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Forty nosocomial respiratory viral infections were diagnosed in 38 patients during 1 year, predominantly involving rhino/enterovirus in both pediatric and adult patients. Our data are strikingly similar to a study done nearly 40 years ago. These authors found an incidence of 55 nosocomial respiratory viral infections per 10 000 pediatric hospital admissions, and 4 such infections per 10 000 adult medical admissions. Overall, 1 in 229 admissions to our pediatric hospital developed a nosocomial respiratory viral infection. However, at its peak in the fall, 1 in 139 admissions to our pediatric hospital developed such an infection. Based on our data and the number of US hospital admissions during fiscal year 2014, we estimate that there are approximately 15 834 adult and 3121 pediatric cases of nosocomial respiratory viral infections in US acute care hospitals yearly.
Fever and/or cough were the most common presenting symptoms often leading to initiation of antibacterial therapy. Approximately half of the pediatric cases were under 1 year of age, and these patients appear to be at greater risk of acquiring such infections. Twelve percent of cases were associated with ICU admission, and 15% required intubation a mean of 1.8 days after symptom onset. One fatal case involved a nosocomial RSV infection, and another involved nosocomial metapneumovirus infection; however, both cases were associated with deterioration requiring intubation and ECMO. Autopsy data have confirmed that nosocomial respiratory viral infections can cause or contribute to mortality.
Respiratory viruses are clearly important pathogens causing hospital-acquired infections [8, 9]. In one study, 23% of severe nosocomial pneumonia in adults were due to respiratory viruses. For decades, it has been known that nosocomial respiratory viral infections are a particular problem in pediatric patients. In one study, 1 in 6 children under the age of 4 hospitalized for 1 week or more during winter or spring developed a nosocomial respiratory viral infection. However, detailed studies of noninfluenza nosocomial respiratory viral infections are limited, and, to our knowledge, our study is the only one that broadly assessed the incidence of these infections in both adult and pediatric patients in a nonepidemic setting in approximately 40 years (Table 4). We found that rhinovirus and/or enterovirus were the predominant viruses identified among nosocomial respiratory viral infections. A previous prospective cohort study demonstrated that rhinovirus was the most commonly detected virus among children with viral respiratory infections, and approximately 20% of these infections were hospital acquired. Similar to our findings, a pediatric study found that 73% of nosocomial respiratory infections were due to rhinovirus. However, another pediatric study found that RSV and influenza were associated with 51% and 19% of such cases, respectively. This may reflect differences in virologic diagnostic testing performed as well as the recognition of RSV in patients diagnosed with bronchiolitis at admission.
Seventy-nine percent and 81% of our hospital rooms are single occupancy for our adult and pediatric patients, respectively. During the study period, our hospital infection control policy stated that adult and pediatric patients presenting with influenza-like illness should be placed in contact and droplet precautions. However, we realize that influenza-like illness may be insensitive indicator for some respiratory viral infections. Nevertheless, such patients were placed in a private room, or if no private room was available, they were cohorted with patients identified to have the same respiratory virus. Despite this policy, nosocomial respiratory viral infections occurred. This most likely reflects inadequate screening of ill visitors and family or ill healthcare workers reporting for duty despite symptoms of a respiratory viral infection because these have not been stressed in recent educational efforts, and our hospital did not have a formal screening program for visitors and staff. However, based on an educational campaign and compliance monitoring, we believe that transmission of such infections in the hospital setting was less likely to be due to noncompliance with the policy, inadequate decontamination of the inanimate environment, or suboptimal hand hygiene compliance. Our hospital occupational health policy followed the Centers for Disease Control and Prevention guidelines for mitigating risk of influenza transmission from infected healthcare workers to patients that uses fever as a determining factor for which healthcare workers should not have patient contact. However, such guidelines may be inadequate as previously noted. Unfortunately, fever is an insensitive indicator of influenza infection in adult healthcare workers at onset of symptoms when there may be maximal risk of transmission [18, 19]. At least 1 reported influenza outbreak involved healthcare providers who apparently worked with mild illness. Nevertheless, the vast majority of our patients’ nosocomial respiratory viral infections were not due to influenza. Thus, hospital policies and national guidelines should focus on reducing patient risk from all respiratory viruses, not just influenza.
Unfortunately, many community hospitals may not perform testing for respiratory viruses beyond rapid influenza testing. Thus, cases of nosocomial respiratory viral infections are often unrecognized. In addition, healthcare providers may not have a high index of suspicion for such hospital-acquired viral infections. As more hospitals use improved laboratory testing for such viruses, there will be a greater appreciation of the risk of such infections in hospitalized patients, a better understanding of their modes of transmission, and ultimately fewer such cases in the future. Educating healthcare providers regarding the risk they pose to their patients when they are infected with respiratory viruses is vitally important, as well as changes in the culture of healthcare providers by dealing with the guilt they feel when they do not report to work with symptoms of a respiratory viral infection.
Our study has several potential limitations. It is unclear whether all of the viruses identified were the cause of active infection, or whether their presence in some cases reflected respiratory tract colonization or recent respiratory viral infection. Although diagnostic testing is recommended in our hospital policy for patients admitted with suspected respiratory viral infections, we do not know the compliance with this policy, and we may have underestimated the incidence of such infections. We also may have missed cases in patients who had symptom onset after hospital discharge. Our data was collected over 1 year on 1 hospital campus in the Northeastern United States, and it may not reflect the risk of such infections in different geographic regions, in hospitals with different patient populations, or those with different infection control and occupational health policies. Finally, the retrospective nature of our study required us to rely on established documentation in the patient’s medical record. Despite these limitations, we hope our findings will lead to a greater awareness of such infections and changes in hospital infection control policies regarding testing of patients with suggestive symptomatology, assessment of visitor restriction policies, and review of sick leave policies to potentially mitigate risk of such infections in future patients.
Statistically significant possible related risk factors for viral infections in multivariate analysis were decreasing age upon study entry, increasing weight, and lower educational level of the father (Table 4). The frequency of RSV decreased with increasing age upon study entry and gestational age at birth (Table 5), as we can observe that nearly half of all children hospitalized with RSV LRTI (49%, n = 127) are in the less than 6 months age group. Proportionally, RSV positivity was higher among children born with gestational age <35 weeks (50%, n = 29) compared to children born with a gestational age of >35 weeks (39%, n = 175). For RSV infection, statistically significant risk factors in multivariate analysis were decreasing age upon study entry, decreasing gestational age, attendance of daycare or other collective environment, and lower educational level of the father (Table 4). No statistically significant risk factors were found for other viruses in multivariate analysis, except for increasing age upon study entry in the case of influenza and the following factors in the case of metapneumovirus: increasing gestational age, the presence of bronchopulmonary dysplasia, higher educational level of the mother, and lower educational level of the father (data not shown).
