal polysaccharide vaccine is injected only once. A second dose is applied only in some conditions.
Research Questions
What is the effectiveness of the influenza vaccination and the pneumococcal vaccination compared with no vaccination in COPD patients?
What is the safety of these 2 vaccines in COPD patients?
What is the budget impact and cost-effectiveness of these 2 vaccines in COPD patients?
Research Methods
Literature search
Search Strategy
A literature search was performed on July 5, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2000 to July 5, 2010. The search was updated monthly through the AutoAlert function of the search up to January 31, 2011. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Data extraction was carried out by the author.
Inclusion Criteria
studies comparing clinical efficacy of the influenza vaccine or the pneumococcal vaccine with no vaccine or placebo;
randomized controlled trials published between January 1, 2000 and January 31, 2011;
studies including patients with COPD only;
studies investigating the efficacy of types of vaccines approved by Health Canada;
English language studies.
Exclusion Criteria
non-randomized controlled trials;
studies investigating vaccines for other diseases;
studies comparing different variations of vaccines;
studies in which patients received 2 or more types of vaccines;
studies comparing different routes of administering vaccines;
studies not reporting clinical efficacy of the vaccine or reporting immune response only;
studies investigating the efficacy of vaccines not approved by Health Canada.
Outcomes of Interest
Primary Outcomes
Influenza vaccination: Episodes of acute respiratory illness due to the influenza virus.
Pneumococcal vaccination: Time to the first episode of community-acquired pneumonia either due to pneumococcus or of unknown etiology.
Secondary Outcomes
rate of hospitalization and mechanical ventilation
mortality rate
adverse events
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses. The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Efficacy of the Influenza Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The influenza vaccination was associated with significantly fewer episodes of influenza-related acute respiratory illness (ARI). The incidence density of influenza-related ARI was:
All patients: vaccine group: (total of 4 cases) = 6.8 episodes per 100 person-years; placebo group: (total of 17 cases) = 28.1 episodes per 100 person-years, (relative risk [RR], 0.2; 95% confidence interval [CI], 0.06−0.70; P = 0.005).
Patients with severe airflow obstruction (forced expiratory volume in 1 second [FEV1] < 50% predicted): vaccine group: (total of 1 case) = 4.6 episodes per 100 person-years; placebo group: (total of 7 cases) = 31.2 episodes per 100 person-years, (RR, 0.1; 95% CI, 0.003−1.1; P = 0.04).
Patients with moderate airflow obstruction (FEV1 50%−69% predicted): vaccine group: (total of 2 cases) = 13.2 episodes per 100 person-years; placebo group: (total of 4 cases) = 23.8 episodes per 100 person-years, (RR, 0.5; 95% CI, 0.05−3.8; P = 0.5).
Patients with mild airflow obstruction (FEV1 ≥ 70% predicted): vaccine group: (total of 1 case) = 4.5 episodes per 100 person-years; placebo group: (total of 6 cases) = 28.2 episodes per 100 person-years, (RR, 0.2; 95% CI, 0.003−1.3; P = 0.06).
The Kaplan-Meier survival analysis showed a significant difference between the vaccinated group and the placebo group regarding the probability of not acquiring influenza-related ARI (log-rank test P value = 0.003). Overall, the vaccine effectiveness was 76%. For categories of mild, moderate, or severe COPD the vaccine effectiveness was 84%, 45%, and 85% respectively.
With respect to hospitalization, fewer patients in the vaccine group compared with the placebo group were hospitalized due to influenza-related ARIs, although these differences were not statistically significant. The incidence density of influenza-related ARIs that required hospitalization was 3.4 episodes per 100 person-years in the vaccine group and 8.3 episodes per 100 person-years in the placebo group (RR, 0.4; 95% CI, 0.04−2.5; P = 0.3; log-rank test P value = 0.2). Also, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD.
Fewer patients in the vaccine group compared with the placebo group required mechanical ventilation due to influenza-related ARIs. However, these differences were not statistically significant. The incidence density of influenza-related ARIs that required mechanical ventilation was 0 episodes per 100 person-years in the vaccine group and 5 episodes per 100 person-years in the placebo group (RR, 0.0; 95% CI, 0−2.5; P = 0.1; log-rank test P value = 0.4). In addition, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD. The effectiveness of the influenza vaccine in preventing influenza-related ARIs and influenza-related hospitalization was not related to age, sex, severity of COPD, smoking status, or comorbid diseases.
safety
Overall, significantly more patients in the vaccine group than the placebo group experienced local adverse reactions (vaccine: 17 [27%], placebo: 4 [6%]; P = 0.002). Significantly more patients in the vaccine group than the placebo group experienced swelling (vaccine 4, placebo 0; P = 0.04) and itching (vaccine 4, placebo 0; P = 0.04). Systemic reactions included headache, myalgia, fever, and skin rash and there were no significant differences between the 2 groups for these reactions (vaccine: 47 [76%], placebo: 51 [81%], P = 0.5).
With respect to lung function, dyspneic symptoms, and exercise capacity, there were no significant differences between the 2 groups at 1 week and at 4 weeks in: FEV1, maximum inspiratory pressure at residual volume, oxygen saturation level of arterial blood, visual analogue scale for dyspneic symptoms, and the 6 Minute Walking Test for exercise capacity.
There was no significant difference between the 2 groups with regard to the probability of not acquiring total ARIs (influenza-related and/or non-influenza-related); (log-rank test P value = 0.6).
Summary of Efficacy of the Pneumococcal Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The Kaplan-Meier survival analysis showed no significant differences between the group receiving the penumoccocal vaccination and the control group for time to the first episode of community-acquired pneumonia due to pneumococcus or of unknown etiology (log-rank test 1.15; P = 0.28). Overall, vaccine efficacy was 24% (95% CI, −24 to 54; P = 0.33).
With respect to the incidence of pneumococcal pneumonia, the Kaplan-Meier survival analysis showed a significant difference between the 2 groups (vaccine: 0/298; control: 5/298; log-rank test 5.03; P = 0.03).
Hospital admission rates and median length of hospital stays were lower in the vaccine group, but the difference was not statistically significant. The mortality rate was not different between the 2 groups.
Subgroup Analysis
The Kaplan-Meier survival analysis showed significant differences between the vaccine and control groups for pneumonia due to pneumococcus and pneumonia of unknown etiology, and when data were analyzed according to subgroups of patients (age < 65 years, and severe airflow obstruction FEV1 < 40% predicted). The accumulated percentage of patients without pneumonia (due to pneumococcus and of unknown etiology) across time was significantly lower in the vaccine group than in the control group in patients younger than 65 years of age (log-rank test 6.68; P = 0.0097) and patients with a FEV1 less than 40% predicted (log-rank test 3.85; P = 0.0498).
Vaccine effectiveness was 76% (95% CI, 20−93; P = 0.01) for patients who were less than 65 years of age and −14% (95% CI, −107 to 38; P = 0.8) for those who were 65 years of age or older. Vaccine effectiveness for patients with a FEV1 less than 40% predicted and FEV1 greater than or equal to 40% predicted was 48% (95% CI, −7 to 80; P = 0.08) and −11% (95% CI, −132 to 47; P = 0.95), respectively. For patients who were less than 65 years of age (FEV1 < 40% predicted), vaccine effectiveness was 91% (95% CI, 35−99; P = 0.002).
Cox modelling showed that the effectiveness of the vaccine was dependent on the age of the patient. The vaccine was not effective in patients 65 years of age or older (hazard ratio, 1.53; 95% CI, 0.61−a2.17; P = 0.66) but it reduced the risk of acquiring pneumonia by 80% in patients less than 65 years of age (hazard ratio, 0.19; 95% CI, 0.06−0.66; P = 0.01).
safety
No patients reported any local or systemic adverse reactions to the vaccine.
PMCID: PMC3384373  PMID: 23074431
5.  Carriage of Mycoplasma pneumoniae in the Upper Respiratory Tract of Symptomatic and Asymptomatic Children: An Observational Study 
PLoS Medicine  2013;10(5):e1001444.
In order to determine the possible asymptomatic carriage of Mycoplasma pneumoniae in the upper respiratory tracts of children, Emiel Spuesens and colleagues investigate the prevalence of M. pneumoniae in symptomatic and asymptomatic children at a hospital in The Netherlands.
Please see later in the article for the Editors' Summary
Background
Mycoplasma pneumoniae is thought to be a common cause of respiratory tract infections (RTIs) in children. The diagnosis of M. pneumoniae RTIs currently relies on serological methods and/or the detection of bacterial DNA in the upper respiratory tract (URT). It is conceivable, however, that these diagnostic methods also yield positive results if M. pneumoniae is carried asymptomatically in the URT. Positive results from these tests may therefore not always be indicative of a symptomatic infection. The existence of asymptomatic carriage of M. pneumoniae has not been established. We hypothesized that asymptomatic carriage in children exists and investigated whether colonization and symptomatic infection could be differentiated by current diagnostic methods.
