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There was no difference in the rates of bacterial infections post-vaccination, (17.5% of the total) compared to 24% pre-vaccination (p=0.258). Overall, identified pneumococcal infections were not different between the studies (p=0.557). They represent 17.4% among children tested post-vaccination (14 (15%) out of 93 and 10 (22.2%) out of 45 in those aged <5 years and >5 years, respectively). This was compared to 14.7% pre-vaccination (28 (15.6%) out of 180 and seven (12%) out of 58 among those aged <5 years and >5 years, respectively). In the post-vaccine study, diagnosis of pneumococcal infection improved when PCR was used (21 (21.6%) out of 97) compared to culture (eight (6%) out of 132) (p=0.0004). A serotype was identified in 75% (18 out of 24) in the post-vaccine study. These were serotypes 1 (44.4%), 3 (27.8%), 19A (22.2%) and 7A/F (5.6%). The rate of positive blood culture post-vaccination was almost double (5.6%) that pre-vaccination (3.2%).
Group A streptococcal infections were confirmed in a greater proportion of children (10.5%) post-vaccination than in the pre-vaccination group (7%). These infections were associated with severe disease, and in two-thirds of cases with empyema. M. pneumoniae was identified from acute serology in 9.9% of children post-vaccination, with 4% (two out of 51) in those aged <5 years and 20% (six out of 30) in patients aged >5 years. The rate of detected mycoplasma infection was higher pre-vaccination (12.5%) when paired acute and convalescent samples were available, with 7% (nine out of 128) in those aged <5 years and 27% (13 out of 48) in those aged >5 years.
Among 67 children enrolled during this period, the causative pathogen was identified in 37 (55%). S. pneumoniae was identified in 18.3% (11 out of 60) compared to 16.7% (13 out of 78) during the first year of PCV13 vaccination (p=0.824). Rates of infections were 22.4% bacterial, 22.4% viral and 10.5% mixed. The rate of bacterial infection is similar to the figures from the pre- and entire post-vaccine studies. There was no difference between the rates of viral infection before and after the introduction of PCV13 during the post-vaccine study (p=0.079).
The relationship between nasopharyngeal pathogen load and the disease severity had been previously assessed in data from several pneumonia epidemiological studies. These studies have demonstrated that nasopharyngeal pathogen load could predict the severity of pneumonia in children. A study in the USA among infants reported that a higher RSV load was associated with longer hospitalisation, respiratory failure and admission to intensive care unit.46 In Vietnam, children with radiological confirmed pneumonia had higher pneumococcal load compared with children with other respiratory illness and the load of pneumococcus was a 15-fold higher in children with viral coinfection compared with no viral coinfection.47 Other studies in Kenya and the Netherlands reported the higher nasopharyngeal RSV loads in children with severe respiratory infections compared with less severe infections.48 49
Among HIV-infected children, the RT-PCR viral panel was positive in 274 (53.0%) LRTI-episodes for at least one of the newly-tested viruses; Table 3. The prevalence of any of the newly-tested respiratory viruses was similar between PCV9- and placebo-recipients in HIV-infected children, except for WUPyV (11.2% vs. 6.3%; p = 0.047, respectively) and hBoV (12.5% vs. 7.0%; p = 0.034, respectively); Table S3. In HIV-infected children hRV was the most frequently detected virus (31.7%) followed by CoV-OC43 (12.2%), hBoV (9.5%), KIPyV (8.9%), WUPyV (8.5), CoV-NL63 (1.7%) and CoV-HKU1 (1.4%); Table 3. The newly-tested viruses were frequently identified as co-infecting viruses among HIV-infected children, including 49.4% of LRTI-episodes associated with hRV; Table 4. The most common viral co-infections with hRV included KIPyV (14.6%), WUPyV (11.6%), CoV-OC43 and hBoV (11.0%, each); Table 4. Among the 486 children on whom blood culture was done, bacteria were isolated on 38 (7.8%) occasions, 20 (52.6%) of which were associated with concomitant detection of one of the newly-tested viruses and 22 (57.9%) of any of the viruses.
In HIV-uninfected children at least one newly-tested virus was detected in 509 (54.0%) LRTI-episodes, with hRV also being the most common (32.0%), followed by hBoV (13.3%), WUPyV (11.9%), KIPyV (4.8%), CoV-OC43 (3.6%), CoV-NL63 (2.6%), CoV-HKU1 (1.6%) and CoV-229E (0.42%); Table 3. Comparing HIV-uninfected PCV9 and placebo recipients, differences in the prevalence of newly-tested viruses were evident for KIPyV (2.1% vs. 7.4%; p<0.001), CoV-HKU1 (0.21% vs. 2.9%; p = 0.001), CoV-OC43 (2.1% vs. 5.0%; p = 0.017) and hRV (36.2% vs. 27.9%; p = 0.007); Table S3. Of the 302 LRTI-episodes in which hRV was identified, 51.3% had at least one other virus detected, including 13.6% with RSV, 12.3% with WUPyV or hBoV and 2.0% (N = 6) with both WUPyV and hBoV; Table 5. The prevalence of bacteraemia in HIV-uninfected children among those with blood culture results was 2.7% (N = 24/881) of which 12 (50.0%) occurred in the presence of infection with one of the newly-tested viruses and 15 (62.5%) in presence of any of the studied viruses.
By multivariate analysis, adjusting for PCV-vaccination status, period of collection and age, single infections with a newly-tested virus were more frequent in HIV-infected (30.2%) than HIV-uninfected children (25.5%) (adjusted odds ratio [aOR] 1.3; p = 0.033); Table 3. Also, HIV-infected compared to HIV-uninfected children had a higher prevalence of KIPyV (aOR 2.14; p = 0.002) and CoV-OC43 (aOR 3.67; p<0.001) and a lower prevalence of hBoV (aOR 0.69; p = 0.043) and WUPyV (aOR 0.66; p = 0.035); Table 3. Concurrent bacteraemia and infection with at least one of the newly-tested viruses was more frequent in HIV-infected (7.7%) compared to HIV-uninfected children (2.5%, aOR 3.49; p = 0.001). There were no differences in the frequency of bacteraemia comparing children in whom newly-tested viruses were detected and those without viral detection both in HIV-infected (7.7% vs. 8.0%; p = 0.911) and HIV-uninfected children (2.5% vs. 2.9%; p = 0.713).
At least 1 microorganism was detected on nasal swabs in 96.6% of cases and 82.3% of controls (crude OR = 6.4, 95% confidence interval [95% CI]: 2.1–19.7, P<0.001). Overall, 78.8% of cases and 54.2% of controls were co-infected or co-colonized (crude OR = 3.3, 95% CI: 1.8–6.0, P<0.001). Co-detection on nasal swab of S. pneumoniae and RSV was more frequent in cases than in controls (respectively, 15.2% [N = 18] vs. 2.0% [N = 2], P = 0.001). Co-detection of S. pneumoniae and rhinovirus was not different in cases and controls (respectively, 16.1% [N = 19] vs. 12.2% [N = 12], P = 0.42; co-detection RSV and rhinovirus was not different between cases and controls (respectively, 5.9% [N = 7] vs. 3.1% [N = 3], P = 0.32). A dose-response relationship was apparent between the number of microorganisms found in nasal swabs and the risk of being a case (Fig 1). Distribution of S. pneumoniae and RSV differed by season with higher rates of S. pneumoniae in January-June and of RSV in July-September (Fig 2).
Univariate analysis revealed that S. pneumoniae, human metapneumovirus, RSV, and influenza A virus detection in nasal swabs were significantly associated with pneumonia in Mali (Table 3). Multivariate analysis reinforced linkage of these pathogens with pneumonia, independently of patient age, gender, period per quarter and the presence of other pathogens significantly coupled with increased risk of pneumonia (Table 3). PAF was the highest for S. pneumoniae (PAF = 46%, 95% CI: 30–59%). Contribution of human metapneumovirus, RSV, and influenza A were lower, with PAFs of 9% (95% CI: 7–11%), 21% (95% CI: 16–25%) and, 8% (95% CI: 6–10%), respectively.
Fig 3 reports the distribution of pneumococcal serotypes detected in nasal swabs from cases and controls. The most prevalent serotype in pneumonia cases and controls was serotype 6A/B (18.6% vs. 11.2%, P = 0.13). Serotypes 1 and 5 were more frequent in pneumonia cases than in the controls: 6.8% vs. 0%, P = 0.009, and 4.2% vs. 0%, P = 0.04, respectively.
