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Acute bronchitis is an inflammation of the large airways that is characterized by cough and/or sputum that usually lasts one to three weeks. It is one of the most common illnesses among outpatients, and many patients receive antibiotic therapy [1–3].
Traditionally, viruses have been considered the main causative agent of acute bronchitis, possibly explaining the limited benefits of antibiotics [3–5]. However, data regarding the causative microorganisms are still limited. In previous studies, viruses were isolated in 8–23% of community-based cases, not frequently enough to conclude that viruses are the main causal agents for acute bronchitis. Macfarlane et al. identified viruses in only 19% of patients, while typical and atypical bacteria were identified in 25.9% and 23.7% of patients, respectively. In other studies, bacteria were detected in sputum samples in 45% of acute bronchitis patients [8, 9]. In addition, several authors suggested that some patients with acute bronchitis had mixed infections involving both viruses and bacteria. However, the exact prevalence and clinical characteristics of mixed infections have not been well studied. Moreover, it is not clear which subgroup of patients with acute bronchitis could benefit from antibiotic treatments. Recent big data from the UK show that antibiotics substantially reduce the risk of pneumonia after acute bronchitis, particularly in elderly people in whom the risk is highest.
Therefore, in the present study, we aimed to investigate the frequencies and characteristics of viral, bacterial, and mixed infections in acute bronchitis in the community. We also hypothesized that the frequencies of these etiologies would vary with underlying lung co-morbidities and age.
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.
Adult patients with acute bronchitis were prospectively recruited at 31 Korean hospital outpatient departments and primary clinics between July 2011 and June 2012 (6 university-affiliated teaching hospitals, 5 non-teaching community hospitals, and 20 primary clinics). Sputum samples for Gram stains, conventional cultures, and polymerase chain reaction (PCR) were collected from each patient before any medications (including antibiotics) were prescribed. Medications were chosen at the physicians’ discretion. The study protocol was approved by the Institutional Review Board of Hallym University Sacred Heart Hospital (the principal institute, 2011-I049) and each participating hospital. All participants provided informed written consent.
Patients were eligible if they were ≥18 years old and visited the outpatient clinic because of cough (duration < 1 month) with sputum production. Acute bronchitis is a clinical diagnosis, and therefore, a wrong diagnosis is possible. Coughing symptom may have almost all respiratory illnesses as a differential diagnosis. However, symptoms such as sputum production, after carefully discriminating from postnasal drip, could also lead to a diagnosis of lower respiratory inflammation. Patients with typical upper respiratory infection (URI) and symptoms of influenza or influenza-like illness (ILI) during the epidemic period were excluded by participating physicians. We tried to rule out URI by conducting detailed medical interviews, throat examination, and by auscultation. Typically, URI was defined as an infection affecting patients presenting with key symptoms such as sore throat, and nasal symptoms (nasal obstruction, runny nose) with cough. ILI was defined as an abrupt onset of fever with non-productive cough or sore throat. The period of the influenza epidemic was determined by means of a national respiratory virus surveillance system which was broadcast weekly. In some cases, chest radiographs were done at the investigating physician’s discretion, in order to rule out pneumonia. Other exclusion criteria were: 1) history of antibiotic treatment < 7 days before the visit, 2) exacerbation of chronic lung disease within 6 months, 3) active lesion on the chest or paranasal sinus radiographs (when available), 4) immunocompromised status, and 5) confirmed alternative cause for the cough (e.g., drugs [newly started on angiotensin-converting enzyme inhibitors], pneumonia, allergic rhinitis, sinusitis, or gastro-esophageal reflux). Stable chronic lung disease patients were not excluded.
A common severe clinical manifestation of patients infected with influenza A virus subtype H1N1 is severe ARDS. During recovery, pulmonary fibrosis is the major pathological change observed during recovery. In addition, abnormal pulmonary function is manifested as decreased diffusion function and restrictive ventilatory disorder. There is precedence for long term negative effects from pulmonary infection, as viral pneumonia-caused ARDS is a typical manifestation of severe acute respiratory syndrome (SARS) infections. Specifically, SARS patients presented with decreased pulmonary diffusion function during recovery [7–10]. Furthermore, a study by Neff et al revealed that among 16 survivors of severe ARDS, 9 had abnormal pulmonary function, while four presented with obstructive ventilatory disorder and four with restrictive ventilatory disorder. In addition, a study by Li et al found the incidence of obstructive ventilatory disorder and restrictive ventilatory disorder was approximately 30% following infection. Interestingly small airway dysfunction was also reported in a small number of SARS patients during recovery. This is the first study to assess the long term effects of mild influenza A virus subtype H1N1.
