Respiratory viruses represent an important role in the etiology of community-acquired pneumonia in adults. Respiratory viruses are also the leading cause of acute exacerbations of chronic obstructive pulmonary disease (COPD)/asthma patients, resulting in frequent consultations with a general practitioner and hospitalisations. In some cases, invasive ventilation is required. The number of studies that document the presence of viruses in respiratory samples of critically ill patients is currently growing in the literature. What is really needed, however, are more data on the clinical significance of these findings, particularly as regards morbidity and mortality.

In a previous work we investigated the incidence of nosocomial viral ventilator-associated pneumonia. The aims of the present study were to determine the epidemiology of and risk factors for virus-positive respiratory samples taken at the time of intubation in acutely ill patients, and to compare clinical outcome (survival and time to ventilated acquired pneumonia) with and without respiratory viruses, according to the presence (group 1) or the absence (group 2) of respiratory disorder at admission.

All consecutively intubated adults admitted to the intensive care unit (ICU) in the University Hospital of Caen between September 2003 and September 2004 were screened, as previously reported.

A one-year pulmonary function follow up of was performed in 48 (48%, 26 men and 22 women) of the 102 (54 men and 48 women) patients diagnosed with mild influenza A virus subtype H1N1 at the First Hospital, Jilin University, China in 2009. Each patient was diagnosed by a physician according to the inclusion criteria of Influenza A Virus Subtype H1N1 Diagnosis and Treatment Protocol (Edition 3, 2009), issued by China’s Ministry of Health. To ensure patients were not examined during or shortly after airway infections, all participants answered a questionnaire detailing any complaints of dyspnea, tiredness, cough, expectoration, medical treatment and smoking habits. The Modified Medical Research Council Dyspnea Scale was used to evaluate dyspnea of patients with abnormal pulmonary function (a score of 4 points, 2 cases; 3 points, 4 cases; 2 points, 14 cases;1 point, 4 cases; and 0 points, 2 cases) and with normal pulmonary function (a score of 4 points, 2 cases; 3 points, 2 cases; 2 points, 8 cases;1 point, 10 cases; and 0 points, 2 cases). Of these 48 patients, 38 were diagnosed by members of the Department of Respiratory Medicine and ten were diagnosed by members of the Department of Infection. The study included 26 male and 22 female patients with an average age of 29.5 years (range 27–39.5). Of the original 102 patients, eight (7.8%) had died: one from pneumonia and seven from disorders that could not be attributed to pulmonary disease. Forty-six (45.1%) patients were not re-examined due to practical problems. However, based on the data from 2009, these 46 patients did not differ from the 48 re-examined patients with respect to age, sex, disease duration, or degree of pulmonary function. Patients with chronic respiratory system disease (i.e. chronic obstructive pulmonary disease, asthma, pulmonary fibrosis, silicosis), chronic heart disease, or nervous and mental diseases were excluded. Written informed consent was obtained from each subject.

In order to assess the potential long term effects of mild H1N1 influenza infection patients were first assessed at approximately one year following recovery and hospital discharge. At this time, 29.2% (14/48) were observed to have obvious respiratory tract infection symptoms and 41.7% (20/48) had difficulties in performing physical activities. Pulse oxygen saturation was greater than 95% in all patients and no abnormal vital signs. We then tested each patient for pulmonary function and found 45.8% (22/48) had normal pulmonary function while 54.2% (26/48) had abnormal pulmonary function, all presenting with changes of mild to moderate H1N1 influenza. Several changes caused by abnormal pulmonary function were found, including diffusion disorder, small airway function disorder, and weakened storing function (Table 1).

Of the 22 patients having normal pulmonary function, each had respiratory tract infection symptoms while six were observed to have a decreased ability to perform general physical activities. Of the 26 patients tested to have abnormal pulmonary function, 12 had respiratory tract infection systems and 14 had decreased ability to perform general physical activities. There was a clear correlation between respiratory tract infection symptoms and pulmonary function. Patients that tested for abnormal pulmonary function had a higher percentage respiratory tract infection symptoms when compared with the group of patients with normal pulmonary function (P = 0.047). Furthermore, patients with abnormal pulmonary function had a slightly, but not significant, greater influence on daily activities than normal pulmonary function (P = 0.188) (Table 2). Finally, ten patients were observed to have greater than three abnormal pulmonary function indices, manifesting as respiratory tract infection symptoms and resulting in decreased general physical activates.

Using the Modified Medical Research Council Dyspnea Scale, scores of four (two cases), three (four cases), two (14 cases), one (four cases) and zero (two cases) were observed for patients with abnormal pulmonary function. Similarly, for patients with normal pulmonary function, scores of four (two cases), three (two cases), two (eight cases), one (ten cases) and zero (two cases) were observed. There were no significant differences in pulmonary function and ARDS scores between patients with abnormal pulmonary function and patients with normal pulmonary function. In addition, there were no significant differences in total hospital days and poorest oxygenation index between patients with normal pulmonary function and patients with abnormal pulmonary function. Taken together, these result do not represent a correlation between pulmonary function at one year after discharge and the severity of the initial influenza infection (Table 3).