In pneumonia cases, S. pneumoniae was positive in 16 (13.6%) patients, S. aureus in 6 (5.1%) patients and H. influenza in 5 (4.2%) patients by PCR blood sample detection. Most patients with S. pneumoniae detection by PCR had also S. pneumoniae nasal carriage (93.5%, 15/16), while only 17.6% (15/85) of patients with S. pneumoniae nasal carriage had positive detection by PCR (P = 0.04). Concordance of serotype 1 detected in nasal swabs and blood in pneumonia cases was high (κ = 0.70, P<0.001). Coronavirus 63 was identified from pleural effusion in 1 patient. Microbiological findings, including S. pneumoniae serotypes distribution, from PCR nasal swab or blood sample were not different in pneumonia cases according to the result of urine antibiotic testing (data not shown). Blood culture was positive in 36 (30.5%) pneumonia cases; most microorganisms were probably related to contamination of samples. The following bacteria were detected: coagulase-negative staphyloccoci (n = 26), Salmonella spp. (n = 3), Gram-positive bacilli (n = 2), Acinetobacter baumannii (n = 1), Aerococcus viridans (n = 1), Enterococcus faecium (n = 1), Granulicatella elegans (n = 1), and Staphylococcus aureus (n = 1).
Of 230 cases and 230 controls, one or more respiratory viruses were identified in 56.5% and 28.6%, respectively (OR: 3.2; 95% CI: 2.1 to 4.7), and at least one bacterial species was detected in 71.7% and 79.5%, respectively (OR: 0.6; 95% CI: 0.4 to 1.0). The distribution of respiratory viruses and bacteria among cases and controls is summarised in table 2. Detection of both viruses and bacteria was observed in 104 cases (45.2%) and in 56 controls (24.3%). Cases were more likely than controls to have multiple (two or more) viruses detected (OR: 5.1, 95% CI: 1.7 to 15.1) but not multiple bacterial species (OR: 1.0, 95% CI: 0.7 to 1.4).
There is evidence that respiratory viruses may have a role in facilitating bacterial colonisation, enhancing bacterial infection and/or in enhancing disease severity either directly or indirectly. Viruses disrupt the respiratory epithelium barrier and also alter the defence mechanism of host epithelium potentially leading to bacterial entrance and enabling secondary bacterial infection.35 36 The incidence of invasive pneumococcal infection has been observed to be higher during increased seasonal activity of some respiratory viruses including influenza, RSV, parainfluenza 3 and adenovirus.37 38 Further, in clinical trials in South Africa, conjugate pneumococcal vaccination resulted in overall decrease in virus-associated pneumonia, suggesting interactions between respiratory viruses and pneumococcus in causing pneumonia in children.39 In Australia, ecological data have demonstrated a reduction in viral pneumonia following introduction of PCV vaccines.40 RSV has been reported to facilitate bacterial colonisation with H. influenzae, Streptococcus pyogenes, Staphylococcus aureus, and M. catarrhalis in the nasopharynx of young children with acute respiratory infection.41 Another study in Australia identified Streptococcus pneumoniae, H. influenzae and Staphylococcus aureus in 25% patients in intensive care who were admitted with severe influenza A infection during 2009 influenza pandemic.42 The patients with viral–bacterial coinfection has been reported to suffer for treatment failure, longer ventilator support and increased likelihood of intensive care unit admission.12 43–45
The multivariate logistic regression showed that after adjusting for demographic differences, antibiotic exposure in the preceding 7 days, and presence of other pathogens, RSV, HMPV, influenza virus and adenovirus were detected significantly more often among cases than controls with aOR 58.4 (95% CI: 15.6 to 217.5), 37.2 (95% CI: 7.8 to 177.7), 10.1 (95% CI: 1.8 to 57.1) and 12.1 (95% CI: 1.4 to 104.4), respectively (table 2). None of the influenza-positive cases (n=16) or controls (n=3) had received influenza vaccine during the preceding influenza season. RV speciation was available for 57 (69%) of 83 positive samples (26 cases; 31 controls). RV-A was detected in 13 cases (50%) and 15 controls (48.3%), RV-B in 1 (3.8%) case and 2 (6.4%) controls and RV-C was detected in 12 (46.1%) cases and 14 (45.1%) controls.
Respiratory viruses were detected more commonly among children <5 years compared with other age groups (figure 1). More than 75% of cases positive for RSV, HPIV, HMPV and adenovirus were aged less than 3 years. Respiratory viruses were detected throughout the year with frequent detection during the Australian winter months (June to August). RV was detected throughout the year, while RSV, influenza and HMPV were mostly detected between May and November and HPIV between December and April; virus distribution among cases and control children was similar along the year calendar (figures 2 and 3).
Various other factors—including underlying medical conditions and smoking—can increase the risk of pneumonia by compromising pulmonary clearance mechanisms and the host immune response, potentially influencing the selection of pathogens in both the URT and LRT . Age plays a major role in pneumonia risk. In developed countries, such as the USA, the risk of pneumonia is highest in individuals who are 65 years or over (Fig. 1). The elevated risk in the elderly is likely due to impaired host defenses and an increase in comorbidities—heart failure, liver disease and underlying lung disease—which increase risk of aspiration pneumonia that can occur from dysphagia and gastroesophageal reflux disease (reviewed by Akgün et al.). In developing countries, the burden of pneumonia is greatest in young children due to their inability to physically remove and immunologically deal with bacterial pathogens (reviewed by Siegrist). Very young children also have the greatest prevalence in the nasopharynx of common bacterial pneumonia pathogens: S. pneumoniae, H. influenzae and M. catarrhalis [23, 51]. Increased carriage may be an important risk factor for pneumonia if the URT bacterial community structure is a determinant of pneumonia etiology. Unfortunately, the majority of carriage studies have been conducted among children <5 years of age, which limits our ability to establish the role of nasopharyngeal carriage in other age groups.
Regardless of age, viral infection is an important risk factor for bacterial pneumonia. Viruses can lead to rapid, drastic increases in morbidity and mortality in all age groups as seen in historic influenza epidemics and pandemics, making it a major public health concern.
Our results confirm that respiratory infections were very common among French Hajj pilgrims, with more than 80% of them reporting at least one symptom during the 2014–2017 Hajj seasons. Our result is in line with the previous results obtained from cohort studies conducted among French pilgrims21 and from a large cohort study enrolling pilgrims from 13 different countries22. We also document the significant acquisition of almost all viral and bacterial pathogens included in our survey, following participation to the Hajj, as reported previously3,23.
We found that male gender was independently associated with a decreased risk for ILI and for the acquisition of coronaviruses and K. pneumoniae. We have no explanation for this unexpected observation. Older age (≥60 years) was associated with the acquisition of influenza viruses, HCoV and S. pneumoniae. Although older age was not correlated with the increase in the proportion of respiratory symptoms in our study, our results support the current French recommendations that indicate influenza vaccination for all pilgrims and IPD vaccination for pilgrims aged ≥60 years old (or with chronic conditions)24,25. Furthermore, we showed that influenza vaccination was significantly associated with a lower prevalence of ILI in our survey. Similarly, in a meta-analysis, Alfelali et al. have shown that, influenza vaccine decreases the prevalence of ILI26. We also demonstrate here that vaccination against IPD with a decrease in the acquisition of S. pneumoniae, but had no effect on respiratory symptoms. A protective effect of pneumococcal vaccination against S. pneumoniae post-Hajj carriage was observed in only one out of 5 studies so far9. However, all studies showing no effect of pneumococcal vaccination were conducted on small groups of pilgrims (ranging 55 to 107 individuals), while in the two studies showing a protective effect, the number of pilgrims was much higher (1178 and 468) which may indicate that small surveys lacked statistical power. Finally, as expected, patients suffering from chronic respiratory diseases were more likely to suffer from cough and ILI but also to acquire H. influenzae. Our results confirm the need for influenza and IPD vaccination among the identified pilgrim populations at risk of RTIs and acquisition of respiratory pathogens. Vaccination rates in our cohort were clearly sub-optimal: 26.7% of pilgrims were vaccinated against influenza and 30.5% against IPD among those with an indication.