Pulmonary diffusion disorder during H1N1 influenza infection recovery is similar to ARDS, however, a large proportion of patients recovering from influenza infection also show signs of small airway obstruction. In addition, this study reveals that approximately half of patients recovering from H1N1 influenza had abnormal pulmonary function, one third had diffusion dysfunction, a third had small airway obstruction, and another third presented with decreased ventilation function. The pathological changes following H1N1 influenza-induced severe pneumonia include three types: diffuse alveolar lesion, necrotizing bronchiolitis and widespread pulmonary hemorrhage. This suggests that necrotizing bronchiolitis is likely to be the pathological basis of small airway obstruction. Here, we found 25% of patients had respiratory tract infection symptoms including cough, expectoration, or gasping, while 41.7% of patients had difficulties in performing general physical activities. Interestingly, the observed clinical symptoms correlated with patients having greater than three abnormal pulmonary function indices. In this study, we did not identify a relationship between abnormal pulmonary function of patients with H1N1 influenza and the severity of pulmonary function impairment during hospitalization, possibly because mild H1N1 influenza patients and a small number of H1N1 influenza patients were involved. This is consistent with previous studies investigating the effects of ARDS on pulmonary function [14, 15]. Several variables were not included in this study that may have also had an effect on the recovery of pulmonary function following influenza infection, including age, obesity, gender, recovery time, heart function, and the amount of physical rehabilitation exercise.
While some patients still have respiratory tract infection symptoms and limited physical activity one year after recovering from H1N1 infection. While no correlations were drawn between severity of infection and these symptoms, care should be paid to these patients, including follow-up pulmonary function tests to guide patients to the proper rehabilitation treatment, with the ultimate goal of improving patients’ quality of life.
Contagious upper airway infections in dogs occur regularly and are most commonly caused by canine parainfluenza virus (CPIV) or Bordetella bronchiseptica, amongst other agents. This clinical syndrome has also been named infectious tracheobronchitis (ITB), canine infectious respiratory disease (CIRD), “kennel cough” or “kennel croup”, so named due to its occurrence in environments where many dogs live or stay close together for shorter periods of time. Characteristic clinical signs include a self-limiting paroxysmal cough lasting for up to two weeks, which usually resolves without treatment. In Norway, immunisation against CIRD is performed using live attenuated viruses, annually with CPIV and every third year against canine adenovirus type 2 (CAV-2). However, in spite of vaccination, outbreaks of CIRD remain common. Some dogs with CIRD will develop serious pneumonia due to an immature immune system or other causes of immunodeficiency. Occasionally, bacteria such as Streptococcus equi subsp. zooepidemicus can cause fatal pneumonia.
This case-report describes the first canine outbreak of haemorrhagic pneumonia in the Nordic countries caused by S. equi subsp. zooepidemicus. Most of the animals in the pack of athletic sled dogs showed symptoms of CIRD with three dogs demonstrating symptoms of severe peracute infection. One sled dog died while two were successfully treated, rehabilitated and returned to competition. To the author’s knowledge, this is the first report documenting the chronology from onset of clinical signs, through convalescence to complete recovery for peracute haemorrhagic pneumonia in dogs. The vaccination regimen related to season and extreme training will also be discussed.
This form is seen in infants and children. With improved control of tuberculosis in western societies, however, more people reach adulthood without exposure, and primary patterns of disease are being seen with increasing frequency in adulthood and represents about 23–34% of all adult cases of tuberculosis.
Although primary tuberculosis typically presents with radiographic manifestations, chest radiograph may be normal in 15% of cases. Lymphadenopathy is the most common manifestation of primary tuberculosis in children and occurs with or without pneumonia. In adults hilar or mediastinal lymphadenopathy is less common declining to about 50% of cases in the older population. Pleural effusion occurs in children, who usually have parenchymal or nodal disease, or in teenagers and young adults, when it is frequently isolated.