Methods and Findings
This study was conducted at the Erasmus MC–Sophia Children's Hospital and the after-hours General Practitioners Cooperative in Rotterdam, The Netherlands. Asymptomatic children (n = 405) and children with RTI symptoms (n = 321) aged 3 mo to 16 y were enrolled in a cross-sectional study from July 1, 2008, to November 30, 2011. Clinical data, pharyngeal and nasopharyngeal specimens, and serum samples were collected. The primary objective was to differentiate between colonization and symptomatic infection with M. pneumoniae by current diagnostic methods, especially real-time PCR. M. pneumoniae DNA was detected in 21.2% (95% CI 17.2%–25.2%) of the asymptomatic children and in 16.2% (95% CI 12.2%–20.2%) of the symptomatic children (p = 0.11). Neither serology nor quantitative PCR nor culture differentiated asymptomatic carriage from infection. A total of 202 children were tested for the presence of other bacterial and viral pathogens. Two or more pathogens were found in 56% (63/112) of the asymptomatic children and in 55.5% (50/90) of the symptomatic children. Finally, longitudinal sampling showed persistence of M. pneumoniae in the URT for up to 4 mo. Fifteen of the 21 asymptomatic children with M. pneumoniae and 19 of the 22 symptomatic children with M. pneumoniae in this longitudinal follow-up tested negative after 1 mo.
Conclusions
Although our study has limitations, such as a single study site and limited sample size, our data indicate that the presence of M. pneumoniae in the URT is common in asymptomatic children. The current diagnostic tests for M. pneumoniae are unable to differentiate between asymptomatic carriage and symptomatic infection.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pneumonia (a form of acute respiratory infection) is the single largest cause of death in children worldwide, killing an estimated 1.2 million children aged five and under every year, particularly in South Asia and sub-Saharan Africa. In these settings, bacterial infections with Streptococcus pneumoniae and Haemophilus influenzae are the most common causes of bacterial pneumonia. However, in high-income settings, bacterial infection with Mycoplasma pneumoniae is a major cause of upper and lower respiratory tract infections in children: over one-third of childhood cases of community-acquired pneumonia that require admission to a hospital are caused by M. pneumoniae. Currently, diagnosis of M. pneumoniae infections relies on the detection of antibodies against M. pneumoniae in the blood or detection of bacterial DNA in samples from the upper respiratory tract through polymerase chain reaction (PCR) tests.
Why Was This Study Done?
Other bacteria, such as Streptococcus pneumoniae, are commonly present in children without causing infection, a situation known as asymptomatic carriage. However, to date, it is unknown whether M. pneumoniae is also commonly carried in the upper respiratory tract of children without causing symptoms or leading to infection. The possibility of asymptomatic carriage of M. pneumoniae could have major implications for the interpretation of the results of diagnostic tests and also for clinical management. So in this study conducted in The Netherlands, the researchers investigated whether asymptomatic carriage of M. pneumoniae exists and also whether symptomatic infection could be differentiated from asymptomatic carriage by current diagnostic methods.
What Did the Researchers Do and Find?
Between 2008 and 2011, the researchers recruited children aged between three months and 16 years attending a hospital in Rotterdam for an elective surgical procedure (asymptomatic group) or admitted with a respiratory tract infection (symptomatic group). All children had blood tests and respiratory samples (nasopharyngeal swab) taken on admission and were tested for other pathogens. The researchers invited children who tested positive for M. pneumoniae by PCR to attend for further follow-up and tested them monthly for the presence of M. pneumoniae DNA in the upper respiratory tract until the test was negative on two occasions. Using these methods, the researchers recruited 726 children over the study period—405 in the asymptomatic group and 321 in the symptomatic group. The researchers found that the prevalence of M. pneumoniae did not differ between the asymptomatic group and the symptomatic group, with prevalences of 21.2% and 16.2%, respectively (the prevalence of M. pneumoniae also did not differ significantly between those with lower versus upper respiratory infection). There were also no differences in prevalence in the asymptomatic and symptomatic groups when diagnosed using blood tests. The researchers found a high rate of multiple, coexisting bacterial and viral pathogens in both asymptomatic and symptomatic children: two or more pathogens were found in 56% (63/112) of the asymptomatic children and in 55.5% (50/90) of the symptomatic children. Furthermore, season and the year of enrollment affected the prevalence of M. pneumoniae in the asymptomatic group, ranging from 3% during the spring of 2009 to 58% during the summer of 2010. Finally, of the 21 children from the asymptomatic group who participated in the follow-up study, 15 (71%) tested negative within one month, and in the symptomatic group, 19 of 22 children (86%) tested negative after the first visit.
What Do These Findings Mean?
These findings show that M. pneumoniae is carried at high rates in the upper respiratory tracts of healthy children, and that this asymptomatic carriage cannot be differentiated from symptomatic respiratory tract infection by diagnostic tests (serology or PCR). As the prevalence of M. pneumoniae varied between year and season, carriage of M. pneumoniae may follow a cyclic epidemic pattern. This study is from a single study site in one city in The Netherlands, with a relatively small number of children, and so these findings may not be generalizable to other populations. However, as this study suggests that current diagnostic tests do not discriminate between carriage and infection, clinicians may need to reconsider the clinical significance of a positive test result. Future studies are needed to address this diagnostic challenge and also to investigate possible factors that may affect the progression of asymptomatic carriage of M. pneumoniae to symptomatic infection.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001444.
MicrobeWiki has more information on M. pneumoniae
Lab Tests Online explains current tests for M. pneumoniae
doi:10.1371/journal.pmed.1001444
PMCID: PMC3653782  PMID: 23690754
6.  Antibiotic Selection Pressure and Macrolide Resistance in Nasopharyngeal Streptococcus pneumoniae: A Cluster-Randomized Clinical Trial 
PLoS Medicine  2010;7(12):e1000377.
Jeremy Keenan and colleagues report that during a cluster-randomized clinical trial in Ethiopia, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to receive azithromycin compared with untreated control communities.
Background
It is widely thought that widespread antibiotic use selects for community antibiotic resistance, though this has been difficult to prove in the setting of a community-randomized clinical trial. In this study, we used a randomized clinical trial design to assess whether macrolide resistance was higher in communities treated with mass azithromycin for trachoma, compared to untreated control communities.
Methods and Findings
In a cluster-randomized trial for trachoma control in Ethiopia, 12 communities were randomized to receive mass azithromycin treatment of children aged 1–10 years at months 0, 3, 6, and 9. Twelve control communities were randomized to receive no antibiotic treatments until the conclusion of the study. Nasopharyngeal swabs were collected from randomly selected children in the treated group at baseline and month 12, and in the control group at month 12. Antibiotic susceptibility testing was performed on Streptococcus pneumoniae isolated from the swabs using Etest strips. In the treated group, the mean prevalence of azithromycin resistance among all monitored children increased from 3.6% (95% confidence interval [CI] 0.8%–8.9%) at baseline, to 46.9% (37.5%–57.5%) at month 12 (p = 0.003). In control communities, azithromycin resistance was 9.2% (95% CI 6.7%–13.3%) at month 12, significantly lower than the treated group (p<0.0001). Penicillin resistance was identified in 0.8% (95% CI 0%–4.2%) of isolates in the control group at 1 year, and in no isolates in the children-treated group at baseline or 1 year.
Conclusions
This cluster-randomized clinical trial demonstrated that compared to untreated control communities, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to intensive azithromycin treatment. Mass azithromycin distributions were given more frequently than currently recommended by the World Health Organization's trachoma program. Azithromycin use in this setting did not select for resistance to penicillins, which remain the drug of choice for pneumococcal infections.
Trial registration
www.ClinicalTrials.gov NCT00322972
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 1928, Alexander Fleming discovered penicillin, the first antibiotic (a drug that kills bacteria). By the early 1940s, scientists were able to make large quantities of penicillin and, in the following decades, several other classes of powerful antibiotics were discovered. For example, erythromycin—the first macrolide antibiotic—was developed in the early 1950s. For a time, it looked like bacteria and the diseases that they cause had been defeated. But bacteria rapidly become resistant to antibiotics. Under the “selective pressure” of an antibiotic, bacteria that have acquired a random change in their DNA that allows them to survive in the antibiotic's presence outgrow nonresistant bacteria. What's more, bacteria can transfer antibiotic resistance genes between themselves. Nowadays, antibiotic resistance is a major public health concern. Almost every type of disease-causing bacteria has developed resistance to one or more antibiotic in clinical use and multi-drug resistant bacteria are causing outbreaks of potentially fatal diseases in hospitals and in the community.
Why Was This Study Done?
Although epidemiological studies (investigations of the causes, distribution, and control of disease in population) show a correlation between antibiotic use and antibiotic resistance in populations, such studies cannot prove that antibiotic use actually causes antibiotic resistance. It could be that the people who use more antibiotics share other characteristics that increase their chance of developing antibiotic resistance (so-called “confounding”). A causal link between antibiotic use and the development of antibiotic resistance can only be established by doing a randomized controlled trial. In such trials, groups of individuals are chosen at random to avoid confounding, given different treatments, and outcomes in the different groups compared. Here, the researchers undertake a randomized clinical trial to assess whether macrolide resistance is higher in communities treated with azithromycin for trachoma than in untreated communities. Azithromycin—an erythromycin derivative—is used to treat common bacterial infections such as middle ear infections caused by Streptococcus pneumoniae. Trachoma—the world's leading infectious cause of blindness—is caused by Chlamydia trachomatis. The World Health Organization's trachoma elimination strategy includes annual azithromycin treatment of at-risk communities.