The results of our analysis of risk factors associated with 28 day mortality are given in Table 5. The overall 28 day mortality rate in the study population was 35.9% (94/262) and the in-hospital mortality rate was 49.2% (129/262). The median ICU stay was 12 days (IQR 7−20). The 28 day mortality rate was 29.5% (46/156) for bacterial infections, 30.8% (40/130) for sole bacterial infections, 35.6% (21/59) for viral infections, 38.7% (12/31) for sole viral infections and 19.0% (4/21) for bacterial-viral coinfections.
In multiple logistic regression analysis, independent predictors of 28 day mortality were associated with presence of shock (aOR 1.99, 95% CI 1.15 to 3.46, p = 0.01) and immunocompromised state (aOR 2.63, 95% CI 1.51 to 4.60, p<0.001).
The main finding of the present study is that viral infection is not uncommon in critically ill adult patients with severe HAP. Viruses were identified in 22.5% (59/262) of severe HAP patients, of whom 43 (72.9%) were immunocompromised and 16 (27.1%) were non-immunocompromised. Non-immunocompromised patients were older than immunocompromised patients and more commonly had COPD, tuberculous destroyed lung disease, and/or chronic kidney disease. Viral infection was associated with comparable mortality rates to bacterial infection. To our knowledge, this is the first study that was focused on respiratory viral pathogens in adult patients with severe HAP. The strength of our study is that viruses were detected from BAL fluid specimens in nearly two-thirds of our subject patients (62.7%, 37/59), which suggests that considerable numbers of identified viruses can be regarded as actual pathogens.
In our results, respiratory syncytial virus (27.1%), parainfluenza virus (27.1%) and rhinovirus (25.4%) were the most common viral pathogens, observed in 79.7% (47/59) of patients with viral infection. Prior studies regarding patients with hematologic malignancy or hematopoietic stem cell transplant, or solid organ transplants–, also showed that respiratory syncytial virus, influenza virus and parainfluenza virus were major viral pathogens in those populations. Rhinovirus, a well-known cause of the common cold, is increasingly being recognized as an important cause of lower respiratory tract infection, mainly in severely immunocompromised patients, such as hematopoietic stem cell transplant patients,. In our current study cohort, rhinovirus was found to be the third most commonly identified pathogen and to be more commonly associated with severe HAP compared with influenza virus. However, the significance of rhinovirus detection in respiratory specimens from pneumonia patients is a subject of some debate. Earlier studies have indicated that chronic shedding of rhinoviruses for more than 4 weeks is not uncommon in both immunocompetent individuals and immunocompromised patients,. In our present study, rhinoviruses were identified in the BAL fluid from 10 out of 15 rhinovirus-positive cases, which suggests that, at least in these cases, these viruses would be significant pathogens rather than colonizers. In our present study, compared with our previous results regarding CAP or HCAP, the proportion of human metapneumovirus was found to be much lower in severe HAP cases (CAP or HCAP, 18.1% [13/72] vs. HAP, 3.4% [2/59]). Notably, viral infection in non-immunocompromised patients was not uncommon (11.1%, 16/143), although it was not as frequent as that in immunocompromised patients (36.4%, 43/119). Compared with immunocompromised patients, non-immunocompromised patients were older and more likely to have underlying COPD, tuberculous destroyed lung disease, and/or chronic kidney disease (Table 4). Taken together, our data suggest that, even in patients who are not known to be immunocompromised, viral infection should be considered when patients are elderly, especially in those with structural lung disease or chronic kidney disease.
The impact of coinfection with respiratory viruses and other organisms is an important issue. Prior studies of viral pneumonia in patients with hematologic malignancy or who received haematopoietic stem cell transplant have reported a lower incidence of coinfection ranging from 8.8% to 14.3%,. In our present analyses, as found previously in adult CAP, coinfection was commonly identified. Of 59 patients with identified viral pathogens, 23 (39.0%) were infected by a single virus, 21 (35.6%) were coinfected with bacteria and 11 (16.9%) were coinfected with another virus. In CAP, some reports have shown that polymicrobial infection can be associated with poorer outcomes–, most of these coinfections were influenza plus pneumococcal infections,. In our results, however, clinical manifestation and outcomes in patients with or without coinfection were not significantly different (Table S2) and none of the combinations of polymicrobial pathogens were dominantly observed. The 28 day mortalities of our patients with bacterial infections, viral infections and bacterial-viral coinfections were 29.5% (46/156), 35.6% (21/59) and 19.0% (4/21) (p = 0.321), respectively. However, considering the relatively small number of patients with various combinations of pathogens, the severity of underlying disease and comorbidities, further investigation is required with larger populations.
The seasonal distribution of respiratory viral infections from HAP was very similar to that of infections from CAP. That is, respiratory syncytial virus and influenza virus were frequent in winter and spring, parainfluenza virus was mainly present in summer to autumn, and rhinovirus was found throughout the year. This indicates that hospital-acquired viral infection occurs coincident with the spread of viral infection in the community. Therefore, watchful monitoring of community-level viral infection could be helpful for the prediction of hospital-acquired viral infection.
Our study has several limitations. First, the study was conducted at a single center and included only patients with severe pneumonia who were admitted to the medical ICU; thus, the results may not be generalizable. Second, since our study was an observational one, we could not intervene in terms of specific procedures or laboratory tests. Therefore, some patients did not undergo bronchoscopic BAL or testing for respiratory virus. This means that the actual rate of viral infection might be higher than that indicated by our results. Third, among 59 patients with viral infection, viruses were isolated solely from nasopharyngeal specimens in 22 patients (37.3%). These cases might include cases of coincidental upper respiratory viral infection. Finally, we did not perform virus testing for herpes simplex virus, which is known to cause pneumonia, especially in immunocompromised patients with hematologic malignancy.
In conclusion, viral pathogens are not uncommonly identified in adult patients with severe HAP who required intensive care. As these viruses could be responsible for severe HAP, and could represent a potential source of intra- or inter-hospital transmission, further investigation is required to delineate the prevalence and role of viral pathogens in severe HAP more precisely.
Numerous viruses can cause viral myocarditis, including Coxsackie viruses group A and B (Table 1). Most patients recover, but persistent cardiac dysfunction is associated with 20% one-year mortality. The majority of patients with acute myocarditis have evidence of heart failure. In severe cases mechanical ventricular assist device support is necessary until resolution or cardiac transplantation is available. Although immunosuppressive medicines including corticosteroids were applied in many studies with viral myocarditis, meta-analyses have shown that their effects remain controversial since they do not reduce mortality. In a systematic review, the use of intravenous immunoglobulins (IVIGs) in viral myocarditis was not recommended. Experimental strategies for treatment of viral myocarditis have been developed [13, 113, 200].