Primary infection with EBV occurs early in life and presents as infectious mononucleosis with the typical triad of fever, pharyngitis, and lymphadenopathy, often accompanied by splenomegaly. Mild, asymptomatic pneumonitis occurs in about 5–10% of cases of infectious mononucleosis. The CT manifestations of EBV pneumonia are similar to those of other viral pneumonias. The findings usually consist of lobar consolidation, diffuse and focal parenchymal haziness, irregular reticular opacities, and multiple miliary nodules or small nodules with associated areas of ground-glass attenuation (“halo”).
Pertussis, also known as whooping cough, is an acute respiratory tract infection caused by Bordetella pertussis. Although the incidence rate of pertussis has significantly decreased following the wide use of pertussis vaccine, B. pertussis infection is continuously occurring as a small outbreak even in several developed countries with high vaccination coverage (1-4). There has been the resurgence of reported pertussis cases primarily in infants younger than 1 yr old, especially less than 3 months of age, in adolescents and young adults worldwide (5, 6). The possible causes of increased incidence in adolescents and adults include waning of vaccine immunity, adaptation of circulating B. pertussis strains, development of diagnostic methods, and active surveillance due to increased awareness of pertussis (7-9). Household contact with infected adolescents and adults also becomes the major source of pertussis infection in infants who are not fully immunized, and this problematic circulation may consequently threaten overall public health (10, 11).
The epidemiological characteristics of pertussis can vary depending on the definition of case, diagnostic method of confirmed case, national reporting system, network organization for epidemiological investigation, and the local vaccination schedule. National immunization program (NIP) of Korea consists of three primary series of diphtheria-tetanus-acellular pertussis vaccine (DTaP) at 2, 4, and 6 months, followed by a first booster at 15-18 months and a second booster between 4 and 6 yr of age. Recently, a tetanus toxoid, reduced diphtheria and acellular pertussis (Tdap) booster vaccine in adolescents aged 11-12 yr is added to Korean NIP in 2012. The vaccination rate of primary DTaP continues to be approximately 94% (12, 13), and there is a mandatory notification system in Korea. An annual average of about 11.5 cases of pertussis has been reported to the Korea Center for Disease Control and Prevention (KCDC), however, the reported cases of pertussis have increased since the 2000s. In addition, the KCDC reported that the incidence of pertussis was markedly increased (more than about 5.5 times) in 2009, compared to the previous (14). Also, the incidence of pertussis in 2011 was more than two times compared with the incidence in 2009 (15). We may predict the substantial outbreak in the future in our country.
Given the importance of accurately determining the epidemiological features of infant pertussis and the lack of reliable existing data in Korea, this study was conducted to describe the clinical characteristics of laboratory confirmed cases less than 1 yr of age and to evaluate the relative importance of family members on infants who are vulnerable to B. pertussis transmission.
The study was conducted in the PICU of Children’s Hospital Béchir Hamza of Tunis. The PICU is in a university-affiliated children’s hospital and provides intensive care services to a national pediatric population of 850 000 children less than 15 years old. The hospital has 360 beds, and the PICU has 16 beds (500 admissions/year).
Pneumonia: If a child presents with severe malnutrition with any sign of pneumonia (any of the WHO defined signs of pneumonia or severe pneumonia or radiological pneumonia) would be considered as pneumonia.
A child with severe malnutrition with cough or respiratory difficulty with the presence of end point consolidation or other infiltrates, or pleural effusion in chest X-ray defined by WHO, as assessed by a qualified radiologist.
Clinical characteristics of pneumonia: According to WHO, a child with a history of cough with respiratory difficulty or age-specific fast breathing or lower chest wall indrawing will be defined as pneumonia.
According to WHO, a child with a history of cough and/or respiratory difficulty plus oxygen saturation < 90% or central cyanosis, or severe respiratory distress (grunting, very severe chest in-drawing), or signs of pneumonia with a general danger sign (inability to breastfeed or drink, lethargy or reduced level of consciousness, convulsions), auscultatory findings of decreased or bronchial breath sounds or signs of pleural effusion or empyema will be defined as severe pneumonia.
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.
