Prediction model for pneumonia in primary care patients with an acute respiratory tract infection: role of symptoms, signs, and biomarkers.

BACKGROUND: Diagnosing pneumonia can be challenging in general practice but is essential to distinguish from other respiratory tract infections because of treatment choice and outcome prediction. We determined predictive signs, symptoms and biomarkers for the presence of pneumonia in patients with acute respiratory tract infection in primary care. METHODS: From March 2012 until May 2016 we did a prospective observational cohort study in three radiology departments in the Leiden-The Hague area, The Netherlands. From adult patients we collected clinical characteristics and biomarkers, chest X ray results and outcome. To assess the predictive value of C-reactive protein (CRP), procalcitonin and midregional pro-adrenomedullin for pneumonia, univariate and multivariate binary logistic regression were used to determine risk factors and to develop a prediction model. RESULTS: Two hundred forty-nine patients were included of whom 30 (12%) displayed a consolidation on chest X ray. Absence of runny nose and whether or not a patient felt ill were independent predictors for pneumonia. CRP predicts pneumonia better than the other biomarkers but adding CRP to the clinical model did not improve classification (- 4%); however, CRP helped guidance of the decision which patients should be given antibiotics. CONCLUSIONS: Adding CRP measurements to a clinical model in selected patients with an acute respiratory infection does not improve prediction of pneumonia, but does help in giving guidance on which patients to treat with antibiotics. Our findings put the use of biomarkers and chest X ray in diagnosing pneumonia and for treatment decisions into some perspective for general practitioners.

Burden of disease in children with respiratory tract infections in primary care: diary-based cohort study.

BACKGROUND: Respiratory tract infections (RTIs) are a common reason for children to consult in general practice. Antibiotics are often prescribed, in part due to miscommunication between parents and GPs. The duration of specific respiratory symptoms has been widely studied. Less is known about illness-related symptoms and the impact of these symptoms on family life, including parental production loss. Better understanding of the natural course of illness-related symptoms in RTI in children and impact on family life may improve GP-parent communication during RTI consultations. OBJECTIVE: To describe the general impact of RTI on children and parents regarding illness-related symptoms, absenteeism from childcare, school and work, use of health care facilities, and the use of over-the-counter (OTC) medication. METHODS: Prospectively collected diary data from two randomized clinical trials in children with RTI in primary care (n = 149). Duration of symptoms was analysed using survival analysis. RESULTS: Disturbed sleep, decreased intake of food and/or fluid, feeling ill and/or disturbance at play or other daily activities are very common during RTI episodes, with disturbed sleep lasting longest. Fifty-two percent of the children were absent for one or more days from childcare or school, and 28% of mothers and 20% of fathers reported absence from work the first week after GP consultation. Re-consultation occurred in 48% of the children. OTC medication was given frequently, particularly paracetamol and nasal sprays. CONCLUSION: Appreciation of, and communication about the general burden of disease on children and their parents, may improve understanding between GPs and parents consulting with their child.

Rapid early weight gain is associated with wheeze and reduced lung function in childhood.

The aim of our study was to investigate the association between rapid weight gain in the first 3 months of life and the prevalence of wheeze in the first years of life and lung function at 5 yrs of age. The infants selected were participating in an ongoing birth cohort. Information on growth and respiratory symptoms was collected during the first year of life, and on primary care consultations during total follow-up. Forced expiratory volume in 1 s (FEV(1)) and forced expiratory flow at 25-75% of forced vital capacity (FEF(25-75%)) were measured at 5 yrs of age. Information on growth and respiratory symptoms was obtained for 1,431 infants, out of whom 235 children had already had 5 yrs of follow-up. Every one-point z-score increase in weight gain resulted in a 37% increase in days with wheeze (incidence rate ratio 1.37, 95% CI 1.27-1.47; p<0.001) and in associated consultations by 16% (incidence rate ratio 1.16, 95% CI 1.01-1.34; p=0.04). Children with rapid weight gain reported significantly more physician-diagnosed asthma. FEV(1) and FEF(25-75%) were reduced by 34 mL (adjusted regression coefficient -0.034, 95% CI -0.056- -0.013; p=0.002) and 82 mL (adjusted regression coefficient -0.082, 95% CI -0.140- -0.024; p=0.006) per every one-point z-score increase in weight gain, respectively. These associations were independent of birthweight. Rapid early weight gain is a risk factor for clinically relevant wheezing illnesses in the first years of life and lower lung function in childhood.