Acute bronchiolitis was diagnosed in 316 infants younger than 24 months of age. Overall, at least one respiratory virus was detected in 75% (237/316) of the cases at Ege University Children’s Hospital. The results of the incidence of respiratory viruses in infants hospitalized with AB during the study period are shown in Table 3. RSV was identified in 127 (40.1%) of the 316 infants hospitalized for AB, and RSV was the most common agent. Of the 127 RSV-positive infants, 76 (59.8%) were sole pathogen for RSV and 51 infants had RSV-coinfection, which was responsible for respiratory tract infection. The second prevalent viral agent was rhinovirus, identified in 78 (24.6%) of the subjects, and as a single pathogen in 35 (44.8%). Furthermore, in this study, influenza virus types A and B (n = 28/316, 8.8%), human metapneumovirus (n = 27/316, 8.5%), adenovirus (n = 23/316, 7.2%), human bocavirus (n = 20/316, 6.3%), parainfluenza virus (n = 18/316, 5.6%), and human coronavirus (n = 10/316, 3.1%) were determined (Table 3). A single virus in 156/316 (49.3%), dual infections in 67/316 (21.2%), triple infections in 13/316 (4.1%), and quadruple infections in 1/316 (0.3%) were detected. Of the 81 infants with multiple agents, RSV (51 cases) was the most common virus followed by rhinovirus (n = 43, 53%), influenza virus (n = 18, 22.2%), human metapneumovirus (n = 16, 19.7%), PIV (n = 10, 12.3%), adenovirus (n = 16, 19.7%), human bocavirus (n = 13, 16%), parainfluenza virus (n = 10, 12.3%), and human coronavirus (n = 8, 9.8%). Among dual co-infections, the combination of RSV and rhinovirus had the the highest number (n = 15, 22.3%). The age distribution of infants is shown in Figure 1 for RSV, rhinovirus, adenovirus, and dual infections. In particular, most viral agents were identified in children of all months, whereas RSV was detected in infants aged under 6 months (n = 93/127, 73.2%) and in 15.7% (n = 20/127) of the 127 RSV-positive infants aged under 1 year of age, which was the case in most of our patients. The monthly incidence of bronchiolitis in infants due to common respiratory pathogens is shown in Figure 2. The majority of the cases were admitted to hospital in the winter time with a peak occurring in January, February, and March; detection rates were also high during these months (26.2%, 25.3%, and 17%, respectively). Other respiratory virus epidemics were seen also during the winter season (Figure 3). Fifteen cases infected with parainfluenza virus, adenovirus, and human bocavirus were seen in the summer time.
The monthly frequency of each viral infection along 1 year is shown in Figure 1; as expected from its predominance in this age group, RSV frequency is the major driver of the frequency of viral infections in general.
Statistically significant associations were found between the frequency of viral infections in general and both temperature and humidity. For temperature, such correlation was moderate and positive (Spearman correlation coefficient, 0.401), whereas it was moderate and negative for humidity (Spearman correlation coefficient, −0.416). On the other hand, generalized linear models disclosed statistically significant correlations between the number of cases of viral infections in general and both temperature and precipitation (Figure 2; Table 6). There was statistically significant association between the relative frequency of RSV infection and both temperature and humidity (Table 6). There were no statistically significant correlations between the frequency of other viral infections and any of the meteorological variables investigated, except for parainfluenza, whose relative frequency was moderately and negatively correlated with precipitation (Spearman correlation coefficient, −0.383), and moderately and positively correlated with solar radiation (Spearman correlation coefficient, 0.354). With regard to the numbers of other viral infections investigated in the study, some statistically significant correlations were found between the frequency of such infections and some of the meteorological variables investigated (data not shown). There were negative correlations between temperature and the number of cases of both influenza and adenovirus infections, as well as a positive correlation between precipitation and the number of cases of bocavirus infections.
We report the second study that comprehensively investigated adult and pediatric patients with nosocomial respiratory viral infections. The first such study involving patients hospitalized from 1977 through 1979 had a very similar incidence of such pediatric and adult infections compared with our findings. That study tested for fewer respiratory viruses than our study; nevertheless, the data suggest that little has changed regarding the risk of such hospital-acquired infections now nearly 40 years later. We hope that our findings will provide additional support for more frequent testing to identify respiratory viruses, beyond influenza, in hospitalized patients with new onset of respiratory symptoms suggestive of possible viral infection to aid in focusing infection control efforts and to stimulate a search for effective therapies and vaccines.
We wanted to determine whether bacterial or viral agents were responsible for causing the majority of CAP cases in the enrolled patients. Table 2 shows the broad category of etiological agents identified in pediatric CAP patients from Beijing Children's Hospital. Infection by a single bacteria was observed in 6.5% (n = 24) of the patients, infection by multiple bacteria was observed in 2.2% of patients (n = 8), infection by both bacterial and viral agents was observed in 17.8% of patients (n = 66), infection by a single viral agent was observed in 35.3% of patients (n = 131), and finally, infection by multiple viruses was observed in 11.6% of patients (n = 43). In approximately one quarter (26.7%, n = 99) of the patients the category of the etiological agent was not identifiable.
We next want to identify the prevalence of specific viral and/or bacterial pathogens that were contributing to CAP. Table 3 shows the bacterial and/or viral pathogens likely to be the causative agent for disease identified in the CAP patients. Bacterial infections accounted for 30.5% (n = 113) of the total CAP cases. The most prevalent were S. pneumoniae (20.8%; n = 77) and H. inﬂuenzae (9.7%; n = 36). Of the cases associated with S. pneumoniae, 77.9% (n = 60) were co-infected with viruses and/or bacteria. The majority (n = 45) were viral coinfection. In the CAP cases associated with H. inﬂuenzae, 80.1% (n = 29) were coinfections with viruses and/or bacteria. Viral coinfection occurred in 14 cases (48.3%).
In fact, the majority of CAP cases were associated with viral infection. Viral agents were detected in 330 of the patients (88.9%). As shown in Table 3, the predominant infection was with respiratory syncytial virus which accounted for 43.9% (n = 163) of the viral infections. Of the remaining viruses rhinovirus was associated with 14.8% (n = 55) of the CAP cases, parainﬂuenza virus with 9.4% (n = 35), adenovirus with 8.6% (n = 32), human bocavirus with 3.8% (n = 14), human coronaviruses (NL63, OC43, 229E and HKU1) with 3.8% (n = 14), inﬂuenza virus B with 1.9% (n = 7), and human metapneumovirus with 1.3% (n = 5). Influenza infections were detected in only five of the CAP patients. The seasonal influenza (H3N2) strain was detected in three patients (0.8%) and swine influenza (H1N1) was detected in two patients (0.5%). In the majority of inﬂuenza virus B (57.1%), respiratory syncytial virus (51.5%), and human coronavirus (42.9%) infections only a single agent was detected which was higher than for other viral infections. In contrast, the four major viral pathogens (respiratory syncytial virus, rhinovirus, parainﬂuenza virus, and adenovirus) were detected more frequently in coinfections with other bacterial or viral agents. In patients infected with rhinovirus, parainﬂuenza virus, and adenovirus a greater percentage of coinfections were with viruses than bacteria.