What Did the Researchers Do and Find?
In this cluster-randomized trial (a study that randomly assigns groups of people rather than individuals to different treatments), 12 Ethiopian communities received mass azithromycin treatment of children aged 1–10 years old at 0, 3, 6, and 9 months, and 12 control communities received the antibiotic only at 12 months. The researchers took nasopharyngeal (nose and throat) swabs from randomly selected treated children at 0 and 12 months and from randomly selected control children at 12 months. They isolated S. pneumoniae from the swabs and tested the isolates for antibiotic susceptibility. 70%–80% of the children tested had S. pneumoniae in their nose or throat. In the treated group, 3.6% of monitored children were carrying azithromycin-resistant S. pneumoniae at 0 months, whereas 46.9% were doing so at 12 months—a statistically significant increase. Only 9.2% of the monitored children in the untreated group were carrying azithromycin-resistant S. pneumoniae at 12 months, a significantly lower prevalence than in the treated group. Importantly, there was no resistance to penicillin in any S. pneumoniae isolates obtained from the treated children at 0 or 12 months; one penicillin-resistant isolate was obtained from the control children.
What Do These Findings Mean?
These findings indicate that macrolide resistance is higher in nasopharyngeal S. pneumoniae in communities receiving intensive azithromycin treatment than in untreated communities. Thus, they support the idea that frequent antibiotic use selects for antibiotic resistance in populations. Although the study was undertaken in Ethiopian communities with high rates of nasopharyngeal S. pneumoniae carriage, this finding is likely to be generalizable to other settings. Importantly, these findings have no bearing on current trachoma control activities, which use less frequent antibiotic treatments and are less likely to select for azithromycin resistance. The lack of any increase in penicillin resistance, which is usually the first-line therapy for S. pneumoniae infections, is also reassuring. However, although these findings suggest that the benefits of mass azithromycin treatment for trachoma outweigh any potential adverse affects, they nonetheless highlight the importance of continued monitoring for the secondary effects of mass antibiotic distributions.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000377.
The Bugs and Drugs website provides information about antibiotic resistance and links to other resources
The US National Institute of Allergy and Infectious Diseases provides information on antimicrobial drug resistance and on diseases caused by S. pneumoniae (pneumococcal diseases)
The US Centers for Disease Control and Prevention also have information on antibiotic resistance (in English and Spanish)
The World Health Organization has information about the global threat of antimicrobial resistance and about trachoma (in several languages)
More information about the trial described in this paper is available on ClinicalTrials.gov
doi:10.1371/journal.pmed.1000377
PMCID: PMC3001893  PMID: 21179434
7.  Ambulatory Visit Rates and Antibiotic Prescribing for Children With Pneumonia, 1994–2007 
Pediatrics  2011;127(3):411-418.
BACKGROUND:
The incidence of pediatric hospitalizations for community-acquired pneumonia (CAP) has declined after the widespread use of the heptavalent pneumococcal conjugate vaccine. The national incidence of outpatient visits for CAP, however, is not well established. Although no pediatric CAP treatment guidelines are available, current data support narrow-spectrum antibiotics as the first-line treatment for most patients with CAP.
OBJECTIVE:
To estimate the incidence rates of outpatient CAP, examine time trends in antibiotics prescribed for CAP, and determine factors associated with broad-spectrum antibiotic prescribing for CAP.
PATIENTS AND METHODS:
The National Ambulatory and National Hospital Ambulatory Medical Care Surveys (1994–2007) were used to identify children aged 1 to 18 years with CAP using a validated algorithm. We determined age group–specific rates of outpatient CAP and examined trends in antibiotic prescribing for CAP. Data from 2006–2007 were used to study factors associated with broad-spectrum antibiotic prescribing.
RESULTS:
Overall, annual CAP visit rates ranged from 16.9 to 22.4 per 1000 population, with the highest rates occurring in children aged 1 to 5 years (range: 32.3–49.6 per 1000). Ambulatory CAP visit rates did not change between 1994 and 2007. Antibiotics commonly prescribed for CAP included macrolides (34% of patients overall), cephalosporins (22% overall), and penicillins (14% overall). Cephalosporin use increased significantly between 2000 and 2007 (P = .002). Increasing age, a visit to a nonemergency department office, and obtaining a radiograph or complete blood count were associated with broad-spectrum antibiotic prescribing.
CONCLUSIONS:
The incidence of pediatric ambulatory CAP visits has not changed significantly between 1994 and 2007, despite the introduction of heptavalent pneumococcal conjugate vaccine in 2000. Broad-spectrum antibiotics, particularly macrolides, were frequently prescribed despite evidence that they provide little benefit over penicillins.
doi:10.1542/peds.2010-2008
PMCID: PMC3387910  PMID: 21321038
pneumonia; physician practice patterns; antibiotic use; epidemiology; pneumococcal conjugate vaccine
8.  Etiological analysis and predictive diagnostic model building of community-acquired pneumonia in adult outpatients in Beijing, China 
BMC Infectious Diseases  2013;13:309.
Background
Etiological epidemiology and diagnosis are important issues in adult community-acquired pneumonia (CAP), and identifying pathogens based on patient clinical features is especially a challenge. CAP-associated main pathogens in adults include viruses as well as bacteria. However, large-scale epidemiological investigations of adult viral CAP in China are still lacking. In this study, we analyzed the etiology of adult CAP in Beijing, China and constructed diagnostic models based on combinations of patient clinical factors.
Methods
A multicenter cohort was established with 500 adult CAP outpatients enrolled in Beijing between November 2010 to October 2011. Multiplex and quantitative real-time fluorescence PCR were used to detect 15 respiratory viruses and mycoplasma pneumoniae, respectively. Bacteria were detected with culture and enzyme immunoassay of the Streptococcus pneumoniae urinary antigen. Univariate analysis, multivariate analysis, discriminatory analysis and Receiver Operating Characteristic (ROC) curves were used to build predictive models for etiological diagnosis of adult CAP.
Results
Pathogens were detected in 54.2% (271/500) of study patients. Viruses accounted for 36.4% (182/500), mycoplasma pneumoniae for 18.0% (90/500) and bacteria for 14.4% (72/500) of the cases. In 182 of the patients with viruses, 219 virus strains were detected, including 166 single and 53 mixed viral infections. Influenza A virus represented the greatest proportion with 42.0% (92/219) and 9.1% (20/219) in single and mixed viral infections, respectively. Factors selected for the predictive etiological diagnostic model of viral CAP included cough, dyspnea, absence of chest pain and white blood cell count (4.0-10.0) × 109/L, and those of mycoplasma pneumoniae CAP were being younger than 45 years old and the absence of a coexisting disease. However, these models showed low accuracy levels for etiological diagnosis (areas under ROC curve for virus and mycoplasma pneumoniae were both 0.61, P < 0.05).
Conclusions
Greater consideration should be given to viral and mycoplasma pneumoniae infections in adult CAP outpatients. While predictive etiological diagnostic models of viral and mycoplasma pneumoniae based on combinations of demographic and clinical factors may provide indications of etiology, diagnostic confirmation of CAP remains dependent on laboratory pathogen test results.
doi:10.1186/1471-2334-13-309
PMCID: PMC3728139  PMID: 23834931
Community-acquired pneumonia; Etiology; Epidemiology; Diagnosis; Pneumonia; Virus; Polymerase chain reaction; ROC curve
9.  Mycoplasma pneumoniae as a causative agent of community-acquired pneumonia in children: clinical features and laboratory diagnosis 
Background
Mycoplasma pneumoniae is a common cause of community-acquired pneumonia (CAP) in children. The aim of this study was to assess the prevalence of Mycoplasma pneumoniae infection in children with CAP and find clinical, radiological and laboratory features helpful to diagnose Mycoplasma pneumoniae pneumonia. Furthermore, we evaluated the value of serology, real-time PCR (RT-PCR) and culture for the accurate diagnosis of Mycoplasma pneumoniae pneumonia.
Methods
The study included 166 children aged between 1 and 15 years with radiologically confirmed pneumonia. Throat swab specimens were cultured and assessed by RT-PCR for the presence of Mycoplasma pneumoniae. Mycoplasma pneumoniae-specific IgM and IgG antibodies were determined using ELISA in paired sera.
Results
Mycoplasma pneumoniae pneumonia was diagnosed in 14.5% CAP cases. Cough (p=0.029), headache (p=0.001) and wheezing (p=0.036) were more frequent in children with Mycoplasma pneumoniae pneumonia compared to children with pneumonia caused by other pathogens. Logistic regression analysis showed that headache (odds ratio [OR] =36.077, p=0.001) and wheezing (OR=5.681, p=0.003) were significantly associated with MP pneumonia. Neither radiological findings, nor common laboratory parameters distinguished Mycoplasma pneumoniae infection in children with CAP. Using IgG serology in paired sera as the gold standard, we found that sensitivity of IgM serology, RT-PCR and culture was equal (81.82%), while specificity values were 100%, 98.6% and 100% respectively. We observed that combination of IgM detection in acute-phase serum and RT-PCR was positive for 91.7% of cases with Mycoplasma pneumoniae infection.