Trends in primary-care consultations, comorbidities, and antibiotic prescriptions for respiratory infections in The Netherlands before implementation of pneumococcal vaccines for infants.

The burden of respiratory infections is mainly seen in primary healthcare. To evaluate the potential impact of new preventive strategies against respiratory infections, such as the implementation of pneumococcal conjugate vaccines for infants in 2006 in The Netherlands, we conducted a baseline retrospective cohort study of electronic primary-care patient records to assess consultation rates, comorbidities and antibiotic prescription rates for respiratory infections in primary care. We found that between 1995 and 2005, overall registered consultation rates for lower respiratory tract infections had increased by 42·4%, upper respiratory infections declined by 4·9%, and otitis media remained unchanged. Concomitantly, there was a steady rise in overall comorbidity (75·7%) and antibiotic prescription rates (67·7%). Since Dutch primary-care rates for respiratory infections changed considerably between 1995 and 2005, these changes must be taken into account to properly evaluate the effect of population-based preventive strategies on primary-care utilization.

Predicting benign course and prolonged illness in lower respiratory tract infections: a 13 European country study.

BACKGROUND: Clinicians and patients are often uncertain about the likely clinical course of community-acquired lower respiratory tract infection (LRTI) in individual patients. We therefore set out to develop a prediction rule to identify patients at risk of prolonged illness and those with a benign course. METHODS: We determined which signs and symptoms predicted prolonged illness (moderately bad symptoms lasting >3 weeks after consultation) in 2690 adults presenting in primary care with LRTI in 13 European countries by using multilevel modelling. RESULTS: 212 (8.1%) patients experienced prolonged illness. Illness that had lasted >5 days at the time of presentation, >1 episode of cough in the preceding year, chronic use of inhaled pulmonary medication and diarrhoea independently predicted prolonged illness. Applying a rule based on these four variables, 3% of the patients with ≤ 1 variable present (n = 955, 37%) had prolonged illness. Patients with all four variables present had a 30% chance of prolonged illness (n = 71, 3%). CONCLUSIONS: Most patients with acute cough (>90%) recover within 3 weeks. A prediction rule containing four clinical items had predictive value for the risk of prolonged illness, but given its imprecision, appeared to have little clinical utility. Patients should be reassured that they are most likely to recover within three weeks and advised to re-consult if their symptoms persist beyond that period.

Antibiotic prescribing for adults with acute cough/lower respiratory tract infection: congruence with guidelines.

European guidelines for treating acute cough/lower respiratory tract infection (LRTI) aim to reduce nonevidence-based variation in prescribing, and better target and increase the use of first-line antibiotics. However, their application in primary care is unknown. We explored congruence of both antibiotic prescribing and antibiotic choice with European Respiratory Society (ERS)/European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for managing LRTI. The present study was an analysis of prospective observational data from patients presenting to primary care with acute cough/LRTI. Clinicians recorded symptoms on presentation, and their examination and management. Patients were followed up with self-complete diaries. 1,776 (52.7%) patients were prescribed antibiotics. Given patients' clinical presentation, clinicians could have justified an antibiotic prescription for 1,915 (71.2%) patients according to the ERS/ESCMID guidelines. 761 (42.8%) of those who were prescribed antibiotics received a first-choice antibiotic (i.e. tetracycline or amoxicillin). Ciprofloxacin was prescribed for 37 (2.1%) and cephalosporins for 117 (6.6%). A lack of specificity in definitions in the ERS/ESCMID guidelines could have enabled clinicians to justify a higher rate of antibiotic prescription. More studies are needed to produce specific clinical definitions and indications for treatment. First-choice antibiotics were prescribed to the minority of patients who received an antibiotic prescription.

Relationship between parental lung function and their children's lung function early in life.