Adenovirus (ADV) is one of the most common respiratory pathogens in childhood, and 13-17% of children hospitalized with a viral respiratory tract infection are diagnosed with an ADV infection. Although most cases are self-limiting, ADV infection can lead to more severe complications and death. Specific serotypes of the ADV (serotypes 1, 3, 5, 7, 8, 21, and 55), a younger age (less than one year), and immunocompromised hosts have been reported as risk factors for severe ADV infection.

Recently, multiplex polymerase chain reaction (PCR) tests, which are more sensitive and cost-effective than conventional antigen detection and culture methods, have been used for diagnosing respiratory viral infections. More cases of multiple respiratory viral infections have been diagnosed using these multiplex PCR tests than were reported before using conventional testing methods. Consequently, the clinical impact of respiratory viral coinfections, especially coinfection with respiratory syncytial virus (RSV), has been evaluated since the 2000s. In a recently published meta-analysis, respiratory viral coinfections were not reported to result in a significant increase in the clinical severity of respiratory infections compared with single viral infections. However, their clinical effects vary depending on the coinfected viruses and the subjects enrolled in each study. Therefore, while respiratory viral coinfections reportedly manifest as more severe illnesses in some studies, other investigators report a lack of association between viral coinfection and disease severity in ADV infected children. Furthermore, even as ADV infection occurs steadily all year round in Korea, the clinical impact of respiratory viral coinfection on childhood ADV infection has rarely been reported. In addition, previous studies on ADV coinfections included only children younger than 1 or 3 years of age, or children with lower respiratory tract infections. This retrospective study was performed to investigate the clinical impact of respiratory viral coinfections in Korean children with ADV infection.

Human metapneumovirus (hMPV) was first identified in 2001, the Netherlands from a pediatric patient who had symptoms similar to those of respiratory syncytial virus (RSV) infection. It is a member of the paramyxovirus family and is genetically similar to RSV. Typically hMPV infections occur between March and April, and account for 7% of respiratory tract infections.

A hMPV infection commonly occurs in children less than 2 years old and manifests as mild flu-like symptoms, similar to RSV. Furthermore, hMPV is a major contributor to the burden of wintertime respiratory illness in older adults that is peak incidence at 65 years of age and immunocompromised individuals. hMPV infections in children are usually mild and self-limiting, but in elderly and immunocompromised patients, the clinical course can progress to acute respiratory distress syndrome (ARDS). Studies of patients with hMPV who develop severe illness have focused on children; few have involved adults. Nosocomial infection has been reported in several studies as a mode of transmission. Nosocomial hMPV infection of adults occurs predominantly in human immunodeficiency virus-infected persons.

There are few studies on hMPV infection of adults in Korea. And the number of immunocompromised patients is increasing in hospitals. These patients are also vulnerable to previously neglected pathogens. Therefore, we designed a retrospective review of hMPV-infected adults. The clinical characteristics of the patients—including demographic data, comorbidities, presence of pneumonia or ARDS, acquisition site (community-acquired or nosocomial), and risk factors for ARDS—were reviewed.

Respiratory syncytial virus (RSV) is the major infectious cause of lower respiratory tract illness in infants and young children around the world.1, 2 It has also been recognized as an important etiologic agent of pneumonia and other respiratory tract infections in adults and elderly patients.3, 4 The clinical presentation of this infection varies widely, from mild upper respiratory tract disease to bronchiolitis and pneumonia.5 This virus is responsible for the majority of bronchiolitis cases and causes approximately 50% of pneumonia cases during the first years of life.6 In children, host factors such as young age, prematurity, and chronic cardiopulmonary diseases have been associated with severe disease. In addition, other factors such as lower socioeconomic status, exposure to cigarette smoke, air pollution, crowded households, and the lack of breastfeeding have also been associated with severe disease.7 Viral factors associated with virulence leading to severe disease are not sufficiently understood.8

Human RSV is a member of the Paramyxoviridae family. Outbreaks of RSV infections occur between fall and spring in temperate climates and tend to last up to 5 months.9, 10 RSV isolates can be divided into two groups: group A and group B based on antigenic and genetic characteristics.8 These two groups cocirculate in the human population, with group A being more prevalent. Several studies have compared the severity of disease between infants infected with RSV group A and group B with mixed results. Most studies have not found significant clinical differences between both subtypes.8 However, a possible effect of different viral strains on disease severity remains an open question.

Despite the recognized importance of RSV as a cause of respiratory illness, the information regarding the epidemiology of this virus in Latin America, particularly among adults, is limited.11 In the present study, 570 cases of RSV infection identified during four epidemic years in Mexico were evaluated to clarify the epidemiology of this infection and to assess the possible variations in demographic and clinical characteristics according to viral groups.