Conclusions
There are no characteristic radiological findings, or routine laboratory tests that would distinguish CAP caused by Mycoplasma pneumoniae from other CAP. It was found that clinical features such as headache and wheezing are indicative for Mycoplasma pneumoniae infection. Furthermore, it was found that during the acute phase of disease, detection of IgM antibodies in combination with RT-PCR allows for precise and reliable diagnosis of Mycoplasma pneumoniae infections in children.
doi:10.1186/s13052-014-0104-4
PMCID: PMC4279889  PMID: 25518734
Children; Community-acquired pneumonia; Diagnosis; Mycoplasma pneumoniae; Polymerase chain reaction
10.  Association between Respiratory Syncytial Virus Activity and Pneumococcal Disease in Infants: A Time Series Analysis of US Hospitalization Data 
PLoS Medicine  2015;12(1):e1001776.
Daniel Weinberger and colleagues examine a possible interaction between two serious respiratory infections in children under 2 years of age.
Please see later in the article for the Editors' Summary
Background
The importance of bacterial infections following respiratory syncytial virus (RSV) remains unclear. We evaluated whether variations in RSV epidemic timing and magnitude are associated with variations in pneumococcal disease epidemics and whether changes in pneumococcal disease following the introduction of seven-valent pneumococcal conjugate vaccine (PCV7) were associated with changes in the rate of hospitalizations coded as RSV.
Methods and Findings
We used data from the State Inpatient Databases (Agency for Healthcare Research and Quality), including >700,000 RSV hospitalizations and >16,000 pneumococcal pneumonia hospitalizations in 36 states (1992/1993–2008/2009). Harmonic regression was used to estimate the timing of the average seasonal peak of RSV, pneumococcal pneumonia, and pneumococcal septicemia. We then estimated the association between the incidence of pneumococcal disease in children and the activity of RSV and influenza (where there is a well-established association) using Poisson regression models that controlled for shared seasonal variations. Finally, we estimated changes in the rate of hospitalizations coded as RSV following the introduction of PCV7. RSV and pneumococcal pneumonia shared a distinctive spatiotemporal pattern (correlation of peak timing: ρ = 0.70, 95% CI: 0.45, 0.84). RSV was associated with a significant increase in the incidence of pneumococcal pneumonia in children aged <1 y (attributable percent [AP]: 20.3%, 95% CI: 17.4%, 25.1%) and among children aged 1–2 y (AP: 10.1%, 95% CI: 7.6%, 13.9%). Influenza was also associated with an increase in pneumococcal pneumonia among children aged 1–2 y (AP: 3.2%, 95% CI: 1.7%, 4.7%). Finally, we observed a significant decline in RSV-coded hospitalizations in children aged <1 y following PCV7 introduction (−18.0%, 95% CI: −22.6%, −13.1%, for 2004/2005–2008/2009 versus 1997/1998–1999/2000). This study used aggregated hospitalization data, and studies with individual-level, laboratory-confirmed data could help to confirm these findings.
Conclusions
These analyses provide evidence for an interaction between RSV and pneumococcal pneumonia. Future work should evaluate whether treatment for secondary bacterial infections could be considered for pneumonia cases even if a child tests positive for RSV.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Respiratory infections—bacterial and viral infections of the lungs and the airways (the tubes that take oxygen-rich air to the lungs)—are major causes of illness and death in children worldwide. Pneumonia (infection of the lungs) alone is responsible for about 15% of all child deaths. The leading cause of bacterial pneumonia in children is Streptococcus pneumoniae, which is transmitted through contact with infected respiratory secretions. S. pneumoniae usually causes noninvasive diseases such as bronchitis, but sometimes the bacteria invade the lungs, the bloodstream, or the covering of the brain, where they cause pneumonia, septicemia, or meningitis, respectively. These potentially fatal invasive pneumococcal diseases can be treated with antibiotics but can also be prevented by vaccination with pneumococcal conjugate vaccines such as PCV7. The leading cause of viral pneumonia is respiratory syncytial virus (RSV), which is also readily transmitted through contact with infected respiratory secretions. Almost all children have an RSV infection before their second birthday—RSV usually causes a mild cold-like illness. However, some children infected with RSV develop pneumonia and have to be admitted to hospital for supportive care such as the provision of supplemental oxygen; there is no specific treatment for RSV infection.
Why Was This Study Done?
Co-infections with bacteria and viruses can sometimes have a synergistic effect and lead to more severe disease than an infection with either type of pathogen (disease-causing organism) alone. For example, influenza infections increase the risk of invasive pneumococcal disease. But does pneumococcal disease also interact with RSV infection? It is important to understand the interaction between pneumococcal disease and RSV to improve the treatment of respiratory infections in young children, but the importance of bacterial infections following RSV infection is currently unclear. Here, the researchers undertake a time series analysis of US hospitalization data to investigate the association between RSV activity and pneumococcal disease in infants. Time series analysis uses statistical methods to analyze data collected at successive, evenly spaced time points.
What Did the Researchers Do and Find?
For their analysis, the researchers used data collected between 1992/1993 and 2008/2009 by the State Inpatient Databases on more than 700,000 hospitalizations for RSV and more than 16,000 hospitalizations for pneumococcal pneumonia or septicemia among children under two years old in 36 US states. Using a statistical technique called harmonic regression to measure seasonal variations in disease incidence (the rate of occurrence of new cases of a disease), the researchers show that RSV and pneumococcal pneumonia shared a distinctive spatiotemporal pattern over the study period. Next, using Poisson regression models (another type of statistical analysis), they show that RSV was associated with significant increases (increases unlikely to have happened by chance) in the incidence of pneumococcal disease. Among children under one year old, 20.3% of pneumococcal pneumonia cases were associated with RSV activity; among children 1–2 years old, 10.1% of pneumococcal pneumonia cases were associated with RSV activity. Finally, the researchers report that following the introduction of routine vaccination in the US against S. pneumoniae with PCV7 in 2000, there was a significant decline in hospitalizations for RSV among children under one year old.
What Do These Findings Mean?
These findings provide evidence for an interaction between RSV and pneumococcal pneumonia and indicate that RSV is associated with increases in the incidence of pneumococcal pneumonia, particularly in young infants. Notably, the finding that RSV hospitalizations declined after the introduction of routine pneumococcal vaccination suggests that some RSV hospitalizations may have a joint viral–bacterial etiology (cause), although it is possible that PCV7 vaccination reduced the diagnosis of RSV because fewer children were hospitalized with pneumococcal disease and subsequently tested for RSV. Because this is an ecological study (an observational investigation that looks at risk factors and outcomes in temporally and geographically defined populations), these findings do not provide evidence for a causal link between hospitalizations for RSV and pneumococcal pneumonia. The similar spatiotemporal patterns for the two infections might reflect another unknown factor shared by the children who were hospitalized for RSV or pneumococcal pneumonia. Moreover, because pooled hospitalization discharge data were used in this study, these results need to be confirmed through analysis of individual-level, laboratory-confirmed data. Importantly, however, these findings support the initiation of studies to determine whether treatment for bacterial infections should be considered for children with pneumonia even if they have tested positive for RSV.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001776.
The US National Heart, Lung, and Blood Institute provides information about the respiratory system and about pneumonia
The US Centers for Disease Control and Prevention provides information on all aspects of pneumococcal disease and pneumococcal vaccination, including personal stories and information about RSV infection
The UK National Health Service Choices website provides information about pneumonia (including a personal story) and about pneumococcal diseases
KidsHealth, a website provided by the US-based non-profit Nemours Foundation, includes information on pneumonia and on RSV (in English and Spanish)
MedlinePlus provides links to other resources about pneumonia, RSV infections, and pneumococcal infections (in English and Spanish)
HCUPnet provides aggregated hospitalization data from the State Inpatient Databases used in this study
doi:10.1371/journal.pmed.1001776
PMCID: PMC4285401  PMID: 25562317
11.  Clinical Presentation, Processes and Outcomes of Care for Patients with Pneumococcal Pneumonia 
OBJECTIVE
To describe the presentation, resolution of symptoms, processes of care, and outcomes of pneumococcal pneumonia, and to compare features of the bacteremic and nonbacteremic forms of this illness.
DESIGN
A prospective cohort study.
SETTING
Five medical institutions in 3 geographic locations.
PARTICIPANTS
Inpatients and outpatients with community-acquired pneumonia (CAP).
MEASUREMENTS
Sociodemographic characteristics, respiratory and nonrespiratory symptoms, and physical examination findings were obtained from interviews or chart review. Severity of illness was assessed using a validated prediction rule for short-term mortality in CAP. Pneumococcal pneumonia was categorized as bacteremic; nonbacteremic, pure etiology; or nonbacteremic, mixed etiology.