This study investigated the relationship between parental lung function and their children's lung function measured early in life. Infants were participants in the Wheezing Illnesses Study Leidsche Rijn (WHISTLER). Lung function was measured before the age of 2 months using the single occlusion technique. Parental data on lung function (spirometry), medical history and environmental factors were obtained from the linked database of the Utrecht Health Project. Parental data on pulmonary function and covariates were available in 546 infants. Univariate linear regression analysis demonstrated a significant positive relationship between the infant's respiratory compliance and parental forced expiratory flow at 25-75% of forced vital capacity (FEF(25-75%))(,) forced expiratory volume in 1 s (FEV(1)) and forced vital capacity. A significant negative relationship was found between the infant's respiratory resistance and parental FEF(25-75%)and FEV(1). No significant relationship was found between the infant's respiratory time constant and parental lung function. Adjusting for body size partially reduced the significance of the observed relationship; adjusting for shared environmental factors did not change the observed results. Parental lung function levels are predictors of the respiratory mechanics of their newborn infants, which can only partially be explained by familial aggregation of body size. This suggests genetic mechanisms in familial aggregation of lung function, which are already detectable early in life.

The impact of using different symptom-based exacerbation algorithms in patients with COPD.

Not all exacerbations are captured by reliance on healthcare contacts. Symptom-based exacerbation definitions have shown to provide more adequate measures of exacerbation rates, severity and duration. However, no consensus has been reached on what is the most useful method and algorithm to identify these events. This article provides an overview of the existing symptom-based definitions and tests the hypothesis that differences in exacerbation characteristics depend on the algorithms used. We systematically reviewed symptom-based methods and algorithms used in the literature, and quantified the impact of the four most referenced algorithms on exacerbation-related outcome using an existing chronic obstructive pulmonary disease (COPD) cohort (n = 137). We identified 51 studies meeting our criteria using 14 widely varying symptom algorithms to define onset, severity and recovery. The most (71%) frequently referenced algorithm (modified Anthonisen) identified an incidence rate of 1.7 episodes·patient-yr⁻¹ (95% CI 1.4-2.1), while for requiring only one major or two major symptoms this was 1.9 episodes·patient-yr⁻¹ (95% CI 1.6-2.3) and 1.5 episodes·patient-yr⁻¹ (95% CI 0.6-1.0), respectively. Studies were generally lacking methods to enhance validity and accuracy of symptom recording. This review revealed large inconsistencies in definitions, methods and accuracy to define symptom-based COPD exacerbations. We demonstrated that minor changes in symptom criteria substantially affect incidence rates, clustering type and classification of exacerbations.

Antibiotic prescribing for discoloured sputum in acute cough/lower respiratory tract infection.

We investigated whether discoloured sputum and feeling unwell were associated with antibiotic prescription and benefit from antibiotic treatment for acute cough/lower respiratory tract infection (LTRI) in a prospective study of 3,402 adults in 13 countries. A two-level model investigated the association between producing discoloured sputum or feeling generally unwell and an antibiotic prescription. A three-level model investigated the association between an antibiotic prescription and symptom resolution. Patients producing discoloured sputum were prescribed antibiotics more frequently than those not producing sputum (OR 3.2, 95% CI 2.1-5.0), unlike those producing clear/white sputum (OR 0.95, 95% CI 0.61-1.48). Antibiotic prescription was not associated with a greater rate or magnitude of symptom score resolution (as measured by a 13-item questionnaire completed by patients each day) among those who: produced yellow (coefficient 0.00; p = 0.68) or green (coefficient -0.01; p = 0.11) sputum; reported any of three categories of feeling unwell; or produced discoloured sputum and felt generally unwell (coefficient -0.01; p = 0.19). Adults with acute cough/LRTI presenting in primary care settings with discoloured sputum were prescribed antibiotics more often compared to those not producing sputum. Sputum colour, alone or together with feeling generally unwell, was not associated with recovery or benefit from antibiotic treatment.

Lower respiratory tract infection in the community: associations between viral aetiology and illness course.