Of the 172 that tested positive for respiratory agents, there were 24 (14.0%) cases with mixed infections of two or three viruses. No patient was infected with more than three viruses. Twenty-one cases were infected with two viruses, with the most frequent mixture being adenovirus and influenza A virus (n = 5). Other frequent viral mixtures were adenovirus and rhinovirus A (n =3) and influenza A virus and coronavirus OC43 (n =3) (Table 3). Adenovirus was present in 62.5% (n = 15) of mixed infections which was almost a half (46.9%) of all detections for this virus. Respiratory syncytial virus B was the only aetiology that was not detected in a mixed infection.
Viruses account for most of the respiratory tract infections in childhood [1, 12, 14]. Viral infections of the respiratory tract are often treated with antibiotics due to the absence of viral diagnostics to identify the viral aetiology. Thus, a proper diagnosis is crucial prior to initiating antibiotic treatment for bacterial ARTI or pneumonia [9, 15]. In developing countries, a lack of availability of diagnostic facilities contributes to the use of antibiotics and thus to development of antimicrobial resistance [9, 10]. The imaging studies and blood cell differential count may give a clue on the type of infective agent. However, in atypical pneumonias, getting an educated guess about the bacterial and viral causes are difficult. Hence, routine viral laboratory diagnosis is crucial and implementation of such facilities is highly warranted.
RSV is the most common respiratory viral pathogen causing hospitalization of thousands of children each year [2, 15]. Many of the affected children do not require hospitalization and some with severe respiratory disease are hospitalized or even managed in the intensive care unit (ICU). The children requiring ICU admission are typically young infants and those with co-morbidities. These children can be severely ill and require intubation and mechanical ventilation but most of the children recover and a very few succumb to the disease. Currently we are seeing the emergence of respiratory pathogens either due to change in antigenicity in influenza viruses or emergence and introduction of newly emerging viral pathogens like hMPV.
In this case series, hMPV infection showed a disease spectrum similar to that seen during RSV infection, common cold to life threatening pneumonia. Children delivered through LSCS appear to have less resistance to infection and in our study also, children delivered through LSCS had a high risk of developing hMPV/RSV co-infection. A child with a birth order > 3 had a high risk of getting hMPV/RSV co-infection and this might be due to lack of care to subsequent children in bigger families. In a few cases, even without co- morbidities, children experienced severe hMPV infection needing ICU care. In many cases, RSV/hMPV co-infection resulted in similar disease spectrum to that of RSV infection.
Specific aetiological diagnosis of childhood ARTI is not performed routinely in Sri Lanka. But if it is done routinely it will invariably guide the clinicians on the use of antibiotics including antivirals. This case series indicates the importance of establishing laboratory diagnosis for viral ARTI. Furthermore, hMPV is a potential pathogen that needs to be tested in children with ARTI. A detailed epidemiological study is in progress to elucidate the prevalence and seasonality of childhood ARTI caused by a wider range of respiratory viruses including hMPV in Sri Lanka.
Acyclovir has significantly improved the prognosis of HSV encephalitis. Although without treatment, the mortality was more than 70% and has now decreased to <20%, many of the survivors have persisting neurological deficits. The prognosis of other viral encephalitides is generally comparable to that of HSV encephalitis.
Extensive studies have not been done to characterize the effect of viral sepsis on outcomes. In a recent study, Hon et al. found no difference in mortality between patients with and without viral infections who were admitted to PICU (172). Shi et al performed a systematic review of RSV infections in 2015 and estimated case fatality rates in children with RSV infection to be around 2.2% (<6 months of age) and 2.4% (6–11 months of age) in developing countries. Case fatality rates in higher income countries were significantly lower (0.2 for <6 months and 0.9 for 6–11 months) (173). In another study, the highest mortality from RSV infection was seen at mean age of 6.2–7.5 months with three quarters of these cases associated with comorbid conditions (174).
Seasonal influenza epidemics and various pandemics have historically led to significant morbidity and mortality in the past, either due to exacerbation of an underlying condition or due to secondary bacterial infections. Mortality with influenza varies not only with season, but with predominant influenza strain and effectiveness of influenza vaccine each season. During the first year of the pandemic 2009 H1N1, global mortality in children aged 0–17 years was estimated to be as high as ~ 45,000 cases, with majority of deaths occurring in Southeast Asia and Africa (175). Both pediatric and adult patients during this pandemic had a very rapid progression to respiratory failure and required prolonged mechanical ventilation and vasopressor support (176, 177). Various extrapulmonary complications secondary to influenza sepsis have been reported in the literature. These include, but are not limited to renal failure, rhabdomyolysis, encephalopathy, myocarditis, and multiorgan failure. These complications also lead to poorer outcomes (178).
Sepsis from HPeV can lead to significant morbidity in neonates and young children. Although, most infections are self-limited, long-term neurological deficits such as learning disability, developmental delay, paralysis and epilepsy have been observed in these patients (179, 180). HPeV infections have also been associated with encephalitis, hepatitis and coagulopathy (18). In addition, rare complications have also been observed in these patients including necrotizing enterocolitis, myocarditis, myositis, hemolytic uremic syndrome, and Reye's syndrome (18). Other enteroviral infections can lead to similar complications and long-term neurological deficits. Hepatic and cardiac dysfunction can also be observed in these patients (181–183). In HSV infection, neurological complications such as developmental delay and seizures have been observed in infected neonates (15). Mortality from systemic HSV infection is usually due to severe coagulopathy, hepatitis and pneumonitis (15). In a multicenter study, Spaeder et al. observed a mortality rate of 9% in patients with severe metapneumovirus infection (184). Increased mortality from metapneumovirus infection has been observed in children with chronic medical conditions, female gender and patients who acquired the infection in the hospital (184). Similarly, RSV, parainfluenza and influenza infections, when acquired in hospital, have been associated with increased mortality (185). Rotavirus infection can lead to extraintestinal complications like seizures and meningoencephalitis (186, 187). In HIV patients, likelihood of progression to AIDS and of mortality are impacted by time of acquisition of HIV, viral load, CD4 count and timing of HAART initiation. Approximately 80% mortality has been observed in developing countries with limited access to HAART (188). Complications that lead to increased morbidity and mortality in these patients include severe CMV infection, encephalopathy, recurrent life-threatening bacterial infections, tuberculosis, and pneumocystis infection (189).
End-organ failure is a major contributor to mortality in sepsis and septic shock, including virus-induced sepsis. Complications such as acute respiratory distress syndrome, disseminated intravascular coagulation, and acute renal injury often leads to a worse prognosis. Developing countries often have disproportionately higher mortality in patients with viral infections (190), likely due to delayed diagnosis and treatment. Risk of severe sepsis is also related to the site of infection, with endocarditis and CNS infections being associated with mortality as high as 20% (1). Besides the site of infection, the type of virus also determines the risk of mortality. For example, meningitis from HPeVs is a common cause of sepsis in neonates and young children but consequent mortality is low in these patients (179). HPeV3 is associated with more severe disease than HPeV1 (113). Moreover, the extent of systemic involvement can predict the development of multiple organ failure and thus mortality (191). Sepsis related mortality has been reported in other viral infections including dengue fever (192). However, further studies are necessary in order to estimate the burden of viral sepsis on outcomes including morbidity, mortality, and health care related costs.