Pertussis is an acute respiratory illness caused by Bordetella pertussis (B. pertussis). Critical pertussis (CP) is defined as pertussis disease that results in pediatric intensive care unit (PICU) admission or death. It is characterized by severe respiratory failure, important leukocytosis, pulmonary hypertension, septic shock and encephalopathy. Despite intensive care management, it causes substantial morbidity and mortality for children especially among young infants. Resurgence of pertussis in the last 20 years is evident from the Centers for Disease Control (CDC).1 Several reasons for this resurgence have been proposed, including genetic changes in Bordetella pertussis, lessened potency of pertussis vaccines, waning of vaccine-induced immunity, greater awareness of pertussis, and the general availability of better laboratory tests.2 A new resurgence was seen in 2013 in Tunisia even in the presence on a high (98%) coverage of childhood vaccination.3 The purpose of this study was to describe the institutional experience in the management of infants with CP admitted in year 2013 at Children’s hospital Bechir Hamza of Tunis, reporting the relationship between method of presentation, therapies and outcome in order to identify factors associated with death.
All children under 5 years old admitted to these three wards were enrolled according to the following criteria: written parental consent to participating in the study; time from onset of symptoms <14 days, fever (axillary temperature >38.0 °C) or history of fever, and at least one respiratory symptom (dyspnea, cough, rhinitis) or abnormal pulmonary auscultation on physical examination.
During the study 50 JIA flares or worsening of JIA activity parameters were observed in 44/70 patients included in at least one of two surveillance periods, and 10 of them (20%) were temporally associated with respiratory infection episodes (7 classified as ILI). In 8 of those episodes we could not identify any other triggering factor possibly associated with the flare (Table 3).
The possible factors associated with the 40 JIA flare episodes not related to respiratory infections were suspension or nonadhearance to medication in twelve episodes, and intercurrent infections in seven episodes: otitis, chickenpox, parotiditis (2), gastroenterocolitis (2) and infection sacroiliitis. In twelve-one episodes there were no identifiable causes for the flares.
There was no significant difference in the total number of flares related to gender, age (< 9 years old and ≥ 9 years old), JIA type of onset (oligoarticular, polyarticular or systemic), use of immunosuppressive therapy, period of surveillance (SV1 or SV2) or administration of influenza vaccine. Flares or worsening of JIA activity parameters associated with ARI were more frequently observed in patients with systemic JIA (5 of the 16 flares that occurred in this group) as compared to patients with polyarticular JIA (2/14 flares, p = 0.03).
Post-infectious bronchiolitis obliterans (PIBO), a syndrome in children most commonly caused by Mycoplasma pneumonia (1, 2) and adenovirus (1) and occasionally Bordetella pertussis (3, 4) is associated with chronic inflammatory and fibrotic lesions of small airways leading to chronic airflow obstruction (5). Treatment is generally supportive therapy and frequently includes glucocorticoids (4–6). In dogs, while many contagious respiratory pathogens cause tracheobronchitis and pneumonia, bronchiolar diseases including PIBO are not well recognized as spontaneous clinical syndromes. Importantly, severe damage to the lung can lead to end-stage and untreatable fibrosis, with most cases in dogs not having a recognizable trigger and thus being termed “idiopathic pulmonary fibrosis.” This report describes a puppy developing PIBO after Bordetella bronchiseptica pneumonia with histologic evidence of small airway changes strongly supporting development of pulmonary fibrosis. Recognizing addressable triggers of fibrotic lung disease could have important implications for delaying progression of end-stage lung lesions.
Demographics and JIA clinical characteristics of the patients are summarized in Table 1.
During the two surveillance periods, 105 ARI episodes were reported: 68 in 44 of 61 (72%) patients during the SV1 and 37 in 26 of 63 (41%) patients during the SV2. We evaluated the data of 9333 child-days in SV1 and 9639 child-days in SV2, 296 (3.1%) and 208 (2.1%) days respectively were contained within an ARI (ARI mean duration:5 days), and 204 and 111 days were subsequent not-at-risk days, leaving 8833 and 9320 days at-risk child-days (including the first day of each ARI) in SV1 and SV2 respectively. This gives an attack rate with 95% confidence interval (95% CI) of 7.6 (5.9-9.8) and 3.9 (2.8-5.5) ARI per 1000 child-days in SV1 and SV2 respectively. Twenty-eight of the 105 episodes (26.6%) were characterized as ILI: 23 during SV1 and 5 during SV2.