OBJECTIVES: This study determined associations between respiratory viruses and subsequent illness course in primary care adult patients presenting with acute cough and/or suspected lower respiratory tract infection. METHODS: A prospective European primary care study recruited adults with symptoms of lower respiratory tract infection between November 2007 and April 2010. Real-time in-house polymerase chain reaction (PCR) was performed to test for six common respiratory viruses. In this secondary analysis, symptom severity (scored 1 = no problem, 2 = mild, 3 = moderate, 4 = severe) and symptom duration were compared between groups with different viral aetiologies using regression and Cox proportional hazard models, respectively. Additionally, associations between baseline viral load (cycle threshold (Ct) value) and illness course were assessed. RESULTS: The PCR tested positive for a common respiratory virus in 1354 of the 2957 (45.8%) included patients. The overall mean symptom score at presentation was 2.09 (95% confidence interval (CI) 2.07-2.11) and the median duration until resolution of moderately bad or severe symptoms was 8.70 days (interquartile range 4.50-11.00). Patients with influenza virus, human metapneumovirus (hMPV), respiratory syncytial virus (RSV), coronavirus (CoV) or rhinovirus had a significantly higher symptom score than patients with no virus isolated (0.07-0.25 points or 2.3-8.3% higher symptom score). Time to symptom resolution was longer in RSV infections (adjusted hazard ratio (AHR) 0.80, 95% CI 0.65-0.96) and hMPV infections (AHR 0.77, 95% CI 0.62-0.94) than in infections with no virus isolated. Overall, baseline viral load was associated with symptom severity (difference 0.11, 95% CI 0.06-0.16 per 10 cycles decrease in Ct value), but not with symptom duration. CONCLUSIONS: In healthy, working adults from the general community presenting at the general practitioner with acute cough and/or suspected lower respiratory tract infection other than influenza impose an illness burden comparable to influenza. Hence, the public health focus for viral respiratory tract infections should be broadened.

Determinants of community-acquired pneumonia in children and young adults in primary care.

Most studies on determinants of community-acquired pneumonia (CAP) in primary care have focused primarily on the elderly. Using a case-control study in four Dutch healthcare centres, determinants of CAP among children and young adults were identified. Cases included 156 young adults (aged 16-40 yrs) and 107 children (aged 0-15 yrs) diagnosed with CAP during 1999-2008. For each case, three controls were selected from the same age group. Separate logistic regression analyses were used to identify determinants in young adults and children. Lower age, asthma and previous upper respiratory tract infections (URTIs) were independently associated with CAP in children. Increasing age, asthma, three or more children at home, current smoking and three or more previous URTIs were independent determinants of CAP in young adults. The present study has three remarkable findings: 1) increasing age was an independent determinant of CAP in young adults; 2) having young children increased the risk of the development of CAP in young adults; and 3) the number of previous URTIs was independently associated with CAP in both children and young adults, possibly due to higher infection susceptibility. Further studies are required in order to better understand the aetiology of CAP and permit better diagnosis and treatment of this serious condition.

Are smokers with acute cough in primary care prescribed antibiotics more often, and to what benefit? An observational study in 13 European countries.

Little is known about actual clinical practice regarding management of smokers compared with ex-smokers and nonsmokers presenting with acute cough in primary care, and whether a lower threshold for prescribing antibiotics benefits smokers. This was a multicentre 13-country European prospective observational study of primary care clinician management of acute cough in consecutive immunocompetent adults presenting with an acute cough of

Antibiotics in the treatment of upper respiratory tract infections in Poland. Is there any improvement?