In general, upper respiratory tract (URT) symptoms include rhinorrhea, sneezing, blocked nose, sore throat, hoarse voice, head or face ache, chill, and fever, while LRT symptoms include symptoms such as wheeze, cough, shortness of breath, and chest tightness (Corne et al., 2002). Tan et al. (2003) reported that virus-positive patients had a significantly increased frequency of URT symptoms of rhinorrhea, sore throat, fever, chills, and malaise. Nicholson et al. (1993) reported that, in adults with asthma, about a quarter of laboratory-confirmed viral and chlamydial acute upper respiratory infections was associated with mean decreases in peak expiratory flow of > 50 L/min, and half was associated with mean decreases of >25 L/min. The report also noted that respiratory pathogens were implicated in almost half of the most severe asthma exacerbations with a > 50 L/min mean decrease in peak expiratory flow. Viral infections have been shown to enhance both the reactivity of the lower airway and the magnitude of bronchoconstriction in response to inhaled contractile substances in asthma. The latter effect can persist for several weeks after infection, presenting as LRT symptoms (Cheung et al., 1995) accompanied by a decrease in peak expiratory flow. Thus, physicians should be aware of decreased peak expiratory flow, URT, or LRT symptoms associated with viral infections.

The non-ARDS group included 88 patients while the ARDS group included 22 patients. The mean age of the non-ARDS group was 59.8 years, while that of the ARDS group was 68.0 years (OR, 1.034; P = 0.040). However, multivariate logistic regression showed age was not significant (Table 3). The pattern of viral and bacterial co-infection did not differ between the ARDS and non-ARDS groups (Table 1). The rates of comorbidities in the hMPV-associated ARDS patients were similar in hMPV-associated ARDS patients, with the exception of congestive heart failure (OR, 5.249; P = 0.044) (Table 3). The inhospital and 1-year all-cause mortality rates of the ARDS patients were 36.4% and 40.9%, respectively (Table 1). Additional analysis showed Kendal rank correalation coefficient was 0.752 (P = 0.001) between in hospital mortality and 1-year mortality. Therefore 1-year all-cause mortality was not independent variable.

Exacerbation of COPD is an event characterized by an acute increase in respiratory symptoms beyond normal day-to-day variation (Vestbo et al., 2013). Clinicians and researchers should always keep in mind that exacerbations of COPD are neither defined consistently nor matched in individual studies. Definitions of exacerbations are roughly divided into two groups, event-based exacerbations and symptom-based exacerbations, depending on the patients’ symptoms or clinical events, respectively. Symptoms were defined and include dyspnea, cough, and sputum volume or purulence. Clinical events were defined as a status requiring additional treatments such as systemic antimicrobials or steroids with or without admission. Diseases such as pneumonia, congestive heart failure, and pulmonary embolism that mimic and/or aggravate exacerbations were generally excluded from exacerbations of COPD.

The medical records of children (below 20 years of age) admitted to the Department of Pediatrics at Seoul St. Mary’s Hospital, and diagnosed with ADV infection between January 2012 and December 2014, were retrospectively reviewed. Children with immunocompromised status (e.g., underlying hematological malignancy, bone marrow failure syndrome, or an autoimmune disorder requiring immunosuppressant therapy) were excluded. The enrolled children were divided into two groups based on the result of multiplex PCR test for common respiratory viruses. The ADV group included children infected by only ADV, whilst the coinfection group included children concurrently infected with two or more viruses including ADV.

Demographic data included age and sex. Clinical data included birth history, the presence of siblings, the presence of underlying medical conditions, duration of fever and hospitalization, presenting symptoms on admission, final diagnosis on discharge, and severity of the ADV infection. Fever was defined when the tympanic membrane temperature was ≥38.0 ºC. Among presenting symptoms, respiratory symptoms included cough, rhinorrhea, sputum, nasal stuffiness and dyspnea, and gastrointestinal symptoms included vomiting, diarrhea and abdominal pain. Ophthalmologic symptoms included conjunctival injection, ocular pruritus, ocular pain and eye discharges. Neurologic symptoms included dizziness, headache and seizure-like motion, and dermatologic symptoms included various types of skin rashes. The ADV infection was considered severe in cases where oxygen therapy was given; the demand for oxygen increased in a child who had already received oxygen therapy; a child was admitted to the intensive care unit (ICU); or a child died due to the ADV infection. On admission, blood tests were performed to assess total and differential white blood cell counts and platelet counts. In addition, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), aspartate transaminase, and alanine transaminase levels were also assessed at admission. Demographic, clinical, and laboratory parameters were compared between the two children groups. This study was approved by the Institutional Review Board of Seoul St. Mary’s Hospital (Approval No.: KC15RISI0767). Informed consent was waived for this study.