During the study period, 418 patients with ARTI were tested and 14 (0.03%) were diagnosed having hMPV infection. Six children had co-infection with RSV. hMPV infected patients were detected on two peaks, the first peak occurred in April 2013 and 2014 and the second peak occurred between December 2013 and January 2014.
Of the 14 hMPV infected children, nine were males (0.66%). Twelve children were from rural areas and 3 were from semi-urban areas. Mean age of the hMPV infected children was 18 months (6–36 months). Nine patients had fever as the presenting complaint; 4 children had only rales and 3 had only wheezing as the presenting complaint. One patient had watery diarrhoea but his stool culture was negative for bacterial pathogens causing diarrhoea.
Three cases were diagnosed having exacerbation of bronchiolitis following hMPV infection. One child had severe bronchiolitis associated with RSV/hMPV co-infection. One child had bilateral lower lobar pneumonia and severe bronchiolitis following hMPV infection; another child had right lower lobe pneumonia and severe bronchiolitis following RSV/hMPV co-infection. These children were admitted to intensive care unit and later discharged with follow-ups by paediatric clinic for the management of bronchiolitis. Two children had infective exacerbation of asthma with hMPV infection and the other had RSV/hMPV co-infection. Two patients had common cold following hMPV infection and one had common cold with RSV/hMPV co-infection. The disease spectrum and severity following hMPV and RSV/hMPV co-infection are described in Table 1.
Risk factor assessment for hMPV infection vs. RSV/hMPV co-infection showed that the children delivered through lower segmental cesarean section (LSCS) had an odds ratio of 3.5 (95% CI 3.5, 2.2–4.8) and birth order > 3 had an odds ratio of 4.3 (95% CI 4.3, 3.2–5.6) for developing RSV/hMPV co-infection compared to hMPV mono-infection. The duration of illness and the average hospital stay did not differ significantly in either hMPV or RSV/hMPV co-infection (Table 2).
Respiratory virus infections have a major impact on health. Acute respiratory illnesses, mostly caused by viruses, are the most common illness experienced by otherwise healthy children and adults worldwide. Upper respiratory tract infections (URIs) such as common cold are exceedingly prevalent in infants and young children and continue to be common in older children and adults. Infants and young children may have 3–8 episodes of cold per year; those who attend daycare centers may have many more episodes per year [1–4]. URI can lead to complications such as acute otitis media, asthma exacerbation, and lower respiratory tract infections (LRIs). While LRIs such as pneumonia, bronchitis, and bronchiolitis occur much less frequently, they cause higher morbidity and some mortality, thus they are associated with high impact and greater healthcare costs. Approximately one third of children develop an LRI in the first year of life; LRI incidence decreases to 5%–10% during early school year, and 5% during preadolescent to healthy adult years [5, 6].
Common respiratory viruses include influenza A and B, respiratory syncytial virus A and B, parainfluenza virus types 1–3, adenovirus, rhinovirus, human metapneumovirus, and coronavirus types OC43 and 229E. Less common respiratory viruses include parainfluenza virus type 4, influenza virus C, and specific types of enteroviruses. The significance of more recently discovered viruses such as human bocavirus, coronavirus NL63, and HKU1 has yet to be elucidated [7, 8].
Clinical presentations of respiratory virus infections overlap among those caused by various viruses. In addition, clinical manifestations may mimic those of diseases caused by bacteria. Therefore, antibiotics are most often used in these infections, most of them unnecessarily. Furthermore, LRIs often require hospitalization for management such as intravenous antibiotics and symptomatic and supportive treatment. Specific antiviral treatment for respiratory virus infections is only available for influenza. Respiratory viral diagnosis is an integral part of patient management. Accurate diagnosis of specific respiratory virus infection not only improves the knowledge of disease the patient has but also can affect patient management and help prevent secondary spread of the infection. Rapid viral diagnosis may result in discontinuation of unnecessary antibiotics, initiation of antiviral drug for influenza, reduction of costs related to reduction of unnecessary investigations, and shortened hospital stay [9–11].
This paper describes up-to-date information on laboratory methods presently available in the diagnostic virology laboratories and those upcoming for detection of respiratory viruses.
Human metapneumovirus (HMPV) was isolated from 26 samples (22.2%) of all children and during the period from S52 to S12 (Fig. 8). The maximum positivity rate was recorded between week S52 (54.5%) and week S01 (42.9%) (Fig. 9).
Secondary bacterial infections are commonly associated with respiratory viral infections (85). In the winter of 1995–96, an outbreak of Streptococcus pneumoniae pneumonia developed in otherwise healthy children who had a preceding influenza A viral illness (86). During the 2009–10 influenza A pandemic, one third of critically ill children afflicted with influenza were diagnosed with concurrent bacterial infections (87). In this study, the leading three bacterial coinfections were Staphylococcus aureus, Pseudomonas spp., and Haemophilus influenza (87). In children hospitalized for RSV, Haemophilus influenzae and Streptococcus pneumoniae were the most common organisms isolated in those who developed bacteremia (88). These secondary bacterial infections may exacerbate innate immune dysfunction (89) and convey substantially increased risk of worse outcomes (90, 91). However, to date, the mechanisms underlying bacterial synergism and increased susceptibility to secondary bacterial infection in the setting of a preceding respiratory viral infection remain unclear. In general, this phenomenon appears to involve impairment of respiratory epithelial and innate immune system defenses. Viral destruction of the airway epithelium affects mucociliary clearance, allowing bacterial attachment to mucins and eventual colonization of the respiratory tract (92, 93). Additionally, viral-induced upregulation of IFN-γ and TNF-α may lead to a dysregulated host T-cell response, decreased neutrophil chemotaxis, and impaired macrophage phagocytosis that increases the host susceptibility to secondary bacterial pathogens (94). Upregulation of the surface platelet-activating factor receptor on epithelial cells and leukocytes by pro-inflammatory cytokines may also increase adhesion and invasion of certain virulent pneumococcal strains (95).
Rotavirus infection has also been associated with secondary bacterial infections (21). Although, the exact mechanisms leading to sepsis and organ dysfunction are unknown, a leading hypothesis entails translocation of bacteria and endotoxin through damaged intestinal epithelium into the splanchnic circulation, systemically increasing production of nitric oxide and circulating pro-inflammatory cytokines like TNF and IL-1β, and high mobility group box 1 protein, resulting in sequential organ failure (96). HIV infection can lead to apoptosis of CD4 T-lymphocytes, defective T and B lymphocyte function, decreased production of IFN-γ, IL-2 and immunoglobulins, and decreased NK cell activity (97–99). This leads to not only increased risk of secondary bacterial infections but also increased susceptibility to other viruses and intracellular organisms such as mycobacteria and Pneumocystis jiroveci.