MAIN RESULTS
One hundred fifty-eight (6.9%) of 2,287 patients (944 outpatients, 1,343 inpatients) with CAP had pneumococcal pneumonia. Sixty-five (41%) of the 158 with pneumococcal pneumonia were bacteremic; 74 (47%) were nonbacteremic with S. pneumoniae as sole pathogen; and 19 (12%) were nonbacteremic with S. pneumoniae as one of multiple pathogens. The pneumococcal bacteremia rate for outpatients was 2.6% and for inpatients it was 6.6%. Cough, dyspnea, and pleuritic pain were common respiratory symptoms. Hemopytsis occurred in 16% to 22% of the patients. A large number of nonrespiratory symptoms were noted. Bacteremic patients were less likely than nonbacteremic patients to have sputum production and myalgias (60% vs 82% and 33% vs 57%, respectively; P <.01 for both), more likely to have elevated blood urea nitrogen and serum creatinine levels, and more likely to receive pencillin therapy. Half of bacteremic patients were in the low risk category for short-term mortality (groups I to III), similar to the nonbacteremic patients. None of the 32 bacteremic patients in risk groups I to III died, while 7 of 23 (30%) in risk group V died. Intensive care unit admissions and pneumonia-related mortality were similar between bacteremic and nonbacteremic groups, although 46% of the bacteremic group had respiratory failure compared with 32% and 37% for the other groups. The nonbacteremic pure etiology patients returned to household activities faster than bacteremic patients. Symptoms frequently persisted at 30 days: cough (50%); dyspnea (53%); sputum production (48%); pleuritic pain (13%); and fatigue (63%).
CONCLUSIONS
There were few differences in the presentation of bacteremic and nonbacteremic pneumococcal pneumonia. About half of bacteremic pneumococcal pneumonia patients were at low risk for mortality. Symptom resolution frequently was slow.
doi:10.1046/j.1525-1497.2000.04429.x
PMCID: PMC1495594  PMID: 11029678
pneumonia; pneumococcal; outcomes
12.  Prior outpatient antibiotic use as predictor for microbial aetiology of community-acquired pneumonia: hospital-based study 
Objective
The causative micro-organism in community-acquired pneumonia (CAP) is often difficult to predict. Different studies have examined chronic morbidity and clinical symptoms as predictors for microbial aetiology of pneumonia. The aim of our study was to assess whether prior outpatient antimicrobial treatment is predictive for determining the microbial aetiology of CAP.
Methods
This was a hospital-based prospective observational study including all patients admitted with CAP between 1 October 2004 and 1 August 2006. Microbial investigations included sputum, blood culture, sputum PCR, antigen testing and serology. Exposure to antimicrobial drugs prior to hospital admission was ascertained through community pharmacy dispensing records. Multivariate logistic regression analysis was conducted to assess whether prior outpatient antimicrobial treatment is a predictor of microbial aetiology. Patient demographics, co-morbidities and pneumonia severity were considered to be other potential predictors.
Results
Overall, 201 patients were included in the study. The microbial aetiology was determined in 64% of the patients. The five most prevalent pathogens were Streptococcus pneumoniae, Heamophilus influenzae, Legionella spp., Mycoplasma pneumoniae and Influenza virus A+B. Forty-seven of the patients (23%) had received initial antimicrobial treatment as outpatients. Multivariate analyses revealed that initial outpatient beta-lactam treatment was associated with a threefold increased chance of finding atypical pathogens and a threefold decreased probability of pneumococcal infection; the corresponding odds ratios were 3.51 (95% CI 1.25–9.99) and 0.30 (95% CI 0.10–0.90), respectively. Patients who received macrolides prior to hospitalisation had an increased probability of viral pneumonia.
Conclusion
Prior outpatient antimicrobial therapy has a predictive value in the diagnostic workup aimed at identifying the causative pathogen and planning corresponding antimicrobial treatment in patients hospitalised for pneumonia.
doi:10.1007/s00228-007-0407-0
PMCID: PMC2254473  PMID: 18060396
Aetiology; Antibiotics; Diagnosis; Outcome assessment; Pneumonia
13.  The aetiology and antibiotic management of community-acquired pneumonia in adults in Europe: a literature review 
The purpose of this paper was to generate up-to-date information on the aetiology of community-acquired pneumonia (CAP) and its antibiotic management in adults across Europe. Structured searches of PubMed identified information on the aetiology of CAP and its antibiotic management in individuals aged >15 years across Europe. We summarise the data from 33 studies published between January 2005 and July 2012 that reported on the pathogens identified in patients with CAP and antibiotic treatment in patients with CAP. Streptococcus pneumoniae was the most commonly isolated pathogen in patients with CAP and was identified in 12.0–85.0 % of patients. Other frequently identified pathogens found to cause CAP were Haemophilus influenzae, Gram-negative enteric bacilli, respiratory viruses and Mycoplasma pneumoniae. We found several age-related trends: S. pneumoniae, H. influenzae and respiratory viruses were more frequent in elderly patients aged ≥65 years, whereas M. pneumoniae was more frequent in those aged <65 years. Antibiotic monotherapy was more frequent than combination therapy, and beta-lactams were the most commonly prescribed antibiotics. Hospitalised patients were more likely than outpatients to receive combination antibiotic therapy. Limited data on antibiotic resistance were available in the studies. Penicillin resistance of S. pneumoniae was reported in 8.4–20.7 % of isolates and erythromycin resistance was reported in 14.7–17.1 % of isolates. Understanding the aetiology of CAP and the changing pattern of antibiotic resistance in Europe, together with an increased awareness of the risk factors for CAP, will help clinicians to identify those patients most at risk of developing CAP and provide guidance on the most appropriate treatment.
Electronic supplementary material
The online version of this article (doi:10.1007/s10096-014-2067-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s10096-014-2067-1
PMCID: PMC4042014  PMID: 24532008
14.  Community acquired pneumonia—a prospective UK study 
Archives of Disease in Childhood  2000;83(5):408-412.
BACKGROUND—There are few data on paediatric community acquired pneumonia (PCAP) in the UK.
AIMS—To investigate the aetiology and most useful diagnostic tests for PCAP in the north east of England.
METHODS—A prospective study of hospital admissions with a diagnosis of PCAP.
RESULTS—A pathogen was isolated from 60% (81/136) of cases, and considered a definite or probable cause of their pneumonia in 51% (70/136). Fifty (37%) had a virus implicated (65% respiratory syncytial virus) and 19 (14%) a bacterium (7% group A streptococcus, 4% Streptococcus pneumoniae), with one mixed infection. Of a subgroup (51 patients) in whom serum antipneumolysin antibody testing was performed, 6% had evidence of pneumococcal infection, and all were under 2 years old. The best diagnostic yield was from paired serology (34%, 31/87), followed by viral immunofluorescence (33%, 32/98).
CONCLUSION—Viral infection accounted for 71% of the cases diagnosed. Group A streptococcus was the most common bacterial infective agent, with a low incidence of both Mycoplasma pneumoniae and S pneumoniae. Pneumococcal pneumonia was the most common bacterial cause of pneumonia in children under 2 years but not in older children. Inflammatory markers and chest x ray features did not differentiate viral from bacterial pneumonia; serology and viral immunofluorescence were the most useful diagnostic tests.


doi:10.1136/adc.83.5.408
PMCID: PMC1718544  PMID: 11040149
15.  Secondary Outcomes of a Pilot Randomized Trial of Azithromycin Treatment for Asthma 
PLoS Clinical Trials  2006;1(2):e11.
Objectives:
The respiratory pathogen Chlamydia pneumoniae (C. pneumoniae) produces acute and chronic lung infections and is associated with asthma. Evidence for effectiveness of antichlamydial antibiotics in asthma is limited. The primary objective of this pilot study was to investigate the feasibility of performing an asthma clinical trial in practice settings where most asthma is encountered and managed. The secondary objectives were to investigate (1) whether azithromycin treatment would affect any asthma outcomes and (2) whether C. pneumoniae serology would be related to outcomes. This report presents the secondary results.
Design:
Randomized, placebo-controlled, blinded (participants, physicians, study personnel, data analysts), allocation-concealed parallel group clinical trial.
Setting:
Community-based health-care settings located in four states and one Canadian province.
Participants:
Adults with stable, persistent asthma.
Interventions:
Azithromycin (six weekly doses) or identical matching placebo, plus usual community care.
Outcome Measures:
Juniper Asthma Quality of Life Questionnaire (Juniper AQLQ), symptom, and medication changes from baseline (pretreatment) to 3 mo posttreatment (follow-up); C. pneumoniae IgG and IgA antibodies at baseline and follow-up.
Results:
Juniper AQLQ improved by 0.25 (95% confidence interval; −0.3, 0.8) units, overall asthma symptoms improved by 0.68 (0.1, 1.3) units, and rescue inhaler use decreased by 0.59 (−0.5, 1.6) daily administrations in azithromycin-treated compared to placebo-treated participants. Baseline IgA antibodies were positively associated with worsening overall asthma symptoms at follow-up (p = 0.04), but IgG was not (p = 0.63). Overall asthma symptom improvement attributable to azithromycin was 28% in high IgA participants versus 12% in low IgA participants (p for interaction = 0.27).