With regard to non-pharmaceutical preventive measures, the use of masks, especially in crowded areas, frequent hand washing with water and soap or disinfectant, especially after coughing and sneezing, and the use of disposable handkerchiefs are recommended by the Saudi Ministry of Health to Hajj pilgrims27. In a meta-analysis including 13 surveys of Hajj pilgrims, significant protection of face masks was found against RITs, but the end points varied considerably12. We found that there was a higher prevalence of ILI and rhinovirus acquisition among pilgrims who reported wearing face masks. Similarly, a higher prevalence of cough was observed among pilgrims who reported using disposable handkerchiefs. It is likely that such results indicate the higher willingness of symptomatic pilgrims to wear a face mask and use disposable handkerchiefs, with the aim of avoiding spreading diseases. In addition, the use of disposable handkerchiefs appears to be correlated with a decrease in the acquisition of S. aureus carriage, which may reflect a better elimination of organisms by cleaning the nasopharynx. We found that increased hand hygiene was not associated with reduced respiratory pathogens acquisition or a lower prevalence of respiratory symptoms. In a recent review paper, it was shown that while hand hygiene using non-alcoholic products was generally well accepted by Hajj pilgrims, there was no conclusive evidence of its effectiveness, which is consistent with our results11.
Relationship between respiratory symptoms and carriage of respiratory pathogens at the Hajj are unclear. Because of the high frequency of respiratory symptoms, the distinction between infection and colonization is difficult to assess. Furthermore, asymptomatic carriage of potential pathogens is also observed among Hajj pilgrims28. Nevertheless, in the final model of multivariate analysis, the acquisition of S. aureus was associated with ILI and the acquisition of rhinovirus was associated with respiratory symptoms. Many studies showed that S. aureus and rhinovirus were among the predominant pathogens isolated from the Hajj pilgrims suffering RTIs9,11,12,21,23–32. Most cases of infections due to HRV are benign, self-limited cold-like illnesses. Nevertheless, HRV is also responsible for severe pneumonia in the elderly and immunocompromised patients, as well as exacerbations of chronic obstructive pulmonary disease and asthma33. HRV spreads mostly via direct contact or contact with a fomite, with inoculation to the eye or nose from fingertips34. The human-to-human transmission of rhinovirus among pilgrims may have been favored by the crowded conditions at pilgrim accommodations or during performing the Hajj rites.
S. aureus is also often part of the human microbiome in the anterior nares35. However, persistent S. aureus nasal carriage is associated with secondary staphylococcal respiratory infection, predisposing to invasive disease, especially in the case of detection of IAV36–38. To date, few studies addressed virus-bacteria carriage in relation with RTIs at the Hajj4,28. In our study, overall carrying virus-bacteria was associated with ILI. Dual H. influenzae-K. pneumoniae carriage was associated with twice the risk of coughing and H. influenzae-S. pneumoniae carriage with 5 times the risk for respiratory symptoms. Further works aiming at better understanding the role of overall carrying virus and bacteria in the pathogenesis of the RTIs at the Hajj are needed.
Our study had some limitations. The study was conducted among French pilgrims only and cannot be generalized to all pilgrims. Observance with individual preventive measures was self-reported and frequency of changing face mask and exact quantification of hand hygiene practice were not assessed. qPCR used to detect respiratory pathogens does not distinguish between dead and living micro-organisms. S. pneumoniae serotypes were not investigated. Moraxella catarrhalis that was recently shown to be relatively frequently acquired by Hajj pilgrims39 was not included in our study. Finally, we did not to be any long-term follow-up to determine what infections might have had delayed presentation after return from the pilgrimage. Nevertheless, our study included a large samples size of pilgrims spanning four Hajj seasons giving it a stronger statistical power. A number of risk factors have been identified to recognize pilgrims at increased risk of RTIs and of acquisition of most common respiratory pathogens encountered in this setting. Also, the study confirmed the effectiveness of vaccination against influenza in reducing ILI symptoms and that of vaccination against IPD in reducing acquisition of S. pneumoniae. Given the limitations of the current study, the use of face mask and a reinforced hand hygiene should still be recommended for Hajj pilgrims until large-scale controlled studies are conducted to truly assess the effectiveness of these measures in the context of Hajj. The use of disposable handkerchief is, de facto, highly frequent among ill pilgrims and at least allows decreasing the acquisition of S. aureus.
Table 1 compares the clinical signs and symptoms at admission between cases and controls, underlying conditions and biological findings. Pneumonia cases differed from controls regarding clinical signs and symptoms as well as vital signs at admission, but not in terms of demographic factors or past medical history. Pneumonia cases were more frequently hypoxemic (defined as oxygen saturation<90%) at admission than the controls (30.5% vs. 0%, P<0.001). PCV coverage was zero in both groups.
The Supplementary Table 1 and Table 3 show univariate and multivariate analyses results for factors associated with respiratory symptoms during the Hajj. Reporting of at least one respiratory symptom was twice as frequent and five times more frequent in rhinovirus carriers (adjusted relative risk (aRR): 1.98, 95%CI [1.03–3.78]) or H. influenzae-S. pneumoniae carriers, respectively (aRR: 4.75, 95%CI [1.17–19.35]) (Table 3). Coughing was twice as frequent in pilgrims suffering from chronic respiratory disease and among those carrying H. influenzae-K. pneumoniae together (aRR: 1.98, 95%CI [1.03–3.78]). Pilgrims who coughed were also more likely to use disposable handkerchiefs. Finally, ILI was more frequent in females, in pilgrims with chronic respiratory disease and among those carrying S. aureus or an association of virus and bacteria. In addition, pilgrims suffering ILI were more likely to use face mask. Influenza virus was not significantly associated with ILI. No significant association was observed between symptoms and vaccination against IPD. However, influenza vaccination was associated with a decrease in the prevalence of ILI (aRR: 0.69, 95%CI [0.52–0.92]).
We found no significant association between persistence of respiratory symptoms at return and pathogen carriage with the exception of H. influenzae carriage in association with viral carriage (aRR: 1.65, 95%CI [1.07–2.53], p = 0.02).
Over the 8-year study period, 329,380 children and adolescents were diagnosed with pneumonia, with a male-to-female ratio of 1:0.8. The age and yearly distribution of pneumonia cases, as well as the rate of hospitalization, are summarized in Table 2. Children 1 to 3 years old comprised the majority of cases (160,093 patients; 48.6% of cases), followed by children under the age of 1 year (57,295 patients; 17.4% of cases). Adolescents, 13 to 18 years old, comprised the smallest proportion (21,012 patients, 6.4% of cases). The yearly prevalence of pediatric pneumonia increased from 30,521 cases in 2007 to 68,451 cases in 2014. Among the 329,380 cases, 45.6% (150,110 patients) were hospitalized and 1.1% (3,770 patients) admitted to the intensive care unit (ICU). The rate of hospitalization was highest among patients under the age of 1 year (63.7%), with the rate decreasing with age to a rate of 30.0% among patients 13 to 18 years old. The ICU admission rate was highest under 1 year old group (3.0%), followed by 13 to 18 years old group (2.56%; Table 2).
Although the incidence rate of ED visit increased from 2007 through 2014, the rate of hospitalization declined, from 63.4% in 2007 to 38.2% in 2014. Peculiarly, the hospitalization rate was markedly lower in 2009, at 22.5%. The yearly ICU admission rate declined over the study period, from 1.9% in 2007 to 0.9% in 2014 (Table 2).
Overall, 66 deaths were reported, with a comparable rate of mortality of 0.01% to 0.03% for children under the age of 18 years (Table 2). Among children who died, 16 deaths (24.2% of death) were caused by aspiration pneumonia, with 11 patients (16.7% of cases) having a neurological disorder or congenital disease.
Over the 8-year period of the study, there were 2 peak patients number in February and November. In 2014, the rate of pneumonia was highest in February. In 2009, the number of patients was peak in November, followed by October (Fig. 1).
The prevalence of bacterial and viral pneumonia is summarized in Table 3. The etiology of pneumonia was not specified in 67.3% of cases (221,723 patients, diagnosis code J18–J18.9). Among the remaining cases with a clear etiology, viral pneumonia were diagnosed 27,607 patients; 8.4% of total pneumonia patients. The yearly prevalence of viral pneumonia varied between a low of 4.5% in 2007 to a high of 31.3% in 2009 during an influenza pandemic. When we broadly consider viral pathogens, including influenza, parainfluenza, and respiratory syncytial virus, as well as adenovirus and human metapneumovirus, the influenza virus was the most prevalent (11,553 patients, 41.8% of viral pneumonia), followed by the respiratory syncytial virus (4,771 patients, 17.3% of viral pneumonia).