ARI and ILI episodes were significantly more frequent in SV1 than in SV2 (p < 0,01), even when adjusting for JIA type of onset, age (younger or older than 9 years), disease activity, use of immunosuppressives or DMARDs or administration of influenza vaccine.
There was no significant difference (p = 0.1) in the frequency of ARI episodes between vaccinated and unvaccinated patients. However, ILI episodes were significantly more common in unvaccinated patients (p = 0.02), although this difference was not maintained after adjusting for the other variables described above (p = 0.96). Of 33 naso-pharyngeal samples collected during the study, 20 (60.6%) were positive for at least one respiratory virus and viral co-infections were detected in 20% of the positive samples (Table 2).
Considering SV1 and SV2, a total of 28 ILI episodes were reported. Positive influenza samples were obtained in 5/14 ILI episodes of SV1 (35%) and in 1/7 ILI episodes during SV2 (14%), in a patient included prior to influenza vaccination. Although the most commonly detected virus during ILI episodes was influenza, detected in 7/28 (25%), HPIV (1 and 3) and HAdv were detected in one ILI episode each (Table 2).
All patients with ARI and ILI had favorable outcomes, except for one patient who developed acute otitis media and pneumonia after an ILI episode caused by HPIV infection.
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.
Post-mortem examination revealed epistaxis and haemorrhagic frothy fluids in the trachea and bronchial airways on cut sections. Haemorrhages were present in the thymus, epicardium, intercostally, and in the pleural space 200 mL of uncoagulated blood were present. The lungs were congested, wet, consolidated and diffusely to cavernous haemorrhagic, these changes being more severe in the left lung lobes (Figure 1).
Histopathology of the lungs revealed a subacute necrotising suppurative pneumonia, with haemorrhagic, often cavernous areas in the lungs and intra-lesional gram-positive cocci. A large number of macrophages with phagocytosed erythrocytes were present (Figures 2 and 3). A subacute pleuritis was also seen.
Streptococcus equi subsp. zooepidemicus was isolated in pure culture from the lung tissue with identification based on morphology, microscopy, Lancefield grouping (Streptococcal grouping kit, Oxoid, Basingstoke, Hampshire, England) and biochemical testing. Properties included β-haemolytic colonies on bovine blood agar, gram-positive, katalase negative cocci belonging to Lancefield group C. Glucose, lactose, and sorbitol were fermented, trehalose was not. The isolate was also tested by using API20STREP (bioMérieux®, Lyon, France) with the same conclusion.
Toxicological diagnostic screening of the liver tissue showed no evidence of anticoagulant poisons.
We conducted a case-control study in which we prospectively screened all severely malnourished children aged <5 years admitted to the Dhaka Hospital of International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b) from April 2015 to December 2017. The Dhaka hospital of icddr,b provides care and treatment for approximately 140,000 patients annually mostly from low-socioeconomic urban or peri-urban communities in Dhaka. Sixty percent of patients are aged <5 years admitted with diarrhea only or with diarrhea and other co-morbidities. According to data from Dhaka hospital of icddr,b during 2017, among 6,035 children <5 years with diarrhoea and other co-morbidities around 23% (1,408) were severely malnourished, 24% (1,453) children had pneumonia and 6% (354) had both SAM and pneumonia.
During April 2015 to March 2017, we enrolled children as cases if they were aged <5 years (0–59 months), severely malnourished (i.e., WHO criteria <-3 z score from the median of weight for height/length, weight for age, or nutritional edema) and met WHO clinical criteria for pneumonia. We also enrolled children as cases if they had SAM, cough, and radiological pneumonia. During February 2016 to December 2017, we enrolled SAM children with no pneumonia on admission as controls if they did not have any additional respiratory symptoms and/or signs of pneumonia as classified by the WHO within the past 10 days prior to admission. The only match that was done for our case and control was severe malnutrition and it was done at recruitment. The information was taken from the parents/caregivers. Children who might have chance of migration to outside Dhaka city within a one-month period from admission were not enrolled in the study as we followed-up with enrolled participants during that period to evaluate the death outcome of children with pneumonia related to different viral etiology. Information on chance of migration was validated from the statement of parents/ caregivers.