Conclusions:
Azithromycin did not improve Juniper AQLQ but appeared to improve overall asthma symptoms. Larger community-based trials of antichlamydial antibiotics for asthma are warranted.
Editorial Commentary
Background: Chlamydia pneumoniae is a common bacterium thought to be responsible for a substantial proportion of community-acquired pneumonia and bronchitis infections. There is some observational evidence associating chronic C. pneumoniae infection with more severe symptoms in people with asthma. However, there are very little data from clinical trials determining whether treatment with antibiotics active against C. pneumoniae has an effect on the control of asthma.
What this trial shows: In this trial, the researchers randomized 45 adults who were being treated for asthma in primary care to receive either azithromycin (an antibiotic active against C. pneumoniae) or placebo, in addition to their usual asthma care. Participants were followed up for 3 mo after completion of treatment, during which time participants recorded data relating to their overall symptoms and daily activities on a 5-point scale, and use of bronchodilators. At the start of the trial, and at 3-mo follow-up, participants also completed a quality-of-life questionnaire using a validated scale. The primary objective of this trial was to investigate the feasibility of running an asthma trial in the primary care setting, and in using IVR telephone systems to collect the outcome data, reported in [13]. In this paper, the asthma outcomes are reported. Participants receiving azithromycin did not show a significant improvement in quality of life at 3-mo follow-up as compared to participants receiving placebo. However, the investigators did see a significant improvement in the overall symptoms recorded by participants receiving azithromycin, as compared to placebo.
Strengths and limitations: The randomization methods in the trial were appropriate, as was the choice of placebo as a comparison for azithromycin. However, the number of participants in the trial was small, and it is likely that many more participants would need to be recruited to conclusively demonstrate or disprove an effect of azithromycin on asthma-related quality of life. Further, the trial used three different measures for asthma outcomes: (1) the quality-of-life questionnaire, (2) measurement of symptoms and daily activities on a 5-point scale, and (3) bronchodilator use. Only the quality-of-life questionnaire is validated, making it difficult to compare the results with those of other asthma trials.
Contribution to the evidence: This trial provides suggestive evidence that azithromycin may have benefits in the treatment of asthma, but should not on its own lead to a change in practice. The study provides a good basis for a larger randomized trial of such treatments, which would need to assess reliably the effect of these drugs not only on symptoms but also on quality of life. Information gained from this trial would help to design several aspects of future studies, e.g., their size, follow-up duration, and suitable outcome measures.
doi:10.1371/journal.pctr.0010011
PMCID: PMC1488900  PMID: 16871333
16.  Combination antibiotic therapy for community-acquired pneumonia 
Community-acquired pneumonia (CAP) is a common and potentially serious illness that is associated with morbidity and mortality. Although medical care has improved during the past decades, it is still potentially lethal. Streptococcus pneumoniae is the most frequent microorganism isolated. Treatment includes mandatory antibiotic therapy and organ support as needed. There are several antibiotic therapy regimens that include β-lactams or macrolides or fluoroquinolones alone or in combination. Combination antibiotic therapy achieves a better outcome compared with monotherapy and it should be given in the following subset of patients with CAP: outpatients with comorbidities and previous antibiotic therapy, nursing home patients with CAP, hospitalized patients with severe CAP, bacteremic pneumococcal CAP, presence of shock, and necessity of mechanical ventilation. Better outcome is associated with combination therapy that includes a macrolide for wide coverage of atypical pneumonia, polymicrobial pneumonia, or resistant Streptococcus pneumoniae. Macrolides have shown different properties other than antimicrobial activity, such as anti-inflammatory properties. Although this evidence comes from observational, most of them retrospective and nonblinded studies, the findings are consistent. Ideally, a prospective, multicenter, randomized trial should be performed to confirm these findings.
doi:10.1186/2110-5820-1-48
PMCID: PMC3248869  PMID: 22113077
17.  Community Case Management of Fever Due to Malaria and Pneumonia in Children Under Five in Zambia: A Cluster Randomized Controlled Trial 
PLoS Medicine  2010;7(9):e1000340.
In a cluster randomized trial, Kojo Yeboah-Antwi and colleagues find that integrated management of malaria and pneumonia in children under five by community health workers is both feasible and effective.
Background
Pneumonia and malaria, two of the leading causes of morbidity and mortality among children under five in Zambia, often have overlapping clinical manifestations. Zambia is piloting the use of artemether-lumefantrine (AL) by community health workers (CHWs) to treat uncomplicated malaria. Valid concerns about potential overuse of AL could be addressed by the use of malaria rapid diagnostics employed at the community level. Currently, CHWs in Zambia evaluate and treat children with suspected malaria in rural areas, but they refer children with suspected pneumonia to the nearest health facility. This study was designed to assess the effectiveness and feasibility of using CHWs to manage nonsevere pneumonia and uncomplicated malaria with the aid of rapid diagnostic tests (RDTs).
Methods and Findings
Community health posts staffed by CHWs were matched and randomly allocated to intervention and control arms. Children between the ages of 6 months and 5 years were managed according to the study protocol, as follows. Intervention CHWs performed RDTs, treated test-positive children with AL, and treated those with nonsevere pneumonia (increased respiratory rate) with amoxicillin. Control CHWs did not perform RDTs, treated all febrile children with AL, and referred those with signs of pneumonia to the health facility, as per Ministry of Health policy. The primary outcomes were the use of AL in children with fever and early and appropriate treatment with antibiotics for nonsevere pneumonia. A total of 3,125 children with fever and/or difficult/fast breathing were managed over a 12-month period. In the intervention arm, 27.5% (265/963) of children with fever received AL compared to 99.1% (2066/2084) of control children (risk ratio 0.23, 95% confidence interval 0.14–0.38). For children classified with nonsevere pneumonia, 68.2% (247/362) in the intervention arm and 13.3% (22/203) in the control arm received early and appropriate treatment (risk ratio 5.32, 95% confidence interval 2.19–8.94). There were two deaths in the intervention and one in the control arm.
Conclusions
The potential for CHWs to use RDTs, AL, and amoxicillin to manage both malaria and pneumonia at the community level is promising and might reduce overuse of AL, as well as provide early and appropriate treatment to children with nonsevere pneumonia.
Trial registration
ClinicalTrials.gov NCT00513500
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about 11 million children die before their fifth birthday. Most of these deaths are in developing countries and most are due to a handful of causes—pneumonia (lung inflammation usually caused by an infection), malaria (a parasitic disease spread by mosquitoes), measles, diarrhea, and birth-related problems. In sub-Saharan Africa, pneumonia and malaria alone are responsible for nearly a third of deaths in young children. Both these diseases can be treated if caught early—pneumonia with antibiotics such as amoxicillin and malaria with artemisinin-based combination therapy (ACT), a treatment that contains several powerful antimalarial drugs. Unfortunately, parents in rural areas in sub-Saharan Africa rarely have easy access to health facilities and sick children are often treated at home by community health workers (CHWs, individuals with some medical training who provide basic health care to their communities), drug sellers, and traditional healers. This situation means that ongoing global efforts to reduce child mortality will require innovative community level interventions if they are to succeed.
Why Was This Study Done?
One community level intervention that the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) recently recommended is integrated management of malaria and pneumonia in countries where these diseases are major childhood killers. One such country is Zambia. In rural areas of Zambia, CHWs treat suspected cases of uncomplicated (mild) malaria with artemether-lumefantrine (AL, an ACT) or with sulfadoxine-pyrimethamine (a non-ACT antimalarial drug combination) and refer children with suspected pneumonia to the nearest health facility. However, because uncomplicated malaria and pneumonia both cause fever, many children are treated inappropriately. This misdiagnosis is worrying because giving antimalarial drugs to children with pneumonia delays their treatment with more appropriate drugs and increases the risk of drug-resistant malaria emerging. The use of rapid diagnostic tests (RDTs) for malaria might be one way to improve the treatment of malaria and pneumonia by CHWs in Zambia. Here, the researchers investigate the feasibility and effectiveness of this approach in a cluster randomized controlled trial, a study that compares the outcomes of groups (clusters) of patients randomly allocated to different interventions.
What Did the Researchers Do and Find?
The researchers randomly allocated 31 community health posts (fixed locations where CHWs provide medical services to several villages) to the study's intervention and control arms. CHWs in the intervention arm did RDTs for malaria on all the children under 5 years old who presented with fever and/or difficult or fast breathing (symptoms of pneumonia), treated test-positive children with AL, and treated those with nonsevere pneumonia (an increased breathing rate) with amoxicillin. CHWs in the control arm did not use RDTs but treated all children with fever with AL and referred those with signs of pneumonia to the nearest health facility. About 3,000 children with fever were treated during the 12-month study. 99.1% of the children in the control arm received AL compared with 27.5% of the children in the intervention arm, a 4-fold reduction in treatment for malaria. Importantly, the CHWs in the intervention arm adhered to treatment guidelines and did not give AL to children with negative RDT results. Of the children classified with nonsevere pneumonia, 13.3% of those in the control arm received early and appropriate treatment with amoxicillin compared to 68.2% of those in the intervention arm, a 5-fold increase in the timely treatment for pneumonia.