Similar to bacterial coinfections, critically ill children can be simultaneously infected by multiple viruses. The course of illness in patients with viral coinfections depend on virus-virus interaction. Various mechanisms for disease virulence in viral coinfections have been proposed, including viral gene interactions, immunologic interactions and alteration in host environment (100). Even though the clinical significance such interactions is unknown, a study by Rhedin et al. reported increased risk of severe respiratory disease in patients with viral coinfections compared to those with single viral infections (101). Approximately 20% of the patients had viral coinfection and RSV, bocavirus and adenovirus were the most common viruses associated with coinfections (101). In another study performed in Canada on patients with respiratory viral infections, approximately 17% of the patients had viral coinfections (102). There was no difference in the risk of hospitalization or the severity of illness in patients with single viral infections and those with viral coinfections (102). Another study done in Greece revealed a much higher viral coinfection rate (42%) with most common coinfections with RSV, influenza, rhinovirus and parainfluenza viruses (103). Increased risk of hospitalization has been observed in patients with viral coinfections (103). However, systematic reviews and meta-analyses of children with viral coinfections have not shown any association with increased clinical severity (104, 105). Patients infected with HIV are at high risk of secondary viral infections such as CMV, HSV and respiratory viruses like RSV, influenza and metapneumovirus.
Influenza and Bocavirus were identified throughout the year, though cases of Influenza were commonly found in May, August and September, and cases of Bocavirus were commonly found in June and November. Influenza B was identified only in the second semester, while the two cases of Influenza A/H2N3 were seen in May. Adenovirus was seen only during the rainy season (April to May and August to November); most cases of Metapneumovirus, Parainfluenza and RSV were seen only in the first semester, specifically in April and May; the two cases of Coronavirus were identified in May (Fig 2).
This study identified viral aetiologies in 46.6% of all ILI cases at two health facilities in Kampala and Entebbe, Uganda, a prevalence level similar to that reported in other studies.22,23,24 The identified aetiologies include influenza A and B virus, adenovirus, rhinovirus A, coronavirus OC43 and 229E, parainfluenza virus 1, 2 and 3, respiratory syncytial virus A and B and human metapneumovirus. A number of these aetiologies have only recently been identified and their circulation in Uganda was unknown previously. These include human metapneumovirus, whose discovery as a causative agent for ILI has been recognised only in the last decade.25
Most of the detected viruses, including parainfluenza virus 1, 2 and 3, influenza B virus, adenovirus, human metapneumovirus and coronaviruses OC43 and 229E, were circulating at prevalence levels that were, in general, similar to those found elsewhere.12,14,26,27 Influenza A virus was detected in 19.2% of ILI cases, which was higher than the 12% prevalence level that was known to exist from previous observations in the same population.8 The higher prevalence observed for this virus could be attributed to the timing of this study which was conducted when rainfall is highest in Uganda. It is probable that an outbreak associated with this virus was ongoing during the study period as observed previously.4,5,6 Conversely, rhinovirus A was detected at 7.9% which is lower than the 10 % – 25% prevalence levels found in other ILI surveillance studies within sub-Saharan tropics.13,14,16,28 In the same studies, the prevalence of respiratory syncytial viruses A and B ranged between 5% – 21% which is higher than our 3.3% total prevalence for the same viruses. The low prevalence levels observed for these viruses could also be associated with their seasonality in the study population – a variable that could not be established with our current cross-sectional data. Also, our ILI case definition was focused more on influenza surveillance and could have been restrictive with regard to the signs and symptoms of other ILI aetiologies.29,30
Mixed infections amongst all cases that tested positive for respiratory agents accounted for 14.0% of the findings, with the majority being double infections. The prevalence of mixed infections ranging from 4.5% – 70% are reported from other studies, depending on the geographical location of the study area, the diagnostic method used or the general degree of illness in the study population.24,31,32,33 The high prevalence of mixed influenza A virus and adenovirus infections during a low circulation cycle of respiratory syncytial virus infection has previously been suggested.34 In our study, the number of mixed infections (n = 24) was not adequate to allow statistical analysis; a more comprehensive study is necessary in order to determine the associations and interactions between these viruses as well as the related clinical outcomes.
In 25 children (21.4%), several respiratory viruses were identified as virus coinfections. Among the viruses found in coinfection, RSV was the most common and accounted for almost three quarters of the coinfections diagnosed (19/25). It was associated with HRV or HMPV (Table 2). For 14.8% of patients, three viruses were isolated: HRV, RSV and HMPV. Thirty-four per cent of children for whom RSV was isolated had a virus coinfection.
Four hundred fifty‐three subjects were enrolled in the study between 13 October 2011 and 15 May 2012. Of these patients, 8 subjects did not meet study criteria and were excluded, resulting in 445 evaluable subjects. Of these, 47 withdrew consent, 47 died, 5 were lost to follow‐up, and 16 withdrew due to other reasons. Thus, 330 (74.2%) subjects completed the study in May 2014 (Figure 1). The mean age of subjects was 66.3 ± 8.3 years with the majority having severe COPD (77.5%), 16.2% had advanced CHF, and 6.3% had both severe COPD and advanced CHF (Table 1).
Over the course of the study, 1111 episodes of MARI illness occurred, of which 300 were hospitalizations, 82 were ER visits, 550 were outpatient visits, and 179 were phone calls to a health care provider. Overall, 92% of illnesses had a nasal PCR performed within 14 days of illness: hospitalizations (87%), ER visits (80%), outpatient visits (96%), and illnesses with phone calls (89%). In addition, 95% of subjects had a serologic analysis of pre‐ and postseason sera.
Forty‐two illnesses met the protocol‐specified definition of RSV‐MARI, of whom 12 were positive by RT‐PCR only, 14 had a >4‐fold increase in serology only, and 16 were RT‐PCR and seropositive. For the RSV seasons combined, the incidence of a protocol‐defined RSV‐MARI was 4.68 events per 100 patient‐seasons (Table 2). The highest incidence of RSV‐MARI occurred in season 1 (6.37 per 100 patient‐seasons) followed by season 2 (5.41 per 100 patient‐seasons) and season 3 (2.80 per 100 patient‐seasons). The rate of inpatient RSV‐MARI was highest for season 1 (3.15 events per 100 patient‐seasons) followed by season 3 (0.93 events per 100 patient‐seasons). The incidence of outpatient visits was greater than inpatient visits for season 2 (4.61 vs 0.76 events per 100 patient‐seasons, respectively) and season 3 (1.86 vs 0.93 events per 100 patient‐seasons, respectively), but was similar for RSV season 1 (3.16 vs 3.15 events per 100 patient‐seasons, respectively).