WHAT IS KNOWN: Acute upper respiratory tract infections are among the most frequent reasons for encounters in primary health care. Relevant data about antibiotics use in respiratory tract infections in Poland are scarce. AIMS AND OBJECTIVES: To evaluate the frequency of use and choice of antibiotics in empirical first-line treatment of upper respiratory tract infections in adults in eastern Poland. METHODS: An analysis of the medical records of 4047 adult patients from 47 health centres in Lublin region (eastern Poland) within the period of 1 year (1 September 2005 to 31 August 2006). RESULTS AND DISCUSSION: In 1267 patient visits, the reasons for encounter were classified by physicians as acute infections of the upper respiratory tract. Most frequently diagnosed were acute pharyngitis and tonsillitis, acute upper respiratory infections of multiple and unspecified sites and the common cold. Overall, antibiotics were used as empirical first-line therapy in 78·7% of cases. Amoxicillin, amoxicillin with clavulanic acid, macrolide and doxycycline were most commonly prescribed. Physician's specialty was not associated with antibiotic use. WHAT IS NEW AND CONCLUSIONS: There is still considerable overuse of antibiotics in primary care patients with respiratory tract infections in Poland. Campaigns aiming at changing prescribing behaviour of primary care physicians and informing the public should be undertaken.

Reduced risk of next exacerbation and mortality associated with antibiotic use in COPD.

The long-term risk of a subsequent exacerbation of chronic obstructive pulmonary disease (COPD) after treatment with oral corticosteroids without (OS) or with antibiotics (OSA) was compared in a historical general practice-based cohort. Eligible patients were >/=50 yrs of age, had a registered diagnosis of COPD, were on maintenance respiratory drugs, and had experienced at least one exacerbation defined as a prescription OS or OSA. Times to second and third exacerbations were assessed using Kaplan-Meier survival analysis; the risk of a subsequent exacerbation was assessed in a Cox proportional hazards analysis; and all-cause mortality was assessed using Kaplan-Meier survival and Cox proportional hazards analyses. A total of 842 patients had one or more exacerbations. The median time from first to second exacerbation was comparable for the OS and OSA groups, but the time from second to third exacerbation differed: 189 versus 258 days, respectively. The protective effect of OSA was most pronounced during the first 3 months following treatment (hazards ratio 0.72, 95% confidence interval 0.62-0.83). Exposure to antibiotics unrelated to a course of oral corticosteroids almost halved the risk of a new exacerbation. Mortality during follow-up was considerably lower in the OSA group. Adding antibiotics to oral corticosteroids was associated with: reduced risk of subsequent exacerbation, particularly in patients with recurrent exacerbations; and reduced risk of all-cause mortality.

Intervention with educational outreach at large scale to reduce antibiotics for respiratory tract infections: a controlled before and after study.

BACKGROUND: A multiple intervention targeted to reduce antibiotic prescribing with an educational outreach programme had proven to be effective in a randomized controlled trial in 12 peer review groups, demonstrating 12% less prescriptions for respiratory tract infections. OBJECTIVE: To assess the effectiveness of a multiple intervention in primary care at a large scale. METHODS: A controlled before and after study in 2006 and 2007 was designed. Participants were from general practices within a geographically defined area in the middle region of The Netherlands. Participants were GPs in 141 practices in 25 peer review groups. A control group of GP practices from the same region, matched for type of practice and mean volume of antibiotic prescribing. The multiple intervention consisted of the following elements: (i) group education meeting and communication training; (ii) monitoring and feedback on prescribing behaviour; (iii) group education for GPs and pharmacists assistants and (iv) patient education material. The main outcome measures are as follows: (i) number of antibiotic prescriptions per 1000 patients per GP and (ii) number of second-choice antibiotics, obtained from claims data from the regional health insurance company. The associations between predictors and outcome measurements were assessed by means of a multiple regression analyses. RESULTS: At baseline, the number of antibiotic prescriptions per 1000 patients was slightly higher in the intervention group than in the control group (184 versus 176). In 2007, the number of prescriptions had increased to 232 and 227, respectively, and not differed between intervention and control group. CONCLUSIONS: The implementation of an already proven effective multiple intervention strategy at a larger scale showed no reduction of antibiotic prescription rates. The failure might be attributed to a less tight monitoring of intervention and audit. Inserting practical tools in the intervention might be more successful and should be studied.

Implementation and evaluation of an antimicrobial stewardship programme in companion animal clinics: A stepped-wedge design intervention study.