What Do These Findings Mean?
These findings indicate that CHWs in Zambia are capable of using RDTs, AL, and amoxicillin to manage malaria and pneumonia. They show that the intervention tested in this study has the potential to reduce the overuse of AL and to provide early and appropriate treatment for nonsevere pneumonia. Although this approach needs to be tested in other settings, these findings suggest that the use of CHWs might be a feasible and effective way to provide integrated management of pneumonia and malaria at the community level in developing countries. Importantly, these results also support the evaluation of the treatment by CHWs of other major childhood diseases and raise the possibility of saving the lives of many children in sub-Saharan Africa and other developing regions of the world through community level interventions.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000340.
WHO provides information on malaria, on rapid diagnostic tests for malaria, on artemisinin-combination therapy, and on global child mortality and efforts to reduce it (in several languages); WHO also provides a country health profile for Zambia
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish)
Kidshealth, a resource maintained by the not-for-profit Nemours Foundation (a not-for-profit organization for children's health), provides information for parents on pneumonia (in English and Spanish)
MedlinePlus provides links to additional information on malaria and on pneumonia (in English and Spanish)
More information about the Zambia Integrated Management of Malaria and Pneumonia Study is available
doi:10.1371/journal.pmed.1000340
PMCID: PMC2943441  PMID: 20877714
18.  Impact on respiratory tract infections of heptavalent pneumococcal conjugate vaccine administered at 3, 5 and 11 months of age 
Respiratory Research  2007;8(1):12.
Background
Medical and public health importance of pneumococcal infections justifies the implementation of measures capable of reducing their incidence and severity, and explains why the recently marketed heptavalent pneumococcal conjugate vaccine (PCV-7) has been widely studied by pediatricians. This study was designed to evaluate the impact of PCV-7 administered at 3, 5 and 11 months of age on respiratory tract infections in very young children.
Methods
A total of 1,571 healthy infants (910 males) aged 75–105 days (median 82 days) were enrolled in this prospective cohort trial to receive a hexavalent vaccine (DTaP/IPV/HBV/Hib) and PCV-7 (n = 819) or the hexavalent vaccine alone (n = 752) at 3, 5 and 11 months of age. Morbidity was recorded for the 24 months following the second dose by monthly telephone interviews conducted by investigators blinded to the study treatment assignment using standardised questionnaires. During these interviews, the caregivers and the children's pediatricians were questioned about illnesses and the use of antibiotics since the previous telephone call. All of the data were analysed using SAS Windows v.12.
Results
Among the 1,555 subjects (98.9%) who completed the study, analysis of the data by the periods of follow-up demonstrated that radiologically confirmed community-acquired pneumonia (CAP) was significantly less frequent in the PCV-7 group during the follow-up as a whole and during the last period of follow-up. Moreover, there were statistically significant between-group differences in the incidence of acute otitis media (AOM) in each half-year period of follow-up except the first, with significantly lower number of episodes in children receiving PCV-7 than in controls. Furthermore, the antibiotic prescription data showed that the probability of receiving an antibiotic course was significantly lower in the PCV-7 group than in the control group.
Conclusion
Our findings show the effectiveness of the simplified PCV-7 schedule (three doses administered at 3, 5 and 11–12 months of age) in the prevention of CAP and AOM, diseases in which Streptococcus pneumoniae plays a major etiological role. A further benefit is that the use of PCV-7 reduces the number of antibiotic prescriptions. All of these advantages may also be important from an economic point of view.
doi:10.1186/1465-9921-8-12
PMCID: PMC1804265  PMID: 17313667
19.  Study of community acquired pneumonia aetiology (SCAPA) in adults admitted to hospital: implications for management guidelines 
Thorax  2001;56(4):296-301.
BACKGROUND—Since the last British study of the microbial aetiology of community acquired pneumonia (CAP) about 20 years ago, new organisms have been identified (for example, Chlamydia pneumoniae), new antibiotics introduced, and fresh advances made in microbiological techniques. Pathogens implicated in CAP in adults admitted to hospital in the UK using modern and traditional microbiological investigations are described.
METHODS—Adults aged 16 years and over admitted to a teaching hospital with CAP over a 12 month period from 4 October 1998 were prospectively studied. Samples of blood, sputum, and urine were collected for microbiological testing by standard culture techniques and new serological and urine antigen detection methods.
RESULTS—Of 309 patients admitted with CAP, 267 fulfilled the study criteria; 135 (50.6%) were men and the mean (SD) age was 65.4 (19.6) years. Aetiological agents were identified from 199 (75%) patients (one pathogen in 124 (46%), two in 53 (20%), and three or more in 22 (8%)): Streptococcus pneumoniae 129 (48%), influenza A virus 50 (19%), Chlamydia pneumoniae 35 (13%), Haemophilus influenzae 20 (7%), Mycoplasma pneumoniae 9 (3%), Legionella pneumophilia 9 (3%), other Chlamydia spp 7 (2%), Moraxella catarrhalis 5 (2%), Coxiella burnetii 2 (0.7%), others 8 (3%). Atypical pathogens were less common in patients aged 75 years and over than in younger patients (16% v 27%; OR 0.5, 95% CI 0.3 to 0.9). The 30 day mortality was 14.9%. Mortality risk could be stratified by the presence of four "core" adverse features. Three of 60 patients (5%) infected with an atypical pathogen died.
CONCLUSION—S pneumoniae remains the most important pathogen to cover by initial antibiotic therapy in adults of all ages admitted to hospital with CAP. Atypical pathogens are more common in younger patients. They should also be covered in all patients with severe pneumonia and younger patients with non-severe infection.


doi:10.1136/thorax.56.4.296
PMCID: PMC1746017  PMID: 11254821
20.  First report on prevalence and risk factors of severe atypical pneumonia in Vietnamese children aged 1–15 years 
BMC Public Health  2014;14(1):1304.
Background
Atypical pathogens such as Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila are increasingly recognized as important causes of community acquired pneumonia (CAP) worldwide. Such etiological data for Vietnam is scarce and clinical doctors lack accurate information on which to base their diagnosis and treatment of pneumonia. This study identifies the prevalence and risk factors of severe community acquired pneumonia due to these atypical pathogens (severe-ApCAP) in children aged 1–15 years with CAP in a pediatric hospital in Hanoi, Vietnam.
Methods
722 hospitalized children with CAP were recruited for detecting those atypical pathogens, using multiplex PCR and ELISA. Clinical and epidemiological data were collected. Multivariate logistic-regression analyses were performed to evaluate the associations of potential risk factors with severe-ApCAP.
Results
Among 215 atypical pathogen-positive CAP cases, 45.12% (97/215) were severe-ApCAP. Among the severe-ApCAP group, 55.67% (54/97) cases were caused by pure atypical pathogens and 44.33% (43/97) resulted from a co-infection with typical respiratory pathogens. M. pneumoniae was the most common, with 86.6% cases (84/97) in the severe-ApCAP group, whereas C. pneumoniae and L. pneumophila were less frequent (6.19% and 7.22%, respectively). The highest rate of severe-ApCAP was in children younger than two years (65.98%). The differences related to age are statistically significant (P = 0.008).
The factors significantly associated with severe-ApCAP were age (OR = 0.84, 95% CI = 0.75-0.93, P = 0.001), co-infection with typical bacteria (OR = 4.86, 95% CI = 2.17-10.9, P < 0.0001), co-infection with respiratory viruses (OR = 4.36, 95% CI = 1.46-13.0, P = 0.008), respiratory/cardiac system malformation (OR = 14.8, 95% CI = 1.12 -196, P = 0.041) and neonatal pneumonia (OR = 11.1, 95% CI = 1.06 -116, P = 0.044).
Conclusions
Severe-ApCAP presented at a significant rate in Vietnamese children. More than 50% of severe-ApCAP cases were associated with pure atypical pathogen infection. M. pneumoniae appeared most frequently. The highest rate of severe-ApCAP was in children younger than two years. Younger age and co-infection with typical bacteria or viruses were the most significant risk factors, while respiratory/cardiac system malformation and neonatal pneumonia were additional potential risk factors, associated with severe-ApCAP in Vietnamese children.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-1304) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2458-14-1304
PMCID: PMC4300840  PMID: 25524126
Pure atypical pathogens; Children; Prevalence; Risk factor; Severe community-acquired pneumonia
21.  Community-Acquired Pneumonia Episode Costs by Age and Risk in Commercially Insured US Adults Aged ≥50 Years 
Background
Community-acquired pneumonia (CAP) causes substantial clinical and economic burden. While several studies have reported the cost to treat CAP, there is little information on the cost to treat by age, risk profile, and hospitalization in US adults aged ≥50 years.
Objective
To quantify the cost, from a payer perspective, of treating CAP at the episode level, stratified by age, risk profile, and hospitalization.