Twelve (29%) of the 42 subjects with per protocol RSV‐related MARI were hospitalized, and one subject was hospitalized with RSV outside the RSV season. Overall health utilization attributable to RSV‐MARI was relatively low, with only 2.9% of subjects hospitalized; 1.8% had increased oxygen needs and 0.6% required intensive care. Forty‐seven (10.5%) subjects died during the study; 8.4% with COPD, 12.5% with CHF, and 32.1% with both conditions. Of the 47 deaths, only 2 had virus‐positive MARI within 4 weeks preceding the death (1 coronavirus and 1 rhinovirus). Two patients had an RSV illness <6 months before death (one 2.3 months and the other 4.8 months before death). However, the site investigators considered these deaths unrelated to RSV. Thirteen deaths were during the summer, outside of the RSV season, and were unlikely related to RSV infection. Thus, overall mortality was 2.68 per 100 patient‐seasons and no death was considered directly RSV related.
An inverse relationship between serum RSV antibody levels and incidence of RSV‐MARI was observed (Figure 2). Higher antibody levels to each of the RSV antigens were associated with a lower incidence of RSV‐MARI, and the relationship was most clearly seen in season 2 possibly due to more subjects with RSV‐MARI and available serology in season 2 versus season 3 (20 vs 8, respectively). Season 1 was not included because subjects were being enrolled throughout the year, and preseason blood was not available for many subjects.
In addition to the 42 subjects with per protocol RSV‐MARI, an additional 57 RSV infections were also identified. Of these, 55 had >4‐fold increases in RSV antibody and 2 subjects were identified with RSV by PCR at nonillness visits (February enrollment and May scheduled visit). Five subjects had evidence of two RSV infections in different seasons (two with PCR‐documented MARI in one season and seroresponse in a subsequent season with no MARI and three with serologic responses with no MARI). Twenty subjects with seroresponses experienced MARI (15 outpatients and 5 inpatients). However, the timing of the seroresponse could not be definitively associated with a specific respiratory illness. Most often, the acute titer had risen from the baseline so that a fourfold rise in titer from acute to convalescent sample was not demonstrated. These illnesses were considered possible RSV‐MARI but were not included in the per protocol incidence rate determinations. If we consider definite plus possible RSV‐MARI cases, outpatient care was sought for 62 of 99 (63%) and hospitalization occurred in 17 of 99 (17%) of all identified RSV infections. When considering all 99 identified RSV infections, the incidence of RSV infection per 100 patient‐seasons was 14.6, 11.6, and 7.0 for seasons 1, 2, and 3, respectively.
Medically attended all‐cause ARI or worsening cardiorespiratory status was common at 63.8 events per 100 patient‐seasons, and a diverse number of viruses were detected by the multiplex PCR assay. The percentages of positive samples in seasons 1, 2, and 3 were: RSV (2.7%, 5.5%, and 4.1%), influenza A (3.0%, 3.6%, and 2.8%), influenza B (0.6%, 4.1%, and 0.5%), adenovirus (0.9%, 2.6%, and 1.4%), coronaviruses (10.6%, 10.5%, and 8.3%), human metapneumovirus (3.0%, 0.4%, and 3.1%), rhinovirus (15.2%, 23.7%, and 19.4%), and parainfluenza viruses (3.0%, 4.1%, and 2.0%). Of note, coronavirus and rhinovirus infection was frequently detected during scheduled nonillness visits, whereas asymptomatic detection was uncommon for other viruses (Figure 3). Twenty‐nine percent of subjects were hospitalized with non‐RSV ARI or worsening cardiorespiratory status. Hospitalization rates for other viruses were as follows: influenza (1.8), adenovirus (0.2), coronaviruses (2.2), human metapneumovirus (0.5), rhinovirus (3.3), and parainfluenza viruses (1.1), respectively, as compared with 1.3 per 100 patient‐seasons noted for RSV. Finally, we assessed the added value of testing sputum samples in addition to nasal sampling using the multiplex PCR platform. For all viruses, the addition of sputum testing resulted in (11.8%‐50.0%) increased viral detections during illness (Table 3).
The current study of the infants hospitalized with bronchiolitis has proved once again that AB is an important cause of hospitalization in infants, mostly younger than 6 months of age. Using multiplex real-time PCR technique we demonstrated that at least one respiratory viral pathogen was responsible for bronchiolitis in 75% of our cases.
Various studies have shown that RSV is the most common etiologic pathogen with a rate of 50% to 80%.18 Almost 30% to 40% of cases are related to other viruses including adenovirus, coronavirus, parainfluenza, influenza, and rhinovirus. In recent years, new human respiratory viruses like human metapneumovirus, human bocavirus, and new human coronaviruses have also been reported as possible pathogens causing AB.19 Today, various viral diagnostic tests allow us to examine the epidemiological differences/clinical characteristics of respiratory viruses and to provide information on their presence. Multiplex PCR has been the most commonly used method due to some significant advantages like permitting simultaneous amplification of several viruses in a single reaction and facilitating cost-effective diagnosis.20 In this study, we evaluated via multiplex PCR technique the variety and burden of viral agents causing AB in infants under 24 months of age.
The findings are in agreement with the results of several studies previously reported, in which RSV was diagnosed in 50% to 80% of infants admitted to hospital with acute bronchiolitis.21-26 RSV was the most common virus identified in 127 infants (40.1%) in our study. Stempel et al26 showed that RSV incidence was 77%, and Antunes et al27 found this as 58.1% in the RSV epidemic season. In our study, RSV was the most frequently identified respiratory virus, accounting for 40.1% of all respiratory viruses. In addition, 24.6% of the infants in our study were positive for rhinovirus, followed by influenza virus (8.8%), human metapneumovirus (8.5%), adenovirus (7.2%), human bocavirus (6.3%), parainfluenza virus (5.6%), and human coronavirus (3.1%). Human rhinoviruses are the most common human respiratory pathogens and are responsible for most upper respiratory infections (eg, common cold). They may also cause severe lower respiratory tract infections, including pneumonia and bronchiolitis.28 Additionally, human rhinoviruses are known as a major pathogen for asthma exacerbations in children and adults. Recently, some studies have shown rhinoviruses to be the second most commonly seen pathogen for AB. A study conducted in the United States found a prevalence of 25.6% for rhinovirus,25 similar to our study. However, other studies reported a lower incidence rate of human rhinoviruses in acute bronchiolitis.24,29,30
Our study showed that the respiratory viral agents exhibited seasonal patterns with the number of RSV and rhinovirus cases peaking in the winter season similar to that already published in previous studies.31 It has been reported that the seasonal distribution of respiratory agents may occur due to meteorological conditions, spreading of infectious pathogens, and pathogen transmission by the host behavior due to different meteorological conditions.32,33 Another important theory on pathogen activity is total sunshine exposure. It is hypothesized that ultraviolet light radiation could affect the spread of RSV by inactivating it.33,34 The city of Izmir in Turkey, located in the west, has Mediterranean climate in which summers are hot and dry and winters are warm and rainy. This climatic feature could explain the seasonal pattern of respiratory viruses in our study.