Bacterial confirmed pneumonia was identified in 1.3% cases (4,316 patients, diagnosis codes J13, J14, J15–J15.9 excluding J15.7, J17.0). The yearly incidence of bacterial pneumonia decreased from 3.07% in 2007 and 0.65% in 2014 (Table 2). Among patients with bacterial pneumonia, 622 patients were diagnosed with pneumococcal pneumonia, with the yearly rate decreasing from 0.47% in 2007 to 0.08% in 2014 (Table 2).
M. pneumoniae pneumonia (MP) was diagnosed in 3.8% of cases (12,635 patients; Table 3). The 8-year monthly prevalence of MP is shown in Fig. 2. There was an increase in the number of patients in 2007. The prevalence of MP rose again in 2010 and 2011, due to a large epidemic, burgeoning again in early 2014 (Table 3, Fig. 2). Pleural effusion was identified in 0.4% of total cases (1,279 patients), accounting for 1.6% (68 patients) of cases of bacterial pneumonia and 2.0% (251 patients) of cases of MP. The yearly rate of patients presenting with pneumonia and pleural effusion is summarized in Table 2 and varied between 0.2%, in 2009 and 2012, and 0.7% in 2007. Empyema was identified in 125 patients (0.03% of cases), with the yearly rate varying between 0.01% in 2009 and 0.07% in 2007 (Table 2).
The annual proportion of patients with pneumococcal pneumonia and age of patients are reported in Table 2, with significant yearly and age-specific differences identified. The expected number of patients with bacterial pneumonia, pneumococcal pneumonia, pleural effusion, and empyema per 100,000 population between the ages of birth and 18 years is shown in Fig. 3. The upsurge of bacterial pneumonia in 2011 is presumed to have been associated with the increased prevalence of pneumonia-related complications, including pleural effusion and empyema, in 2011. The expected number of patients with pneumococcal pneumonia also rose in 2011, although, overall, there was a decreasing trend in the prevalence of bacterial pneumonia, pneumococcal pneumonia, pleural effusion, and empyema compared to that in 2007.
There was no decreasing or increasing trend in the number of patients with bacterial pneumonia, pneumococcal pneumonia, pleural effusion, and empyema per 100,000 population per year during the period from 2007 to 2014 (Table 4). In the annual deaths, stratified by age, the number of deaths per 10 million people in the 13 to 18-year-old group was significantly increased (tau=0.725, P=0.0239) (Table 4). In annual ICU hospitalized patients, an increasing trend was observed in the age group 7-12 years (tau=0.643, P=0.0354) (Table 4). Since Korean Statistical Information Service did not provide the monthly population in 2007, the monthly trend test was conducted for the period from 2008 to 2014. Bacterial pneumonia and empyema showed monotonic trend taking 12-month seasonality into account. The bacterial pneumonia and empyema peaks were in December and May, respectively (Figs. 3, 4; Table 5).
In time series trend test of annual incidence of bacterial pneumonia, pneumococcal pneumonia, pleural effusion and empyema per 100,000 population, there were not significant increasing or decreasing trend (Table 6).
When compared to LRTI-episodes associated with the identification of only a single virus the detection of multiple viruses in HIV-infected children was significantly associated with a higher frequency of bronchial breathing (aOR 2.11; p = 0.015) and in HIV-uninfected children with a higher prevalence of cyanosis (aOR 2.50; p = 0.008) and wheezing (aOR 1.55; p = 0.006); Table 6. No differences were detected in the severity of LRTI-episodes with single and multiple viral infections using the RISC score previously developed.
In both HIV-infected and –uninfected children with bacteria isolated from blood, there were no significant differences in the clinical and laboratory characteristics between children in whom viruses were detected and children without any virus detected. The same was observed restricting the analysis to Streptococcus pneumoniae isolation (data not shown).
KQ 21. For adults who have contracted community-acquired pneumonia, and have the risk factors of S. pneumoniae infection, can vaccination against S. pneumoniae prevent community-acquired pneumonia?
The risk factors of invasive pneumococcal diseases caused include age of 65 years or older, residence in long-term care facilities, dementia, convulsive diseases, congestive heart failure, cardiovascular diseases, chronic obstructive pulmonary diseases, previous history of pneumonia, chronic liver diseases, diabetes, alienia, and chronic cerebrospinal fluid leakage.
According to previous literatures, the 23-valent polysaccharide pneumococcal vaccine prevented invasive pneumococcal diseases in 44-47% of older adults aged 65 years or older, and its effectiveness was slightly reduced in patients with chronic diseases. Numerous cohort studies have recently demonstrated that the vaccine can reduce the incidence of pneumonia, pneumococcal pneumonia, hospitalization due to pneumonia, and deaths by pneumonia. However, some have reported that the vaccine has no preventive effects against pneumonia, or hospitalization due to pneumonia. Patients who have asplenia, who are of advanced age, or who are in a high-risk group must be revaccinated after five years. The safety and immunogenicity of the vaccine have been verified in numerous studies.
In a recent large-scale study, the 13-valent protein conjugate pneumococcal vaccine prevented 45% of pneumococcal pneumonia, and 75% of invasive pneumococcal diseases. However, the vaccine had no preventive effects against other types of pneumonia.
The preventive effects of the polysaccharide pneumococcal vaccine against invasive pneumococcal diseases, as well as those of the protein conjugate pneumococcal vaccine against pneumococcal infections have been verified. Accordingly, a domestic pneumococcal vaccination guideline recommends performing a combined injection of the protein conjugate and polysaccharide vaccines in patients who are of advanced age, or who have the risk factors of pneumococcal infections.
KQ 22. Does smoking cessation education prevent community-acquired pneumonia among adults who have contracted community-acquired pneumonia?
Smoking is known to be a risk factor of invasive pneumococcal diseases even in young people who are not immunosuppressed. Both direct and indirect smoking is a risk factor of community-acquired pneumonia. In addition, smoking is a risk factor of Legionella infections. Smoking cessation education is needed to prevent pneumonia, and for smokers who are hospitalized due to pneumonia, the education must begin during the hospitalization.
The bacterium most frequently identified from the MEF from children diagnosed with AOM, from previous reports across the world, was S. pneumoniae closely followed by H. influenzae (see Table 1). On average, S. pneumoniae detection was significantly higher than H. influenzae when all previous studies were pooled (P<0.036 2-way ANOVA without replication) and these reports included samples collected between 1979 and 2010.
Regionally, in MEF from AOM patients, the average frequency of S. pneumoniae was higher than NTHi detection for all regions, although there was no significant difference between average detection frequencies for these bacteria in the US (27.8% NTHi versus 28.6% S. pneumoniae). In contrast, NTHi was the predominant bacteria, comparing average frequencies of bacterial detection for all 3 regions that reported RAOM/AOMTF; South America, Europe and Oceania. Two studies conducted in Costa Rica showed that S. pneumoniae was predominant in RAOM.
Within each world region, the trend toward more frequent detection of S. pneumoniae, that is, the average frequency of S. pneumoniae was higher than NTHi detection for all regions. Indeed, where multiple reports were available for the same country within a region, reports from a number of countries including Finland, Colombia, USA and Japan showed changes in the predominant bacteria identified. Multiple studies from the USA provide evidence of temporal trends in the detection frequency changing from S. pneumoniae in studies recruiting between 1989–1998 [21–23] to H. influenzae for similar studies recruiting between 2005–2009 [24, 25], then back to S. pneumoniae 2006–2010 (Table 1).
For children experiencing AOM (Table 1), 29/38 of studies reported S. pneumoniae as the predominant bacteria compared to H. influenzae (primarily non-typeable) being clearly predominant bacteria in 6/38 studies (equivalent detection in 3 reports). The overall average frequency of detection for all studies was 27.8% (range 9.9%-49.9%) for S. pneumoniae compared to 23.1% (range 5.0%-54.6%) for H. influenzae, M. catarrhalis was detected in 34/38 studies at an average frequency of detection of 7.0% (range 0.5%–27.8%). Although detected less frequently overall, M. catarrhalis frequency, does not demonstrate a consistent temporal trend toward increasing detection in reports of AOM. Individual countries such as Finland, Costa Rica and Chile exhibit a temporal trend toward increasing rates of identification. In contrast, reports from the USA, Japan and Turkey show no consistent trend in identifications whilst reports from Israel do not support any temporal change in M. catarrhalis detection over time. Previous reports investigated chronic or longer term OM presentations such as RAOM/AOMTF (Table 2) or OME/COME (Table 3).