Acute respiratory tract infection (ARI) represents the most frequent cause of outpatient visits to health care systems and hospitalization.1 ARI is a common illness in children, who experience an average of five to six ARI episodes every year with an increase during the second year of life.2 Lower respiratory tract infections (LRTI) are one of the main complications. Globally, LRTI is the third leading cause of years of life lost3 and is responsible for 16% of all deaths in children under 5 years.4 In 2015, 0.92 million children died of pneumonia; most of them were children <5 years old.

5

Globally, the proportion of severe pneumonia episodes was 8.6% in 2000 and in 2010 an incidence of 11.5% was estimated for low‐and middle‐income countries.6 In Mexico, children less than 5 years of age account for up to 26.8% and 25.5% of all ARI and pneumonia cases, respectively.7

Many studies have sought to determine the viral etiology of ARI in children, and the importance of some viruses, such as influenza and respiratory syncytial virus (RSV), is well known.8, 9 Previous studies have detected one or more viruses in a high proportion of ILI cases, ranging from 76.6% of cases in physicians’ offices,1 65% in outpatients,10, 11, 12 and between 39% and 60% in hospital settings.11, 13 In recent years, the sensitivity of diagnostic tests has improved and the number of detectable pathogens has increased.14 However, in Mexico and other Latin American countries, there is limited information regarding the prevalence and detection of viruses other than RSV and influenza as a cause of severe infections.14, 15, 16, 17

In the present study, we analyzed children 5 years old and younger recruited from the Mexican Emerging Infectious Diseases Clinical Research Network (La Red) ILI‐002 study. The objective of this study was to describe viruses detected in sick children (ambulatory and hospitalized) with ILI in Mexico, and to determine the contribution of these viruses to hospitalization risk.

The primary outcome of interest was admission to the hospital as a marker of a severe ILI. Since the emergency departments (ED) at the participating hospitals were often utilized by patients seeking both emergency and nonemergency care, patients who were in the ED for <24 hours were considered as outpatients. All deaths, regardless of hospitalization status, were considered to have severe ILI. All patients had follow‐up 14 days (by telephone call) and 28 days (clinic visit) after enrollment. Patients initially seen as outpatients who were later admitted to the hospital were included in the hospitalized group for this analysis.

Demographic information and medical histories were obtained from all eligible participants at the baseline study visit. A nasopharyngeal swab or nasal aspirate was collected at the time of recruitment from all patients. Viral pathogens were detected using multiplex real‐time PCR using the RespiFinder19 (April 2010 to May 2012) or RespiFinder 22 (previously RespiFinder Plus, PathoFinder BV, Maastricht, The Netherlands; June 2012 to March 2014); both tests detect the following viral pathogens: rhinovirus, RSV types A and B, influenza A and B, coronavirus (NL63, OC43, 229E), human metapneumovirus (hMPV), parainfluenza virus (PIV) types 1‐4, and adenovirus. RespiFinder 19 also included influenza H5N1, while RespiFinder 22 includes bocavirus, coronavirus HKU1, influenza A H1N1v, and enterovirus, but does not differentiate between rhinovirus and enterovirus. In addition, RespiFinder also detects four bacteria: Bordetella pertussis, Chlamydophila pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae. All samples that were originally tested with RespiFinder 19 were subsequently tested for bocavirus with primers specific for this virus. Because the aim of this study was to assess the severity of viral infections, patients in whom any of these bacterial pathogens were detected (either alone or in combination with viruses) were excluded from further analysis.

Patients ≥1 month old who presented with an ILI to any of the participating hospitals were eligible for participation in the study. ILI was defined by the presence of at least one respiratory symptom (e.g., shortness of breath, nasal congestion, and cough) and one of the two following criteria: (i) fever ≥38°C on examination, or self‐reported fever, or feverishness in the past 24 hours; (ii) one or more non‐respiratory symptoms (e.g., malaise, headache, myalgia, or chest pain). In order to rule out a nosocomial infection, patients who had been hospitalized for more than 48 hours at the time of symptom onset were excluded from the study.

One or more respiratory pathogens were determined in 201 (76.7%) of 262 patients, and 107 patients (40.8%) underwent bronchoscopic BAL for etiologic diagnosis (Figure 1). The distribution of respiratory pathogens is shown in Table 2. Bacterial infections were observed in 156 patients (59.5%). Of these, 130 (49.6%, 130/262) were diagnosed solely with bacterial infection. Viral infections were found in 59 patients (22.5%). Of these, 31 (11.8%, 31/262) were diagnosed solely with viral infections. The coinfected patients included 21 (8.0%, 21/262) with bacterial-viral coinfections and seven (2.7%, 7/262) with viral-fungal coinfections. Viral infections were found in 36.1% (43/119) of immunocompromised patients and 11.2% (16/143) of non-immunocompromised patients (p<0.001). The identification of viral pathogens in accordance with the immunocompromised conditions is summarized in Table S1.