Clinical monitoring of infected chicks reveals at first, apparent respiratory symptoms beginning at day 2 post-inoculation (dpi). Respiratory clinical signs were predominant in all of the inoculated groups and were intense and more severe until 7 dpi, with no clear differences in the pathogenicity of the three strains. The most prominent clinical signs were characterized by gasping, depression, sneezing, difficulty in breathing, cough, pulmonary and tracheal rales, with high scores were reported for all the tested strains with clinical score of 108, 126 and 140 for IBV/RA, IBV/MN and IBV/TU strain respectively, (Tables 1, 2 and 3).
Nasal discharge and watery eyes were also observed but were transient in some of infected by IBV/RA and IBV/MN chicks. These clinical symptoms were persisted in all groups until 12dpi. The birds infected by IBV/MN and IBV/TU appeared lethargic, reluctant to move (Fig. 1), whereas, chicks infected with by IBV/RA were not as apathetic. At autopsy, all infected chicks that were killed at 5 dpi to prevent their suffering were examined for the macroscopic lesions in the trachea, lung and kidney. These gross lesions consisted in hemorrhagic tracheitis, mucosal congestion and catarrhal exudates that mainly progressed. For the three strains used, the signs were observed in the most infected chicks with dominance in the lungs that were hemorrhagic and sometimes cyanotic at one lobe. Therefore, samples were taken at 14 dpi just for a macroscopic examination of organs to confirm whether the absence of clinical signs is correlative with the gross lesions. Whereas, gross lesions of kidney, were not observed in all inoculated chicks. During the experiment, the non-infected control group stayed normally without clinical signs or gross lesions. The statistical analysis was not performed as the three tested strains are phylogentically related to each other and the difference in clinical and tissues scores is not very significant.
In order to test the different between mild and severe HAdV pneumonia cases, comparison of clinical manifestations was undertaken. As shown in Table 3, successful HAdV typing was performed in 174 cases, the results showed no significant differences in clinical manifestations such as cough, wheezing, vomiting, and skin rashes between the mild pneumonia cases and severe pneumonia cases. However, in the severe pneumonia children, severe disease performances such as the shortness of breath, cyanosis, labored breathing, listless, antifeedant, and breathing machine support were noted. The incidence of diarrhea in children with severe pneumonia was higher than that in mild pneumonia children. Besides, compared with mild pneumonia children, children with severe pneumonia showed younger age, longer fever time, higher incidence of fever, and longer hospital stay. No significant difference was observed between the two groups in the percentage of white blood cells and neutrophils, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).
As illustrated in Table 4, the clinical symptoms of mild pneumonia and severe pneumonia in 70 cases of single HAdV infection were found to be similar to the clinical symptoms of mild pneumonia and severe pneumonia in 174 cases of HAdV infection. That is to say, whether it is a single or mixed HAdV infection, severe adenovirus pneumonia is characterized by a small onset age, longer duration of fever, longer hospitalization, and prone to diarrhea. However, among HAdV single infection, children with severe pneumonia were more likely to have wheezing symptoms. According to adenovirus serotype, the 174 patients were divided into 5 groups. Among the children with severe pneumonia, HAdV-7 was more common, followed by HAdV-3. HAdV-1 and HAdV-2 were mostly found in children with light pneumonia. The average viral load of different serotypes were HAdV-1: 2.45 ± 1.89, HAdV-2: 2.66 ± 1.47, HAdV-3: 3.38 ± 2.17, HAdV-7: 3.78 ± 2.28, other types: 2.39 ± 1.55 (log10 copies/μL), and the difference was statistically significant (K-W test, P = 0.015). Pairwise comparison showed that the average viral load of HAdV-7 was higher than that of other types except the HAdV-3, and the difference was statistically significant. No significant difference was noted in other pairwise comparison.
The demographic and clinical features of the 157 RSV patients are shown in Table 2. Over half of the RSV patients (52.2%) were less than one year old, 87.9% were less than 2 years old and all were less than 4 years old (Fig. 1). Figure 2 shows the monthly frequency of RSV patients over the one-year study period. One hundred and forty-four (97.1%) of the RSV patients were detected between May and October, with a clear peak between June and September, corresponding to 84.7% of annual RSV cases. Two RSV patients (1.3%) died.