In keeping with previous studies, we found that the respiratory viruses could occur as co-infection with other respiratory viruses, within a range of 19% to 35% dual, triple, or more, dual being the most frequent.26,35 Ong et al36 showed in their study that RSV bronchiolitis associated with other pathogens was present in 10% of the infants. In a multicenter study, it was reported that the co-infection rate was 9%.25 A study by Papadopoulos et al37 stated that 19.5% of 119 infants were dual-infected, 69% of whom had RSV together with rhinovirus. In this study, we identified co-infection in 81 (25.6%) infants with bronchiolitis, and more than half of 25.6% showed the same dual combination.
In the 1960s, it was reported that the mortality in infants less than 1 year of age diagnosed with bronchiolitis was 4% to 7% for those who were born prematurely and who had an underlying cardiopulmonary disease or immunodeficiency.11 Today, the mortality rate of AB is low due to the fact that the infants are monitored by some preventive measures such as palivizumab and improved health services. However, there is an increase in the number of infants applying to hospital and hospitalization. Hall et al38 reported that the yearly incidence of hospitalization due to RSV bronchiolitis for infants aged under 6 months was 17, emergency department visits were 55, and office visits were 132 per 1000 children. Our study has a number of limitations. First, we only investigated the hospitalized patients with acute bronchiolitis, and not the infants who applied to the emergency services or outpatients policlinics, so our study group was small in number. Second, we did not identify other possible agents such as atypical or bacterial pathogens that could cause acute bronchiolitis. Third, a 3-year study period was not adequate compared to other long-term studies.
This study is the first extensive laboratory surveillance of the etiology of respiratory viruses in ILI patients through teaching hospital-based influenza surveillance in South Korea. The influenza A virus was the predominant agent and the majority of influenza A virus was A(H3N2) during the 2011–2012 season. In addition, 23.1% of the respiratory viruses detected in respiratory specimens from adult patients with ILI were viruses other than influenza viruses.
The respiratory virus detection rates in respiratory specimens from ILI patients ranged from 15.6% to 78.7%, depending on the study period, the characteristics of the study population including age, type of specimens, circulating viruses, and analysis method–. At least one virus was detected in 52.1% of samples in this study. Influenza virus was the predominant agent, and this finding is consistent with other reports–. Since ILI is a clinical definition designed to detect potential influenza cases, the use of ILI as a case-definition makes influenza viruses the viruses most likely to be identified. This case-definition is suitable for the purpose of HIMM surveillance, which is focused on the detection of influenza. Yu et al. investigated respiratory viral etiology in adults with acute respiratory tract infections visiting an ED in China, and the parainfluenza virus was found to be the dominant agent. In their study, enrollment criteria included respiratory symptoms, a body temperature above 37.5°C, and a normal or low leukocyte count, but not radiographic abnormalities on chest. There is a difference in the respiratory viral etiology between children and adults. RSV was the most prevalent virus and was associated with substantial morbidity in children with respiratory virus infection–. In this research, the study population included only adult patients, and the viral etiology of pediatric patients with ILI was not evaluated.
The co-incidence rates of respiratory viruses in ILI patients vary according to study (0.7–15.3%)–. In this study, multiple respiratory viruses were detected in 5.6% of positive specimens and 2.9% of total ILI patient samples. The clinical significance of the co-incidence of respiratory viruses has not been clearly determined. In infants with bronchiolitis, dual viral infection was a risk factor for ICU admission and co-infection with human metapneumovirus and RSV was strongly associated with disease severity,. Additionally, viral co-infections were related to an increased probability for hospitalization in children with respiratory infection. However, the impact of detection of multiple respiratory viral infections on clinical outcome has rarely been investigated in adults. In this study, the disease severity or outcome were not different significantly between patients with single virus and patients with multiple respiratory viruses. In addition, the detection of viral nucleic acid in respiratory specimens does not always suggest that it is the causative agent of the apparent infection. Among respiratory viruses, rhinovirus was the most common virus detected in influenza patients. In one patient, six respiratory viruses were detected simultaneously. This 20 years old female patient was previously healthy, and the outcome was good without hospitalization or any complication or sequelae. Among 58 co-incidence cases, two patients were hospitalized (influenza A virus and rhinovirus, influenza A virus and RSV A). Further research on viral interference, especially between influenza virus and rhinovirus, is required in both animal models and humans.
This study has some limitations. First, the surveillance population was limited to adults who visited an ED with ILI. Second, the evaluation of the causative agents of ILI covered only 15 respiratory viruses, and other bacterial or viral pathogens which can cause acute febrile respiratory illnesses were not investigated. Third, there is a possibility that a low viral titer could not be detected by RT-PCR. Fourth, patients with acute febrile illness but without respiratory illness could be enrolled in this study because the recruitment depended on whether cases met the established ILI criteria or not. Finally, this study described only the result of laboratory data. However, this study is valuable for understanding the respiratory viral etiology of ILI patients during the 2011–2012 season. This study is noteworthy in that it is the first extensive laboratory surveillance of adult ILI patients through a teaching hospital-based influenza surveillance scheme in South Korea.
Among the 383 children included, 377 (98.4%) were positive by real-time PCR for at least one pathogen. 321 (83.8%) of patients included were positive for respiratory viruses, RSV was detected in 157 (41.0%). One hundred and forty-seven (93.6%) RSV-positive samples were also positive for at least one other microorganism, 77 (49.0%) for other respiratory viruses, and 144 (91.7%) for bacteria.
Of the RSV-positive ARI children, a complete list of viruses co-detected is provided as supplemental data (Table S1). Co-detection with viruses known to be frequent causes of acute respiratory infection were observed: Human rhinovirus in 12 (7.6%), Human adenovirus in 6 (3.8%), Human parainfluenza virus in 3 (1.9%), Influenzavirus in 1 (0.6%). Human metapneumovirus was not detected in any RSV-positive patients. The main bacterial species co-detected with RSV were S. pneumoniae and H. influenzae in 98 (62.4%) and 84 (53.5%), respectively.
To determine whether the etiological agent for CAP varied with age, we compared the prevalence of viral and bacterial pathogens in each age group. Table 4 shows the distribution of each pathogenic agent according to CAP patient age. In the pre-kindergarten group, the most common pathogens were respiratory syncytial virus (n = 108, 44.6%), rhinovirus (n = 31, 12.8%) and S. pneumoniae (n = 24, 9.9%). In the kindergarten group, S. pneumoniae (n = 14, 38.9%), respiratory syncytial virus (n = 11, 30.6%), H. inﬂuenzae (n = 7, 19.4%), and adenovirus (n = 7, 19.4%) were the most common infections. Finally, in the school-age group, respiratory syncytial virus (n = 44, 47.3%), S. pneumoniae (n = 39, 41.9%), and rhinovirus (n = 20, 21.5%) accounted for the greatest number of infections.