Hospital-acquired pneumonia (HAP) is the second most common nosocomial infection, and severe HAP requiring treatment in the intensive care unit (ICU) is associated with high morbidity and mortality,. Bacterial pathogens are well known as principal causes of HAP. Such species include Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa, Acinetobacter species, Klebsiella pneumonia, and Escherichia coli

[3],. Traditionally, respiratory viruses have been given minimal attention as a cause of hospital-acquired infection. Although several previous investigators reported on the role of respiratory viruses, those studies were mainly confined to patients with hematologic malignancy, or hematopoietic stem cell or solid organ transplant recipients–[13]. Also, these studies included both upper respiratory tract infections and lower respiratory tract infections, and did not distinguish between hospital-acquired and community-acquired infections. Hospital-acquired respiratory viral infections, including influenza virus,, human respiratory syncytial virus,, human metapneumovirus, and SARS-coronavirus outbreaks, have been demonstrated previously in non-immunocompromised patients as well as immunocompromised patients.

In recent years, the use of molecular diagnostic methods, especially the polymerase chain reaction (PCR) assays, has improved the ability to detect respiratory viruses in clinical specimens, including newly discovered respiratory viruses such as human metapneumovirus, human coronaviruses NL63 and HKU1, and bocavirus,. Several previous investigations that compared PCR with conventional methods (viral culture, antigen detection, and serological assays) for virus identification showed that the incidence of viral infection has been considerably underestimated in the absence of PCR,,. Using multiplex reverse-transcription PCR methods, we previously showed that viral infection is as common as bacterial infection in adult patients from the community with severe pneumonia requiring ICU admission.

Excluding influenza infection, to the best of our knowledge, no investigation has been focused on the role of respiratory viruses as a cause of HAP. The greater understanding of the distribution and role of viral infection might provide new insight into HAP. The objective of the current study was to investigate the incidence and distribution of viruses in adult patients with severe HAP requiring ICU admission.

EV-D68 preferentially causes severe respiratory symptoms in children and adults that have a prior history of asthma. Thus, in addition to naïve mice, HDM-sensitized and -challenged mice also been studied. In mice with allergic airways disease, EV-D68 enhances allergen-induced type 2 inflammation with increased expression of lung IL-5, IL-13 and Muc5ac and augmentation of bronchoalveolar lavage fluid eosinophils and airway responsiveness.

Human rhinoviruses (HRV) are classified into three species (A, B and C) within the genus Enterovirus of the family Picornaviridae. HRVs mainly cause upper respiratory tract infections. However, they can also cause lower respiratory infection and are associated with exacerbations of chronic pulmonary diseases, such as asthma, chronic obstructive pulmonary disease and cystic fibrosis.

Viral persistence has been described for several Enterovirus species, and it was linked to clinical entities, e.g. persistent infection with poliovirus is associated with post-polio syndrome and persistent infection with Coxsackievirus is associated with chronic myocarditis and dilatative cardiomyopathy. A possible link of persistent enterovirus infection and type 1 diabetes is also strongly suspected because several studies detected enteroviral RNA and/or viral proteins in peripheral blood and/or pancreatic tissue of patients with type 1 diabetes.

HRV infection usually presents as an acute infection with viral shedding of up to 42 days as shown by experimental HRV infection. A recent study followed healthy infants in the first year of life and found that HRV RNA rarely persisted beyond 30 days after HRV infection. Persistent HRV infection has been occasionally described in immunosuppressed patients, namely transplant recipients and patients with hypogammaglobulinemia but to date it is unclear how widespread the phenomenon of HRV persistence is. In fact, in a previous study we found no evidence for HRV persistence in asthmatic children.

The objective of the present study was to identify persistent HRV/enterovirus infections and to investigate virologic and clinical characteristics of these. To address this objective, patients with at least two specimens positive for HRV/enterovirus taken 45 days or longer apart were identified retrospectively and the HRV/enteroviruses were typed in order to determine whether it was an infection with the same HRV/enterovirus type (persistent infection) or a reinfection with a different type.

Human respiratory syncytial virus (RSV) is the major cause of serious respiratory disease in infants and young children, usually manifested as a bronchiolitis with wheezing. RSV also produces significant morbidity and mortality in elderly and immune compromised adults. Most infants are infected by 2 years of age, with the incidence of severe disease peaking between 6 weeks and 6 months. RSV regularly re-infects older children and adults, causing colds and, in patients with chronic lung disease, exacerbations of asthma or COPD. As noted above, infants experiencing community RSV infection suffer from asthma-type symptoms like cough and wheeze which resolve by 13 years of age. However, infants with severe RSV bronchiolitis requiring hospitalization may have an increased frequency of asthma in later childhood.