Methods
A retrospective study of claims data from a large US health plan (1 January 2006–31 December 2008) was conducted. Patients aged ≥50 years having at least one medical claim with a primary diagnosis for pneumonia were identified. A CAP episode was defined as the period between the first and last pneumonia ICD-9 code with a chest X-ray claim. Episode-level variables included risk stratum based on presence of an immunocompromising/chronic condition, age group, number and length of inpatient and outpatient CAP episodes, and all-cause and CAP-related healthcare costs (adjusted to 2011 costs).
Results
Among the 27,659 study patients, 28,575 CAP episodes (20,454 outpatient; 8,121 inpatient) occurred. Mean age of patients with a CAP episode was 62.6. Low-risk patients accounted for 44.4 % of all CAP episodes. Mean CAP episode length was 31.8 days for an inpatient episode and 10.2 days for an outpatient episode. Mean all-cause total healthcare cost for an inpatient CAP episode ranged from $11,148 to $51,219 depending on risk stratum and age group. Mean outpatient episode-related costs were much lower than inpatient episode-related costs.
Conclusions
Cost to treat CAP requiring hospitalization is high regardless of age or the presence of underlying comorbidities. Given that almost half of the patients in this study did not have traditional risk factors for CAP, it is clear that better preventative strategies are needed.
Electronic supplementary material
The online version of this article (doi:10.1007/s40258-013-0026-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s40258-013-0026-0
PMCID: PMC3663984  PMID: 23605251
22.  Changing needs of community-acquired pneumonia 
Journal of Antimicrobial Chemotherapy  2011;66(Suppl 3):iii3-iii9.
Community-acquired pneumonia (CAP) is a serious condition associated with significant morbidity and potential long-term mortality. Although the majority of patients with CAP are treated as outpatients, the greatest proportion of pneumonia-related mortality and healthcare expenditure occurs among the patients who are hospitalized. There has been considerable interest in determining risk factors and severity criteria assessments to assist with site-of-care decisions. For both inpatients and outpatients, the most common pathogens associated with CAP include Streptococcus pneumoniae, Haemophilus influenzae, group A streptococci and Moraxella catarrhalis. Atypical pathogens, Gram-negative bacilli, methicillin-resistant Staphylococcus aureus (MRSA) and viruses are also recognized aetiological agents of CAP. Despite the availability of antimicrobial therapies, the recent emergence of drug-resistant pneumococcal and staphylococcal isolates has limited the effectiveness of currently available agents. Because early and rapid initiation of empirical antimicrobial treatment is critical for achieving a favourable outcome in CAP, newer agents with activity against drug-resistant strains of S. pneumoniae and MRSA are needed for the management of patients with CAP.
doi:10.1093/jac/dkr094
PMCID: PMC3143426  PMID: 21482567
antimicrobial therapy; PSI/CURB-65 score; clinical outcomes
23.  Decreased Streptococcus pneumoniae susceptibility to oral antibiotics among children in rural Vietnam: a community study 
Background
Streptococcus pneumoniae is the most significant bacterial cause of community-acquired pneumonia among children under five years worldwide. Updated resistance information of S. pneumoniae among children is essential to adjust the recommendations for empirical treatment of community-acquired pneumonia, which will have immense implications for local and global health. This study investigated the prevalence of antibiotic resistance in isolated strains of S. pneumoniae and relationship with antibiotic use and demographic factors of children under five in rural Vietnam in 2007.
Methods
In Bavi district, 847 children 6 to 60 months were selected from 847 households. The main child-caregivers in the households were interviewed weekly using structured questionnaires to collect information of daily illness symptoms and drug use for the selected child over a four-week period (from March through June 2007). In the 3rd week, the children were invited for a clinical examination and to collect nasopharyngeal samples for S. pneumoniae identification. Etest and disk diffusion were used to test antibiotic susceptibility.
Results
Of 818 participating children, 258 (32%) had ongoing respiratory infections, 421 (52%) carried S. pneumoniae, and 477 (58%) had used antibiotics within the previous three weeks. Of the 421 isolates, 95% were resistant to at least one antibiotic (401/421). Resistance to co-trimoxazole, tetracycline, phenoxymethylpenicillin, erythromycin and ciprofloxacin was 78%, 75%, 75%, 70% and 28%, respectively. Low resistance was noted for amoxicillin (4%), benzylpenicillin (4%), and cefotaxime (2%). The intermediate resistance to amoxicillin was 32%. Multidrug-resistance was seen in 60%. The most common pattern was co-resistance to co-trimoxazole, tetracycline and erythromycin. The proportion of children carrying resistant bacteria was higher among the children who had used antibiotics in the previous three weeks.
Conclusions
Resistance to commonly used antibiotics and multidrug-resistance of S. pneumoniae in the area is remarkably high. High-dose amoxicillin is the only investigated oral antibiotic that can possibly be used for treatment of community-acquired pneumococcal infections. Strategies to promote appropriate prescribing and dispensing of effective antibiotics should be immediately implemented for the benefit of local and global health.
doi:10.1186/1471-2334-10-85
PMCID: PMC2853544  PMID: 20356399
24.  Community-acquired pneumonia 
Clinical Evidence  2008;2008:1503.
Introduction
In the northern hemisphere about 12/1000 people a year (on average) contract pneumonia while living in the community, with most cases caused by Streptococcus pneumoniae. Mortality ranges from about 5-35% depending on severity of disease, with a worse prognosis in older people, men, and people with chronic diseases.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent community-acquired pneumonia? What are the effects of treatments for community-acquired pneumonia in outpatient settings, in people admitted to hospital, and in people receiving intensive care? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (oral, intravenous), different combinations, and prompt administration of antibiotics in intensive-care settings, early mobilisation, influenza vaccine, and pneumococcal vaccine.
Key Points
In the northern hemisphere about 12/1000 people a year (on average) contract pneumonia while living in the community, with most cases caused by Streptococcus pneumoniae. People at greatest risk include those at the extremes of age, smokers, alcohol-dependent people, and people with lung or heart disease or immunosuppression.Mortality ranges from about 5-35% depending on severity of disease, with a worse prognosis in older people, men, and people with chronic diseases.
Deaths from influenza are usually caused by pneumonia. Influenza vaccine reduces the risk of clinical influenza, and may reduce the risk of pneumonia and mortality in elderly people. Pneumococcal vaccine is unlikely to reduce all-cause pneumonia or mortality in immunocompetent adults, but may reduce pneumococcal pneumonia in this group.
Antibiotics lead to clinical cure in 80% or more of people with pneumonia being treated in the community or in hospital, although no one regimen has been shown to be superior to the others in either setting. Early mobilisation may reduce hospital stay compared with usual care in people being treated with antibiotics. Intravenous antibiotics have not been shown to improve clinical cure rates or survival compared with oral antibiotics in people treated in hospital for non-severe community-acquired pneumonia.Continued treatment with oral amoxicillin after initial improvement with intravenous amoxicillin may not improve clinical cure rate compared with intravenous amoxicillin alone.
Prompt administration of antibiotics may improve survival compared with delayed treatment in people receiving intensive care for community-acquired pneumonia, although few studies have been done. We don't know which is the optimum antibiotic regimen to use in these people.
PMCID: PMC2907969  PMID: 19445738
25.  Community-acquired pneumonia 
Clinical Evidence  2010;2010:1503.
Introduction
In the northern hemisphere about 12/1000 people a year (on average) contract pneumonia while living in the community, with most cases caused by Streptococcus pneumoniae. Mortality ranges from about 5% to 35% depending on severity of disease, with a worse prognosis in older people, men, and people with chronic diseases.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent community-acquired pneumonia? What are the effects of treatments for community-acquired pneumonia in outpatient settings, in people admitted to hospital, and in people receiving intensive care? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 15 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (oral, intravenous), different combinations, and prompt administration of antibiotics in intensive-care settings, early mobilisation, influenza vaccine, and pneumococcal vaccine.
Key Points
In the northern hemisphere about 12/1000 people a year (on average) contract pneumonia while living in the community, with most cases caused by Streptococcus pneumoniae. People at greatest risk include those at the extremes of age, smokers, alcohol-dependent people, and people with lung or heart disease or immunosuppression.Mortality ranges from about 5% to 35% depending on severity of disease, with a worse prognosis in older people, men, and people with chronic diseases.
Deaths from influenza are usually caused by pneumonia. Influenza vaccine reduces the risk of clinical influenza, and may reduce the risk of pneumonia and mortality in older people. Pneumococcal vaccine is unlikely to reduce all-cause pneumonia or mortality in immunocompetent adults, but may reduce pneumococcal pneumonia in this group.
Antibiotics lead to clinical cure in at least 80% of people with pneumonia being treated in the community or in hospital, although no one regimen has been shown to be superior to the others in either setting. Early mobilisation may reduce hospital stay compared with usual care in people being treated with antibiotics. Intravenous antibiotics have not been shown to improve clinical cure rates or survival compared with oral antibiotics in people treated in hospital for non-severe community-acquired pneumonia.
Prompt administration of antibiotics may improve survival compared with delayed treatment in people receiving intensive care for community-acquired pneumonia, although we found few studies. We don't know which is the optimum antibiotic regimen to use in these people.
PMCID: PMC3275325  PMID: 21418681

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