Examination of the RAOM/AOMTF reports (n = 7 and n = 3, respectively) did not demonstrate a predominant bacteria overall (Table 2) although the average bacterial detection frequency for H. influenzae was demonstrated as 22.8% (range 12.2%-41.6%) in comparison to 18.6%; (range 5.6%-32.7%) for S. pneumoniae. M. catarrhalis detection was very low (not detected in 3 of 10 reports) and average detection frequency from bacterial culture was 4.1% (range 1.3%-8%). There were no significant regional or temporal trends observed, due to the paucity of studies and the challenge arising from recruitment of overlapping clinical presentations (RAOM/AOMTF) within different study designs.
There were a total of 1272 influenza‐positive patients admitted with a median age of 37 months (IQR 13‐76 months); males constituted 56.5%. Majority were positive for influenza by IF (96.5%) compared to PCR (3.5%). The median length of stay (LOS) was 3 days (IQR 2‐4 days). C‐reactive protein and chest X‐ray were performed in 28.8% and 31.1% of patients, respectively.
Figure 1 shows the burden of influenza hospitalizations by year, age‐groups, and subtypes/lineages (excluding unknown subtypes/lineages). Incidence of hospitalized influenza was highest for <6 months, followed by 6‐month to <5‐year‐age‐group and lowest in ≥10‐year‐age‐group. Figure 2 shows the monthly incidence of influenza A, B, and subtypes/lineages, excluding unknown subtypes/lineages. Influenza cases peaked in June, December 2013, and July 2014. The seasonal peaks were mainly driven by influenza A H3N2. The predominant lineage for influenza B was Yamagata with peaks in September, December 2013, and June 2014. Co‐circulation of all four virus subtypes/lineages was seen throughout both years except August‐December 2014 when influenza B Victoria was undetected.
Table 1 shows the comparison between the age‐groups and whole cohort with significance testing only between age‐groups. Of those <6 months old, 25.1% were <6 weeks and 78.4% were ≤3 months. Viral coinfections occurred in 13 patients (1.02%) due to: 7 RSV, 3 parainfluenza, one each for metapneumovirus, cytomegalovirus, and varicella
The 6‐month to <5‐year‐age‐group (54.0%) and ≥10‐year‐age‐group (11.6%) constituted the largest and smallest proportion, respectively. The 5‐ to <10‐year and ≥10‐year‐age‐groups had the highest rates of influenza B, while <6‐month‐age‐group had the highest rates of influenza A. The <6‐month‐age‐group had the influenza‐related complication rates but the highest bacterial infection rates and antibiotic usage. The 6‐month to <5‐year‐age‐group had the highest seizure rates, cough duration, CRP, and complication rates. The 5‐ to <10‐year‐age‐group had the highest influenza B Yamagata rates and prior seizure history. The ≥10‐year‐age‐group had the highest rates of comorbidity, other complications, ICU/HD admissions, and mean LOS.
Influenza‐unrelated illnesses occurred in 33 patients (2.6%), for example, UTI (n = 12), allergic reactions (n = 8), salmonella gastroenteritis (n = 2), cellulitis (n = 2) mesenteric adenitis (n = 2), eye infections (n = 2), one each for intestinal ileus, appendicitis, eczema flare, H pylori‐related gastroesophageal bleed, hematuria. UTI was mainly from infants <6 months old and allergic reactions in patients ≥10 years old.
Influenza A constituted 76.9% of cases, from H3N2 (54.5%), H1N1 (18.2%), and untypeable (4.2%) subtypes. (Table 2 excluded untypeable) Influenza B constituted 23.1% of cases from Yamagata (16.3%), Victoria (5.7%), untypeable (1.2%) subtypes. One patient had both influenza A H1N1‐2009 and B Yamagata. Influenza A H3N2 dominated in <6 months old, but this decreased with increasing age. The ≥5‐year‐old‐age‐groups had the highest influenza B rates (35.9%‐37.2%). Influenza A patients were younger, had higher complication rates and neurologic complications compared to influenza B (Table 3). In contrast, influenza B patients were older, had developmental delay, higher diarrhea rates, and other complications.
Complicated influenza cases constituted 25.6% (n = 325) of which the vast majority 70.8% had no underlying comorbidity. Fifty‐six (4.4%) cases were admitted ICU or HD. Table 3 lists the type of complications. Neurologic complications were the most frequent (46.5%) followed by pulmonary (37.5%) and other (16.0%). The seven complicated cases with confirmed bacterial coinfection were as follows: two pneumococcal bacteremia, two S pyogenes bacteremia, one each for P aeuginosa pneumonia, Mycoplasma pneumonia, and campylobacter gastroenteritis (admitted for febrile seizure).
Overall, oseltamivir (OSV) usage was 2.0%, especially higher in complicated cases (3.6% vs 1.3%, P = .007), ICU/HD admissions (19.6% vs 1.2%, P < .001), underlying comorbidity (4.5% vs 1.3%, P = .002), cardiac disease (10.7% vs 1.6%, P < .001), and malignancy (30% vs 1.7%, P = .001). In contrast, any antibiotic usage was 28.4%.
Comparing patients with other complications against neurologic and pulmonary complications, they had the highest ICU/HD admissions (34.6% vs 12.6%, 10.7%, respectively, P < .001), highest influenza B rates (36.5% vs 10.6%, 18.9%, respectively, P < .001) and oldest age (mean 90.3 vs 50.6, 42.1 months respectively, P < .001). Pulmonary complications compared to neurologic and other complications had highest ILI rates (91.8% vs 68.2%, 76.9% respectively, P < .001), longest cough duration (6.5 days vs 3.2, 3.7 days, respectively, P = .010). LOS was not significantly different between the type of complications.
The mortality rate in our cohort was 0.2%. The three deaths were as follows: Acute necrotizing encephalitis, invasive pneumococcal disease, decompensated liver failure in a biliary atresia patient post‐ Kasai procedure. One cerebral palsy patient with no prior seizures developed sequelae of epilepsy.
Our study revealed that even though multiple viral detection is frequent in hospitalized children with LT-ARI, this association is not related to either disease severity or to any other clinical features studied. PICU admission, disease severity according to different scales, need for respiratory support, and length of hospital stay followed a similar pattern in viral mono- versus co-infected children. Contrariwise, bacterial superinfection increased the severity of the disease course, while pneumococcal vaccination played a protective role.
The detection of multiple coincident viruses in clinical settings is becoming more common since the introduction of molecular based multiplex tests, but the clinical significance of these findings remains unclear and seems to have no impact in disease severity. Both an increase in disease severity in relation to dual infections [6–9] and the absence of this association [10–19] have been reported. Richard et al. found that co-infected children were almost three times more likely to be admitted to the PICU than those with single viral infections. Compared to our study Richard et al. developed a retrospective and monocentric study in which they only considered dual infections, infants and bronchiolitis.
There is contradictory evidence linking disease severity with specific respiratory viruses. A shorter hospital stay has been reported in children with rhinovirus bronchiolitis than with RSV. Rhinovirus and RSV co-infection is reported to increase the risk of severe disease or the bronchiolitis relapse [21, 22]. Other studies did not find significant differences in severity between co-infection and single infection [12, 18, 23, 24]. In our study we did not find increased severity of illness in children with RSV-rhinovirus dual infection. In our series, only RSV as mono-infection increased oxygen requirements, and rhinovirus as a co-infecting pathogen increased the Wood-Downes score in the Spanish cohort, but these isolated findings arising from the multivariate analysis could not be replicated in the UK cohort.
Several studies have reported increased severity with bocavirus (hBoV) co-infections [13, 25–27]; this was not the case in our series (also in agreement with Pen et al.). hBoV was commonly detected in our patients, with no impact in the severity of the illness. As hBoV was detected in alongside other respiratory viruses with an established pathogenic potential, it is possible that hBoV detection reflects asymptomatic persistence or prolonged viral shedding.