Human RSV is a member of the Pneumoviridae family, Orthopneumovirus genus, along with closely related Orthopneumoviruses, including bovine RSV, ovine RSV and pneumonia virus of mice (PVM). Orthopneumoviruses are enveloped viruses with the genome organized with a negative-sense, non-segmented RNA, which is about 15,000 nucleotides in length and encodes for 11 viral proteins. A two-step process is used for RSV entry, a viral glycoprotein-mediated attachment step and a fusion step through binding of the viral fusion protein (F protein) to the receptor nucleolin. In the lower airway, the airway epithelium is the primary infection site and macrophages in the lung may be infected as well.

The clinical entity of “atypical” pneumonia was recognized in the 1930s many years before the etiological agent was established (McCoy, 1946). The term separated this entity of pneumonia from classical pneumococcal pneumonia due to its lack of response to available antibiotics and the distinct clinical presentation without typical lobar pneumonia and a less severe disease course. That is why the term “walking pneumonia” has been introduced to denote this mild form of pneumonia.

It was in a patient with “atypical” pneumonia in 1944, where Mycoplasma pneumoniae was first isolated from sputum in tissue culture by Eaton et al. (1944). At that time, it was believed to be a virus because it was resistant to penicillin and sulfonamides and passed through bacteria-retaining filters. Experiments with Marine recruits and adult prisoners demonstrated that the so-called Eaton agent caused lower respiratory tract infections in humans (Chanock et al., 1961a,b). In 1963, it was first cultured on cell-free medium and classified as M. pneumoniae (Chanock et al., 1962; Chanock, 1963). Today we know that mycoplasmas are prokaryotes that lack a cell wall and represent the smallest self-replicating organisms (Figure 1). With a size of 816,394 base pairs, the genome of M. pneumoniae is at least five times smaller than that of Escherichia coli (Himmelreich et al., 1996). The absence of a cell wall and the specialized attachment organelle facilitate close contact with the host respiratory epithelium, which supplies the bacterium with the necessary nutrients for its growth and proliferation.

Mycoplasma pneumoniae causes both upper and lower respiratory tract infections, with community-acquired pneumonia (CAP) as the major burden of disease. Although M. pneumoniae infections are generally mild and self-limiting, patients of every age can develop severe and fulminant disease (Kannan et al., 2012). M. pneumoniae can also cause extrapulmonary manifestations that affect almost every organ (Narita, 2010).

In children, M. pneumoniae infections were first reported in 1960 when 16% of 110 children with lower respiratory tract disease were tested positive by a fourfold rise in antibody titers against the Eaton agent (Chanock et al., 1960). To date, it is known that the incidence of M. pneumoniae infections is generally higher in children than in adults (Foy et al., 1979). This review focuses on the characteristics of M. pneumoniae infections in children, and discusses simple clinical decision rules that may further aid clinicians in identifying patients at high risk for M. pneumoniae CAP.

Although CAP is the major burden of disease, milder clinical presentations of M. pneumoniae respiratory infections may be much more common than CAP. These include acute bronchitis and upper respiratory tract infections (Esposito et al., 2000, 2002). M. pneumoniae could be detected by PCR and/or serology in 24% of non-streptococcal pharyngitis cases (Esposito et al., 2002).

It is estimated that 3–10% of children with M. pneumoniae respiratory infection develop CAP and that <5% of CAP cases are severe enough to require hospitalization (Waites and Talkington, 2004). Between 1963 and 1975, M. pneumoniae was detected by culture of respiratory specimens and/or a fourfold titer rise in complement fixation test (CFT) in 15–20% of radiologically confirmed CAP cases in Seattle, U.S. (Foy et al., 1979). In subsequent etiological studies, M. pneumoniae accounted for 4–39% of the isolates identified by PCR and/or serology in children with CAP admitted to the hospital (Juven et al., 2000; Principi et al., 2001; Baer et al., 2003; Michelow et al., 2004). M. pneumoniae was first reported as the most common bacterial cause of CAP in children requiring hospitalization in a U.S. multicenter study from 2011 to 2012 in Nashville and Salt Lake City (Jain et al., 2015). In this study, M. pneumoniae could be detected by PCR in 178 (8%) out of 2179 cases with CAP, whereas Streptococcus pneumoniae was found in 79 cases (4%).

Manifest upper and/or lower respiratory tract infections with M. pneumoniae occur at all ages (Foy et al., 1979). Recent observations have indicated that M. pneumoniae has also a relatively high prevalence in the respiratory tract of children <5 years (Principi et al., 2001; Gadsby et al., 2012). M. pneumoniae CAP, however, was reported to be most frequent among school-aged children from 5 to 15 years of age, with a decline after adolescence and tapering off in adulthood (Figure 2) (Foy et al., 1979). This notion was corroborated in the recent CAP study in the U.S., where M. pneumoniae was detected significantly more frequent in children ≥5 years of age than in younger children (19% vs. 3%) (Jain et al., 2015).