One hundred and thirty-two (84.1%) RSV patients had pneumonia, which was significantly more frequent than in RSV-negative patients (64.2%, p < 0.001) (Table 2). When stratified by age group (Fig. 1A), no significant difference (p > 0.05) was observed, except for the 2 to <3-year-old group (87.5% with pneumonia in RSV-positive, 57.6% with pneumonia in RSV-negative, p = 0.035).
Severe pneumonia was negatively associated with RSV infection (40.7% of severe pneumonia in RSV-negative patients and 29.3% in RSV-positive patients, p = 0.014) (Table 2). When considering RSV patients with pneumonia, the proportion of severe pneumonia (35%) was similar in all age groups (Fig. 1B), whereas in RSV-negative patients with pneumonia, severe pneumonia was associated with the one-year-old group (75.6%) in comparison to the other age groups (42.9–57.9%, p > 0.005, Fig. 1B).
Coryza (95.5%), difficulty breathing (87.0%) chest indrawing (74.2%), and abnormal pulmonary auscultation (91.3%) were significantly associated with RSV infection in ARI patients as well as in ARI patients with pneumonia (Table 2, Supplemental data Table S2).
Influenzavirus, Human parainfluenza virus, Human metapneumovirus, Human adenovirus, and Human rhinovirus were significantly more frequent in RSV-negative patients than in RSV-positive patients (p < 0.05), whereas, S. pneumoniae detection was significantly associated with RSV infection (p = 0.016) (Table 2). When stratified by age group, this association was significant only for patients aged between 1 and <2 years old (p = 0.026, Supplemental data Figure S2). There was no apparent association between H. influenzae and RSV infection status.
Among the <2 year olds, half of the RSV patients (57.1%) had received PCV13, with a similar proportion observed in RSV-negative patients (50.3%, p = 0.268).
A previously healthy 2-year-old boy presented with a 1-month history of cough and dyspnea. He had had a mild cough for 1 week before a sudden deterioration in his condition. The dyspnea increased despite treatment, and he was transferred to the Department of Pediatrics at the Asan Medical Center for further management. On arrival, he was apyrexial and tachypneic (respiratory rate, 66/min). Mild subcostal retraction was observed, and coarse breath sounds without crackles were noted on auscultation. Arterial blood gas analysis (ABGA) showed mild hypoxemia. His white blood cell (WBC) count was 14,300/µL, with 55.8% neutrophils and 36.3% lymphocytes. Radiography and computed tomography (CT) of the chest revealed the presence of fine peribronchial ground-glass opacities in both lungs (Fig. 1A and 1B). Blood, bronchoalveolar lavage (BAL) fluid, and sputum cultures were negative for bacteria, viruses, and fungi. A lung biopsy performed on day 3 of admission showed the organizing phase of DAD distributed mainly in the centrilobular area, with destruction and obliteration of bronchioles by fibroblasts (Fig. 1E). The patient was administered intravenous corticosteroids (2 mg/kg/day), followed by oral prednisolone (which was gradually tapered), hydroxychloroquine, and oral cyclophosphamide. His condition gradually improved, although exercise intolerance persisted. At the 1-year follow-up, a repeat CT scan of the chest revealed a decrease in the extent of ground-glass opacities in the affected areas of both lungs (Fig. 1C and 1D).