Bacterial superinfection was the only factor consistently linked to greater severity. Studies of the pandemic influenza indicate that respiratory viruses predispose to bacterial complication and interaction between viruses and bacteria in respiratory infections has been extensively reported in the literature, but the underlying mechanisms between viral and bacterial synergism are complex and remain unclear. Common respiratory viral infections, such as influenza or respiratory syncytial virus have been linked to seasonal increases in Streptococcus pneumoniae disease. The relationship between bacterial and viral infection is clouded by the low sensitivity of bacterial detection in sterile-site samples by traditional culture methods, and the reliance on non-specific clinical data for the for diagnosis of bacterial co-infection, including inflammatory markers, radiological findings and / or appropriate cultures, resulting in 30% of the cases in the GENDRES cohort and 55% in the UK cohort. Bacterial superinfection increased most measures of severity in both cohorts (PICU admission, respiratory support requirement, GENVIP score, hospital stay length and respiratory distress).
Interestingly, pneumococcal vaccination was revealed as an independent protective factor of disease severity in our patients. Pneumococcal vaccine reduced the severity of viral LT-ARIs through a reduction in oxygen requirement, invasive and non-invasive ventilation, admission to PICU, respiratory distress, and GENVIP score. A reduced incidence of viral alveolar pneumonia has been previously reported after pneumococcal vaccination [31, 32], although there was no demonstrable reduction in the number of confirmed pneumococcal infections. This is likely to reflect the limited sensitivity of culture-proven pneumococcal disease in pneumonia. The protective effect of pneumococcal vaccines found in our study might reinforce the importance of the paradigm of viral-penumococci interaction at nasopharynx level in the pathogenesis and clinical course of the disease Current pneumococcal conjugate vaccines significantly decrease nasopharyngeal carriage of pneumococci and thus reduces the possibility of this viral-pneumococci direct interaction.
One of the limitations of the present study is that our samples were not tested for viral load by quantitative PCR and the viral load of certain viruses–like RSV- has been associated with the co-infection status and the severity. Also, the study did not consider milder or asymptomatic children. In addition, bacterial superinfection rate in our series might be overestimated as diagnosis was accepted as true even without microbiological confirmation, just based on referring physicians’ criteria.
Several studies had shown that viruses can be found in children with no respiratory infections [6, 35], and further research is needed to understand the natural history of respiratory viral carriage and infection. However, our findings were consistent in both independent cohorts very different between them, so this makes the outcomes more robust.
In summary, the severity and course of an acute respiratory episode requiring hospitalization in children did not correlate with the presence of one or more viruses. In contrast, bacterial co-infection was associated with more severe disease, whereas pneumococcal vaccination decreased severity. Future studies are needed to investigate whether particular viruses, or combinations of viruses, influence the risk of bacterial co-infection.
A total of 223 participants were recruited from four hospitals and followed for 4 weeks. Most participants were female (84.3%), with a graduate degree (71.3%) and were not vaccinated for influenza (78.5%) during the study season (Table 1). The mean age of participants was 36.7 years (SD ±9.7 and range 20–65 years) and around half of them were doctors. Thirteen percent (29/223) of participants had at least one pre-existing medical condition and 64% (143/223) had performed high risk procedures during the study period.
Bacteria were isolated from 170 (76.2%) participants at baseline and 127 (57%) participants at the end of the study (Table 2). If co-infections were excluded, bacteria were isolated from 57% participants (128/223) at baseline and 44% (98/223) at end of the study. Overall 196 (88%) participants had bacterial colonisation at start or end of the study - 148 participants (66%) had only bacterial colonisation while 48 (22%) participants had co-infection with a virus (Fig. 1a). Among the total participants, 101 (45.5%) were positive for bacteria at both baseline and end of the study, 68 (30.6%) were positive at baseline and negative at the end, 26 (11.7%) were negative at baseline and positive at the end and 27 (12.2%) were negative at both periods (Fig. 1b). Among all bacterial positive cases, Streptococcus pneumoniae (isolated or co-infected with Haemophilus influenza) was the most commonly isolated organism at baseline (96%, 163/170) and end of the study (72%, 91/127). Sixty-seven cases were positive for Streptococcus pneumoniae at both baseline and end of the study – 18 from respiratory ward (18%, 18/99), 18 from paediatric ward (38%, 18/47), 9 from fever clinics (29%, 9/31) and 22 from emergency ward (48%, 22/46).
There were 35 (15.7%) laboratory confirmed viral infections found at baseline and 20 (9.0%) found at the end of the study (Table 2). Rhinovirus/enterovirus was the most common viral pathogen accounting for 24 (10.8%) and 10 (4.5%) infections at baseline and the end respectively. Other viruses detected included Adenovirus, Coronavirus, H1N1 and H3N2 influenza virus and human metapneumovirus. Rates of bacterial/viral co-infections were 13% (29/223) at baseline and 4.9% (11/223) at the end of the study.
Twelve participants (4.5%) developed clinical respiratory illness (CRI) during the 4 week study period and all of these 12 HCWs had positive bacteria isolation at baseline (n = 11, including 4 co-infection with a virus) or end of the study (n = 1). Among asymptomatic participants, 187 (87%) had bacterial colonisation or co-infection at baseline or end of the study. Viruses were also isolated from 5 (2.4%) of asymptomatic cases (Table 3).
Rates of bacterial colonisation were compared among symptomatic and non-symptomatic participants in the Table 4. In all three outcomes, rates of bacterial colonisation were higher in symptomatic participants, compared to non-symptomatic, although differences were not statistically significant.
In univariate analysis, rates of bacterial colonisation were higher (OR 0.31, 95% confidence interval 0.12 to 0.75) in females (90.4%, 170/188) compared to males (74.3%, 26/35) however this was not statistically significant (Table 5). No other variable was associated with bacterial colonisation.
We found a very high rate of bacterial colonisation in HCWs, especially Streptococcus pneumonia, with fluctuation in infections over a period of weeks. Almost 88% of all HCWs had bacteria detected in the nasopharynx at baseline, the end of the study period or both. This is a much higher rate of colonisation compared to other studies of adults. For example, other studies of adults show rates of 5–20% [27, 28]. We have previously shown only 0.3% of elderly subjects carry pneumococcus in the nasopharynx. The finding of such a high rate in this HCW population may reflect greater exposure to respiratory infections in the hospital setting and confirms the continual, ongoing risk to HCWs in the hospital setting.
Respiratory infections in hospital HCWs are of particular concern due to the risk of transmission to patients who are ill and/or immunocompromised. Respiratory tract infections generally present with symptoms such as fever, tachypnea, shortness of breath and cough. However the relationship of bacterial colonization to symptomatic illness has not been studied extensively. We found a very high and dynamic rate of bacterial colonisation in hospital HCWs, with changes from baseline to the end of the follow up period in the individuals with infection as well as the types of infection.
Colonisation is important as this may progress to invasive disease. Bacterial colonisation may be an important source of horizontal spread of infection within the community. Among 170 HCWs with positive bacterial result at baseline, 68 (40%) became negative at the end of the study. Natural clearance of bacteria in asymptomatic and symptomatic subjects has not yet been studied. The rates of bacterial colonisation in symptomatic HCWs were higher than in asymptomatic HCWs, but this was not significant. Bacterial colonisation in the majority of the HCWs resolved without any treatment or development of symptoms. We found 12 cases of CRI developed over 4 weeks, 11 of which had bacterial colonisation at baseline. If bacterial shedding occurs asymptomatically, then a large amount of undetected transmission may be occurring in hospitals. This may be important for bacteria such as pneumococcus, where the transition from carriage to invasive disease is thought to occur soon after acquisition of infection.
Of interest, we identified 5 cases of asymptomatic viral infection - four rhinovirus/enterovirus and one influenza A(H3N2). Few studies have been conducted on the incidence of asymptomatic viral infection, and of these, the results are often inconsistent. One study examined the rate of asymptomatic infection resulting from inoculation and found that 1/3 of participants did not develop any symptoms whereas a more recent study found the rate of respiratory illness attributable to influenza infection to be 27 respiratory illnesses per 100 persons. Our findings indicated a high rate of asymptomatic infection at baseline, being cleared without the development of symptoms. The clinical significance of such findings is still unknown with limited information on viral shedding and transmission in asymptomatic subjects. It is well known that influenza virus is shed from the respiratory tract in the incubation period in asymptomatic subjects, and asymptomatic infection has also been observed with parainfluenza virus infection. It has also been found that viral shedding of influenza occurs on average for 5 days after infection, indicating that some positive tests could have been in HCWs recovering from influenza. Asymptomatic viral infections pose a significant risk of nosocomial transmission to both patients and HCWs.