In addition to the presentation at school-age, children with CAP due to M. pneumoniae have been found to present with a significantly longer duration of fever compared with other children with CAP (Fischer et al., 2002). Other symptoms that may be associated with M. pneumoniae CAP are the absence of wheeze and the presence of chest pain (Wang et al., 2012). However, there is still a paucity of high quality data regarding clinical signs and symptoms associated with M. pneumoniae infections. A recent Cochrane review therefore concluded that the absence or presence of individual clinical symptoms or signs cannot be used to help clinicians accurately diagnose M. pneumoniae in children and adolescents with CAP (Wang et al., 2012).

Pathogenic effects in the respiratory tract may be caused by M. pneumoniae either directly (by active infection), indirectly (by infection-induced immune mechanisms), or both (Narita, 2010). M. pneumoniae causes direct injury through the generation of activated oxygen. A potential candidate protein of M. pneumoniae that may be involved in causing direct damage to the respiratory tract is a pertussis toxin-like protein termed Community-Acquired Respiratory Distress Syndrome (CARDS) toxin (Kannan and Baseman, 2006; Becker et al., 2015). A recombinant version of the CARDS toxin has been shown to bind with high affinity to surfactant protein A and to exhibit mono-ADP ribosyltransferase and vacuolating activities, which causes disruption of the respiratory epithelium in animal models (Kannan and Baseman, 2006).

In addition to the direct damage resulting from infection by M. pneumoniae, the immunological response following infection generates inflammatory reactions that may cause pulmonary and extrapulmonary symptoms. More severe symptoms of CAP have been observed in older children and adolescents (Waites and Talkington, 2004). This suggests that the age-dependent magnitude and nature of inflammatory responses in childhood may be a major factor contributing to the development of M. pneumoniae-associated disease, similar to what is observed, e.g., in infectious mononucleosis or rheumatic fever. In fact, the severity of M. pneumoniae CAP in children was closely associated with increased concentrations of interleukin (IL)-8 and IL-18 in acute phase serum and pleural fluid samples (Narita and Tanaka, 2007). In addition, it has been demonstrated that cell-mediated immunity contributes to the pathogenesis of M. pneumoniae CAP, as it was shown that the severity of CAP correlated positively with the size of a cutaneous induration following intradermal injection of M. pneumoniae antigens (Mizutani et al., 1971). This study described 20 patients with CAP, of which 19 were children 4–15 years of age, diagnosed by a significant rise in antibody titers against M. pneumoniae with CFT. The strongest skin reactions were seen in patients with severe CAP.

From October 2010 to September 2013 (season 1: Oct 2010–Sep 2011, season 2: Oct 2011–Sep 2012, season 3: Oct 2012–Sep 2013), all patients who fulfilled the following inclusion criteria were enrolled: i) admission to a participating PICU with suspected acute respiratory infection (ARI) of the upper or lower respiratory tract, with ARI-related symptoms (for example, coryza, cough, or sore throat); ii) age at PICU admission due to ARI at least 1 month and below 17 years of age; iii) parental written informed consent. Enrolled children with PCR-confirmed influenza were classed as influenza-associated ARI.

The PICU physician documented demographic characteristics, underlying chronic medical conditions, influenza vaccination status, diagnostic findings, ARI-associated diagnoses and complications, treatment, duration of hospital and PICU stay, and outcome in a structured questionnaire. A respiratory sample, usually a flocked nasopharyngeal or pharyngeal swab, was collected on the day of PICU admission for PCR-confirmation of influenza. Microbiological testing for bacteria or fungi was at the discretion of the PICU physician; pathogens detected at usually sterile sites or in tracheal aspirates were classified as bacterial or fungal co-infection.

Identification of causative micro-organisms in childhood CAP remains an ongoing challenge, affected by both the type of clinical specimens obtained and the testing method used. Previous studies have used a variety of specimens to identify the causative pathogen for childhood pneumonia, including bronchoalveolar lung fluid, blood, nasopharyngeal aspirates, nasopharyngeal swabs and pleural fluid (for complicated cases).3 5 A variety of respiratory viruses and bacteria are associated with childhood CAP in developed countries9–21 (table 1). Other pathogens such as fungi including endemic mycoses are less common causes of CAP.22