On using SRT-PCR with MRT-PCR, 53.8% of the community-ARI episodes were diagnosed as panel virus positive (i.e. positive for at least one of the viruses on the MRT-PCR panel used), including 10 (7.7%) influenza virus positive episodes (8A(H3N2), 1A(H1N1)pdm09 and 1 influenza B) and 60 (46.2%) non-influenza panel virus positive episodes. Two viruses were more common than influenza in community-ARI, with 37 (28.5%) episodes positive for rhinoviruses and 13 (10.0%) for coronaviruses (Table 2). There were no co-infections detected by MRT-PCR in either community-ARI episodes or influenza negative inpatient-ARI. However, 5 influenza positive inpatient-ARI episodes were positive for more than one pathogen, including 4 dual-pathogen (influenza A + influenza B, influenza A + rhinovirus, and influenza B + respiratory syncytial virus) and 1 triple-pathogen (influenza A + adenovirus + Coronavirus) episodes. Another 46 inpatient-ARI episodes were positive only for one influenza type/subtype; 23(50.0%), 9(19.6%) and 14(30.4%) of these episodes were influenza A(H3N2), influenza A(H1N1)pdm09 and influenza B respectively. After excluding episodes with multiple pathogens, only 24 inpatient-ARI episodes were positive for non-influenza panel viruses, with 8 (33.3%) and 7 (29.2%) of these being rhinoviruses and coronaviruses respectively; another 70 episodes were negative for all panel viruses. The ratio of influenza negative to influenza positive episodes was 1.8:1, which reflected the intention of our study design to sample non-influenza to influenza episodes in an approximately 2:1 ratio. However, in routinely ordered diagnostic tests for influenza conducted on 6281 TTSH admission episodes during the study period, 11.0% tested positive (354A(H3N2), 118A(H1N1)pdm09, 176 influenza B and 40 influenza A with undefined subtype detected). Using this to adjust for the effect of our inpatient-ARI sampling strategy, we estimated that only 18.0% of inpatient-ARI were positive for a non-influenza virus, and an estimated 71.0% would be negative for all panel viruses, as compared to 46.2% for community-ARI.
Acute respiratory tract infections (RTIs) are the leading causes of outpatient visits and hospitalizations in all age groups, especially during winter and spring. For children under 5 years of age, RTIs are the second leading cause of death. Most acute RTIs in children are caused by respiratory viruses, such as respiratory syncytial virus (RSV), adenovirus (ADV), rhinovirus (RV) and influenza viruses. In addition to viruses, atypical pathogens are major causes of pediatric RTIs. One of the most common atypical pathogens is Mycoplasma pneumoniae (M. pneumoniae), accounting for 10–40% of hospitalized children with community-acquired pneumonia [2, 3]. In addition to M. pneumoniae, the incidence of pertussis in China has significantly increased since 2010. Nevertheless, multiple epidemiological studies have suggested that the incidence of pertussis in China has been significantly underestimated [4, 5]. The early diagnosis of the pathogen is beneficial for the precise selection of medication, which can largely avoid the overuse or even abuse of the antibiotics and improve the clinical care of patients. More importantly, the early diagnosis of contagious pathogens, such as Bordetella pertussis (B. pertussis) and influenza viruses, can enable early isolation of patients, thus reducing the spread of pathogens.
At present, the routine detection methods for respiratory pathogens in China are mostly based on immunological methods, which include the detection of M. pneumoniae and several major viruses, such as RSV, ADV, RV, parainfluenza virus (Para), influenza A virus (FluA) and influenza B virus (FluB). Other respiratory viruses and atypical bacteria, such as Chlamydophila pneumoniae (C. pneumoniae) and B. pertussis, are typically not routinely detected. Given their poor sensitivity and long turn-around time (TAT), immunological methods usually lead to broad-spectrum therapy and have been gradually replaced by molecular-based methods, such as conventional and real-time polymerase chain reaction (PCR), in developed countries [6, 7]. However, most of these molecular tests are technically challenging and require independent spaces, such as pre-PCR and post-PCR rooms, to eliminate the potential risk of cross-contamination, and such requirement limits their applications in China. Therefore, faster, more sensitive and easy-to-use assays for multiplex respiratory pathogen detection are urgently needed.
FilmArray (BioFire Diagnostics, Utah, USA, owned by bioMérieux) is a small, desktop, fully automated multiplex PCR device. The molecular system includes automated nucleic acid extraction, an initial reverse transcription step and multiplex nested PCR, followed by a melting curve analysis. The FilmArray Respiratory Panel (FilmArray RP) is both FDA-approved and CE IVD-marked. The current version of FilmArray RP (v1.7) is able to detect 16 viral and 3 atypical respiratory organisms. The test is performed in a closed system that requires 5 min of hands-on time and 65 min of instrumentation time. Several comparison studies between FilmArray and other tests for respiratory organisms showed comparable results [9–11].
The aim of this study was to evaluate the application of FilmArray RP for the detection of respiratory organisms, and to provide information about the seasonality and prevalence of these organisms in pediatric patients with RTIs in a large children’s hospital in China.