We found many co-infections in this study. Previous studies have demonstrated that a viral infection may facilitate bacterial colonisation or co-infection with S. pneumoniae. This may be a significant concern as such co-infection has been associated with significantly higher morbidity and mortality. A growing body of evidence suggests that the risk of bacterial respiratory infections is increased by co-infection with viruses and vice-versa, however bacterial respiratory tract infections are generally not considered a major occupational hazard. Despite documented outbreaks of Bordetella pertussis, Chlamydia pneumoniae and Mycoplasma pneumoniae [32–36], there are few prospective studies of bacterial respiratory infections or colonization, nor consideration of the clinical implications for HCWs. The risk of co-infection has been reported in schools and daycare centres with subsequent community transmission, but not in HCWs. It has also been suggested that viral infection may facilitate bacterial colonisation of the respiratory tract particularly with S. pneumoniae. Studies in mice have found that influenza virus infection increases the transmission and burden of pneumococcal disease. Similar findings have been reported in other studies demonstrating significantly higher morbidity and mortality of cases with influenza virus co-infection with S. pneumoniae. This is suggestive that the role and significance of viral infection in the nasopharynx may be complex, highlighting the need for further research into this topic.
Being a healthcare provider has been identified as a major risk factor for respiratory infections [38, 39], however even within HCWs, the risk varies significantly. Hand hygiene, use of personal protective equipment (PPE) and working on intensive care units (ICUs) have been associated with risk of influenza. Interestingly, factors such as vaccination status, performing high-risk procedures, working on respiratory and paediatric wards and smoking were not found to be significant in predicting bacterial colonisation in this study. Smoking, influenza vaccination status and ward type in hospitals have been previously identified as risk factors for respiratory infection in various groups [40, 41] however our findings suggest that such risk factors may not be absolute and may vary in different situations. The effect of vaccination also needs to be studied. Some studies show that pneumococcal vaccination may reduce colonisation with vaccine-serotype pneumococcal infection, though replacement by other strains reduces the overall effect. Previous studies showed that medical masks and respirators reduce the risk of bacterial respiratory infections, which further supports the occurrence of nosocomial transmission of bacteria.
The limitations of this study include that we did not test for bacterial or viral infection at the time of reported symptoms. This would confirm that an infection was the cause of symptom development and also ensure that no other infections were missed within the 4 weeks. Our sample size may have also been too small to detect differences in colonisation between symptomatic and asymptomatic subjects, or for analysis of risk factors such as smoking and underlying disease as there were very few participants in these categories. We were unable to recruit the initially planned sample size so a larger scale study is warranted. The selected follow up period of 4 weeks was the maximal period of follow up possible within the available resources for the study, but longer follow up would be valuable. Finally, these results may not be generalised due to varying geographical distribution of pathogens and vaccine uptake by country.
Most antibiotic treatments for pneumonia depend on the empirical method. Since the distribution of causative bacteria and antibiotic resistance vary between countries, it is necessary to develop an appropriate antibiotic treatment guideline based on domestic epidemiological data. This guideline summarizes domestic research findings on the causative bacteria of community-acquired pneumonia affecting Korean adults, and the current level of antibiotic resistance in Korea.
Community-acquired pneumonia is caused by various bacteria. Similar distributions of these bacteria are seen between Korea and other countries. Bacteria such as Streptococcus pneumoniae, and Haemophilus influenzae, and Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila, which are classified as causative bacteria of atypical pneumonia, and respiratory bacteria can cause pneumonia. However, it is difficult to differentiate between these causative bacteria in the early period after hospital admission. Study findings about the major causative bacteria of community-acquired pneumonia in Korea are summarized in Table 1. The most important causative bacteria of bacterial pneumonia are S. pneumoniae. They account for 27-69% of all causative bacteria of bacterial pneumonia. Haemophilus or Moraxella, which are respiratory pathogens, commonly cause pneumonia in patients with a lung disease. The prevalence of these bacteria varies greatly in domestic data possibly because the separation and identification of these bacteria are difficult. Staphylococcus aureus are also relatively common causative bacteria. They commonly occur after an influenza epidemic. Enteric Gram negative bacilli or Pseudomonas aeruginosa pneumonia commonly occur in patients who have underlying lung diseases, who have alcohol addiction, or who have frequently undergone antibiotic treatment. Domestic data show the ratio of Gram-negative bacteria including Klebsiella pneumoniae and P. aeruginosa to be relatively high. This may be because most domestic studies have been conducted in tertiary university hospitals, and therefore, a large number of patients who are frequently admitted to a hospital for chronic respiratory diseases were included. Studies have reported mixed infections caused by two or more microorganisms to be relatively common. These infections include mixed infections caused by atypical causative bacteria of pneumonia. Distributions of causative bacteria may change depending on underlying diseases and risk factors.
M. pneumoniae, C. pneumoniae, and L. pneumophila are the major causative bacteria of atypical pneumonia. Of the recently published studies on community-acquired pneumonia in Korea, very few have investigated the incidence of atypical pneumonia and its causative bacteria. A large number of published studies have been conducted at a single institution, or use a retrospective design. Therefore, the prevalence of atypical pneumonia in Korea and clinical significance can only be assessed with limited accuracy. In a domestic study on pneumonia, Mycoplasma, C. pneumoniae, and Legionella accounted for 6.3-9.2%, 7.1-13.2%, and 0.5-3% of all cases of pneumonia. Legionella were especially more common for cases of moderate to severe pneumonia requiring ICU admission compared with other atypical pneumococcal bacteria.
Respiratory virus induces pneumonia in children, as well as community-acquired pneumonia in adults. Rapid antigen tests for influenzas and respiratory syncytial virus (RSV) have recently been introduced and used in clinical settings. Multiplex reverse transcriptase polymerase chain reaction (RT-PCR) has also been used against various respiratory viruses. In a recent study involving 456 adults with community-acquired pneumonia, multiplex RT-PCR was performed for 327 patients. Respiratory viruses were detected in 60 patients (18.3%). Influenza virus was the most common (n = 23, 38%), followed by RSV (n = 9, 15%), rhinovirus (n = 7, 12%), coronavirus (n = 6, 10%), adenovirus (n = 6, 10%), metapneumovirus (n = 5, 8%), parainfluenza virus (n = 3, 5%). When a respiratory virus test was performed on patients with community-acquired pneumonia hospitalized in ICU, more than one type of respiratory virus was detected in 72 of 198 patients (36.4%) for whom RT-PCR was performed. Rhinovirus was the most common (n = 17, 23.6%), followed by parainfluenza (n = 15, 20.8%), metapneumovirus (n = 13, 18.1%), influenza virus (n = 12, 16.7%), RSV (n = 10, 13.9%), coronavirus (n = 4. 5.6%), and adenovirus (n = 1, 1.4%). Other causative bacteria of atypical pneumonia in Korea include Mycobacterium tuberculosis, non-tuberculous mycobacteria, Orientia tsutsugamushi, Leptospira, Coxiella burnetii. Since the prevalence of tuberculosis is still quite high, the possibility of tuberculosis being one of the causes of pneumonia must always be considered. When a patient shows delayed response to antibiotic treatment, or has underlying diseases such as diabetes, chronic obstructive respiratory disease, chronic kidney diseases, and long-term steroid use, tuberculosis must be considered as a possible cause of pneumonia. In addition, pneumonia caused by M. tuberculosis can occur as typical bacterial pneumonia or atypical pneumonia. Since tsutsugamushi disease and leptospirosis, which are febrile illnesses that usually occur in the fall, are sometimes accompanied by atypical pneumonia, when a patient has a febrile illness accompanied by pneumonia in the fall, pneumonia must be differentiated with the possibility of febrile illnesses in mind. Furthermore, as there have been reports of pneumonia caused by C. burnetii in Korea, it is necessary to differentiate C. burnetii, which may possibly be the causative bacteria of pneumonia in persons who come in close direct or indirect contact with livestock. Table 2 lists common causative bacteria of community-acquired pneumonia by epidemiological characteristics and risk factors. Table 3 summarizes common clinical characteristics associated with certain causative bacteria.