Pneumonia is the leading cause of hospitalization in developed countries and is associated with a high mortality rate worldwide. The prevalence and mortality rate of pneumonia is particularly high in underdeveloped countries having poor healthcare resources and poor quality of sanitation. Understanding the incidence rate of pediatric pneumonia and identifying the pathogen for community-acquired pneumonia (CAP) forms the basis for diagnosis, therapeutic treatment, and intervention. In a study of 154 children hospitalized for CAP in the United States, between January 1999 and March 2000, a period prior to the universal use of pneumococcal conjugate vaccine (PCV), Michelow et al., identified a bacterial pathogen in 60% of cases of pneumonia. The Streptococcus pneumoniae bacteria strain was identified in 73% of bacterial pathogen. S. pneumoniae was a common pathogen of CAP at that time. The causal pathogen of CAP was very different in a survey of children under the age of 18 years who were hospitalized for pneumonia in designated hospitals in southern and Western part of US, between January 2010 and June 2012, a period after the universal use of PCV. In this latter survey, a viral or bacterial cause was identified in 81% of cases, with more than one kind of virus detected in 66% of cases. An exclusive bacterial cause was identified in only 8% of cases, with both bacterial and viral causes identified in 7% of cases. Therefore, by 2012, viruses had emerged as more significant pathogens of pneumonia than bacteria.

A multicenter retrospective study undertaken in Korea between 1996 and 2005 identified invasive bacterial infection as the most prevalent cause of pneumonia in children, with S. pneumoniae being the most common pathogen for bacterial pneumonia, meningitis and bacteremia among children 3 months to 5 years of age. S. pneumoniae was also reported as a major pathogen for pediatric empyema in a multicenter survey conducted in Korea between 1999 and 2004. A single center in Korea identified the cause of lobar/lobular pneumonia among children 2 to 15 years of age, between June 2006 and May 2008. Mycoplasma pneumoniae (50.7%) was the most common organism in all age groups and bacteria was 5.9%. S. pneumoniae (88.9%) was the major cause of bacterial pneumonia including mixed infection.

S. pneumoniae and Haemophilus influenzae were major bacterial pathogens of pneumonia. S. pneumoniae had caused 11% of deaths in children aged under 5 years globally in the pre-PCV era. As medical costs associated with pneumonia are substantial, there have been continuous worldwide efforts to reduce the rate of pneumoniaassociated morbidity and mortality, including the use of vaccines. Changes in complications, morbidity, and the rate of pneumonia of PCV use were analyzed in the United States but not in Korea. The aim of the study was to describe the epidemiology of CAP in Korea, including yearly trends in incidence, frequency of viral and bacterial pathogens and the impact of PCV.

The respiratory syncytial virus (RSV) is an important cause of acute respiratory tract infection in young children. The common respiratory manifestations are bronchiolitis, pneumonia, bronchitis, and croup. By the age of 2 years, approximately 90% children are infected by RSV, and approximately 45% of the RSV-related hospital admissions occur in children younger than 6 months.

As in other common viral infections, RSV may be associated with neurological manifestations, including seizures, encephalopathy, extraocular movement disorder, and central apnea. Although the pathogenesis of the neurologic complications are not fully understood, the possible contributions of immune-related cytokine responses, less well-proven direct invasion of virus particles, and brain stem-related mechanisms for respiratory control have been recognized.

The incidence of RSV-associated neurologic complications varies across studies and study populations. Sweetman et al. reported the incidence of RSV-associated neurologic complications to be 1.2%, which did not include cases with simple febrile seizure, and Ng et al. reported the incidence of RSV-associated encephalopathy to be 1.8%. In a pediatric intensive care unit (PICU)-based study, Kho et al. reviewed the cases of children between birth and 2 years of age with acute neurological symptoms and identified 39.1% of them as RSV-positive. In contrast, Millichap and Wainwright reported that only 1% of the RSV-positive patients were admitted to the PICU with neurologic complications. In a study comparing the common viruses responsible for febrile seizure, Chung and Wong revealed that the incidence of febrile seizure for RSV was 5.3%, and among them, complex febrile seizure was observed in 13.6% of cases, which was lower than the percentage of such cases for influenza and adenovirus.

In a previous study in Korea during November 2002 and June 2007, Yoon et al. reported that the overall incidences of RSVassociated neurologic complications and seizures were 7.1% and 1.9%, respectively. Another study in Korea by Park et al. reported that the incidence of RSV-associated encephalitis was 0.08%. The same study showed that RSV-associated brain magnetic resonance imaging (MRI) findings may resemble those of other viral and limbic encephalitis, and no abnormality on diffusion-weighted imaging (DWI) was found.

Although the study by Yoon et al. was the first and the only study on the overall RSV-associated neurologic complications in Korea, further analysis of patients with seizure based on presumed causes was needed. In addition, most of the previous studies were regarding encephalopathy or relatively severe patients, and did not focus on overall features of RSV-associated seizures. It has not yet been fully determined whether the clinical characteristics of the RSV-associated febrile seizure are similar to those of the general febrile seizure, and whether RSV-associated afebrile seizures are benign situation-related seizures, as reported by Miyama and Goto. Based on this background, we aimed to investigate the RSV-associated neurologic manifestations in children who presented with seizures. Furthermore, we report a transient DWI change in a young child with acute encephalopathy symptoms exhibiting seizures.