BACKGROUND: To curb increasing resistance rates, responsible antimicrobial use (AMU) is needed, both in human and veterinary medicine. In human healthcare, antimicrobial stewardship programmes (ASPs) have been implemented worldwide to improve appropriate AMU. No ASPs have been developed for and implemented in companion animal clinics yet. OBJECTIVES: The objective of the present study was to implement and evaluate the effectiveness of an ASP in 44 Dutch companion animal clinics. The objectives of the ASP were to increase awareness on AMU, to decrease total AMU whenever possible and to shift AMU towards 1st choice antimicrobials, according to Dutch guidelines on veterinary AMU. METHODS: The study was designed as a prospective, stepped-wedge, intervention study, which was performed from March 2016 until March 2018. The multifaceted intervention was developed using previous qualitative and quantitative research on current prescribing behaviour in Dutch companion animal clinics. The number of Defined Daily Doses for Animal (DDDAs) per clinic (total, 1st, 2nd and 3rd choice AMU) was used to quantify systemic AMU. Monthly AMU data were described using a mixed effect time series model with auto-regression. The effect of the ASP was modelled using a step function and a change in the (linear) time trend. RESULTS: A statistically significant decrease of 15% (7%-22%) in total AMU, 15% (5%-24%) in 1st choice AMU and 26% (17%-34%) in 2nd choice AMU was attributed to participation in the ASP, on top of the already ongoing time trends. Use of 3rd choice AMs did not significantly decrease by participation in the ASP. The change in total AMU became more prominent over time, with a 16% (4%-26%) decrease in (linear) time trend per year. CONCLUSIONS: This study shows that, although AMU in Dutch companion animal clinics was already decreasing and changing, AMU could be further optimised by participation in an antimicrobial stewardship programme.

Incidence and predictive factors of lower respiratory tract infections among the very elderly in the general population. The Leiden 85-plus Study.

OBJECTIVES: To target preventive strategies in old age, which of the very elderly are predisposed to developing lower respiratory tract infections was investigated. DESIGN: Prospective observational follow-up study. SETTING: General population. PARTICIPANTS: Unselected cohort of 587 participants aged 85 years in Leiden, The Netherlands. MEASUREMENTS: As reported in the literature, predictive factors were selected and assessed at baseline. During a 5 year follow-up period, information on the development of lower respiratory tract infections was obtained from general practitioners or nursing home physicians. Associations between predictive factors were analysed with Cox regression, and population attributable risks were calculated. RESULTS: The incidence of lower respiratory tract infections among persons aged 85-90 years was 94 (95% CI 80-108) per 1000 person years. After multivariate analysis, history of chronic obstructive pulmonary disease (COPD), smoking, oral glucocorticosteroid use, severe cognitive impairment, history of stroke and declined functional status remained independently associated with the occurrence of lower respiratory tract infections. Smoking was the greatest contributor with a population attributable risk of 32%. CONCLUSION: In the very old, smoking, COPD, stroke and declined functional status were associated with the occurrence of lower respiratory tract infections and provide a means of targeting patients at risk of severe health complications.

Rationale and design of CAPITA: a RCT of 13-valent conjugated pneumococcal vaccine efficacy among older adults.

The burden of community-acquired pneumonia (CAP) among the elderly is high and has increased over the last decades. Streptococcus pneumoniae is the most common cause of CAP and in 10% the infection may be fatal. Although the 23-valent polysaccharide pneumococcal vaccine (23vPS) is considered effective in the prevention of invasive pneumococcal disease in the elderly population, the evidence is mainly from nonrandomised observational studies and effects on the occurrence of pneumonia have not been demonstrated. Conjugated pneumococcal vaccines which also stimulate T-cell dependent immune responses induced antibody responses in elderly persons which are similar to those induced by a primary series of 7-valent conjugated pneumococcal vaccine (7vPnC) in infants, and the response appeared similar or superior for all vaccine serotypes to that induced by 23vPS. The primary objective of the planned trial entitled CAPITA (Community Acquired Pneumonia Immunization Trial in Adults) is to establish the efficacy of a 13-valent PnC vaccine in the prevention of a first episode of vaccine-serotype specific pneumococcal CAP in 85,000 community-dwelling adult persons aged 65 years and older. This is a parallel group, randomised, placebo-controlled trial, with a 1:1 random allocation to vaccine or placebo vaccine. The occurrence of the primary outcome of vaccine-serotype specific (VT)-CAP will be established in hospitals on the basis of three sets of criteria: (1) a clinical definition of CAP; (2) independent interpretation of chest radiograph consistent with pneumonia: and (3) determination of S. pneumonia serotype. the trial will be critical to determine the position of conjugate pneumococcal vaccines in the prevention of pneumococcal disease.