According to our estimates, aspiration was the leading cause of pneumonia, and the burden of pneumonia associated with aspiration was higher than that associated with any single pathogen, including S. pneumoniae. The burden was particularly high among the elderly population; 85.8% of aspiration-associated pneumonia cases occurred in patients aged ≥65 years. The in-hospital mortality for aspiration-associated pneumonia (10.9%) was higher than that for other pneumonia categories (6%).
Aspiration-associated pneumonia has been overlooked in current pneumonia control programs. Although previous studies have shown that this condition is common among hospitalized pneumonia patients [2, 31], its burden has never been evaluated at the population level in the past. Aspiration-associated pneumonia is a multi-factorial condition observed in older people. Impaired swallowing and an abnormal cough reflex increase the risk of oropharyngeal aspiration; the aspiration of colonized pathogens and gastric acid causes lower respiratory tract infection and/or lung injury. Compromised immunity, comorbidity and changes in lung function in this age group underlie this condition and are associated with the high mortality. Nursing home residents are at high risk for aspiration, but HCAP and aspiration-associated pneumonia are not identical conditions. In fact, in our study, 25.4% of CAP and 64.3% of HCAP cases were associated with aspiration.
Effective clinical management and preventive measures targeting aspiration-associated pneumonia remain underdeveloped. ATS guidelines recommend using β-lactam/β-lactamase inhibitors for this condition [1, 13], but the management of recurrent and refractory cases is challenging. For prevention, oral hygiene care and dysphagia rehabilitation have been suggested for reducing the risk of aspiration pneumonia, but with limited supporting evidence. The burden of aspiration-associated pneumonia may further increase as the number of elderly people who require long-term care increases. Effective clinical and public health intervention measures are urgently needed.
In the current study, S. pneumoniae was the leading single etiological pathogen and was associated with 20–28% of pneumonia, confirming previous reports. Recent studies in Japan have shown that the positivity of S. pneumoniae among CAP cases was 17% to 24%. According to a recent meta-analysis, the proportion of pneumococcal pneumonia among CAP cases was 26–28%. The proportion of pneumococcal pneumonia among all pneumonia cases is declining in high-income countries, reflecting the wide use of antibiotics and pneumococcal vaccines. In our study, the positivity of S. pneumoniae by sputum culture was only 9%. Considering the low sensitivity of sputum culture, we included urinary antigen test-positive cases for the standard estimation and further included PCR-positive cases for the maximum estimation. The true value must lie between these values (i.e., 20 to 28%). The proportion of bacteremia among pneumococcal pneumonia cases was 6% in our study. A meta-analysis showed that approximately 25% of pneumococcal pneumonia is bacteremic; our figure was lower than this estimate. However, our results showed that the incidence of bacteremic pneumococcal pneumonia among Japanese adults was 12 per 100,000 PY, a figure that was comparable with those reported for other countries, such as the United States and Australia. The findings suggest that pneumococcal pneumonia, either bacteremic or non-bacteremic, remains the leading target for pneumonia control programs in Japan.
PPV23 reduces the risk of invasive pneumococcal diseases (IPDs) among adults; however, its effectiveness against pneumococcal pneumonia is still controversial, particularly for the elderly. The recently approved PCV13 is expected to prevent almost half of the pneumococcal pneumonia cases in the elderly [38, 39]; however, the vaccine covers only 13 serotypes of pneumococcus, and its long-term effects remain unknown. In Japan, before the introduction of PCV7 for children in 2010, 85% of IPD isolates were PPV23 serotypes, and 62% were PCV13 serotypes. In the current study, 67% of the isolates were PPV23 serotypes, and 54% were PCV13 serotypes. The vaccination policy for pneumococcus has been dramatically changing in Japan. PCV7 for children was replaced by PCV13 in late 2013, and PPV23 was also included in the Ministry of Health, Labour and Welfare recommended vaccines for elderly people in late 2014. The proportion of vaccine-covered serotypes is known to decline after widespread use of PCV; thus, these figures will decrease in coming years. The true efficacy of PCV13 for adult pneumonia among the Japanese population must be evaluated along with cost-effectiveness analyses before it is introduced into the national immunization program.
A substantial proportion of pneumonia was associated with RVs (23% of all pneumonia cases). Recent studies suggest that RVs play crucial roles in the development of pneumonia, including severe cases [10, 22, 42–44]; however, their biological mechanisms remain largely unknown. RVs such as influenza, RSV, and human metapneumovirus (HMPV) cause outbreaks among the elderly in nursing homes [45, 46], and these RVs are potential targets for vaccination. Currently, only seasonal influenza vaccines are available for adults, but their effects on pneumonia prevention have not yet been established. Further investigations are needed to clarify the public health impact of RV-associated pneumonia in aging societies.
Our findings have important implications for effective pneumonia control programs in the aging society. The burden of pneumonia is higher in older people, and the pneumonia etiology largely varies by age group: the incidences of aspiration-, S. pneumoniae-, H. influenzae-, RV-, and PDR pathogen-associated pneumonia increase with age, while the incidence of atypical bacteria-associated pneumonia decreases. It must be noted that the proportion of pneumonia caused by unknown pathogens is higher among elderly people. This category most likely represents multifactorial conditions. Therefore, in coming decades, the pneumonia burden will likely increase, and its etiology will become more diverse. In this situation, the current etiology-specific approach (i.e., vaccinations for pneumococcus and influenza, guidelines for appropriate antibiotics use) must have only a limited impact. A multidimensional approach integrating vaccination programs, clinical management guidelines, training for health care workers, and education for people must be needed; further studies are warranted.
Overall, MEF samples from patients diagnosed with OME/COME were less likely to be culture positive for the 3 predominant bacteria in comparison to MEF samples from patients diagnosed with AOM. This is evidenced by the average frequency of detection for H. influenzae and S. pneumoniae from OME/COME patients being approximately half that reported from AOM patients (11.6% vs 23% and 6.5% vs 27%) for these bacteria respectively.
Globally, H. influenzae was the predominant bacteria identified within the MEF of patients experiencing OME/COME (P<0.001 2-way ANOVA without replication) with the average detection frequency was 11.6% (range 3.2%-21.6%) compared to S. pneumoniae detection 6.5% (range 1.3%-16.2%).
Regionally, H. influenzae was identified most frequently from patients with OME/COME in South and North America, Europe, Asia, Africa and Oceania however in the Asian and European regions, four of the nine (44%) and two of nine (22%) of studies reported that S. pneumoniae was predominant, respectively.
Within this review, the bacterial pathogens associated with OM in the MEF were examined regionally and evidence of development of antibiotic resistance recorded. Where resistance was reported, it was included in the summary for each region provided below.
There are few data available with which to characterize the role of viral infection in the pathogenesis of bronchiectasis in children. However, recent data from two separate, prospective Australian studies of children with bronchiectasis indicate that attention to viruses is warranted. Respiratory viruses were associated with 48% of exacerbations in 69 Queensland children with bronchiectasis (154) and detected in the BAL of 44% of 68 clinically stable children, primarily Indigenous, in the Northern Territory (16). Furthermore, in a study of bronchiectasis in 58 adults in Guangdong, China, respiratory viruses were detected during 49% of 100 exacerbations (155). In the two pediatric studies, rhinovirus was the most commonly detected virus, while coronavirus, followed by rhinovirus and influenza were most common in the adult study. Whether this difference in viral dominance is demographically driven or associated with disease severity is unknown. However, in both children and adults, the presence of virus during respiratory exacerbation was associated with more severe symptoms.
Respiratory viruses are an important cause of exacerbations in other chronic respiratory illnesses including asthma and COPD (156, 157). It has been postulated that viruses may alter immune responses and promote respiratory exacerbations from bacterial infection (158). Furthermore, bacteria/virus coinfections reportedly result in more severe symptoms (158, 159). Australian Indigenous children carry a high burden of respiratory bacteria from a very young age (135, 160). Increased nasopharyngeal NTHi density has been shown in the presence of any one of several respiratory viruses in Indigenous children with acute OM; the most commonly detected viruses being rhinovirus, polyomavirus, and adenovirus (161). Adenovirus has also been associated with suppurative lung conditions in children, particularly with respect to bacterial coinfection (162).
Respiratory viruses are likely an under-recognized factor contributing to acute exacerbations and persistent airway inflammation in children with bronchiectasis. Large, population-based pediatric studies investigating the effect of viruses on airway immunopathology are important to fully appreciate the contribution of viruses to chronic inflammation and the pathogenesis of bronchiectasis in children.