Amoxicillin for acute lower respiratory tract infection in primary care: subgroup analysis by bacterial and viral aetiology.

OBJECTIVE: We aimed to assess the effects of amoxicillin treatment in adult patients presenting to primary care with a lower respiratory tract infection (LRTI) who were infected with a potential bacterial, viral, or mixed bacterial/viral infection. METHODS: This multicentre randomized controlled trial focused on adults with LRTI not suspected for pneumonia. Patients were randomized to receive either antibiotic (amoxicillin 1 g) or placebo three times daily for 7 consecutive days using computer-generated random numbers (follow-up 28 days). In this secondary analysis of the trial, symptom duration (primary outcome), symptom severity (scored 0-6), and illness deterioration (reconsultation with new or worsening symptoms, or hospital admission) were analysed in pre-specified subgroups using regression models. Subgroups of interest were patients with a (strictly) bacterial, (strictly) viral, or combined infection, and patients with elevated values of procalcitonin, C-reactive protein, or blood urea nitrogen. RESULTS: 2058 patients (amoxicillin n = 1036; placebo n = 1022) were randomized. Treatment did not affect symptom duration (n = 1793). Patients from whom a bacterial pathogen only was isolated (n = 207) benefited from amoxicillin in that symptom severity (n = 804) was reduced by 0.26 points (95% CI -0.48 to -0.03). The odds of illness deterioration (n = 2024) was 0.24 (95% CI 0.11 to 0.53) times lower from treatment with amoxicillin when both a bacterial and a viral pathogen were isolated (combined infection; n = 198). CONCLUSIONS: Amoxicillin may reduce the risk of illness deterioration in patients with a combined bacterial and viral infection. We found no clinically meaningful benefit from amoxicillin treatment in other subgroups.

Aetiology of lower respiratory tract infection in adults in primary care: a prospective study in 11 European countries.

OBJECTIVES: To describe the role of bacteria (including bacterial resistance), viruses (including those recently described) and mixed bacterial-viral infections in adults presenting to primary care with lower respiratory tract infection (LRTI). METHODS: In all, 3104 adults with LRTI were enrolled, of whom 141 (4.5%) had community-acquired pneumonia (CAP), and 2985 matched controls in a prospective study in 16 primary care networks in Europe, and followed patients up at 28-35 days. We detected Streptococcus pneumoniae and Haemophilus influenzae and assessed susceptibility, atypical bacteria and viruses. RESULTS: A potential pathogen was detected in 1844 (59%) (in 350 (11%) bacterial pathogens only, in 1190 (38%) viral pathogens only, and in 304 (10%) both bacterial and viral pathogens). The most common bacterial pathogens isolated were S. pneumoniae (5.5% overall, 9.2% in CAP patients) and H. influenzae (5.4% overall, 14.2% in CAP patients). Less than 1% of S. pneumoniae were highly resistant to penicillin and 12.6% of H. influenzae were ß-lactamase positive. The most common viral pathogens detected were human rhinovirus (20.1%), influenza viruses (9.9%), and human coronavirus (7.4%). Influenza virus, human parainfluenza viruses and human respiratory syncytial virus as well as human rhinovirus, human coronavirus and human metapneumovirus were detected significantly more frequently in LRTI patients than in controls. CONCLUSIONS: A bacterial pathogen is identified in approximately one in five adult patients with LRTI in primary care, and a viral pathogen in just under half, with mixed infections in one in ten. Penicillin-resistant pneumococci and ß-lactamase-producing H. influenzae are uncommon. These new findings support a restrictive approach to antibiotic prescribing for LRTI and the use of first-line, narrow-spectrum agents in primary care.